Bleeding Disorders

ORLANDO – Conventional wisdom holds that persons with hemophilia are at lower risk for death from cardiovascular events than the general population, but there are conflicting data from studies attempting to confirm or refute this notion.

In a prospective, multicenter European study of more than 500 patients with hemophilia, the predicted cardiovascular disease (CVD) event rate was less than half of what was expected, reported Paul R. van der Valk, MD, from University Medical Center in Utrecht, the Netherlands, and colleagues.

In patients with hemophilia, “the leading cause of death seems to be malignancy related and intracranial hemorrhage. Atrial fibrillation is quite common,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

But a second study of 100 patients with hemophilia showed that the bleeding disorder did not appear to offer protection against cardiovascular or thrombotic adverse events, Beatriz Delgado, MD, and colleagues at the Centro Hospitalar São João in Porto, Portugal, also presented in a poster session.

Risk scores considered

The prospective study by Dr. van der Valk and colleagues was designed to assess the incidence of CVD in patients with hemophilia in the Netherlands and the United Kingdom, compared with the general population. They used the QRISK2 cardiovascular risk score (2011 version). This instrument is used to calculate risk of CVD events in adults from 30 to 84 with no history of CVD or statin use.

Among 557 patients with a calculable QRISK2 score at 2 years of follow-up, there were four CVD events, including two cases of ischemic heart disease, one ischemic stroke, and one intracranial hemorrhage. The median 2-year QRISK2 score was 1.7%, and the 10-year risk was 9.0%, which translated in to an expected 9.5 CVD events during 2 years of follow-up.

Among the additional 104 patients who could not have a QRISK2 score calculated because of age over 84, statin use, or history of CVD, there were four CVD events: ischemic heart disease, transient ischemic attack/carotid artery stenosis, myocardial infarction, and intracranial hemorrhage.

Other CVD events occurring in both groups included atrial fibrillation in eight patients, other arrhythmia in three, and, in one patient each, aortic valve pathology, pericarditis, and carotid artery plaque.

Portuguese experience

Dr, Delgado and colleagues noted that although hemophilia has traditionally been regarded as protective against ischemic heart disease or thrombotic events, modern management “has prolonged life expectancy of people with hemophilia and consequently, an associated increase in incidence and prevalence of conditions that affect the general older population, such as cardiovascular disease and hypertension, are expected.”

They conducted a retrospective analysis of 100 adults (69 with hemophilia A, and 31 with hemophilia B) treated at their center. Overall, 29 patients had severe hemophilia A, 20 moderate hemophilia A, and 20 mild hemophilia A. Among patients with hemophilia B, 11 had severe, 15 moderate, and 5 mild disease.­

Two patients (one with moderate and one with severe hemophilia) had angina episodes with coronary artery disease and underwent multiple coronary bypass grafts. The patient with severe disease had a disabling ischemic stroke during recovery from bypass surgery, and the patient with moderate hemophilia had an acute myocardial infarction prior to bypass surgery.

Two other patients had transient ischemic strokes from which they recovered without disability.

The main cardiovascular risk factors identified in this population were hypertension, diabetes mellitus, heavy smoking, obesity, and dyslipidemia. All patients were screened for prothrombotic risk, and all patients had negative test results.

“Hemophilia does not seem to have a protective effect against thrombotic/cardiovascular events, mainly in [patients with] coronary artery disease,” the investigators wrote.

Endothelial function

In a study presented in an oral abstract session, Shannon Jackson, MD, of the University of British Columbia in Vancouver found that men with hemophilia appear to have better macrovascular endothelial function but worse microvascular endothelial function than did men with normal clotting parameters.

“Based on endothelial function, contemporary hemophilia cohorts may have a different profile of cardiovascular risk than healthy controls,” she said.

Although they do not have an obvious mechanistic explanation for the differences in microvascular function among patients with hemophilia vs. healthy controls, there is evidence to show that microvascular function is predictive of cardiovascular events independent of other risk factors in otherwise healthy people. Their findings indicate that further study of the association between endothelial function, cardiovascular risk factors, and atherosclerosis among patients with hemophilia is warranted, she said.

Dr. van der Valk and colleagues and Dr. Delgado and colleagues did not disclose funding or conflicts of interest. The study by Dr. Jackson and colleagues was supported by the Canadian Hemophilia Society and Pfizer. She disclosed honoraria for speaking engagements for Biogen, Baxalta, and Pfizer and for participating in scientific advisory boards for Bayer, Pfizer, Baxalta, CLS Behring, and Novo Nordisk.

ORLANDO – Conventional wisdom holds that persons with hemophilia are at lower risk for death from cardiovascular events than the general population, but there are conflicting data from studies attempting to confirm or refute this notion.

In a prospective, multicenter European study of more than 500 patients with hemophilia, the predicted cardiovascular disease (CVD) event rate was less than half of what was expected, reported Paul R. van der Valk, MD, from University Medical Center in Utrecht, the Netherlands, and colleagues.

In patients with hemophilia, “the leading cause of death seems to be malignancy related and intracranial hemorrhage. Atrial fibrillation is quite common,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

But a second study of 100 patients with hemophilia showed that the bleeding disorder did not appear to offer protection against cardiovascular or thrombotic adverse events, Beatriz Delgado, MD, and colleagues at the Centro Hospitalar São João in Porto, Portugal, also presented in a poster session.

Risk scores considered

The prospective study by Dr. van der Valk and colleagues was designed to assess the incidence of CVD in patients with hemophilia in the Netherlands and the United Kingdom, compared with the general population. They used the QRISK2 cardiovascular risk score (2011 version). This instrument is used to calculate risk of CVD events in adults from 30 to 84 with no history of CVD or statin use.

Among 557 patients with a calculable QRISK2 score at 2 years of follow-up, there were four CVD events, including two cases of ischemic heart disease, one ischemic stroke, and one intracranial hemorrhage. The median 2-year QRISK2 score was 1.7%, and the 10-year risk was 9.0%, which translated in to an expected 9.5 CVD events during 2 years of follow-up.

Among the additional 104 patients who could not have a QRISK2 score calculated because of age over 84, statin use, or history of CVD, there were four CVD events: ischemic heart disease, transient ischemic attack/carotid artery stenosis, myocardial infarction, and intracranial hemorrhage.

Other CVD events occurring in both groups included atrial fibrillation in eight patients, other arrhythmia in three, and, in one patient each, aortic valve pathology, pericarditis, and carotid artery plaque.

Portuguese experience

Dr, Delgado and colleagues noted that although hemophilia has traditionally been regarded as protective against ischemic heart disease or thrombotic events, modern management “has prolonged life expectancy of people with hemophilia and consequently, an associated increase in incidence and prevalence of conditions that affect the general older population, such as cardiovascular disease and hypertension, are expected.”

They conducted a retrospective analysis of 100 adults (69 with hemophilia A, and 31 with hemophilia B) treated at their center. Overall, 29 patients had severe hemophilia A, 20 moderate hemophilia A, and 20 mild hemophilia A. Among patients with hemophilia B, 11 had severe, 15 moderate, and 5 mild disease.­

Two patients (one with moderate and one with severe hemophilia) had angina episodes with coronary artery disease and underwent multiple coronary bypass grafts. The patient with severe disease had a disabling ischemic stroke during recovery from bypass surgery, and the patient with moderate hemophilia had an acute myocardial infarction prior to bypass surgery.

Two other patients had transient ischemic strokes from which they recovered without disability.

The main cardiovascular risk factors identified in this population were hypertension, diabetes mellitus, heavy smoking, obesity, and dyslipidemia. All patients were screened for prothrombotic risk, and all patients had negative test results.

“Hemophilia does not seem to have a protective effect against thrombotic/cardiovascular events, mainly in [patients with] coronary artery disease,” the investigators wrote.

Endothelial function

In a study presented in an oral abstract session, Shannon Jackson, MD, of the University of British Columbia in Vancouver found that men with hemophilia appear to have better macrovascular endothelial function but worse microvascular endothelial function than did men with normal clotting parameters.

“Based on endothelial function, contemporary hemophilia cohorts may have a different profile of cardiovascular risk than healthy controls,” she said.

Although they do not have an obvious mechanistic explanation for the differences in microvascular function among patients with hemophilia vs. healthy controls, there is evidence to show that microvascular function is predictive of cardiovascular events independent of other risk factors in otherwise healthy people. Their findings indicate that further study of the association between endothelial function, cardiovascular risk factors, and atherosclerosis among patients with hemophilia is warranted, she said.

Dr. van der Valk and colleagues and Dr. Delgado and colleagues did not disclose funding or conflicts of interest. The study by Dr. Jackson and colleagues was supported by the Canadian Hemophilia Society and Pfizer. She disclosed honoraria for speaking engagements for Biogen, Baxalta, and Pfizer and for participating in scientific advisory boards for Bayer, Pfizer, Baxalta, CLS Behring, and Novo Nordisk.

ORLANDO – Conventional wisdom holds that persons with hemophilia are at lower risk for death from cardiovascular events than the general population, but there are conflicting data from studies attempting to confirm or refute this notion.

In a prospective, multicenter European study of more than 500 patients with hemophilia, the predicted cardiovascular disease (CVD) event rate was less than half of what was expected, reported Paul R. van der Valk, MD, from University Medical Center in Utrecht, the Netherlands, and colleagues.

In patients with hemophilia, “the leading cause of death seems to be malignancy related and intracranial hemorrhage. Atrial fibrillation is quite common,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

But a second study of 100 patients with hemophilia showed that the bleeding disorder did not appear to offer protection against cardiovascular or thrombotic adverse events, Beatriz Delgado, MD, and colleagues at the Centro Hospitalar São João in Porto, Portugal, also presented in a poster session.

Risk scores considered

The prospective study by Dr. van der Valk and colleagues was designed to assess the incidence of CVD in patients with hemophilia in the Netherlands and the United Kingdom, compared with the general population. They used the QRISK2 cardiovascular risk score (2011 version). This instrument is used to calculate risk of CVD events in adults from 30 to 84 with no history of CVD or statin use.

Among 557 patients with a calculable QRISK2 score at 2 years of follow-up, there were four CVD events, including two cases of ischemic heart disease, one ischemic stroke, and one intracranial hemorrhage. The median 2-year QRISK2 score was 1.7%, and the 10-year risk was 9.0%, which translated in to an expected 9.5 CVD events during 2 years of follow-up.

Among the additional 104 patients who could not have a QRISK2 score calculated because of age over 84, statin use, or history of CVD, there were four CVD events: ischemic heart disease, transient ischemic attack/carotid artery stenosis, myocardial infarction, and intracranial hemorrhage.

Other CVD events occurring in both groups included atrial fibrillation in eight patients, other arrhythmia in three, and, in one patient each, aortic valve pathology, pericarditis, and carotid artery plaque.

Portuguese experience

Dr, Delgado and colleagues noted that although hemophilia has traditionally been regarded as protective against ischemic heart disease or thrombotic events, modern management “has prolonged life expectancy of people with hemophilia and consequently, an associated increase in incidence and prevalence of conditions that affect the general older population, such as cardiovascular disease and hypertension, are expected.”

They conducted a retrospective analysis of 100 adults (69 with hemophilia A, and 31 with hemophilia B) treated at their center. Overall, 29 patients had severe hemophilia A, 20 moderate hemophilia A, and 20 mild hemophilia A. Among patients with hemophilia B, 11 had severe, 15 moderate, and 5 mild disease.­

Two patients (one with moderate and one with severe hemophilia) had angina episodes with coronary artery disease and underwent multiple coronary bypass grafts. The patient with severe disease had a disabling ischemic stroke during recovery from bypass surgery, and the patient with moderate hemophilia had an acute myocardial infarction prior to bypass surgery.

Two other patients had transient ischemic strokes from which they recovered without disability.

The main cardiovascular risk factors identified in this population were hypertension, diabetes mellitus, heavy smoking, obesity, and dyslipidemia. All patients were screened for prothrombotic risk, and all patients had negative test results.

“Hemophilia does not seem to have a protective effect against thrombotic/cardiovascular events, mainly in [patients with] coronary artery disease,” the investigators wrote.

Endothelial function

In a study presented in an oral abstract session, Shannon Jackson, MD, of the University of British Columbia in Vancouver found that men with hemophilia appear to have better macrovascular endothelial function but worse microvascular endothelial function than did men with normal clotting parameters.

“Based on endothelial function, contemporary hemophilia cohorts may have a different profile of cardiovascular risk than healthy controls,” she said.

Although they do not have an obvious mechanistic explanation for the differences in microvascular function among patients with hemophilia vs. healthy controls, there is evidence to show that microvascular function is predictive of cardiovascular events independent of other risk factors in otherwise healthy people. Their findings indicate that further study of the association between endothelial function, cardiovascular risk factors, and atherosclerosis among patients with hemophilia is warranted, she said.

Dr. van der Valk and colleagues and Dr. Delgado and colleagues did not disclose funding or conflicts of interest. The study by Dr. Jackson and colleagues was supported by the Canadian Hemophilia Society and Pfizer. She disclosed honoraria for speaking engagements for Biogen, Baxalta, and Pfizer and for participating in scientific advisory boards for Bayer, Pfizer, Baxalta, CLS Behring, and Novo Nordisk.

ORLANDO – The frequency of prophylactic clotting factor infusions does not appear to adversely affect adherence to hemophilia therapy in children, but age seems to play a role in compliance to prescribed regimens, investigators in two separate studies report.

A study of pediatric patients with moderate to severe hemophilia A or B on bleeding prophylaxis showed no significant differences in adherence between patients receiving two clotting factor infusions per week and those receiving three or four per week, reported Karen Strike, a physiotherapist at McMaster Children’s Hospital in Hamilton, Ont., and colleagues.

“This study demonstrates that our patients have a very high degree of adherence, and it doesn’t appear to be related to infusion frequency,” she said in an interview at a scientific poster session at the World Federation of Hemophilia World Congress.

Although their sample size was small – just 23 patients – the median levels of adherence were high for both twice-weekly infusers (99.5%) and 3-4 times per week infusers (96%; P = .053).

Ms. Strike acknowledges that the borderline P value could be due to the small sample size instead of a lack of association. Additionally, because the patients are managed by a regional hemophilia treatment center, they tend to be more engaged and more likely to cooperate with clinician instructions, she said.

“Basically, patients are either going to do what’s prescribed or they’re not. What that actual prescription is doesn’t seem to matter. If they prescribe you twice a week or they prescribe me every other day, you’re going to be adherent to twice a week or you’re not.

The investigators have expanded their study to include adult patients on primary prophylaxis and to look at additional co-variates that might have an effect on adherence, including interactions with a health care team, geographical distance from a hemophilia treatment center, joint health status, and infusion delivery method (peripheral vs. port).

Age may be a factor

In a separate study, German investigators report that adherence appears to vary by age.

Wolfgang Miesbach, MD, from Goethe University Hospital in Frankfurt, Germany, and colleagues asked all members of the German hemophilia patient organization with moderate or severe hemophilia to fill out the VERITAS-PRO (Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis) questionnaire and compared scores across age groups.

Data were available on a total of 364 patients. The investigators found that among 131 children from birth to age 19, adherence to prescribed regimens was 100%. In contrast, the adherence rate among 189 adults aged 20-59 was 88.1%. After age 59, adherence rates began to improve as those 60 and older (44 patients) reported 93.9% adherence.

“Within the patients aged 20+, care by a hemophilia center was the only significant indicator for better adherence. The tendency of better adherence of patients aged greater than 60 compared to patients 20-59 may be explained by the significant association of the occurrence of pain with increasing age although a significant influence of pain on the adherence levels could not be demonstrated,” the investigators wrote.

Their findings point the way to possible interventions to facilitate adherence to prophylaxis among patients with hemophilia, they wrote.

Both studies were internally funded. The authors reported no relevant disclosures.

ORLANDO – The frequency of prophylactic clotting factor infusions does not appear to adversely affect adherence to hemophilia therapy in children, but age seems to play a role in compliance to prescribed regimens, investigators in two separate studies report.

A study of pediatric patients with moderate to severe hemophilia A or B on bleeding prophylaxis showed no significant differences in adherence between patients receiving two clotting factor infusions per week and those receiving three or four per week, reported Karen Strike, a physiotherapist at McMaster Children’s Hospital in Hamilton, Ont., and colleagues.

“This study demonstrates that our patients have a very high degree of adherence, and it doesn’t appear to be related to infusion frequency,” she said in an interview at a scientific poster session at the World Federation of Hemophilia World Congress.

Although their sample size was small – just 23 patients – the median levels of adherence were high for both twice-weekly infusers (99.5%) and 3-4 times per week infusers (96%; P = .053).

Ms. Strike acknowledges that the borderline P value could be due to the small sample size instead of a lack of association. Additionally, because the patients are managed by a regional hemophilia treatment center, they tend to be more engaged and more likely to cooperate with clinician instructions, she said.

“Basically, patients are either going to do what’s prescribed or they’re not. What that actual prescription is doesn’t seem to matter. If they prescribe you twice a week or they prescribe me every other day, you’re going to be adherent to twice a week or you’re not.

The investigators have expanded their study to include adult patients on primary prophylaxis and to look at additional co-variates that might have an effect on adherence, including interactions with a health care team, geographical distance from a hemophilia treatment center, joint health status, and infusion delivery method (peripheral vs. port).

Age may be a factor

In a separate study, German investigators report that adherence appears to vary by age.

Wolfgang Miesbach, MD, from Goethe University Hospital in Frankfurt, Germany, and colleagues asked all members of the German hemophilia patient organization with moderate or severe hemophilia to fill out the VERITAS-PRO (Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis) questionnaire and compared scores across age groups.

Data were available on a total of 364 patients. The investigators found that among 131 children from birth to age 19, adherence to prescribed regimens was 100%. In contrast, the adherence rate among 189 adults aged 20-59 was 88.1%. After age 59, adherence rates began to improve as those 60 and older (44 patients) reported 93.9% adherence.

“Within the patients aged 20+, care by a hemophilia center was the only significant indicator for better adherence. The tendency of better adherence of patients aged greater than 60 compared to patients 20-59 may be explained by the significant association of the occurrence of pain with increasing age although a significant influence of pain on the adherence levels could not be demonstrated,” the investigators wrote.

Their findings point the way to possible interventions to facilitate adherence to prophylaxis among patients with hemophilia, they wrote.

Both studies were internally funded. The authors reported no relevant disclosures.

ORLANDO – The frequency of prophylactic clotting factor infusions does not appear to adversely affect adherence to hemophilia therapy in children, but age seems to play a role in compliance to prescribed regimens, investigators in two separate studies report.

A study of pediatric patients with moderate to severe hemophilia A or B on bleeding prophylaxis showed no significant differences in adherence between patients receiving two clotting factor infusions per week and those receiving three or four per week, reported Karen Strike, a physiotherapist at McMaster Children’s Hospital in Hamilton, Ont., and colleagues.

“This study demonstrates that our patients have a very high degree of adherence, and it doesn’t appear to be related to infusion frequency,” she said in an interview at a scientific poster session at the World Federation of Hemophilia World Congress.

Although their sample size was small – just 23 patients – the median levels of adherence were high for both twice-weekly infusers (99.5%) and 3-4 times per week infusers (96%; P = .053).

Ms. Strike acknowledges that the borderline P value could be due to the small sample size instead of a lack of association. Additionally, because the patients are managed by a regional hemophilia treatment center, they tend to be more engaged and more likely to cooperate with clinician instructions, she said.

“Basically, patients are either going to do what’s prescribed or they’re not. What that actual prescription is doesn’t seem to matter. If they prescribe you twice a week or they prescribe me every other day, you’re going to be adherent to twice a week or you’re not.

The investigators have expanded their study to include adult patients on primary prophylaxis and to look at additional co-variates that might have an effect on adherence, including interactions with a health care team, geographical distance from a hemophilia treatment center, joint health status, and infusion delivery method (peripheral vs. port).

Age may be a factor

In a separate study, German investigators report that adherence appears to vary by age.

Wolfgang Miesbach, MD, from Goethe University Hospital in Frankfurt, Germany, and colleagues asked all members of the German hemophilia patient organization with moderate or severe hemophilia to fill out the VERITAS-PRO (Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis) questionnaire and compared scores across age groups.

Data were available on a total of 364 patients. The investigators found that among 131 children from birth to age 19, adherence to prescribed regimens was 100%. In contrast, the adherence rate among 189 adults aged 20-59 was 88.1%. After age 59, adherence rates began to improve as those 60 and older (44 patients) reported 93.9% adherence.

“Within the patients aged 20+, care by a hemophilia center was the only significant indicator for better adherence. The tendency of better adherence of patients aged greater than 60 compared to patients 20-59 may be explained by the significant association of the occurrence of pain with increasing age although a significant influence of pain on the adherence levels could not be demonstrated,” the investigators wrote.

Their findings point the way to possible interventions to facilitate adherence to prophylaxis among patients with hemophilia, they wrote.

Both studies were internally funded. The authors reported no relevant disclosures.

Sickle cell trait doesn’t raise the risk of death but does raise the risk of exertional rhabdomyolysis among black soldiers, “a population that is known to engage consistently in regular and strenuous exercise while protected by exertional-injury precautions,” investigators reported. The study was published online Aug. 4 in the New England Journal of Medicine.

A number of high-profile deaths among athletes and military personnel involving exertional rhabdomyolysis have been attributed to sickle cell trait. The National Collegiate Athletic Association, the U.S. Air Force, and the U.S. Navy all require universal screening for sickle cell trait.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

“However, concerns have been raised by the American Society of Hematology and other professional organizations about the possibility of stigmatization and discrimination resulting from the mandated screening for sickle cell trait,” which predominantly affects people of African descent and some of Hispanic ancestry, but usually not whites, wrote D. Alan Nelson, PhD, of Stanford (Calif.) University, and his associates.

“These concerns warrant consideration, especially given the absence of published evidence that such screening is effective in preventing exertion-related events,” added the researchers.

The U.S. Army primarily screens for sickle cell trait among personnel deployed for combat and certain specialists whose work at high altitudes puts them at risk. To study a large enough population to generate accurate data about this rare blood abnormality, the investigators analyzed data for 47,944 black soldiers who had been tested for sickle cell trait and who served on active duty during a recent 3-year period.

The researchers assessed all inpatient and outpatient health care visits at military and civilian facilities. There were 391 exertional rhabdomyolysis events and 96 deaths from all causes during 1.61 million person-months of observation. A total of 7.4% of the study cohort carried sickle cell trait. These participants were similar to noncarriers in demographic characteristics and health predictors.

Soldiers with sickle cell trait did not have a greater risk of death than did those without sickle cell trait (hazard ratio, 0.99), and there also was no difference between carriers and noncarriers in either battle-related or non–battle-related mortality rates.

However, sickle cell trait was associated with a 54% greater risk of exertional rhabdomyolysis (HR, 1.54), Dr. Nelson and his associates noted (N Engl J Med. 2016 Aug 4. doi: 10.1056/NEJMoa1516257).

It is important to note that factors other than sickle cell trait raised the risk of exertional rhabdomyolysis to a similar or even greater degree, including obesity (HR, 1.39) and tobacco use (HR, 1.54). Recent use of antipsychotic medication tripled the risk for exertional rhabdomyolysis (HR, 3.02), and statin use nearly tripled it (HR, 2.89).

“These findings are compelling because case reports dominate the relevant literature and emphasize the presence of sickle cell trait as a risk factor for adverse outcomes, including exertional rhabdomyolysis and sudden death,” the researchers wrote. “A large longitudinal study involving a population fully tested for sickle cell trait that has formally investigated [these outcomes] while also examining other known major risk factors, such as medications, has been lacking.”

The study found that women were at much lower risk for exertional rhabdomyolysis than were men (HR, 0.51), and that risk increased with increasing age, so that soldiers aged 36 years and older had a 57% greater risk compared with those in the youngest age group.

The National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences supported the study. Dr. Nelson and his associates reported having no relevant financial disclosures.

Sickle cell trait doesn’t raise the risk of death but does raise the risk of exertional rhabdomyolysis among black soldiers, “a population that is known to engage consistently in regular and strenuous exercise while protected by exertional-injury precautions,” investigators reported. The study was published online Aug. 4 in the New England Journal of Medicine.

A number of high-profile deaths among athletes and military personnel involving exertional rhabdomyolysis have been attributed to sickle cell trait. The National Collegiate Athletic Association, the U.S. Air Force, and the U.S. Navy all require universal screening for sickle cell trait.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

“However, concerns have been raised by the American Society of Hematology and other professional organizations about the possibility of stigmatization and discrimination resulting from the mandated screening for sickle cell trait,” which predominantly affects people of African descent and some of Hispanic ancestry, but usually not whites, wrote D. Alan Nelson, PhD, of Stanford (Calif.) University, and his associates.

“These concerns warrant consideration, especially given the absence of published evidence that such screening is effective in preventing exertion-related events,” added the researchers.

The U.S. Army primarily screens for sickle cell trait among personnel deployed for combat and certain specialists whose work at high altitudes puts them at risk. To study a large enough population to generate accurate data about this rare blood abnormality, the investigators analyzed data for 47,944 black soldiers who had been tested for sickle cell trait and who served on active duty during a recent 3-year period.

The researchers assessed all inpatient and outpatient health care visits at military and civilian facilities. There were 391 exertional rhabdomyolysis events and 96 deaths from all causes during 1.61 million person-months of observation. A total of 7.4% of the study cohort carried sickle cell trait. These participants were similar to noncarriers in demographic characteristics and health predictors.

Soldiers with sickle cell trait did not have a greater risk of death than did those without sickle cell trait (hazard ratio, 0.99), and there also was no difference between carriers and noncarriers in either battle-related or non–battle-related mortality rates.

However, sickle cell trait was associated with a 54% greater risk of exertional rhabdomyolysis (HR, 1.54), Dr. Nelson and his associates noted (N Engl J Med. 2016 Aug 4. doi: 10.1056/NEJMoa1516257).

It is important to note that factors other than sickle cell trait raised the risk of exertional rhabdomyolysis to a similar or even greater degree, including obesity (HR, 1.39) and tobacco use (HR, 1.54). Recent use of antipsychotic medication tripled the risk for exertional rhabdomyolysis (HR, 3.02), and statin use nearly tripled it (HR, 2.89).

“These findings are compelling because case reports dominate the relevant literature and emphasize the presence of sickle cell trait as a risk factor for adverse outcomes, including exertional rhabdomyolysis and sudden death,” the researchers wrote. “A large longitudinal study involving a population fully tested for sickle cell trait that has formally investigated [these outcomes] while also examining other known major risk factors, such as medications, has been lacking.”

The study found that women were at much lower risk for exertional rhabdomyolysis than were men (HR, 0.51), and that risk increased with increasing age, so that soldiers aged 36 years and older had a 57% greater risk compared with those in the youngest age group.

The National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences supported the study. Dr. Nelson and his associates reported having no relevant financial disclosures.

Sickle cell trait doesn’t raise the risk of death but does raise the risk of exertional rhabdomyolysis among black soldiers, “a population that is known to engage consistently in regular and strenuous exercise while protected by exertional-injury precautions,” investigators reported. The study was published online Aug. 4 in the New England Journal of Medicine.

A number of high-profile deaths among athletes and military personnel involving exertional rhabdomyolysis have been attributed to sickle cell trait. The National Collegiate Athletic Association, the U.S. Air Force, and the U.S. Navy all require universal screening for sickle cell trait.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

“However, concerns have been raised by the American Society of Hematology and other professional organizations about the possibility of stigmatization and discrimination resulting from the mandated screening for sickle cell trait,” which predominantly affects people of African descent and some of Hispanic ancestry, but usually not whites, wrote D. Alan Nelson, PhD, of Stanford (Calif.) University, and his associates.

“These concerns warrant consideration, especially given the absence of published evidence that such screening is effective in preventing exertion-related events,” added the researchers.

The U.S. Army primarily screens for sickle cell trait among personnel deployed for combat and certain specialists whose work at high altitudes puts them at risk. To study a large enough population to generate accurate data about this rare blood abnormality, the investigators analyzed data for 47,944 black soldiers who had been tested for sickle cell trait and who served on active duty during a recent 3-year period.

The researchers assessed all inpatient and outpatient health care visits at military and civilian facilities. There were 391 exertional rhabdomyolysis events and 96 deaths from all causes during 1.61 million person-months of observation. A total of 7.4% of the study cohort carried sickle cell trait. These participants were similar to noncarriers in demographic characteristics and health predictors.

Soldiers with sickle cell trait did not have a greater risk of death than did those without sickle cell trait (hazard ratio, 0.99), and there also was no difference between carriers and noncarriers in either battle-related or non–battle-related mortality rates.

However, sickle cell trait was associated with a 54% greater risk of exertional rhabdomyolysis (HR, 1.54), Dr. Nelson and his associates noted (N Engl J Med. 2016 Aug 4. doi: 10.1056/NEJMoa1516257).

It is important to note that factors other than sickle cell trait raised the risk of exertional rhabdomyolysis to a similar or even greater degree, including obesity (HR, 1.39) and tobacco use (HR, 1.54). Recent use of antipsychotic medication tripled the risk for exertional rhabdomyolysis (HR, 3.02), and statin use nearly tripled it (HR, 2.89).

“These findings are compelling because case reports dominate the relevant literature and emphasize the presence of sickle cell trait as a risk factor for adverse outcomes, including exertional rhabdomyolysis and sudden death,” the researchers wrote. “A large longitudinal study involving a population fully tested for sickle cell trait that has formally investigated [these outcomes] while also examining other known major risk factors, such as medications, has been lacking.”

The study found that women were at much lower risk for exertional rhabdomyolysis than were men (HR, 0.51), and that risk increased with increasing age, so that soldiers aged 36 years and older had a 57% greater risk compared with those in the youngest age group.

The National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences supported the study. Dr. Nelson and his associates reported having no relevant financial disclosures.

ORLANDO –A recombinant form of factor XIII was effective at preventing serious bleeding episodes in young children with factor XIII-A subunit deficiency, a rare and serious bleeding disorder.

In a small international phase III trial, there were no major bleeding episodes among six young children treated for at least 1 year with recombinant factor XIII (rFXIII; trade name Tretten), reported Susan L. Kearney, MD, of Children’s Hospitals and Clinics of Minnesota in Minneapolis.

©benjaminalbiach/ThinkStock

“Prophylaxis was effective. The annualized bleeding rate was zero and the mean trough [FXIII activity] was greater than 10%,” she said at a moderated poster session at the World Federation of Hemophilia World Congress. “We feel that recombinant factor XIII is safe and effective in pediatric subjects less than 6 years of age with congenital factor XIII-A subunit deficiency, similar to the older age cohort.”

Factor XIII-A subunit deficiency is a rare and serious heritable bleeding disorder associated with spontaneous intracranial hemorrhage and other unpredictable types of serious bleeding.

In a previous phase III trial, 77 patients, ranging in age from 7 to 60 years, received rFXIII for bleeding prophylaxis. When given monthly, the recombinant factor was effective at preventing serious bleeding in 90% of patients. The most commonly reported adverse events were headache, pain in the extremities, and injection site pain.

Based on these results, the Food and Drug Administration granted rFXIII orphan-drug designation for treatment of patients 6 and older with factor XIII-A subunit deficiency.

In the trial reported here, investigators from the United States, United Kingdom, Israel, and Denmark enrolled three boys and three girls under age 6 who had previously completed a single dose efficacy and safety study of rFXIII. The patients received intravenous rFXIII at a dose of 35 IU/kg every 28 days for a minimum of 52 weeks.

The total treatment duration ranged from 1.8 to 3.5 years, for a total of 16.6 patient years.

There were no thromboembolic events or systemic allergic reactions, the primary safety endpoint of the study. One patient experienced three incidences of atopic dermatitis, however; two serious adverse events related to head injuries from falls during play occurred in one patient, who did not experience intracranial hemorrhage.

Two adverse events were deemed to be probably or possibly related to rFXIII: a case of viral gastroenteritis affected one patient who recovered without a change in dose, and mild fluctuating lymphocytopenia seen at baseline persisted in another patient throughout the trial.

There were no inhibitory or noninhibitory antibodies to rFXIII detected in any patient during the trial, and there were no bleeding episodes requiring additional treatment. The 14 minor bleeding episodes seen in five patients did not require treatment with an FXIII-containing product, the authors noted.

“It’s a very rare disorder, but ... the phenotype is quite severe and patients are severely affected. So this product is very useful,” said Lakshmi Srivaths, MD, a pediatric hematologist at Texas Children’s Hospital in Houston. She was not involved in the study. Unlike patients with hemophilia A or B, who require frequent factor infusions, the long half-life of this product means patients need just once-a-month infusions “that change the phenotype very significantly.”

Dr. Kearney disclosed grant/research support from Novo Nordisk, which funded the study. Some coauthors reported consulting or employment with the company.

ORLANDO –A recombinant form of factor XIII was effective at preventing serious bleeding episodes in young children with factor XIII-A subunit deficiency, a rare and serious bleeding disorder.

In a small international phase III trial, there were no major bleeding episodes among six young children treated for at least 1 year with recombinant factor XIII (rFXIII; trade name Tretten), reported Susan L. Kearney, MD, of Children’s Hospitals and Clinics of Minnesota in Minneapolis.

©benjaminalbiach/ThinkStock

“Prophylaxis was effective. The annualized bleeding rate was zero and the mean trough [FXIII activity] was greater than 10%,” she said at a moderated poster session at the World Federation of Hemophilia World Congress. “We feel that recombinant factor XIII is safe and effective in pediatric subjects less than 6 years of age with congenital factor XIII-A subunit deficiency, similar to the older age cohort.”

Factor XIII-A subunit deficiency is a rare and serious heritable bleeding disorder associated with spontaneous intracranial hemorrhage and other unpredictable types of serious bleeding.

In a previous phase III trial, 77 patients, ranging in age from 7 to 60 years, received rFXIII for bleeding prophylaxis. When given monthly, the recombinant factor was effective at preventing serious bleeding in 90% of patients. The most commonly reported adverse events were headache, pain in the extremities, and injection site pain.

Based on these results, the Food and Drug Administration granted rFXIII orphan-drug designation for treatment of patients 6 and older with factor XIII-A subunit deficiency.

In the trial reported here, investigators from the United States, United Kingdom, Israel, and Denmark enrolled three boys and three girls under age 6 who had previously completed a single dose efficacy and safety study of rFXIII. The patients received intravenous rFXIII at a dose of 35 IU/kg every 28 days for a minimum of 52 weeks.

The total treatment duration ranged from 1.8 to 3.5 years, for a total of 16.6 patient years.

There were no thromboembolic events or systemic allergic reactions, the primary safety endpoint of the study. One patient experienced three incidences of atopic dermatitis, however; two serious adverse events related to head injuries from falls during play occurred in one patient, who did not experience intracranial hemorrhage.

Two adverse events were deemed to be probably or possibly related to rFXIII: a case of viral gastroenteritis affected one patient who recovered without a change in dose, and mild fluctuating lymphocytopenia seen at baseline persisted in another patient throughout the trial.

There were no inhibitory or noninhibitory antibodies to rFXIII detected in any patient during the trial, and there were no bleeding episodes requiring additional treatment. The 14 minor bleeding episodes seen in five patients did not require treatment with an FXIII-containing product, the authors noted.

“It’s a very rare disorder, but ... the phenotype is quite severe and patients are severely affected. So this product is very useful,” said Lakshmi Srivaths, MD, a pediatric hematologist at Texas Children’s Hospital in Houston. She was not involved in the study. Unlike patients with hemophilia A or B, who require frequent factor infusions, the long half-life of this product means patients need just once-a-month infusions “that change the phenotype very significantly.”

Dr. Kearney disclosed grant/research support from Novo Nordisk, which funded the study. Some coauthors reported consulting or employment with the company.

ORLANDO –A recombinant form of factor XIII was effective at preventing serious bleeding episodes in young children with factor XIII-A subunit deficiency, a rare and serious bleeding disorder.

In a small international phase III trial, there were no major bleeding episodes among six young children treated for at least 1 year with recombinant factor XIII (rFXIII; trade name Tretten), reported Susan L. Kearney, MD, of Children’s Hospitals and Clinics of Minnesota in Minneapolis.

©benjaminalbiach/ThinkStock

“Prophylaxis was effective. The annualized bleeding rate was zero and the mean trough [FXIII activity] was greater than 10%,” she said at a moderated poster session at the World Federation of Hemophilia World Congress. “We feel that recombinant factor XIII is safe and effective in pediatric subjects less than 6 years of age with congenital factor XIII-A subunit deficiency, similar to the older age cohort.”

Factor XIII-A subunit deficiency is a rare and serious heritable bleeding disorder associated with spontaneous intracranial hemorrhage and other unpredictable types of serious bleeding.

In a previous phase III trial, 77 patients, ranging in age from 7 to 60 years, received rFXIII for bleeding prophylaxis. When given monthly, the recombinant factor was effective at preventing serious bleeding in 90% of patients. The most commonly reported adverse events were headache, pain in the extremities, and injection site pain.

Based on these results, the Food and Drug Administration granted rFXIII orphan-drug designation for treatment of patients 6 and older with factor XIII-A subunit deficiency.

In the trial reported here, investigators from the United States, United Kingdom, Israel, and Denmark enrolled three boys and three girls under age 6 who had previously completed a single dose efficacy and safety study of rFXIII. The patients received intravenous rFXIII at a dose of 35 IU/kg every 28 days for a minimum of 52 weeks.

The total treatment duration ranged from 1.8 to 3.5 years, for a total of 16.6 patient years.

There were no thromboembolic events or systemic allergic reactions, the primary safety endpoint of the study. One patient experienced three incidences of atopic dermatitis, however; two serious adverse events related to head injuries from falls during play occurred in one patient, who did not experience intracranial hemorrhage.

Two adverse events were deemed to be probably or possibly related to rFXIII: a case of viral gastroenteritis affected one patient who recovered without a change in dose, and mild fluctuating lymphocytopenia seen at baseline persisted in another patient throughout the trial.

There were no inhibitory or noninhibitory antibodies to rFXIII detected in any patient during the trial, and there were no bleeding episodes requiring additional treatment. The 14 minor bleeding episodes seen in five patients did not require treatment with an FXIII-containing product, the authors noted.

“It’s a very rare disorder, but ... the phenotype is quite severe and patients are severely affected. So this product is very useful,” said Lakshmi Srivaths, MD, a pediatric hematologist at Texas Children’s Hospital in Houston. She was not involved in the study. Unlike patients with hemophilia A or B, who require frequent factor infusions, the long half-life of this product means patients need just once-a-month infusions “that change the phenotype very significantly.”

Dr. Kearney disclosed grant/research support from Novo Nordisk, which funded the study. Some coauthors reported consulting or employment with the company.

ORLANDO – An integrated care model that includes a hematologist, a specialized hematology nurse, a physical therapist, a social worker, and 24/7 access to a specialized coagulation laboratory is recommended in a new hemophilia care guideline jointly developed by the National Hemophilia Foundation and McMaster University in Hamilton, Ontario.

The guideline has been formally accepted for inclusion in the National Guideline Clearinghouse (NGC), the National Hemophilia Foundation announced at its annual meeting, held immediately before the World Hemophilia Foundation World Congress here.

©designer491/Thinkstock

“The integrated care model, as is utilized within the U.S. federally funded network of hemophilia treatment centers (HTCs), should be advocated for optimal care of persons with hemophilia,” wrote guideline coauthors Steven W. Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, and Craig M. Kessler, MD, from Georgetown University in Washington, in an introduction to the guideline, published in the journal Hemophilia.

Developed according to evidence-based principles, the guideline is hoped to “promote harmonization of care delivery and reduce practice variations within the U.S. HTC network. This guideline will inform the HTC network how best to prioritize additional ‘high-value’ research to fill data gaps or strengthen the evidence base as outlined in the manuscript,” they added.

The guideline authors recognized three basic models of care in use in the United States:

The integrated care, comprehensive care, or HTC model, which generally assumes that all aspects of care will be delivered in a specialized center.

Specialist-based care, under which a hematologist may or may not have training in the management of patients with hemophilia, is provided in a hospital or medical office, but not in a specialized center.

Non-specialist care, delivered in an emergency department or primary care practitioners office.

“We believe that the ‘No Care’ model, theoretically indicating complete absence of care, does not currently operate in the U.S. Yet, this is likely the de facto model of care for many individuals with hemophilia who do not have access to care due to profound resource constraints, particularly in developing countries or underserved minorities,” the authors wrote.

The guideline’s main recommendation – that the integrated-care model is preferable to the non-integrated care model – is conditional, with moderate certainty in the evidence.

For persons with hemophilia with inhibitors to clotting factors, however, the integrated-care model recommendation is considered to be strong, with moderate certainty.

The guideline development panel found that there were significant gaps in evidence for the benefits of integrated care for specific populations such as older patients and populations with poor access to care, and called for additional studies to clarify these questions.

Additionally, the panelists call for study into which specific interventions or aspects of care should be included in the integrated model, and for more in-depth studies into the effects on patient-important outcomes.

“This collaborative project constitutes an important milestone on a critical component of evidence-based guideline methodology,” Alfonso Iorio, MD, PhD, from the Department of Clinical Epidemiology and Biostatistics at McMaster University, said in a press statement. “It demonstrates how a patient advocacy organization can promote and support a guideline process, in the true spirit of patient involvement in research and care process, without compromising a rigorous and transparent conflict of interest management process.”

The guidelines were funded by the National Hemophilia Foundation. Several guideline panelists reported financial relationships with companies that make clotting factors and other products for persons with hemophilia.

ORLANDO – An integrated care model that includes a hematologist, a specialized hematology nurse, a physical therapist, a social worker, and 24/7 access to a specialized coagulation laboratory is recommended in a new hemophilia care guideline jointly developed by the National Hemophilia Foundation and McMaster University in Hamilton, Ontario.

The guideline has been formally accepted for inclusion in the National Guideline Clearinghouse (NGC), the National Hemophilia Foundation announced at its annual meeting, held immediately before the World Hemophilia Foundation World Congress here.

©designer491/Thinkstock

“The integrated care model, as is utilized within the U.S. federally funded network of hemophilia treatment centers (HTCs), should be advocated for optimal care of persons with hemophilia,” wrote guideline coauthors Steven W. Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, and Craig M. Kessler, MD, from Georgetown University in Washington, in an introduction to the guideline, published in the journal Hemophilia.

Developed according to evidence-based principles, the guideline is hoped to “promote harmonization of care delivery and reduce practice variations within the U.S. HTC network. This guideline will inform the HTC network how best to prioritize additional ‘high-value’ research to fill data gaps or strengthen the evidence base as outlined in the manuscript,” they added.

The guideline authors recognized three basic models of care in use in the United States:

The integrated care, comprehensive care, or HTC model, which generally assumes that all aspects of care will be delivered in a specialized center.

Specialist-based care, under which a hematologist may or may not have training in the management of patients with hemophilia, is provided in a hospital or medical office, but not in a specialized center.

Non-specialist care, delivered in an emergency department or primary care practitioners office.

“We believe that the ‘No Care’ model, theoretically indicating complete absence of care, does not currently operate in the U.S. Yet, this is likely the de facto model of care for many individuals with hemophilia who do not have access to care due to profound resource constraints, particularly in developing countries or underserved minorities,” the authors wrote.

The guideline’s main recommendation – that the integrated-care model is preferable to the non-integrated care model – is conditional, with moderate certainty in the evidence.

For persons with hemophilia with inhibitors to clotting factors, however, the integrated-care model recommendation is considered to be strong, with moderate certainty.

The guideline development panel found that there were significant gaps in evidence for the benefits of integrated care for specific populations such as older patients and populations with poor access to care, and called for additional studies to clarify these questions.

Additionally, the panelists call for study into which specific interventions or aspects of care should be included in the integrated model, and for more in-depth studies into the effects on patient-important outcomes.

“This collaborative project constitutes an important milestone on a critical component of evidence-based guideline methodology,” Alfonso Iorio, MD, PhD, from the Department of Clinical Epidemiology and Biostatistics at McMaster University, said in a press statement. “It demonstrates how a patient advocacy organization can promote and support a guideline process, in the true spirit of patient involvement in research and care process, without compromising a rigorous and transparent conflict of interest management process.”

The guidelines were funded by the National Hemophilia Foundation. Several guideline panelists reported financial relationships with companies that make clotting factors and other products for persons with hemophilia.

ORLANDO – An integrated care model that includes a hematologist, a specialized hematology nurse, a physical therapist, a social worker, and 24/7 access to a specialized coagulation laboratory is recommended in a new hemophilia care guideline jointly developed by the National Hemophilia Foundation and McMaster University in Hamilton, Ontario.

The guideline has been formally accepted for inclusion in the National Guideline Clearinghouse (NGC), the National Hemophilia Foundation announced at its annual meeting, held immediately before the World Hemophilia Foundation World Congress here.

©designer491/Thinkstock

“The integrated care model, as is utilized within the U.S. federally funded network of hemophilia treatment centers (HTCs), should be advocated for optimal care of persons with hemophilia,” wrote guideline coauthors Steven W. Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, and Craig M. Kessler, MD, from Georgetown University in Washington, in an introduction to the guideline, published in the journal Hemophilia.

Developed according to evidence-based principles, the guideline is hoped to “promote harmonization of care delivery and reduce practice variations within the U.S. HTC network. This guideline will inform the HTC network how best to prioritize additional ‘high-value’ research to fill data gaps or strengthen the evidence base as outlined in the manuscript,” they added.

The guideline authors recognized three basic models of care in use in the United States:

The integrated care, comprehensive care, or HTC model, which generally assumes that all aspects of care will be delivered in a specialized center.

Specialist-based care, under which a hematologist may or may not have training in the management of patients with hemophilia, is provided in a hospital or medical office, but not in a specialized center.

Non-specialist care, delivered in an emergency department or primary care practitioners office.

“We believe that the ‘No Care’ model, theoretically indicating complete absence of care, does not currently operate in the U.S. Yet, this is likely the de facto model of care for many individuals with hemophilia who do not have access to care due to profound resource constraints, particularly in developing countries or underserved minorities,” the authors wrote.

The guideline’s main recommendation – that the integrated-care model is preferable to the non-integrated care model – is conditional, with moderate certainty in the evidence.

For persons with hemophilia with inhibitors to clotting factors, however, the integrated-care model recommendation is considered to be strong, with moderate certainty.

The guideline development panel found that there were significant gaps in evidence for the benefits of integrated care for specific populations such as older patients and populations with poor access to care, and called for additional studies to clarify these questions.

Additionally, the panelists call for study into which specific interventions or aspects of care should be included in the integrated model, and for more in-depth studies into the effects on patient-important outcomes.

“This collaborative project constitutes an important milestone on a critical component of evidence-based guideline methodology,” Alfonso Iorio, MD, PhD, from the Department of Clinical Epidemiology and Biostatistics at McMaster University, said in a press statement. “It demonstrates how a patient advocacy organization can promote and support a guideline process, in the true spirit of patient involvement in research and care process, without compromising a rigorous and transparent conflict of interest management process.”

The guidelines were funded by the National Hemophilia Foundation. Several guideline panelists reported financial relationships with companies that make clotting factors and other products for persons with hemophilia.

Medicaid’s three most expensive drugs by spending per prescription were for treatment of hemophilia, with the cost leader coming in at almost $59,000, according to an analysis by the Kaiser Family Foundation covering 2014 and the first half of 2015.

The trio of hemophilia drugs was topped by NovoSeven RT (coagulation factor VIIa [recombinant]), with Koate-DVI (antihemophilic factor [human]) second at $57,000 per prescription and Feiba (anti-inhibitor coagulant complex) third at $48,000 for each prescription.

None of the Medicaid costs include rebates since those data are unavailable to the public, Kaiser noted.

The fourth and fifth most expensive drugs were Adagen (pegademase bovine), which is used in the treatment of severe combined immunodeficiency disease associated with a deficiency of adenosine deaminase and cost Medicaid $45,000 per prescription, and the multiple sclerosis drug HP Acthar (repository corticotropin), which went for almost $44,000 a prescription, Kaiser said in its analysis, which used State Drug Utilization Data that are part of the Medicaid Drug Rebate Program.

[email protected]

Medicaid’s three most expensive drugs by spending per prescription were for treatment of hemophilia, with the cost leader coming in at almost $59,000, according to an analysis by the Kaiser Family Foundation covering 2014 and the first half of 2015.

The trio of hemophilia drugs was topped by NovoSeven RT (coagulation factor VIIa [recombinant]), with Koate-DVI (antihemophilic factor [human]) second at $57,000 per prescription and Feiba (anti-inhibitor coagulant complex) third at $48,000 for each prescription.

None of the Medicaid costs include rebates since those data are unavailable to the public, Kaiser noted.

The fourth and fifth most expensive drugs were Adagen (pegademase bovine), which is used in the treatment of severe combined immunodeficiency disease associated with a deficiency of adenosine deaminase and cost Medicaid $45,000 per prescription, and the multiple sclerosis drug HP Acthar (repository corticotropin), which went for almost $44,000 a prescription, Kaiser said in its analysis, which used State Drug Utilization Data that are part of the Medicaid Drug Rebate Program.

[email protected]

Medicaid’s three most expensive drugs by spending per prescription were for treatment of hemophilia, with the cost leader coming in at almost $59,000, according to an analysis by the Kaiser Family Foundation covering 2014 and the first half of 2015.

The trio of hemophilia drugs was topped by NovoSeven RT (coagulation factor VIIa [recombinant]), with Koate-DVI (antihemophilic factor [human]) second at $57,000 per prescription and Feiba (anti-inhibitor coagulant complex) third at $48,000 for each prescription.

None of the Medicaid costs include rebates since those data are unavailable to the public, Kaiser noted.

The fourth and fifth most expensive drugs were Adagen (pegademase bovine), which is used in the treatment of severe combined immunodeficiency disease associated with a deficiency of adenosine deaminase and cost Medicaid $45,000 per prescription, and the multiple sclerosis drug HP Acthar (repository corticotropin), which went for almost $44,000 a prescription, Kaiser said in its analysis, which used State Drug Utilization Data that are part of the Medicaid Drug Rebate Program.

[email protected]

“The liver, not the spleen, is the major on-demand site of red blood cell elimination and iron recycling,” according to Filip Swirski, PhD, of the Massachusetts General Hospital Center for Systems Biology, and his colleagues.

The liver relies on a buffer system consisting of bone marrow–derived monocytes that consume damaged red blood cells (RBCs) in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling, the researchers concluded in a study published in Nature Medicine.

© pavlen/iStockphoto

The study was designed to examine how the body clears old and damaged RBCs without releasing toxic levels of free iron. Damaged RBCs can release unbound forms of iron-carrying hemoglobin, which can cause kidney injury and can lead to anemia.

The researchers used several different models of RBC damage to examine RBC clearance and iron recycling in a mouse model. Damaged RBCs in the bloodstream prompted an increase in monocytes that took up the damaged cells and traveled to both the liver and the spleen. Within hours, almost all of the damaged RBCs were located within specialized macrophages seen only in the liver. Chemokines drew the monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1–expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+Tim-4^neg macrophages are transient, reside alongside embryonically derived T-cell immunoglobulin and mucin domain containing 4^high Kupffer cells, and depend on the growth factor Csf1 and the transcription factor Nrf2, the researchers wrote.

Blocking that process resulted in impaired RBC clearance, toxic levels of free iron and hemoglobin, and signs of liver and kidney damage.

“If overactive, (the mechanism) could remove too many RBCs, but if (the mechanism is) sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions,” Dr. Swirski said in a press release.

The researchers had no financial conflicts of interest. The study was funded by the National Institutes of Health.

[email protected]

On Twitter @maryjodales

“The liver, not the spleen, is the major on-demand site of red blood cell elimination and iron recycling,” according to Filip Swirski, PhD, of the Massachusetts General Hospital Center for Systems Biology, and his colleagues.

The liver relies on a buffer system consisting of bone marrow–derived monocytes that consume damaged red blood cells (RBCs) in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling, the researchers concluded in a study published in Nature Medicine.

© pavlen/iStockphoto

The study was designed to examine how the body clears old and damaged RBCs without releasing toxic levels of free iron. Damaged RBCs can release unbound forms of iron-carrying hemoglobin, which can cause kidney injury and can lead to anemia.

The researchers used several different models of RBC damage to examine RBC clearance and iron recycling in a mouse model. Damaged RBCs in the bloodstream prompted an increase in monocytes that took up the damaged cells and traveled to both the liver and the spleen. Within hours, almost all of the damaged RBCs were located within specialized macrophages seen only in the liver. Chemokines drew the monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1–expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+Tim-4^neg macrophages are transient, reside alongside embryonically derived T-cell immunoglobulin and mucin domain containing 4^high Kupffer cells, and depend on the growth factor Csf1 and the transcription factor Nrf2, the researchers wrote.

Blocking that process resulted in impaired RBC clearance, toxic levels of free iron and hemoglobin, and signs of liver and kidney damage.

“If overactive, (the mechanism) could remove too many RBCs, but if (the mechanism is) sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions,” Dr. Swirski said in a press release.

The researchers had no financial conflicts of interest. The study was funded by the National Institutes of Health.

[email protected]

On Twitter @maryjodales

“The liver, not the spleen, is the major on-demand site of red blood cell elimination and iron recycling,” according to Filip Swirski, PhD, of the Massachusetts General Hospital Center for Systems Biology, and his colleagues.

The liver relies on a buffer system consisting of bone marrow–derived monocytes that consume damaged red blood cells (RBCs) in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling, the researchers concluded in a study published in Nature Medicine.

© pavlen/iStockphoto

The study was designed to examine how the body clears old and damaged RBCs without releasing toxic levels of free iron. Damaged RBCs can release unbound forms of iron-carrying hemoglobin, which can cause kidney injury and can lead to anemia.

The researchers used several different models of RBC damage to examine RBC clearance and iron recycling in a mouse model. Damaged RBCs in the bloodstream prompted an increase in monocytes that took up the damaged cells and traveled to both the liver and the spleen. Within hours, almost all of the damaged RBCs were located within specialized macrophages seen only in the liver. Chemokines drew the monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1–expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+Tim-4^neg macrophages are transient, reside alongside embryonically derived T-cell immunoglobulin and mucin domain containing 4^high Kupffer cells, and depend on the growth factor Csf1 and the transcription factor Nrf2, the researchers wrote.

Blocking that process resulted in impaired RBC clearance, toxic levels of free iron and hemoglobin, and signs of liver and kidney damage.

“If overactive, (the mechanism) could remove too many RBCs, but if (the mechanism is) sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions,” Dr. Swirski said in a press release.

The researchers had no financial conflicts of interest. The study was funded by the National Institutes of Health.

[email protected]

On Twitter @maryjodales

Red blood cells

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan designation for Coversin for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Coversin is a second-generation complement inhibitor that acts on complement component-C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is being developed by Akari Therapeutics.

In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and the drug can achieve full complement inhibition in the blood of PNH patients who are resistant to the drug eculizumab.

In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.

Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is administering the drug to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. And the only drug-related adverse event has been occasional local and transient irritation at the injection site.

Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Red blood cells

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan designation for Coversin for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Coversin is a second-generation complement inhibitor that acts on complement component-C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is being developed by Akari Therapeutics.

In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and the drug can achieve full complement inhibition in the blood of PNH patients who are resistant to the drug eculizumab.

In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.

Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is administering the drug to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. And the only drug-related adverse event has been occasional local and transient irritation at the injection site.

Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Red blood cells

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan designation for Coversin for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Coversin is a second-generation complement inhibitor that acts on complement component-C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is being developed by Akari Therapeutics.

In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and the drug can achieve full complement inhibition in the blood of PNH patients who are resistant to the drug eculizumab.

In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.

Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is administering the drug to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. And the only drug-related adverse event has been occasional local and transient irritation at the injection site.

Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

In patients with acquired autoimmune thrombotic thrombocytopenic purpura, elevated plasma levels of human neutrophil proteins 1-3 inhibit proteolytic cleavage of von Willebrand factor by ADAMTS13, Vikram G. Pillai, PhD, of the University of Alabama at Birmingham, and colleagues reported.

The finding may explain how inflammation triggers microvascular thrombosis in these patients and potentially others with immune thrombotic disorders, according to the researchers (Blood 2016;128:110-9).

Wikimedia Commons/ Erhabor Osaro/CC-SA 3.0

They performed enzyme-linked immunosorbent assays and found markedly increased levels of plasma human neutrophil proteins (HNPs) 1-3 in most of the patients with acquired autoimmune thrombotic thrombocytopenic purpura (TTP). The median levels in the 19 patients were 170 ng/mL, compared with 23 ng/mL in 18 healthy controls, a statistically significant difference (P less than .0001).

Liquid chromatography plus tandem mass spectrometry similarly confirmed statistically significant increases in HNP1, HNP2, and HNP3 in patient samples (P less than .001).

Measures of HNPs 1-3 by both methods correlated well, and the researchers concluded that HNPs 1-3 likely inhibit ADAMTS13 activity by binding to the central A2 domain of von Willebrand factor and physically blocking ADAMTS13 binding.

The researchers had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

In patients with acquired autoimmune thrombotic thrombocytopenic purpura, elevated plasma levels of human neutrophil proteins 1-3 inhibit proteolytic cleavage of von Willebrand factor by ADAMTS13, Vikram G. Pillai, PhD, of the University of Alabama at Birmingham, and colleagues reported.

The finding may explain how inflammation triggers microvascular thrombosis in these patients and potentially others with immune thrombotic disorders, according to the researchers (Blood 2016;128:110-9).

Wikimedia Commons/ Erhabor Osaro/CC-SA 3.0

They performed enzyme-linked immunosorbent assays and found markedly increased levels of plasma human neutrophil proteins (HNPs) 1-3 in most of the patients with acquired autoimmune thrombotic thrombocytopenic purpura (TTP). The median levels in the 19 patients were 170 ng/mL, compared with 23 ng/mL in 18 healthy controls, a statistically significant difference (P less than .0001).

Liquid chromatography plus tandem mass spectrometry similarly confirmed statistically significant increases in HNP1, HNP2, and HNP3 in patient samples (P less than .001).

Measures of HNPs 1-3 by both methods correlated well, and the researchers concluded that HNPs 1-3 likely inhibit ADAMTS13 activity by binding to the central A2 domain of von Willebrand factor and physically blocking ADAMTS13 binding.

The researchers had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

In patients with acquired autoimmune thrombotic thrombocytopenic purpura, elevated plasma levels of human neutrophil proteins 1-3 inhibit proteolytic cleavage of von Willebrand factor by ADAMTS13, Vikram G. Pillai, PhD, of the University of Alabama at Birmingham, and colleagues reported.

The finding may explain how inflammation triggers microvascular thrombosis in these patients and potentially others with immune thrombotic disorders, according to the researchers (Blood 2016;128:110-9).

Wikimedia Commons/ Erhabor Osaro/CC-SA 3.0

They performed enzyme-linked immunosorbent assays and found markedly increased levels of plasma human neutrophil proteins (HNPs) 1-3 in most of the patients with acquired autoimmune thrombotic thrombocytopenic purpura (TTP). The median levels in the 19 patients were 170 ng/mL, compared with 23 ng/mL in 18 healthy controls, a statistically significant difference (P less than .0001).

Liquid chromatography plus tandem mass spectrometry similarly confirmed statistically significant increases in HNP1, HNP2, and HNP3 in patient samples (P less than .001).

Measures of HNPs 1-3 by both methods correlated well, and the researchers concluded that HNPs 1-3 likely inhibit ADAMTS13 activity by binding to the central A2 domain of von Willebrand factor and physically blocking ADAMTS13 binding.

The researchers had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

Dematin is newly recognized as a protein that is crucial to red blood cell (RBC) membrane integrity, and dematin’s absence in mice resulted in severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia, Yunzhe Lu of Tufts University, Boston, and her colleagues reported in the journal Blood.

The finding indicates that dematin is the major determinant of membrane stability within the junctional protein complex.

©GuidoVrola/thinkstockphotos.com

The researchers defined the role of dematin by designing a mouse model that lacked the protein. Affected mice developed severe anemia and had abnormally shaped erythrocytes with unstable membranes.

They examined the mechanism behind erythrocyte membrane instability in the mice by using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements. Although many membrane and cytoskeletal proteins remained at their normal levels, spectrin, adducin, and actin were greatly reduced in these erythrocytes. The findings indicate that dematin plays a critical role in maintaining the fundamental properties of the erythrocyte’s membrane cytoskeleton complex, the researchers wrote (Blood 2016;128:93-103).

[email protected]

On Twitter @maryjodales

Dematin is newly recognized as a protein that is crucial to red blood cell (RBC) membrane integrity, and dematin’s absence in mice resulted in severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia, Yunzhe Lu of Tufts University, Boston, and her colleagues reported in the journal Blood.

The finding indicates that dematin is the major determinant of membrane stability within the junctional protein complex.

©GuidoVrola/thinkstockphotos.com

The researchers defined the role of dematin by designing a mouse model that lacked the protein. Affected mice developed severe anemia and had abnormally shaped erythrocytes with unstable membranes.

They examined the mechanism behind erythrocyte membrane instability in the mice by using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements. Although many membrane and cytoskeletal proteins remained at their normal levels, spectrin, adducin, and actin were greatly reduced in these erythrocytes. The findings indicate that dematin plays a critical role in maintaining the fundamental properties of the erythrocyte’s membrane cytoskeleton complex, the researchers wrote (Blood 2016;128:93-103).

[email protected]

On Twitter @maryjodales

Dematin is newly recognized as a protein that is crucial to red blood cell (RBC) membrane integrity, and dematin’s absence in mice resulted in severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia, Yunzhe Lu of Tufts University, Boston, and her colleagues reported in the journal Blood.

The finding indicates that dematin is the major determinant of membrane stability within the junctional protein complex.

©GuidoVrola/thinkstockphotos.com

The researchers defined the role of dematin by designing a mouse model that lacked the protein. Affected mice developed severe anemia and had abnormally shaped erythrocytes with unstable membranes.

They examined the mechanism behind erythrocyte membrane instability in the mice by using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements. Although many membrane and cytoskeletal proteins remained at their normal levels, spectrin, adducin, and actin were greatly reduced in these erythrocytes. The findings indicate that dematin plays a critical role in maintaining the fundamental properties of the erythrocyte’s membrane cytoskeleton complex, the researchers wrote (Blood 2016;128:93-103).

[email protected]

On Twitter @maryjodales