Bleeding Disorders

For more than a year, NeDina Brocks-Capla avoided one room in her large, brightly colored San Francisco house – the bathroom on the second floor.

“It was really hard to bathe in here, and I found myself not wanting to touch the walls,” she explained. The bathroom is where Ms. Brocks-Capla’s son Kareem Jones died in 2013 at age 36, from sickle cell disease.

It’s not just the loss of her son that upsets Ms. Brocks-Capla; she believes that if Mr. Jones had gotten the proper medical care, he might still be alive today.

Sickle cell disease is an inherited disorder that causes some red blood cells to bend into a crescent shape. The misshapen, inflexible cells clog the blood vessels, preventing blood from circulating oxygen properly, which can cause chronic pain, multiorgan failure, and stroke. About 100,000 people in the United States have sickle cell disease, and most of them are African American.

Patients and experts alike say it’s no surprise then that while life expectancy for almost every major malady is improving, patients with sickle cell disease can expect to die younger than they did 20 years ago. In 1994, life expectancy for sickle cell patients was 42 for men and 48 for women. By 2005, life expectancy had dipped to 38 for men and 42 for women.

Sickle cell disease is “a microcosm of how issues of race, ethnicity and identity come into conflict with issues of health care,” said Keith Wailoo, PhD, a professor at Princeton University who writes about the history of the disease.

It is also an example of the broader discrimination experienced by African Americans in the medical system. Nearly a third report that they have experienced discrimination when going to the doctor, according to a poll by NPR, Robert Wood Johnson Foundation, and Harvard T.H. Chan School of Public Health.

“One of the national crises in health care is the care for adult sickle cell,” said leading researcher and physician Elliott Vichinsky, MD, who started the sickle cell center at UCSF Benioff Children’s Hospital Oakland in 1978. “This group of people can live much longer with the management we have, and they’re dying because we don’t have access to care.”

Indeed, with the proper care, Dr. Vichinsky’s center and the handful of other specialty clinics like it across the country have been able to increase life expectancy for sickle cell patients well into their 60s.

Dr. Vichinsky’s patient Derek Perkins, 45, knows he has already beaten the odds. He sits in an exam room decorated with cartoon characters at Children’s Hospital Oakland, but this is the adult sickle cell clinic. He’s been Dr. Vichinsky’s patient since childhood.

“Without the sickle cell clinic here in Oakland, I don’t know what I would do. I don’t know anywhere else I could go,” Mr. Perkins said.

When Mr. Perkins was 27, he once ended up at a different hospital where doctors misdiagnosed his crisis. He went into a coma and was near death before his mother insisted he be transferred.

“Dr. Vichinsky was able to get me here to Children’s Hospital, and he found out what was wrong and within 18 hours – all I needed was an emergency blood transfusion and I was awake,” Mr. Perkins recalled.

Kareem Jones lived just across the bay from Mr. Perkins, but he had a profoundly different experience.

Mr. Jones’ mother, Ms. Brocks-Capla, said her son received excellent medical care as a child, but once he turned 18 and aged out of his pediatric program, it felt like falling off a cliff. Mr. Jones was sent to a clinic at San Francisco General Hospital, but it was open only for a half-day, one day each week. If he was sick any other day, he had two options: leave a voicemail for a clinic nurse or go to the emergency room. “That’s not comprehensive care – that’s not consistent care for a disease of this type,” said Ms. Brocks-Capla.

Ms. Brocks-Capla is a retired supervisor at a worker’s compensation firm. She knew how to navigate the health care system, but she couldn’t get her son the care he needed. Like most sickle cell patients, Mr. Jones had frequent pain crises. Usually he ended up in the emergency department where, Ms. Brocks-Capla said, the doctors didn’t seem to know much about sickle cell disease.

When she tried to explain her son’s pain to the doctors and nurses, she recalled, “they say have a seat. ‘He can’t have a seat! Can’t you see him?’ ”

Studies have found that sickle cell patients have to wait up to 50% longer for help in the emergency department than do other pain patients. The opioid crisis has made things even worse, Dr. Vichinsky added, as patients in terrible pain are likely to be seen as drug seekers with addiction problems rather than patients in need.

Despite his illness, Mr. Jones fought to have a normal life. He lived with his girlfriend, had a daughter, and worked as much as he could between pain crises. He was an avid San Francisco Giants fan.

For years, he took hydroxyurea, but it had side effects, and after a while Mr. Jones had to stop taking it. “And that was it, because you know there isn’t any other medication out there,” said Ms. Brocks-Capla.

Indeed, hydroxyurea, which the Food and Drug Administration first approved in 1967 as a cancer drug, was the only drug on the market to treat sickle cell during Mr. Jones’ lifetime. In July, the FDA approved a second drug, Endari (L-glutamine oral powder), specifically to treat patients with sickle cell disease.

Funding by the federal government and private foundations for the disease pales in comparison to other disorders. Cystic fibrosis offers a good comparison. It is another inherited disorder that requires complex care and most often occurs in Caucasians. Cystic fibrosis gets 7-11 times more funding per patient than does sickle cell disease, according to a 2013 study in the journal Blood. From 2010 to 2013 alone, the FDA approved five new drugs for the treatment of cystic fibrosis.

“There’s no question in my mind that class and color are major factors in impairing their survival. Without question,” Dr. Vichinsky said of sickle cell patients. “The death rate is increasing. The quality of care is going down.”

Without a new medication, Mr. Jones got progressively worse. At 36, his kidneys began to fail, and he had to go on dialysis. He ended up in the hospital, with the worst pain of his life. The doctors stabilized him and gave him pain meds but did not diagnose the underlying cause of the crisis. He was released to his mother’s care, still in incredible pain.

At home, Ms. Brocks-Capla ran him a warm bath to try to soothe his pain and went downstairs to get him a change of clothes. As she came back up the stairs, she heard loud banging against the bathroom walls.

“So I run into the bathroom and he’s having a seizure. And I didn’t know what to do. I was like, ‘Oh come on, come on. Don’t do this. Don’t do this to me.’ ”

She called 911. The paramedics came but couldn’t revive him. “He died here with me,” she said.

It turned out Mr. Jones had a series of small strokes. His organs were in failure, something Ms. Brocks-Capla said the hospital missed. She believes his death could have been prevented with consistent care – the kind he got as a child. Dr. Vichinsky thinks she is probably right.

“I would say 40% or more of the deaths I’ve had recently have been preventable – I mean totally preventable,” he said, but he got to the cases too late. “It makes me so angry. I’ve spent my life trying to help these people, and the harder part is you can change this – this isn’t a knowledge issue. It’s an access issue.”

Dr. Vichinsky’s center and others like it have made major advances in screening patients for the early signs of organ failure and intervening to prevent premature death. Patients at these clinics live 2 decades longer than the average sickle cell patient.

Good care for sickle cell requires time and training for physicians, but it often doesn’t pay well, because many patients are on Medicaid or other government insurance programs. The result is that most adult sickle cell patients still struggle even to access treatments that have been around for decades, Dr. Vichinsky said.

The phenomenon is nothing new — the disease that used to be known as sickle cell anemia has had a long and sordid past. It was first identified in 1910 and helped launch the field of molecular biology. But most of the research was used to study science rather than improving care for sickle cell patients, Dr. Vichinsky said.

In the 1960s and 1970s, sickle cell became a lightning rod for the civil rights movement. At the time, the average patient died before age 20. The Black Panther Party took up the cause and began testing people at its “survival conferences” across the country.

“I’m sure we tested over four-and-a-half-thousand people for sickle cell anemia last night – and I think that the voter registration is running neck and neck with it,” Black Panther Party Chairman Bobby Seale told news crews at an event in Oakland in 1972.

The movement grew, and Washington listened. “It is a sad and shameful fact that the causes of this disease have been largely neglected throughout our history,” President Richard Nixon told Congress in 1971. “We cannot rewrite this record of neglect, but we can reverse it. To this end, this administration is increasing its budget for research and treatment of sickle cell disease.”

For a while, funding did increase, newborn screening took hold, and by the 1990s, life expectancy had doubled, with patients living into their 40s. But over time, funding waned, clinics closed, and life expectancy started dropping again.

Dr. Vichinsky pushes against that trend for patients like Derek Perkins. The father of four looks healthy and robust, but like most sickle cell patients, he has episodes of extreme pain and has problems with his kidneys, heart, hips, and breathing. Keeping him thriving requires regular checkups and constant monitoring for potential problems.

“The program Dr. Vichinsky is running here, I feel I owe my life to [it],” said Mr. Perkins. “If it wasn’t for him and the things that he did for me, my family wouldn’t have me.”
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage of children’s health care issues is supported in part by a grant from The Heising-Simons Foundation.

For more than a year, NeDina Brocks-Capla avoided one room in her large, brightly colored San Francisco house – the bathroom on the second floor.

“It was really hard to bathe in here, and I found myself not wanting to touch the walls,” she explained. The bathroom is where Ms. Brocks-Capla’s son Kareem Jones died in 2013 at age 36, from sickle cell disease.

It’s not just the loss of her son that upsets Ms. Brocks-Capla; she believes that if Mr. Jones had gotten the proper medical care, he might still be alive today.

Sickle cell disease is an inherited disorder that causes some red blood cells to bend into a crescent shape. The misshapen, inflexible cells clog the blood vessels, preventing blood from circulating oxygen properly, which can cause chronic pain, multiorgan failure, and stroke. About 100,000 people in the United States have sickle cell disease, and most of them are African American.

Patients and experts alike say it’s no surprise then that while life expectancy for almost every major malady is improving, patients with sickle cell disease can expect to die younger than they did 20 years ago. In 1994, life expectancy for sickle cell patients was 42 for men and 48 for women. By 2005, life expectancy had dipped to 38 for men and 42 for women.

Sickle cell disease is “a microcosm of how issues of race, ethnicity and identity come into conflict with issues of health care,” said Keith Wailoo, PhD, a professor at Princeton University who writes about the history of the disease.

It is also an example of the broader discrimination experienced by African Americans in the medical system. Nearly a third report that they have experienced discrimination when going to the doctor, according to a poll by NPR, Robert Wood Johnson Foundation, and Harvard T.H. Chan School of Public Health.

“One of the national crises in health care is the care for adult sickle cell,” said leading researcher and physician Elliott Vichinsky, MD, who started the sickle cell center at UCSF Benioff Children’s Hospital Oakland in 1978. “This group of people can live much longer with the management we have, and they’re dying because we don’t have access to care.”

Indeed, with the proper care, Dr. Vichinsky’s center and the handful of other specialty clinics like it across the country have been able to increase life expectancy for sickle cell patients well into their 60s.

Dr. Vichinsky’s patient Derek Perkins, 45, knows he has already beaten the odds. He sits in an exam room decorated with cartoon characters at Children’s Hospital Oakland, but this is the adult sickle cell clinic. He’s been Dr. Vichinsky’s patient since childhood.

“Without the sickle cell clinic here in Oakland, I don’t know what I would do. I don’t know anywhere else I could go,” Mr. Perkins said.

When Mr. Perkins was 27, he once ended up at a different hospital where doctors misdiagnosed his crisis. He went into a coma and was near death before his mother insisted he be transferred.

“Dr. Vichinsky was able to get me here to Children’s Hospital, and he found out what was wrong and within 18 hours – all I needed was an emergency blood transfusion and I was awake,” Mr. Perkins recalled.

Kareem Jones lived just across the bay from Mr. Perkins, but he had a profoundly different experience.

Mr. Jones’ mother, Ms. Brocks-Capla, said her son received excellent medical care as a child, but once he turned 18 and aged out of his pediatric program, it felt like falling off a cliff. Mr. Jones was sent to a clinic at San Francisco General Hospital, but it was open only for a half-day, one day each week. If he was sick any other day, he had two options: leave a voicemail for a clinic nurse or go to the emergency room. “That’s not comprehensive care – that’s not consistent care for a disease of this type,” said Ms. Brocks-Capla.

Ms. Brocks-Capla is a retired supervisor at a worker’s compensation firm. She knew how to navigate the health care system, but she couldn’t get her son the care he needed. Like most sickle cell patients, Mr. Jones had frequent pain crises. Usually he ended up in the emergency department where, Ms. Brocks-Capla said, the doctors didn’t seem to know much about sickle cell disease.

When she tried to explain her son’s pain to the doctors and nurses, she recalled, “they say have a seat. ‘He can’t have a seat! Can’t you see him?’ ”

Studies have found that sickle cell patients have to wait up to 50% longer for help in the emergency department than do other pain patients. The opioid crisis has made things even worse, Dr. Vichinsky added, as patients in terrible pain are likely to be seen as drug seekers with addiction problems rather than patients in need.

Despite his illness, Mr. Jones fought to have a normal life. He lived with his girlfriend, had a daughter, and worked as much as he could between pain crises. He was an avid San Francisco Giants fan.

For years, he took hydroxyurea, but it had side effects, and after a while Mr. Jones had to stop taking it. “And that was it, because you know there isn’t any other medication out there,” said Ms. Brocks-Capla.

Indeed, hydroxyurea, which the Food and Drug Administration first approved in 1967 as a cancer drug, was the only drug on the market to treat sickle cell during Mr. Jones’ lifetime. In July, the FDA approved a second drug, Endari (L-glutamine oral powder), specifically to treat patients with sickle cell disease.

Funding by the federal government and private foundations for the disease pales in comparison to other disorders. Cystic fibrosis offers a good comparison. It is another inherited disorder that requires complex care and most often occurs in Caucasians. Cystic fibrosis gets 7-11 times more funding per patient than does sickle cell disease, according to a 2013 study in the journal Blood. From 2010 to 2013 alone, the FDA approved five new drugs for the treatment of cystic fibrosis.

“There’s no question in my mind that class and color are major factors in impairing their survival. Without question,” Dr. Vichinsky said of sickle cell patients. “The death rate is increasing. The quality of care is going down.”

Without a new medication, Mr. Jones got progressively worse. At 36, his kidneys began to fail, and he had to go on dialysis. He ended up in the hospital, with the worst pain of his life. The doctors stabilized him and gave him pain meds but did not diagnose the underlying cause of the crisis. He was released to his mother’s care, still in incredible pain.

At home, Ms. Brocks-Capla ran him a warm bath to try to soothe his pain and went downstairs to get him a change of clothes. As she came back up the stairs, she heard loud banging against the bathroom walls.

“So I run into the bathroom and he’s having a seizure. And I didn’t know what to do. I was like, ‘Oh come on, come on. Don’t do this. Don’t do this to me.’ ”

She called 911. The paramedics came but couldn’t revive him. “He died here with me,” she said.

It turned out Mr. Jones had a series of small strokes. His organs were in failure, something Ms. Brocks-Capla said the hospital missed. She believes his death could have been prevented with consistent care – the kind he got as a child. Dr. Vichinsky thinks she is probably right.

“I would say 40% or more of the deaths I’ve had recently have been preventable – I mean totally preventable,” he said, but he got to the cases too late. “It makes me so angry. I’ve spent my life trying to help these people, and the harder part is you can change this – this isn’t a knowledge issue. It’s an access issue.”

Dr. Vichinsky’s center and others like it have made major advances in screening patients for the early signs of organ failure and intervening to prevent premature death. Patients at these clinics live 2 decades longer than the average sickle cell patient.

Good care for sickle cell requires time and training for physicians, but it often doesn’t pay well, because many patients are on Medicaid or other government insurance programs. The result is that most adult sickle cell patients still struggle even to access treatments that have been around for decades, Dr. Vichinsky said.

The phenomenon is nothing new — the disease that used to be known as sickle cell anemia has had a long and sordid past. It was first identified in 1910 and helped launch the field of molecular biology. But most of the research was used to study science rather than improving care for sickle cell patients, Dr. Vichinsky said.

In the 1960s and 1970s, sickle cell became a lightning rod for the civil rights movement. At the time, the average patient died before age 20. The Black Panther Party took up the cause and began testing people at its “survival conferences” across the country.

“I’m sure we tested over four-and-a-half-thousand people for sickle cell anemia last night – and I think that the voter registration is running neck and neck with it,” Black Panther Party Chairman Bobby Seale told news crews at an event in Oakland in 1972.

The movement grew, and Washington listened. “It is a sad and shameful fact that the causes of this disease have been largely neglected throughout our history,” President Richard Nixon told Congress in 1971. “We cannot rewrite this record of neglect, but we can reverse it. To this end, this administration is increasing its budget for research and treatment of sickle cell disease.”

For a while, funding did increase, newborn screening took hold, and by the 1990s, life expectancy had doubled, with patients living into their 40s. But over time, funding waned, clinics closed, and life expectancy started dropping again.

Dr. Vichinsky pushes against that trend for patients like Derek Perkins. The father of four looks healthy and robust, but like most sickle cell patients, he has episodes of extreme pain and has problems with his kidneys, heart, hips, and breathing. Keeping him thriving requires regular checkups and constant monitoring for potential problems.

“The program Dr. Vichinsky is running here, I feel I owe my life to [it],” said Mr. Perkins. “If it wasn’t for him and the things that he did for me, my family wouldn’t have me.”
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage of children’s health care issues is supported in part by a grant from The Heising-Simons Foundation.

For more than a year, NeDina Brocks-Capla avoided one room in her large, brightly colored San Francisco house – the bathroom on the second floor.

“It was really hard to bathe in here, and I found myself not wanting to touch the walls,” she explained. The bathroom is where Ms. Brocks-Capla’s son Kareem Jones died in 2013 at age 36, from sickle cell disease.

It’s not just the loss of her son that upsets Ms. Brocks-Capla; she believes that if Mr. Jones had gotten the proper medical care, he might still be alive today.

Sickle cell disease is an inherited disorder that causes some red blood cells to bend into a crescent shape. The misshapen, inflexible cells clog the blood vessels, preventing blood from circulating oxygen properly, which can cause chronic pain, multiorgan failure, and stroke. About 100,000 people in the United States have sickle cell disease, and most of them are African American.

Patients and experts alike say it’s no surprise then that while life expectancy for almost every major malady is improving, patients with sickle cell disease can expect to die younger than they did 20 years ago. In 1994, life expectancy for sickle cell patients was 42 for men and 48 for women. By 2005, life expectancy had dipped to 38 for men and 42 for women.

Sickle cell disease is “a microcosm of how issues of race, ethnicity and identity come into conflict with issues of health care,” said Keith Wailoo, PhD, a professor at Princeton University who writes about the history of the disease.

It is also an example of the broader discrimination experienced by African Americans in the medical system. Nearly a third report that they have experienced discrimination when going to the doctor, according to a poll by NPR, Robert Wood Johnson Foundation, and Harvard T.H. Chan School of Public Health.

“One of the national crises in health care is the care for adult sickle cell,” said leading researcher and physician Elliott Vichinsky, MD, who started the sickle cell center at UCSF Benioff Children’s Hospital Oakland in 1978. “This group of people can live much longer with the management we have, and they’re dying because we don’t have access to care.”

Indeed, with the proper care, Dr. Vichinsky’s center and the handful of other specialty clinics like it across the country have been able to increase life expectancy for sickle cell patients well into their 60s.

Dr. Vichinsky’s patient Derek Perkins, 45, knows he has already beaten the odds. He sits in an exam room decorated with cartoon characters at Children’s Hospital Oakland, but this is the adult sickle cell clinic. He’s been Dr. Vichinsky’s patient since childhood.

“Without the sickle cell clinic here in Oakland, I don’t know what I would do. I don’t know anywhere else I could go,” Mr. Perkins said.

When Mr. Perkins was 27, he once ended up at a different hospital where doctors misdiagnosed his crisis. He went into a coma and was near death before his mother insisted he be transferred.

“Dr. Vichinsky was able to get me here to Children’s Hospital, and he found out what was wrong and within 18 hours – all I needed was an emergency blood transfusion and I was awake,” Mr. Perkins recalled.

Kareem Jones lived just across the bay from Mr. Perkins, but he had a profoundly different experience.

Mr. Jones’ mother, Ms. Brocks-Capla, said her son received excellent medical care as a child, but once he turned 18 and aged out of his pediatric program, it felt like falling off a cliff. Mr. Jones was sent to a clinic at San Francisco General Hospital, but it was open only for a half-day, one day each week. If he was sick any other day, he had two options: leave a voicemail for a clinic nurse or go to the emergency room. “That’s not comprehensive care – that’s not consistent care for a disease of this type,” said Ms. Brocks-Capla.

Ms. Brocks-Capla is a retired supervisor at a worker’s compensation firm. She knew how to navigate the health care system, but she couldn’t get her son the care he needed. Like most sickle cell patients, Mr. Jones had frequent pain crises. Usually he ended up in the emergency department where, Ms. Brocks-Capla said, the doctors didn’t seem to know much about sickle cell disease.

When she tried to explain her son’s pain to the doctors and nurses, she recalled, “they say have a seat. ‘He can’t have a seat! Can’t you see him?’ ”

Studies have found that sickle cell patients have to wait up to 50% longer for help in the emergency department than do other pain patients. The opioid crisis has made things even worse, Dr. Vichinsky added, as patients in terrible pain are likely to be seen as drug seekers with addiction problems rather than patients in need.

Despite his illness, Mr. Jones fought to have a normal life. He lived with his girlfriend, had a daughter, and worked as much as he could between pain crises. He was an avid San Francisco Giants fan.

For years, he took hydroxyurea, but it had side effects, and after a while Mr. Jones had to stop taking it. “And that was it, because you know there isn’t any other medication out there,” said Ms. Brocks-Capla.

Indeed, hydroxyurea, which the Food and Drug Administration first approved in 1967 as a cancer drug, was the only drug on the market to treat sickle cell during Mr. Jones’ lifetime. In July, the FDA approved a second drug, Endari (L-glutamine oral powder), specifically to treat patients with sickle cell disease.

Funding by the federal government and private foundations for the disease pales in comparison to other disorders. Cystic fibrosis offers a good comparison. It is another inherited disorder that requires complex care and most often occurs in Caucasians. Cystic fibrosis gets 7-11 times more funding per patient than does sickle cell disease, according to a 2013 study in the journal Blood. From 2010 to 2013 alone, the FDA approved five new drugs for the treatment of cystic fibrosis.

“There’s no question in my mind that class and color are major factors in impairing their survival. Without question,” Dr. Vichinsky said of sickle cell patients. “The death rate is increasing. The quality of care is going down.”

Without a new medication, Mr. Jones got progressively worse. At 36, his kidneys began to fail, and he had to go on dialysis. He ended up in the hospital, with the worst pain of his life. The doctors stabilized him and gave him pain meds but did not diagnose the underlying cause of the crisis. He was released to his mother’s care, still in incredible pain.

At home, Ms. Brocks-Capla ran him a warm bath to try to soothe his pain and went downstairs to get him a change of clothes. As she came back up the stairs, she heard loud banging against the bathroom walls.

“So I run into the bathroom and he’s having a seizure. And I didn’t know what to do. I was like, ‘Oh come on, come on. Don’t do this. Don’t do this to me.’ ”

She called 911. The paramedics came but couldn’t revive him. “He died here with me,” she said.

It turned out Mr. Jones had a series of small strokes. His organs were in failure, something Ms. Brocks-Capla said the hospital missed. She believes his death could have been prevented with consistent care – the kind he got as a child. Dr. Vichinsky thinks she is probably right.

“I would say 40% or more of the deaths I’ve had recently have been preventable – I mean totally preventable,” he said, but he got to the cases too late. “It makes me so angry. I’ve spent my life trying to help these people, and the harder part is you can change this – this isn’t a knowledge issue. It’s an access issue.”

Dr. Vichinsky’s center and others like it have made major advances in screening patients for the early signs of organ failure and intervening to prevent premature death. Patients at these clinics live 2 decades longer than the average sickle cell patient.

Good care for sickle cell requires time and training for physicians, but it often doesn’t pay well, because many patients are on Medicaid or other government insurance programs. The result is that most adult sickle cell patients still struggle even to access treatments that have been around for decades, Dr. Vichinsky said.

The phenomenon is nothing new — the disease that used to be known as sickle cell anemia has had a long and sordid past. It was first identified in 1910 and helped launch the field of molecular biology. But most of the research was used to study science rather than improving care for sickle cell patients, Dr. Vichinsky said.

In the 1960s and 1970s, sickle cell became a lightning rod for the civil rights movement. At the time, the average patient died before age 20. The Black Panther Party took up the cause and began testing people at its “survival conferences” across the country.

“I’m sure we tested over four-and-a-half-thousand people for sickle cell anemia last night – and I think that the voter registration is running neck and neck with it,” Black Panther Party Chairman Bobby Seale told news crews at an event in Oakland in 1972.

The movement grew, and Washington listened. “It is a sad and shameful fact that the causes of this disease have been largely neglected throughout our history,” President Richard Nixon told Congress in 1971. “We cannot rewrite this record of neglect, but we can reverse it. To this end, this administration is increasing its budget for research and treatment of sickle cell disease.”

For a while, funding did increase, newborn screening took hold, and by the 1990s, life expectancy had doubled, with patients living into their 40s. But over time, funding waned, clinics closed, and life expectancy started dropping again.

Dr. Vichinsky pushes against that trend for patients like Derek Perkins. The father of four looks healthy and robust, but like most sickle cell patients, he has episodes of extreme pain and has problems with his kidneys, heart, hips, and breathing. Keeping him thriving requires regular checkups and constant monitoring for potential problems.

“The program Dr. Vichinsky is running here, I feel I owe my life to [it],” said Mr. Perkins. “If it wasn’t for him and the things that he did for me, my family wouldn’t have me.”
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage of children’s health care issues is supported in part by a grant from The Heising-Simons Foundation.

Antihemophilic factor

New research suggests prophylaxis with a recombinant factor VIII Fc fusion protein (rFVIIIFc) can improve joint health over time in patients with hemophilia A.

Patients saw continuous improvement in joint health over a nearly 3-year period, regardless of prior treatment regimen, severity of joint damage, or target joints.

“Gradual joint destruction, which is the leading cause of morbidity for people with hemophilia, remains a significant challenge in the treatment of hemophilia A,” said Johannes Oldenburg, MD, of University Clinic Bonn in Germany.

“This is the first study to show that functional joint health can continue to improve using prophylactic treatment with an extended half-life factor therapy, even for those who have severe joint disease at the start of treatment.”

Dr Oldenburg and his colleagues reported these findings in Haemophilia. The research was sponsored by Biogen/Bioverativ and Sobi, the companies marketing rFVIIIFc (or efmoroctocog alfa) as Eloctate or Elocta.

This interim post hoc analysis was an evaluation of joint health in adults and adolescents who received rFVIIIFc prophylaxis in the A-LONG and ASPIRE studies.

In A-LONG, patients age 12 and older who had severe hemophilia A received rFVIIIFc at 25-65 IU/kg every 3 to 5 days (arm 1), at 65 IU/kg weekly (arm 2), or as episodic treatment (arm 3). Patients who completed A-LONG could then enroll in the ASPIRE extension study.

For the current analysis, Dr Oldenburg and his colleagues assessed joint health in ASPIRE enrollees using a modified version of the Hemophilia Joint Health Score (mHJHS). This tool grades joints by specific domains, including swelling, muscle atrophy, alignment, range of motion, joint pain, strength, and global gait.

The researchers examined mHJHS measurements (a decrease in score reflecting improvement) taken at A-LONG baseline, ASPIRE baseline, and annually thereafter for roughly 2.8 years of treatment.

There were 47 patients who had mHJHS data at both study baselines, ASPIRE year 1, and ASPIRE year 2.

These patients had a mean improvement in joint health score of -4.1 at ASPIRE year 2, compared with A-LONG baseline (P=0.001).

The mean improvement was -2.4 (P=0.09) for patients who received pre-study prophylaxis and -7.2 (P=0.003) for those who received pre-study episodic treatment.

The mean improvement was -5.6 (P=0.005) in patients with target joints and -8.8 (P=0.02) in those with severe joint destruction.

The mHJHS components with the greatest improvement at ASPIRE year 2 were swelling (-1.4, P=0.008), range of motion (-1.1, P=0.03), and strength (-0.8, P=0.04).

Antihemophilic factor

New research suggests prophylaxis with a recombinant factor VIII Fc fusion protein (rFVIIIFc) can improve joint health over time in patients with hemophilia A.

Patients saw continuous improvement in joint health over a nearly 3-year period, regardless of prior treatment regimen, severity of joint damage, or target joints.

“Gradual joint destruction, which is the leading cause of morbidity for people with hemophilia, remains a significant challenge in the treatment of hemophilia A,” said Johannes Oldenburg, MD, of University Clinic Bonn in Germany.

“This is the first study to show that functional joint health can continue to improve using prophylactic treatment with an extended half-life factor therapy, even for those who have severe joint disease at the start of treatment.”

Dr Oldenburg and his colleagues reported these findings in Haemophilia. The research was sponsored by Biogen/Bioverativ and Sobi, the companies marketing rFVIIIFc (or efmoroctocog alfa) as Eloctate or Elocta.

This interim post hoc analysis was an evaluation of joint health in adults and adolescents who received rFVIIIFc prophylaxis in the A-LONG and ASPIRE studies.

In A-LONG, patients age 12 and older who had severe hemophilia A received rFVIIIFc at 25-65 IU/kg every 3 to 5 days (arm 1), at 65 IU/kg weekly (arm 2), or as episodic treatment (arm 3). Patients who completed A-LONG could then enroll in the ASPIRE extension study.

For the current analysis, Dr Oldenburg and his colleagues assessed joint health in ASPIRE enrollees using a modified version of the Hemophilia Joint Health Score (mHJHS). This tool grades joints by specific domains, including swelling, muscle atrophy, alignment, range of motion, joint pain, strength, and global gait.

The researchers examined mHJHS measurements (a decrease in score reflecting improvement) taken at A-LONG baseline, ASPIRE baseline, and annually thereafter for roughly 2.8 years of treatment.

There were 47 patients who had mHJHS data at both study baselines, ASPIRE year 1, and ASPIRE year 2.

These patients had a mean improvement in joint health score of -4.1 at ASPIRE year 2, compared with A-LONG baseline (P=0.001).

The mean improvement was -2.4 (P=0.09) for patients who received pre-study prophylaxis and -7.2 (P=0.003) for those who received pre-study episodic treatment.

The mean improvement was -5.6 (P=0.005) in patients with target joints and -8.8 (P=0.02) in those with severe joint destruction.

The mHJHS components with the greatest improvement at ASPIRE year 2 were swelling (-1.4, P=0.008), range of motion (-1.1, P=0.03), and strength (-0.8, P=0.04).

Antihemophilic factor

New research suggests prophylaxis with a recombinant factor VIII Fc fusion protein (rFVIIIFc) can improve joint health over time in patients with hemophilia A.

Patients saw continuous improvement in joint health over a nearly 3-year period, regardless of prior treatment regimen, severity of joint damage, or target joints.

“Gradual joint destruction, which is the leading cause of morbidity for people with hemophilia, remains a significant challenge in the treatment of hemophilia A,” said Johannes Oldenburg, MD, of University Clinic Bonn in Germany.

“This is the first study to show that functional joint health can continue to improve using prophylactic treatment with an extended half-life factor therapy, even for those who have severe joint disease at the start of treatment.”

Dr Oldenburg and his colleagues reported these findings in Haemophilia. The research was sponsored by Biogen/Bioverativ and Sobi, the companies marketing rFVIIIFc (or efmoroctocog alfa) as Eloctate or Elocta.

This interim post hoc analysis was an evaluation of joint health in adults and adolescents who received rFVIIIFc prophylaxis in the A-LONG and ASPIRE studies.

In A-LONG, patients age 12 and older who had severe hemophilia A received rFVIIIFc at 25-65 IU/kg every 3 to 5 days (arm 1), at 65 IU/kg weekly (arm 2), or as episodic treatment (arm 3). Patients who completed A-LONG could then enroll in the ASPIRE extension study.

For the current analysis, Dr Oldenburg and his colleagues assessed joint health in ASPIRE enrollees using a modified version of the Hemophilia Joint Health Score (mHJHS). This tool grades joints by specific domains, including swelling, muscle atrophy, alignment, range of motion, joint pain, strength, and global gait.

The researchers examined mHJHS measurements (a decrease in score reflecting improvement) taken at A-LONG baseline, ASPIRE baseline, and annually thereafter for roughly 2.8 years of treatment.

There were 47 patients who had mHJHS data at both study baselines, ASPIRE year 1, and ASPIRE year 2.

These patients had a mean improvement in joint health score of -4.1 at ASPIRE year 2, compared with A-LONG baseline (P=0.001).

The mean improvement was -2.4 (P=0.09) for patients who received pre-study prophylaxis and -7.2 (P=0.003) for those who received pre-study episodic treatment.

The mean improvement was -5.6 (P=0.005) in patients with target joints and -8.8 (P=0.02) in those with severe joint destruction.

The mHJHS components with the greatest improvement at ASPIRE year 2 were swelling (-1.4, P=0.008), range of motion (-1.1, P=0.03), and strength (-0.8, P=0.04).

Photo courtesy of Biogen

The Saudi Food and Drug Authority has approved eftrenonacog alfa (Alprolix®) for the treatment of hemophilia B in the Kingdom of Saudi Arabia.

Eftrenonacog alfa is a recombinant factor IX Fc fusion protein indicated for on-demand treatment and prophylaxis in hemophilia B patients of all ages.

Eftrenonacog alfa is engineered by fusing factor IX to the Fc portion of immunoglobulin G subclass 1. This enables eftrenonacog alfa to use a naturally occurring pathway to prolong the time the therapy remains in the body.

Eftrenonacog alfa is approved to treat hemophilia B in the European Union, Iceland, Liechtenstein, Kuwait, Norway, and Switzerland (where it is marketed by Sobi). The product is also approved in the US, Canada, Japan, Australia, New Zealand, and other countries (where it is marketed by Bioverativ).

The approvals of eftrenonacog alfa are based on results from a pair of phase 3 trials—the B-LONG study and the Kids B-LONG study.

B-LONG study

The B-LONG study included 123 males with severe hemophilia B who were 12 years of age or older. They had no current or previous factor IX inhibitors and a history of 100 or more documented prior exposure days to factor IX products.

Patients received eftrenonacog alfa in 1 of 4 treatment arms:

• Weekly prophylaxis starting at 50 IU/kg, with pharmacokinetic (PK)-driven dose adjustments (n=63)
• Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
• On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
• Perioperative management (n=12, including 8 from arms 1-3).

Researchers assessed control of bleeding in all patients who experienced a bleeding episode while on study. In total, 90.4% of bleeding episodes were controlled by a single injection of eftrenonacog alfa.

The overall median annualized bleeding rates (ABRs)—including spontaneous and traumatic bleeds—were 2.95 in the weekly prophylaxis arm, 1.38 in the individualized interval prophylaxis arm, and 17.69 in the episodic treatment arm.

The perioperative management arm consisted of 12 patients undergoing 14 major surgical procedures. The treating physicians rated the hemostatic efficacy of eftrenonacog alfa as “excellent” or “good” in all surgeries.

Eftrenonacog alfa was considered generally well-tolerated. None of the patients developed inhibitors, and none reported anaphylaxis.

The most common adverse events—with an incidence of 5% or greater—occurring outside of the perioperative management arm were nasopharyngitis, influenza, arthralgia, upper respiratory infection, hypertension, and headache.

One serious adverse event may have been drug-related. The patient experienced obstructive uropathy in the setting of hematuria. However, he continued to receive eftrenonacog alfa, and the event resolved with medical management.

Kids B-LONG

In Kids B-LONG, researchers tested eftrenonacog alfa in 30 previously treated males younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Children who received eftrenonacog alfa prophylactically had an overall median ABR of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of eftrenonacog alfa.

None of the patients developed inhibitors. There were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events.

None of the patients discontinued the study due to an adverse event. One adverse event—decreased appetite occurring in 1 patient—was considered related to eftrenonacog alfa.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the B-LONG study.

Photo courtesy of Biogen

The Saudi Food and Drug Authority has approved eftrenonacog alfa (Alprolix®) for the treatment of hemophilia B in the Kingdom of Saudi Arabia.

Eftrenonacog alfa is a recombinant factor IX Fc fusion protein indicated for on-demand treatment and prophylaxis in hemophilia B patients of all ages.

Eftrenonacog alfa is engineered by fusing factor IX to the Fc portion of immunoglobulin G subclass 1. This enables eftrenonacog alfa to use a naturally occurring pathway to prolong the time the therapy remains in the body.

Eftrenonacog alfa is approved to treat hemophilia B in the European Union, Iceland, Liechtenstein, Kuwait, Norway, and Switzerland (where it is marketed by Sobi). The product is also approved in the US, Canada, Japan, Australia, New Zealand, and other countries (where it is marketed by Bioverativ).

The approvals of eftrenonacog alfa are based on results from a pair of phase 3 trials—the B-LONG study and the Kids B-LONG study.

B-LONG study

The B-LONG study included 123 males with severe hemophilia B who were 12 years of age or older. They had no current or previous factor IX inhibitors and a history of 100 or more documented prior exposure days to factor IX products.

Patients received eftrenonacog alfa in 1 of 4 treatment arms:

• Weekly prophylaxis starting at 50 IU/kg, with pharmacokinetic (PK)-driven dose adjustments (n=63)
• Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
• On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
• Perioperative management (n=12, including 8 from arms 1-3).

Researchers assessed control of bleeding in all patients who experienced a bleeding episode while on study. In total, 90.4% of bleeding episodes were controlled by a single injection of eftrenonacog alfa.

The overall median annualized bleeding rates (ABRs)—including spontaneous and traumatic bleeds—were 2.95 in the weekly prophylaxis arm, 1.38 in the individualized interval prophylaxis arm, and 17.69 in the episodic treatment arm.

The perioperative management arm consisted of 12 patients undergoing 14 major surgical procedures. The treating physicians rated the hemostatic efficacy of eftrenonacog alfa as “excellent” or “good” in all surgeries.

Eftrenonacog alfa was considered generally well-tolerated. None of the patients developed inhibitors, and none reported anaphylaxis.

The most common adverse events—with an incidence of 5% or greater—occurring outside of the perioperative management arm were nasopharyngitis, influenza, arthralgia, upper respiratory infection, hypertension, and headache.

One serious adverse event may have been drug-related. The patient experienced obstructive uropathy in the setting of hematuria. However, he continued to receive eftrenonacog alfa, and the event resolved with medical management.

Kids B-LONG

In Kids B-LONG, researchers tested eftrenonacog alfa in 30 previously treated males younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Children who received eftrenonacog alfa prophylactically had an overall median ABR of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of eftrenonacog alfa.

None of the patients developed inhibitors. There were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events.

None of the patients discontinued the study due to an adverse event. One adverse event—decreased appetite occurring in 1 patient—was considered related to eftrenonacog alfa.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the B-LONG study.

Photo courtesy of Biogen

The Saudi Food and Drug Authority has approved eftrenonacog alfa (Alprolix®) for the treatment of hemophilia B in the Kingdom of Saudi Arabia.

Eftrenonacog alfa is a recombinant factor IX Fc fusion protein indicated for on-demand treatment and prophylaxis in hemophilia B patients of all ages.

Eftrenonacog alfa is engineered by fusing factor IX to the Fc portion of immunoglobulin G subclass 1. This enables eftrenonacog alfa to use a naturally occurring pathway to prolong the time the therapy remains in the body.

Eftrenonacog alfa is approved to treat hemophilia B in the European Union, Iceland, Liechtenstein, Kuwait, Norway, and Switzerland (where it is marketed by Sobi). The product is also approved in the US, Canada, Japan, Australia, New Zealand, and other countries (where it is marketed by Bioverativ).

The approvals of eftrenonacog alfa are based on results from a pair of phase 3 trials—the B-LONG study and the Kids B-LONG study.

B-LONG study

The B-LONG study included 123 males with severe hemophilia B who were 12 years of age or older. They had no current or previous factor IX inhibitors and a history of 100 or more documented prior exposure days to factor IX products.

Patients received eftrenonacog alfa in 1 of 4 treatment arms:

• Weekly prophylaxis starting at 50 IU/kg, with pharmacokinetic (PK)-driven dose adjustments (n=63)
• Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
• On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
• Perioperative management (n=12, including 8 from arms 1-3).

Researchers assessed control of bleeding in all patients who experienced a bleeding episode while on study. In total, 90.4% of bleeding episodes were controlled by a single injection of eftrenonacog alfa.

The overall median annualized bleeding rates (ABRs)—including spontaneous and traumatic bleeds—were 2.95 in the weekly prophylaxis arm, 1.38 in the individualized interval prophylaxis arm, and 17.69 in the episodic treatment arm.

The perioperative management arm consisted of 12 patients undergoing 14 major surgical procedures. The treating physicians rated the hemostatic efficacy of eftrenonacog alfa as “excellent” or “good” in all surgeries.

Eftrenonacog alfa was considered generally well-tolerated. None of the patients developed inhibitors, and none reported anaphylaxis.

The most common adverse events—with an incidence of 5% or greater—occurring outside of the perioperative management arm were nasopharyngitis, influenza, arthralgia, upper respiratory infection, hypertension, and headache.

One serious adverse event may have been drug-related. The patient experienced obstructive uropathy in the setting of hematuria. However, he continued to receive eftrenonacog alfa, and the event resolved with medical management.

Kids B-LONG

In Kids B-LONG, researchers tested eftrenonacog alfa in 30 previously treated males younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Children who received eftrenonacog alfa prophylactically had an overall median ABR of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of eftrenonacog alfa.

None of the patients developed inhibitors. There were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events.

None of the patients discontinued the study due to an adverse event. One adverse event—decreased appetite occurring in 1 patient—was considered related to eftrenonacog alfa.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the B-LONG study.

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has accepted an investigational new drug application for SHP654 (also known as BAX 888) and granted the therapy orphan drug designation.

SHP654 is an investigational factor VIII (FVIII) gene therapy intended to treat hemophilia A using an adeno-associated virus serotype 8 vector to deliver codon-optimized, B-domain-deleted FVIII specifically to a patient’s liver, where FVIII would then be produced and used to manage bleeds.

Shire, the company developing SHP654, received FDA clearance for an investigational new drug application to initiate a global, phase 1/2 study of SHP654.

In this study, researchers will evaluate the safety and optimal dose of SHP654 needed to boost FVIII activity levels and affect hemophilic bleeding. Shire expects this study will begin by the end of this year.

The FDA also granted orphan designation to SHP654. The agency grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

“This important orphan drug designation highlights Shire’s commitment to patients with rare diseases, and, for hemophilia patients specifically, our aim is to help them achieve zero bleeds,” said Paul Monahan, MD, senior medical director of gene therapy at Shire.

“We know that hemophilia care is not one-size-fits-all and that every patient is unique, which is why we continue to focus on optimizing personal outcomes for hemophilia patients by developing innovations to transform care.”

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has accepted an investigational new drug application for SHP654 (also known as BAX 888) and granted the therapy orphan drug designation.

SHP654 is an investigational factor VIII (FVIII) gene therapy intended to treat hemophilia A using an adeno-associated virus serotype 8 vector to deliver codon-optimized, B-domain-deleted FVIII specifically to a patient’s liver, where FVIII would then be produced and used to manage bleeds.

Shire, the company developing SHP654, received FDA clearance for an investigational new drug application to initiate a global, phase 1/2 study of SHP654.

In this study, researchers will evaluate the safety and optimal dose of SHP654 needed to boost FVIII activity levels and affect hemophilic bleeding. Shire expects this study will begin by the end of this year.

The FDA also granted orphan designation to SHP654. The agency grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

“This important orphan drug designation highlights Shire’s commitment to patients with rare diseases, and, for hemophilia patients specifically, our aim is to help them achieve zero bleeds,” said Paul Monahan, MD, senior medical director of gene therapy at Shire.

“We know that hemophilia care is not one-size-fits-all and that every patient is unique, which is why we continue to focus on optimizing personal outcomes for hemophilia patients by developing innovations to transform care.”

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has accepted an investigational new drug application for SHP654 (also known as BAX 888) and granted the therapy orphan drug designation.

SHP654 is an investigational factor VIII (FVIII) gene therapy intended to treat hemophilia A using an adeno-associated virus serotype 8 vector to deliver codon-optimized, B-domain-deleted FVIII specifically to a patient’s liver, where FVIII would then be produced and used to manage bleeds.

Shire, the company developing SHP654, received FDA clearance for an investigational new drug application to initiate a global, phase 1/2 study of SHP654.

In this study, researchers will evaluate the safety and optimal dose of SHP654 needed to boost FVIII activity levels and affect hemophilic bleeding. Shire expects this study will begin by the end of this year.

The FDA also granted orphan designation to SHP654. The agency grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

“This important orphan drug designation highlights Shire’s commitment to patients with rare diseases, and, for hemophilia patients specifically, our aim is to help them achieve zero bleeds,” said Paul Monahan, MD, senior medical director of gene therapy at Shire.

“We know that hemophilia care is not one-size-fits-all and that every patient is unique, which is why we continue to focus on optimizing personal outcomes for hemophilia patients by developing innovations to transform care.”

Photo from GlaxoSmithKline

Eltrombopag can provide long-term disease control for chronic/persistent immune thrombocytopenia (ITP), according to research published in Blood.

In the EXTEND study, investigators evaluated patients exposed to eltrombopag for a median of 2.4 years.

Most patients achieved a response to the drug, and more than half of them maintained that response for at least 25 weeks.

More than a third of patients were able to discontinue at least 1 concomitant ITP medication.

Most adverse events (AEs) were grade 1 or 2. However, 32% of patients had serious AEs, and 14% of patients withdrew from the study due to AEs.

This research was sponsored by GlaxoSmithKline, the company that previously owned eltrombopag. Now, the drug is a product of Novartis.

Patients

EXTEND is an open-label extension study of 4 trials (TRA100773A, TRA100773B, TRA102537/RAISE, and TRA108057/REPEAT), which enrolled 302 adults with chronic/persistent ITP.

Patients had completed the treatment and follow-up periods as defined in their previous study protocol and did not experience eltrombopag-related toxicity or other drug intolerance on a prior eltrombopag study. Patients who discontinued a previous study due to toxicity were only eligible if they had received a placebo.

The patients’ median time from diagnosis to enrollment in EXTEND was 58.8 months (range, 9-552). Their median age was 50 (range, 18-86), and 67% were female.

Most patients (70%) had a baseline platelet count below 30×10⁹/L. Thirty-three percent of patients were using concomitant ITP medications, 53% had received at least 3 prior ITP treatments, and 38% had undergone splenectomy.

Treatment

Eltrombopag was started at a dose of 50 mg/day and titrated to 25-75 mg/day or less often based on platelet counts. Maintenance dosing continued after minimization of concomitant ITP medication and optimization of eltrombopag dosing.

The overall median duration of eltrombopag exposure was 2.37 years (range, 2 days to 8.76 years), and the mean average daily dose was 50.2 mg/day (range, 1-75).

One hundred and thirty-five patients (45%) completed the study, and 75 patients (25%) were treated for 4 or more years. The most common reasons for study withdrawal included AEs (n=41), patient decision (n=39), lack of efficacy (n=32), and “other” reasons (n=39).

Safety

AEs leading to study withdrawal (occurring at least twice) included hepatobiliary AEs (n=7), cataracts (n=4), deep vein thrombosis (n=3), cerebral infarction (n=2), headache (n=2), and myelofibrosis (n=2).

The overall incidence of AEs was 92%. The most frequent AEs were headache (28%), nasopharyngitis (25%), and upper respiratory tract infection (23%).

Twenty-six percent of patients had grade 3 AEs, 6% had grade 4 AEs, and 32% had serious AEs. Serious AEs included cataracts (5%), pneumonia (3%), anemia (2%), ALT increase (2%), epistaxis (1%), AST increase, (1%), bilirubin increase (1%), and deep vein thrombosis (1%).

Three percent of patients reported a malignancy while on study, including basal cell carcinoma, intramucosal adenocarcinoma, breast cancer, metastases to the lung, ovarian cancer, squamous cell carcinoma, transitional cell carcinoma, lymphoma, unclassifiable B-cell lymphoma (low grade), and Hodgkin lymphoma.

Efficacy

In all, 85.8% (259/302) of patients had a response to eltrombopag, which was defined as achieving a platelet count of at least 50×10⁹/L at least once without rescue therapy.

Fifty-two percent (133/257) of patients achieved a continuous response lasting at least 25 weeks.

Thirty-four percent (34/101) of patients who were on concomitant ITP medication discontinued at least 1 medication. Thirty-nine percent (39/101) reduced or permanently stopped at least 1 ITP medication without receiving rescue therapy.

Fifty-seven percent of patients (171/302) had bleeding symptoms at baseline. This decreased to 16% (13/80) at 1 year.

“The EXTEND data published in Blood validate [eltrombopag] as an important oral treatment option that, by often increasing platelet counts, significantly decreased bleeding rates and reduced the need for concurrent therapies in certain patients with chronic/persistent immune thrombocytopenia,” said study author James Bussel, MD, of Weill Cornell Medicine in New York, New York.

“With this information, physicians can better optimize long-term disease management for appropriate patients living with this chronic disease.”

Photo from GlaxoSmithKline

Eltrombopag can provide long-term disease control for chronic/persistent immune thrombocytopenia (ITP), according to research published in Blood.

In the EXTEND study, investigators evaluated patients exposed to eltrombopag for a median of 2.4 years.

Most patients achieved a response to the drug, and more than half of them maintained that response for at least 25 weeks.

More than a third of patients were able to discontinue at least 1 concomitant ITP medication.

Most adverse events (AEs) were grade 1 or 2. However, 32% of patients had serious AEs, and 14% of patients withdrew from the study due to AEs.

This research was sponsored by GlaxoSmithKline, the company that previously owned eltrombopag. Now, the drug is a product of Novartis.

Patients

EXTEND is an open-label extension study of 4 trials (TRA100773A, TRA100773B, TRA102537/RAISE, and TRA108057/REPEAT), which enrolled 302 adults with chronic/persistent ITP.

Patients had completed the treatment and follow-up periods as defined in their previous study protocol and did not experience eltrombopag-related toxicity or other drug intolerance on a prior eltrombopag study. Patients who discontinued a previous study due to toxicity were only eligible if they had received a placebo.

The patients’ median time from diagnosis to enrollment in EXTEND was 58.8 months (range, 9-552). Their median age was 50 (range, 18-86), and 67% were female.

Most patients (70%) had a baseline platelet count below 30×10⁹/L. Thirty-three percent of patients were using concomitant ITP medications, 53% had received at least 3 prior ITP treatments, and 38% had undergone splenectomy.

Treatment

Eltrombopag was started at a dose of 50 mg/day and titrated to 25-75 mg/day or less often based on platelet counts. Maintenance dosing continued after minimization of concomitant ITP medication and optimization of eltrombopag dosing.

The overall median duration of eltrombopag exposure was 2.37 years (range, 2 days to 8.76 years), and the mean average daily dose was 50.2 mg/day (range, 1-75).

One hundred and thirty-five patients (45%) completed the study, and 75 patients (25%) were treated for 4 or more years. The most common reasons for study withdrawal included AEs (n=41), patient decision (n=39), lack of efficacy (n=32), and “other” reasons (n=39).

Safety

AEs leading to study withdrawal (occurring at least twice) included hepatobiliary AEs (n=7), cataracts (n=4), deep vein thrombosis (n=3), cerebral infarction (n=2), headache (n=2), and myelofibrosis (n=2).

The overall incidence of AEs was 92%. The most frequent AEs were headache (28%), nasopharyngitis (25%), and upper respiratory tract infection (23%).

Twenty-six percent of patients had grade 3 AEs, 6% had grade 4 AEs, and 32% had serious AEs. Serious AEs included cataracts (5%), pneumonia (3%), anemia (2%), ALT increase (2%), epistaxis (1%), AST increase, (1%), bilirubin increase (1%), and deep vein thrombosis (1%).

Three percent of patients reported a malignancy while on study, including basal cell carcinoma, intramucosal adenocarcinoma, breast cancer, metastases to the lung, ovarian cancer, squamous cell carcinoma, transitional cell carcinoma, lymphoma, unclassifiable B-cell lymphoma (low grade), and Hodgkin lymphoma.

Efficacy

In all, 85.8% (259/302) of patients had a response to eltrombopag, which was defined as achieving a platelet count of at least 50×10⁹/L at least once without rescue therapy.

Fifty-two percent (133/257) of patients achieved a continuous response lasting at least 25 weeks.

Thirty-four percent (34/101) of patients who were on concomitant ITP medication discontinued at least 1 medication. Thirty-nine percent (39/101) reduced or permanently stopped at least 1 ITP medication without receiving rescue therapy.

Fifty-seven percent of patients (171/302) had bleeding symptoms at baseline. This decreased to 16% (13/80) at 1 year.

“The EXTEND data published in Blood validate [eltrombopag] as an important oral treatment option that, by often increasing platelet counts, significantly decreased bleeding rates and reduced the need for concurrent therapies in certain patients with chronic/persistent immune thrombocytopenia,” said study author James Bussel, MD, of Weill Cornell Medicine in New York, New York.

“With this information, physicians can better optimize long-term disease management for appropriate patients living with this chronic disease.”

Photo from GlaxoSmithKline

Eltrombopag can provide long-term disease control for chronic/persistent immune thrombocytopenia (ITP), according to research published in Blood.

In the EXTEND study, investigators evaluated patients exposed to eltrombopag for a median of 2.4 years.

Most patients achieved a response to the drug, and more than half of them maintained that response for at least 25 weeks.

More than a third of patients were able to discontinue at least 1 concomitant ITP medication.

Most adverse events (AEs) were grade 1 or 2. However, 32% of patients had serious AEs, and 14% of patients withdrew from the study due to AEs.

This research was sponsored by GlaxoSmithKline, the company that previously owned eltrombopag. Now, the drug is a product of Novartis.

Patients

EXTEND is an open-label extension study of 4 trials (TRA100773A, TRA100773B, TRA102537/RAISE, and TRA108057/REPEAT), which enrolled 302 adults with chronic/persistent ITP.

Patients had completed the treatment and follow-up periods as defined in their previous study protocol and did not experience eltrombopag-related toxicity or other drug intolerance on a prior eltrombopag study. Patients who discontinued a previous study due to toxicity were only eligible if they had received a placebo.

The patients’ median time from diagnosis to enrollment in EXTEND was 58.8 months (range, 9-552). Their median age was 50 (range, 18-86), and 67% were female.

Most patients (70%) had a baseline platelet count below 30×10⁹/L. Thirty-three percent of patients were using concomitant ITP medications, 53% had received at least 3 prior ITP treatments, and 38% had undergone splenectomy.

Treatment

Eltrombopag was started at a dose of 50 mg/day and titrated to 25-75 mg/day or less often based on platelet counts. Maintenance dosing continued after minimization of concomitant ITP medication and optimization of eltrombopag dosing.

The overall median duration of eltrombopag exposure was 2.37 years (range, 2 days to 8.76 years), and the mean average daily dose was 50.2 mg/day (range, 1-75).

One hundred and thirty-five patients (45%) completed the study, and 75 patients (25%) were treated for 4 or more years. The most common reasons for study withdrawal included AEs (n=41), patient decision (n=39), lack of efficacy (n=32), and “other” reasons (n=39).

Safety

AEs leading to study withdrawal (occurring at least twice) included hepatobiliary AEs (n=7), cataracts (n=4), deep vein thrombosis (n=3), cerebral infarction (n=2), headache (n=2), and myelofibrosis (n=2).

The overall incidence of AEs was 92%. The most frequent AEs were headache (28%), nasopharyngitis (25%), and upper respiratory tract infection (23%).

Twenty-six percent of patients had grade 3 AEs, 6% had grade 4 AEs, and 32% had serious AEs. Serious AEs included cataracts (5%), pneumonia (3%), anemia (2%), ALT increase (2%), epistaxis (1%), AST increase, (1%), bilirubin increase (1%), and deep vein thrombosis (1%).

Three percent of patients reported a malignancy while on study, including basal cell carcinoma, intramucosal adenocarcinoma, breast cancer, metastases to the lung, ovarian cancer, squamous cell carcinoma, transitional cell carcinoma, lymphoma, unclassifiable B-cell lymphoma (low grade), and Hodgkin lymphoma.

Efficacy

In all, 85.8% (259/302) of patients had a response to eltrombopag, which was defined as achieving a platelet count of at least 50×10⁹/L at least once without rescue therapy.

Fifty-two percent (133/257) of patients achieved a continuous response lasting at least 25 weeks.

Thirty-four percent (34/101) of patients who were on concomitant ITP medication discontinued at least 1 medication. Thirty-nine percent (39/101) reduced or permanently stopped at least 1 ITP medication without receiving rescue therapy.

Fifty-seven percent of patients (171/302) had bleeding symptoms at baseline. This decreased to 16% (13/80) at 1 year.

“The EXTEND data published in Blood validate [eltrombopag] as an important oral treatment option that, by often increasing platelet counts, significantly decreased bleeding rates and reduced the need for concurrent therapies in certain patients with chronic/persistent immune thrombocytopenia,” said study author James Bussel, MD, of Weill Cornell Medicine in New York, New York.

“With this information, physicians can better optimize long-term disease management for appropriate patients living with this chronic disease.”

Image by Erhabor Osaro

Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.

In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.

Patients who received caplacizumab had a significant reduction in time to platelet count response.

In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.

The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.

“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.

“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”

Treatment

The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).

Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.

If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.

In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.

Baseline characteristics

At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.

The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.

Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.

The mean platelet count at baseline was 32.0 x 10⁹/L in the caplacizumab arm and 39.1 x 10⁹/L in the placebo arm.

Efficacy

The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).

The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.

A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).

Safety

The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.

The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.

The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.

The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.

During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

Image by Erhabor Osaro

Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.

In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.

Patients who received caplacizumab had a significant reduction in time to platelet count response.

In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.

The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.

“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.

“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”

Treatment

The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).

Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.

If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.

In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.

Baseline characteristics

At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.

The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.

Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.

The mean platelet count at baseline was 32.0 x 10⁹/L in the caplacizumab arm and 39.1 x 10⁹/L in the placebo arm.

Efficacy

The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).

The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.

A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).

Safety

The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.

The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.

The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.

The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.

During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

Image by Erhabor Osaro

Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.

In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.

Patients who received caplacizumab had a significant reduction in time to platelet count response.

In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.

The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.

“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.

“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”

Treatment

The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).

Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.

If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.

In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.

Baseline characteristics

At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.

The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.

Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.

The mean platelet count at baseline was 32.0 x 10⁹/L in the caplacizumab arm and 39.1 x 10⁹/L in the placebo arm.

Efficacy

The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).

The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.

A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).

Safety

The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.

The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.

The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.

The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.

During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

Photo by Bill Branson

Japan’s Ministry of Health, Labor and Welfare has approved lonoctocog alfa (AFSTYLA®), a recombinant single-chain coagulation factor VIII product, for use in patients with hemophilia A.

The product is approved for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding, and for perioperative management.

Lonoctocog alfa is the first and only single-chain recombinant factor VIII product specifically designed to treat hemophilia A.

According to CSL Behring, the company developing lonoctocog alfa, the product was designed to provide greater molecular stability and longer duration of action. Lonoctocog alfa uses a covalent bond to form one structural entity, a single polypeptide chain, to improve the stability of factor VIII and provide factor VIII activity with the option of twice-weekly dosing.

Lonoctocog alfa is also approved in the European Union, US, Canada, Switzerland, and Australia.

AFFINITY trials

Japan’s approval of lonoctocog alfa is based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).

Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12.

In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.

Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.

Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.

Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).

One patient withdrew from treatment due to hypersensitivity.

None of the patients developed neutralizing antibodies to factor VIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.

Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were published in the Journal of Thrombosis and Haemostasis in March 2017.

Photo by Bill Branson

Japan’s Ministry of Health, Labor and Welfare has approved lonoctocog alfa (AFSTYLA®), a recombinant single-chain coagulation factor VIII product, for use in patients with hemophilia A.

The product is approved for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding, and for perioperative management.

Lonoctocog alfa is the first and only single-chain recombinant factor VIII product specifically designed to treat hemophilia A.

According to CSL Behring, the company developing lonoctocog alfa, the product was designed to provide greater molecular stability and longer duration of action. Lonoctocog alfa uses a covalent bond to form one structural entity, a single polypeptide chain, to improve the stability of factor VIII and provide factor VIII activity with the option of twice-weekly dosing.

Lonoctocog alfa is also approved in the European Union, US, Canada, Switzerland, and Australia.

AFFINITY trials

Japan’s approval of lonoctocog alfa is based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).

Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12.

In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.

Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.

Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.

Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).

One patient withdrew from treatment due to hypersensitivity.

None of the patients developed neutralizing antibodies to factor VIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.

Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were published in the Journal of Thrombosis and Haemostasis in March 2017.

Photo by Bill Branson

Japan’s Ministry of Health, Labor and Welfare has approved lonoctocog alfa (AFSTYLA®), a recombinant single-chain coagulation factor VIII product, for use in patients with hemophilia A.

The product is approved for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding, and for perioperative management.

Lonoctocog alfa is the first and only single-chain recombinant factor VIII product specifically designed to treat hemophilia A.

According to CSL Behring, the company developing lonoctocog alfa, the product was designed to provide greater molecular stability and longer duration of action. Lonoctocog alfa uses a covalent bond to form one structural entity, a single polypeptide chain, to improve the stability of factor VIII and provide factor VIII activity with the option of twice-weekly dosing.

Lonoctocog alfa is also approved in the European Union, US, Canada, Switzerland, and Australia.

AFFINITY trials

Japan’s approval of lonoctocog alfa is based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).

Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12.

In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.

Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.

Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.

Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).

One patient withdrew from treatment due to hypersensitivity.

None of the patients developed neutralizing antibodies to factor VIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.

Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were published in the Journal of Thrombosis and Haemostasis in March 2017.

Antihemophilic factor

The US Food and Drug Administration (FDA) has granted orphan drug designation to CB 2679d/ISU304, a clinical stage drug candidate for hemophilia B.

CB 2679d/ISU304 is a next-generation coagulation factor IX variant that may allow for subcutaneous prophylactic treatment of patients with hemophilia B.

The product is being developed by Catalyst Biosciences, Inc. and ISU Abxis.

The companies are currently conducting a phase 1/2 trial of CB 2679d/ISU304 in patients with severe hemophilia B.

Catalyst Biosciences and ISU Abxis plan to have interim, top-line results from this trial by the end of 2017 and complete results in early 2018.

CB 2679d/ISU304 also has orphan medicinal product designation from the European Commission.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Antihemophilic factor

The US Food and Drug Administration (FDA) has granted orphan drug designation to CB 2679d/ISU304, a clinical stage drug candidate for hemophilia B.

CB 2679d/ISU304 is a next-generation coagulation factor IX variant that may allow for subcutaneous prophylactic treatment of patients with hemophilia B.

The product is being developed by Catalyst Biosciences, Inc. and ISU Abxis.

The companies are currently conducting a phase 1/2 trial of CB 2679d/ISU304 in patients with severe hemophilia B.

Catalyst Biosciences and ISU Abxis plan to have interim, top-line results from this trial by the end of 2017 and complete results in early 2018.

CB 2679d/ISU304 also has orphan medicinal product designation from the European Commission.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Antihemophilic factor

The US Food and Drug Administration (FDA) has granted orphan drug designation to CB 2679d/ISU304, a clinical stage drug candidate for hemophilia B.

CB 2679d/ISU304 is a next-generation coagulation factor IX variant that may allow for subcutaneous prophylactic treatment of patients with hemophilia B.

The product is being developed by Catalyst Biosciences, Inc. and ISU Abxis.

The companies are currently conducting a phase 1/2 trial of CB 2679d/ISU304 in patients with severe hemophilia B.

Catalyst Biosciences and ISU Abxis plan to have interim, top-line results from this trial by the end of 2017 and complete results in early 2018.

CB 2679d/ISU304 also has orphan medicinal product designation from the European Commission.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

Antihemophilic factor

The European Medicines Agency (EMA) has concluded there is “no clear and consistent evidence” of a difference in inhibitor development between the 2 classes of factor VIII (FVIII) products.

A review of data from several studies has suggested that hemophilia A patients are no more likely to develop inhibitors if they receive a recombinant FVIII product rather than a plasma-derived FVIII product.

The review began after publication of the SIPPET study¹, which suggested that patients who received plasma-derived FVIII had a lower incidence of inhibitors than patients treated with recombinant FVIII.

To test this conclusion, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed data on all FVIII products authorized for use in the European Union. This includes products containing the active substances human coagulation FVIII, efmoroctocog alfa, moroctocog alfa, octocog alfa, simoctocog alfa, susoctocog alfa, and turoctocog alfa.

The PRAC examined data from the SIPPET study and additional clinical trials and observational studies.^2-5

The data did not show any statistically significant or clinically meaningful difference in inhibitor risk between FVIII classes.

The PRAC said results of the SIPPET study cannot be extrapolated to individual products, as the study only included a small number of FVIII products.

The PRAC’s conclusion was sent to the EMA’s Committee for Medicinal Products for Human Use (CHMP) for adoption of the EMA’s final opinion. And the CHMP has adopted the opinion that there is “no clear and consistent evidence” of a difference in inhibitor development.

The CHMP’s opinion will be forwarded to the European Commission, which will issue a final, legally binding decision applicable in all European Union member states. The European Commission typically adheres to the CHMP’s recommendations.

The EMA said prescribing information for FVIII products will be updated as appropriate to add inhibitor development as a very common side effect in previously untreated patients and as uncommon in previously treated patients.

The warning on inhibitor development will be amended to state that low titers of inhibitors pose less risk of insufficient response than high titers.

1. Peyvandi F, Mannucci PM, Garagiola I et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med (2016), 374:2054-64.

2. Gouw SC et al. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood (2007), 109:4648-54.

3. Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med (2013), 368:231-9.

4. Iorio A et al. Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia (2017), 23:255-63.

5. Fischer K et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost (2015) 113:968-75.

Antihemophilic factor

The European Medicines Agency (EMA) has concluded there is “no clear and consistent evidence” of a difference in inhibitor development between the 2 classes of factor VIII (FVIII) products.

A review of data from several studies has suggested that hemophilia A patients are no more likely to develop inhibitors if they receive a recombinant FVIII product rather than a plasma-derived FVIII product.

The review began after publication of the SIPPET study¹, which suggested that patients who received plasma-derived FVIII had a lower incidence of inhibitors than patients treated with recombinant FVIII.

To test this conclusion, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed data on all FVIII products authorized for use in the European Union. This includes products containing the active substances human coagulation FVIII, efmoroctocog alfa, moroctocog alfa, octocog alfa, simoctocog alfa, susoctocog alfa, and turoctocog alfa.

The PRAC examined data from the SIPPET study and additional clinical trials and observational studies.^2-5

The data did not show any statistically significant or clinically meaningful difference in inhibitor risk between FVIII classes.

The PRAC said results of the SIPPET study cannot be extrapolated to individual products, as the study only included a small number of FVIII products.

The PRAC’s conclusion was sent to the EMA’s Committee for Medicinal Products for Human Use (CHMP) for adoption of the EMA’s final opinion. And the CHMP has adopted the opinion that there is “no clear and consistent evidence” of a difference in inhibitor development.

The CHMP’s opinion will be forwarded to the European Commission, which will issue a final, legally binding decision applicable in all European Union member states. The European Commission typically adheres to the CHMP’s recommendations.

The EMA said prescribing information for FVIII products will be updated as appropriate to add inhibitor development as a very common side effect in previously untreated patients and as uncommon in previously treated patients.

The warning on inhibitor development will be amended to state that low titers of inhibitors pose less risk of insufficient response than high titers.

1. Peyvandi F, Mannucci PM, Garagiola I et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med (2016), 374:2054-64.

2. Gouw SC et al. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood (2007), 109:4648-54.

3. Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med (2013), 368:231-9.

4. Iorio A et al. Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia (2017), 23:255-63.

5. Fischer K et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost (2015) 113:968-75.

Antihemophilic factor

The European Medicines Agency (EMA) has concluded there is “no clear and consistent evidence” of a difference in inhibitor development between the 2 classes of factor VIII (FVIII) products.

A review of data from several studies has suggested that hemophilia A patients are no more likely to develop inhibitors if they receive a recombinant FVIII product rather than a plasma-derived FVIII product.

The review began after publication of the SIPPET study¹, which suggested that patients who received plasma-derived FVIII had a lower incidence of inhibitors than patients treated with recombinant FVIII.

To test this conclusion, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed data on all FVIII products authorized for use in the European Union. This includes products containing the active substances human coagulation FVIII, efmoroctocog alfa, moroctocog alfa, octocog alfa, simoctocog alfa, susoctocog alfa, and turoctocog alfa.

The PRAC examined data from the SIPPET study and additional clinical trials and observational studies.^2-5

The data did not show any statistically significant or clinically meaningful difference in inhibitor risk between FVIII classes.

The PRAC said results of the SIPPET study cannot be extrapolated to individual products, as the study only included a small number of FVIII products.

The PRAC’s conclusion was sent to the EMA’s Committee for Medicinal Products for Human Use (CHMP) for adoption of the EMA’s final opinion. And the CHMP has adopted the opinion that there is “no clear and consistent evidence” of a difference in inhibitor development.

The CHMP’s opinion will be forwarded to the European Commission, which will issue a final, legally binding decision applicable in all European Union member states. The European Commission typically adheres to the CHMP’s recommendations.

The EMA said prescribing information for FVIII products will be updated as appropriate to add inhibitor development as a very common side effect in previously untreated patients and as uncommon in previously treated patients.

The warning on inhibitor development will be amended to state that low titers of inhibitors pose less risk of insufficient response than high titers.

1. Peyvandi F, Mannucci PM, Garagiola I et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med (2016), 374:2054-64.

2. Gouw SC et al. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood (2007), 109:4648-54.

3. Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med (2013), 368:231-9.

4. Iorio A et al. Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia (2017), 23:255-63.

5. Fischer K et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost (2015) 113:968-75.