Bleeding Disorders

The real strength of the 4T score for heparin-induced thrombocytopenia (HIT) is its negative predictive value, according to hematologist Adam Cuker, MD, of the department of medicine at the University of Pennsylvania, Philadelphia.

The score assigns patients points based on degree of thrombocytopenia, timing of platelet count fall in relation to heparin exposure, presence of thrombosis and other sequelae, and the likelihood of other causes of thrombocytopenia.

A low score – 3 points or less – has a negative predictive value of 99.8%, “so HIT is basically ruled out; you do not need to order lab testing for HIT or manage the patient empirically for HIT,” and should look for other causes of thrombocytopenia, said Dr. Cuker, lead author of the American Society of Hematology’s most recent HIT guidelines.

Intermediate scores of 4 or 5 points, and high scores of 6-8 points, are a different story. The positive predictive value of an intermediate score is only 14%, and of a high score, 64%, so although they don’t confirm the diagnosis, “you have to take the possibility of HIT seriously.” Discontinue heparin, start a nonheparin anticoagulant, and order a HIT immunoassay. If it’s positive, order a functional assay to confirm the diagnosis, he said.

Suspicion of HIT “is perhaps the most common consult that we get on the hematology service. These are tough consults because it is a high-stakes decision.” There is about a 6% risk of thromboembolism, amputation, and death for every day treatment is delayed. “On the other hand, the nonheparin anticoagulants are expensive, and they carry about a 1% daily risk of major bleeding,” Dr. Cuker explained during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

ELISA immunoassay detects antiplatelet factor 4 heparin antibodies but doesn’t tell whether or not they are able to activate platelets and cause HIT. Functional tests such as the serotonin-release assay detect only those antibodies able to do so, but the assays are difficult to perform, and often require samples to be sent out to a reference lab.

ASH did not specify a particular nonheparin anticoagulant in its 2018 guidelines because “the best choice for your patient” depends on which drugs you have available, your familiarity with them, and patient factors, Dr. Cuker said at the conference sponsored by MedscapeLive.

It makes sense, for instance, to use a short-acting agent such as argatroban or bivalirudin in patients who are critically ill, at high risk of bleeding, or likely to need an urgent unplanned procedure. Fondaparinux or direct oral anticoagulants (DOACs) make sense if patients are clinically stable with good organ function and no more than average bleeding risk, because they are easier to administer and facilitate transition to the outpatient setting.

DOACs are newcomers to ASH’s guidelines. Just 81 patients had been reported in the literature when they were being drafted, but only 2 patients had recurrence or progression of thromboembolic events, and there were no major bleeds. The results compared favorably with other options.

The studies were subject to selection and reporting biases, “but, nonetheless, the panel felt the results were positive enough that DOACs ought to be listed as an option,” Dr. Cuker said.

The guidelines note that parenteral options may be the best choice for life- or limb-threatening thrombosis “because few such patients have been treated with a DOAC.” Anticoagulation must continue until platelet counts recover.

Dr. Cuker is a consultant for Synergy and has institutional research support from Alexion, Bayer, Sanofi, and other companies. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

The real strength of the 4T score for heparin-induced thrombocytopenia (HIT) is its negative predictive value, according to hematologist Adam Cuker, MD, of the department of medicine at the University of Pennsylvania, Philadelphia.

The score assigns patients points based on degree of thrombocytopenia, timing of platelet count fall in relation to heparin exposure, presence of thrombosis and other sequelae, and the likelihood of other causes of thrombocytopenia.

A low score – 3 points or less – has a negative predictive value of 99.8%, “so HIT is basically ruled out; you do not need to order lab testing for HIT or manage the patient empirically for HIT,” and should look for other causes of thrombocytopenia, said Dr. Cuker, lead author of the American Society of Hematology’s most recent HIT guidelines.

Intermediate scores of 4 or 5 points, and high scores of 6-8 points, are a different story. The positive predictive value of an intermediate score is only 14%, and of a high score, 64%, so although they don’t confirm the diagnosis, “you have to take the possibility of HIT seriously.” Discontinue heparin, start a nonheparin anticoagulant, and order a HIT immunoassay. If it’s positive, order a functional assay to confirm the diagnosis, he said.

Suspicion of HIT “is perhaps the most common consult that we get on the hematology service. These are tough consults because it is a high-stakes decision.” There is about a 6% risk of thromboembolism, amputation, and death for every day treatment is delayed. “On the other hand, the nonheparin anticoagulants are expensive, and they carry about a 1% daily risk of major bleeding,” Dr. Cuker explained during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

ELISA immunoassay detects antiplatelet factor 4 heparin antibodies but doesn’t tell whether or not they are able to activate platelets and cause HIT. Functional tests such as the serotonin-release assay detect only those antibodies able to do so, but the assays are difficult to perform, and often require samples to be sent out to a reference lab.

ASH did not specify a particular nonheparin anticoagulant in its 2018 guidelines because “the best choice for your patient” depends on which drugs you have available, your familiarity with them, and patient factors, Dr. Cuker said at the conference sponsored by MedscapeLive.

It makes sense, for instance, to use a short-acting agent such as argatroban or bivalirudin in patients who are critically ill, at high risk of bleeding, or likely to need an urgent unplanned procedure. Fondaparinux or direct oral anticoagulants (DOACs) make sense if patients are clinically stable with good organ function and no more than average bleeding risk, because they are easier to administer and facilitate transition to the outpatient setting.

DOACs are newcomers to ASH’s guidelines. Just 81 patients had been reported in the literature when they were being drafted, but only 2 patients had recurrence or progression of thromboembolic events, and there were no major bleeds. The results compared favorably with other options.

The studies were subject to selection and reporting biases, “but, nonetheless, the panel felt the results were positive enough that DOACs ought to be listed as an option,” Dr. Cuker said.

The guidelines note that parenteral options may be the best choice for life- or limb-threatening thrombosis “because few such patients have been treated with a DOAC.” Anticoagulation must continue until platelet counts recover.

Dr. Cuker is a consultant for Synergy and has institutional research support from Alexion, Bayer, Sanofi, and other companies. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

The real strength of the 4T score for heparin-induced thrombocytopenia (HIT) is its negative predictive value, according to hematologist Adam Cuker, MD, of the department of medicine at the University of Pennsylvania, Philadelphia.

The score assigns patients points based on degree of thrombocytopenia, timing of platelet count fall in relation to heparin exposure, presence of thrombosis and other sequelae, and the likelihood of other causes of thrombocytopenia.

A low score – 3 points or less – has a negative predictive value of 99.8%, “so HIT is basically ruled out; you do not need to order lab testing for HIT or manage the patient empirically for HIT,” and should look for other causes of thrombocytopenia, said Dr. Cuker, lead author of the American Society of Hematology’s most recent HIT guidelines.

Intermediate scores of 4 or 5 points, and high scores of 6-8 points, are a different story. The positive predictive value of an intermediate score is only 14%, and of a high score, 64%, so although they don’t confirm the diagnosis, “you have to take the possibility of HIT seriously.” Discontinue heparin, start a nonheparin anticoagulant, and order a HIT immunoassay. If it’s positive, order a functional assay to confirm the diagnosis, he said.

Suspicion of HIT “is perhaps the most common consult that we get on the hematology service. These are tough consults because it is a high-stakes decision.” There is about a 6% risk of thromboembolism, amputation, and death for every day treatment is delayed. “On the other hand, the nonheparin anticoagulants are expensive, and they carry about a 1% daily risk of major bleeding,” Dr. Cuker explained during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

ELISA immunoassay detects antiplatelet factor 4 heparin antibodies but doesn’t tell whether or not they are able to activate platelets and cause HIT. Functional tests such as the serotonin-release assay detect only those antibodies able to do so, but the assays are difficult to perform, and often require samples to be sent out to a reference lab.

ASH did not specify a particular nonheparin anticoagulant in its 2018 guidelines because “the best choice for your patient” depends on which drugs you have available, your familiarity with them, and patient factors, Dr. Cuker said at the conference sponsored by MedscapeLive.

It makes sense, for instance, to use a short-acting agent such as argatroban or bivalirudin in patients who are critically ill, at high risk of bleeding, or likely to need an urgent unplanned procedure. Fondaparinux or direct oral anticoagulants (DOACs) make sense if patients are clinically stable with good organ function and no more than average bleeding risk, because they are easier to administer and facilitate transition to the outpatient setting.

DOACs are newcomers to ASH’s guidelines. Just 81 patients had been reported in the literature when they were being drafted, but only 2 patients had recurrence or progression of thromboembolic events, and there were no major bleeds. The results compared favorably with other options.

The studies were subject to selection and reporting biases, “but, nonetheless, the panel felt the results were positive enough that DOACs ought to be listed as an option,” Dr. Cuker said.

The guidelines note that parenteral options may be the best choice for life- or limb-threatening thrombosis “because few such patients have been treated with a DOAC.” Anticoagulation must continue until platelet counts recover.

Dr. Cuker is a consultant for Synergy and has institutional research support from Alexion, Bayer, Sanofi, and other companies. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Individuals with nonsevere hemophilia A (NSHA) in the United States showed increased mortality based upon increasing age, male sex, and infections, according to the results of a large database analysis.

However, even though inhibitors, which can develop from factor VIII (FVIII) hemophilia therapy, were detected at an earlier age than previously reported, their presence was not associated with an increased risk of mortality according to the report published in Blood Advances (2020;4[19]:4739-47).

The researchers assessed 6,624 individuals born between 1920 and 2018 (5,694 [86.0%] men and 930 women) with NSHA from the ATHNdataset, according to Ming Y. Lim, MBBCH, MS, of the division of hematology and hematologic malignancies, University of Utah, Salt Lake City, and colleagues.

Demographically, the proportion of Black participants in the ATHNdataset was lower at 8.2%, than the 11.6% found in U.S. hemophilia population as a whole. A total of 77.3% (n = 5,122) had documented exposure to FVIII concentrates, 8.4% (n = 555) had no documented exposure, and information was unknown for the remaining 14.3%.
 

Causes of mortality

The researchers found that inhibitors occurred at an early age of 13 years with a prevalence of 2.6%, compared with the commonly reported median age of about 30 years for inhibitor development, but their presence was not associated with an increased risk of mortality, according to the authors. Instead, they found that mortality rates in the NSHA cohort were influenced by age, male sex, and hepatitis C and HIV infections.

The researchers speculated that the earlier age of inhibitor development may be due to the fact of the increased availability of FVIII concentrates over time, and that they may have been used more often from 2010 to 2018, compared with previously reported INSIGHT study (1980-2011).

In a multivariable analysis, men with NSHA were found to have 2.6 times the risk of death. Mortality risk increased twofold with each additional decade of age. Persons with hepatitis C had twice the risk of death and persons with HIV had almost four times the risk, compared with persons without these conditions.

The most common primary cause of death was malignancy (20.0%). The observed number of deaths from liver disease in the NSHA cohort was almost five times the expected death rate at 14%. Hemophilia-related deaths were 5.9%.

“Continued monitoring of persons with NSHA by comprehensive care visits at HTC should occur annually to address hemophilia-related issues and other age-related comorbidities, in collaboration with the primary care physician and other subspecialists. Importantly, we found that in the NSHA cohort, the development of inhibitors occurred at an earlier age than previously reported. This highlights the importance of routine monitoring for inhibitors in the NSHA population, regardless of age, especially if they have recently received intense factor replacement therapy,” the researchers concluded.

Ms. Lim reported no conflicts. Other authors reported research and consulting funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Lim MY et al. Blood Adv. 2020;4(19):4739-47.

Individuals with nonsevere hemophilia A (NSHA) in the United States showed increased mortality based upon increasing age, male sex, and infections, according to the results of a large database analysis.

However, even though inhibitors, which can develop from factor VIII (FVIII) hemophilia therapy, were detected at an earlier age than previously reported, their presence was not associated with an increased risk of mortality according to the report published in Blood Advances (2020;4[19]:4739-47).

The researchers assessed 6,624 individuals born between 1920 and 2018 (5,694 [86.0%] men and 930 women) with NSHA from the ATHNdataset, according to Ming Y. Lim, MBBCH, MS, of the division of hematology and hematologic malignancies, University of Utah, Salt Lake City, and colleagues.

Demographically, the proportion of Black participants in the ATHNdataset was lower at 8.2%, than the 11.6% found in U.S. hemophilia population as a whole. A total of 77.3% (n = 5,122) had documented exposure to FVIII concentrates, 8.4% (n = 555) had no documented exposure, and information was unknown for the remaining 14.3%.
 

Causes of mortality

The researchers found that inhibitors occurred at an early age of 13 years with a prevalence of 2.6%, compared with the commonly reported median age of about 30 years for inhibitor development, but their presence was not associated with an increased risk of mortality, according to the authors. Instead, they found that mortality rates in the NSHA cohort were influenced by age, male sex, and hepatitis C and HIV infections.

The researchers speculated that the earlier age of inhibitor development may be due to the fact of the increased availability of FVIII concentrates over time, and that they may have been used more often from 2010 to 2018, compared with previously reported INSIGHT study (1980-2011).

In a multivariable analysis, men with NSHA were found to have 2.6 times the risk of death. Mortality risk increased twofold with each additional decade of age. Persons with hepatitis C had twice the risk of death and persons with HIV had almost four times the risk, compared with persons without these conditions.

The most common primary cause of death was malignancy (20.0%). The observed number of deaths from liver disease in the NSHA cohort was almost five times the expected death rate at 14%. Hemophilia-related deaths were 5.9%.

“Continued monitoring of persons with NSHA by comprehensive care visits at HTC should occur annually to address hemophilia-related issues and other age-related comorbidities, in collaboration with the primary care physician and other subspecialists. Importantly, we found that in the NSHA cohort, the development of inhibitors occurred at an earlier age than previously reported. This highlights the importance of routine monitoring for inhibitors in the NSHA population, regardless of age, especially if they have recently received intense factor replacement therapy,” the researchers concluded.

Ms. Lim reported no conflicts. Other authors reported research and consulting funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Lim MY et al. Blood Adv. 2020;4(19):4739-47.

Individuals with nonsevere hemophilia A (NSHA) in the United States showed increased mortality based upon increasing age, male sex, and infections, according to the results of a large database analysis.

However, even though inhibitors, which can develop from factor VIII (FVIII) hemophilia therapy, were detected at an earlier age than previously reported, their presence was not associated with an increased risk of mortality according to the report published in Blood Advances (2020;4[19]:4739-47).

The researchers assessed 6,624 individuals born between 1920 and 2018 (5,694 [86.0%] men and 930 women) with NSHA from the ATHNdataset, according to Ming Y. Lim, MBBCH, MS, of the division of hematology and hematologic malignancies, University of Utah, Salt Lake City, and colleagues.

Demographically, the proportion of Black participants in the ATHNdataset was lower at 8.2%, than the 11.6% found in U.S. hemophilia population as a whole. A total of 77.3% (n = 5,122) had documented exposure to FVIII concentrates, 8.4% (n = 555) had no documented exposure, and information was unknown for the remaining 14.3%.
 

Causes of mortality

The researchers found that inhibitors occurred at an early age of 13 years with a prevalence of 2.6%, compared with the commonly reported median age of about 30 years for inhibitor development, but their presence was not associated with an increased risk of mortality, according to the authors. Instead, they found that mortality rates in the NSHA cohort were influenced by age, male sex, and hepatitis C and HIV infections.

The researchers speculated that the earlier age of inhibitor development may be due to the fact of the increased availability of FVIII concentrates over time, and that they may have been used more often from 2010 to 2018, compared with previously reported INSIGHT study (1980-2011).

In a multivariable analysis, men with NSHA were found to have 2.6 times the risk of death. Mortality risk increased twofold with each additional decade of age. Persons with hepatitis C had twice the risk of death and persons with HIV had almost four times the risk, compared with persons without these conditions.

The most common primary cause of death was malignancy (20.0%). The observed number of deaths from liver disease in the NSHA cohort was almost five times the expected death rate at 14%. Hemophilia-related deaths were 5.9%.

“Continued monitoring of persons with NSHA by comprehensive care visits at HTC should occur annually to address hemophilia-related issues and other age-related comorbidities, in collaboration with the primary care physician and other subspecialists. Importantly, we found that in the NSHA cohort, the development of inhibitors occurred at an earlier age than previously reported. This highlights the importance of routine monitoring for inhibitors in the NSHA population, regardless of age, especially if they have recently received intense factor replacement therapy,” the researchers concluded.

Ms. Lim reported no conflicts. Other authors reported research and consulting funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Lim MY et al. Blood Adv. 2020;4(19):4739-47.

As hematologists debated the role of the anti–von Willebrand factor agent caplacizumab for acquired thrombotic thrombocytopenic purpura (TTP), an investigator on the phase 3 trial that led to its approval had a message.

“If we take finances out” of the picture – a course of treatment is $270,000 – “I think almost every patient except those with a bleeding risk or bleeding problem should get it,” said hematologist Spero Cataland, MD, of the department of internal medicine at Ohio State University in Columbus.

If cost is going to be a factor, and it “has to be in our world these days, it’s more of a discussion,” he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

The HERCULES trial Dr. Cataland helped conduct found a median time to platelet count normalization of 2.69 days when caplacizumab was started during plasma exchange versus 2.88 days for placebo; 12% of patients had a TTP recurrence while they continued caplacizumab for 30 days past their last exchange and were followed for an additional 28 days versus 38% randomized to placebo. Caplacizumab subjects needed an average of 5.8 days of plasma exchange versus 9.4 days in the placebo arm (N Engl J Med. 2019 Jan 24;380(4):335-46).

Based on the results, the Food and Drug Administration approved the agent for acquired TTP in combination with plasma exchange and immunosuppressives in Feb. 2019 for 30 days beyond the last plasma exchange, with up to 28 additional days if ADAMTS13 activity remains suppressed. Labeling notes a risk of severe bleeding.

“The data on refractory disease and mortality aren’t quite there yet, but there’s a suggestion [caplacizumab] might impact that as well,” Dr. Cataland said. In its recent TTP guidelines, the International Society on Thrombosis and Haemostasis gave the agent only a conditional recommendation, in part because it’s backed up only by HERCULES and a phase 2 trial.

Also, the group noted that in the phase 2 study caplacizumab patients had a clinically and statistically significant increase in the number of relapses at 12 months: 31% versus 8% placebo. “Caplacizumab may leave patients prone to experience a later recurrence owing to the unresolved ADAMTS13 deficiency and inhibitors,” Dr. Cataland said.

“We do see some early recurrence” when caplacizumab is stopped, suggesting that when the agent’s “protective effect is removed, the risk is still there,” said Dr. Cataland, who was also an author on the ISTH guidelines, as well as the phase 2 trial.

It raises the question of how long patients should be kept on caplacizumab. There are few data on the issue, “but the consensus has been to stop caplacizumab when two consecutive ADAMTS13 measurements show 20% or greater activity,” or perhaps with one reading above 20% in a patient trending in the right direction. “With a bleeding complication, you might stop it sooner,” he said.

Dr. Cataland anticipates TTP management will eventually move away from plasma exchange to more directed therapies, including caplacizumab and perhaps recombinant ADAMTS13, which is in development.

There have been a few reports of TTP patients who refuse plasma exchange on religious grounds being successfully treated with caplacizumab. Dr. Cataland also noted a patient of his with relapsing TTP who didn’t want to be admitted yet again for plasma exchange and steroids at the start of a new episode.

“We managed her with caplacizumab and rituximab, and in a couple weeks she had recovered her ADAMTS13 activity and was able to stop the caplacizumab.” She was a motivated, knowledgeable person, “someone I trusted, so I was comfortable with the approach. I think that may be where we are headed in the future, hopefully,” he said.

Dr. Cataland disclosed research funding and consulting fees from Alexion, caplacizumab’s maker, Sanofi Genzyme, and Takeda,. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

As hematologists debated the role of the anti–von Willebrand factor agent caplacizumab for acquired thrombotic thrombocytopenic purpura (TTP), an investigator on the phase 3 trial that led to its approval had a message.

“If we take finances out” of the picture – a course of treatment is $270,000 – “I think almost every patient except those with a bleeding risk or bleeding problem should get it,” said hematologist Spero Cataland, MD, of the department of internal medicine at Ohio State University in Columbus.

If cost is going to be a factor, and it “has to be in our world these days, it’s more of a discussion,” he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

The HERCULES trial Dr. Cataland helped conduct found a median time to platelet count normalization of 2.69 days when caplacizumab was started during plasma exchange versus 2.88 days for placebo; 12% of patients had a TTP recurrence while they continued caplacizumab for 30 days past their last exchange and were followed for an additional 28 days versus 38% randomized to placebo. Caplacizumab subjects needed an average of 5.8 days of plasma exchange versus 9.4 days in the placebo arm (N Engl J Med. 2019 Jan 24;380(4):335-46).

Based on the results, the Food and Drug Administration approved the agent for acquired TTP in combination with plasma exchange and immunosuppressives in Feb. 2019 for 30 days beyond the last plasma exchange, with up to 28 additional days if ADAMTS13 activity remains suppressed. Labeling notes a risk of severe bleeding.

“The data on refractory disease and mortality aren’t quite there yet, but there’s a suggestion [caplacizumab] might impact that as well,” Dr. Cataland said. In its recent TTP guidelines, the International Society on Thrombosis and Haemostasis gave the agent only a conditional recommendation, in part because it’s backed up only by HERCULES and a phase 2 trial.

Also, the group noted that in the phase 2 study caplacizumab patients had a clinically and statistically significant increase in the number of relapses at 12 months: 31% versus 8% placebo. “Caplacizumab may leave patients prone to experience a later recurrence owing to the unresolved ADAMTS13 deficiency and inhibitors,” Dr. Cataland said.

“We do see some early recurrence” when caplacizumab is stopped, suggesting that when the agent’s “protective effect is removed, the risk is still there,” said Dr. Cataland, who was also an author on the ISTH guidelines, as well as the phase 2 trial.

It raises the question of how long patients should be kept on caplacizumab. There are few data on the issue, “but the consensus has been to stop caplacizumab when two consecutive ADAMTS13 measurements show 20% or greater activity,” or perhaps with one reading above 20% in a patient trending in the right direction. “With a bleeding complication, you might stop it sooner,” he said.

Dr. Cataland anticipates TTP management will eventually move away from plasma exchange to more directed therapies, including caplacizumab and perhaps recombinant ADAMTS13, which is in development.

There have been a few reports of TTP patients who refuse plasma exchange on religious grounds being successfully treated with caplacizumab. Dr. Cataland also noted a patient of his with relapsing TTP who didn’t want to be admitted yet again for plasma exchange and steroids at the start of a new episode.

“We managed her with caplacizumab and rituximab, and in a couple weeks she had recovered her ADAMTS13 activity and was able to stop the caplacizumab.” She was a motivated, knowledgeable person, “someone I trusted, so I was comfortable with the approach. I think that may be where we are headed in the future, hopefully,” he said.

Dr. Cataland disclosed research funding and consulting fees from Alexion, caplacizumab’s maker, Sanofi Genzyme, and Takeda,. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

As hematologists debated the role of the anti–von Willebrand factor agent caplacizumab for acquired thrombotic thrombocytopenic purpura (TTP), an investigator on the phase 3 trial that led to its approval had a message.

“If we take finances out” of the picture – a course of treatment is $270,000 – “I think almost every patient except those with a bleeding risk or bleeding problem should get it,” said hematologist Spero Cataland, MD, of the department of internal medicine at Ohio State University in Columbus.

If cost is going to be a factor, and it “has to be in our world these days, it’s more of a discussion,” he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

The HERCULES trial Dr. Cataland helped conduct found a median time to platelet count normalization of 2.69 days when caplacizumab was started during plasma exchange versus 2.88 days for placebo; 12% of patients had a TTP recurrence while they continued caplacizumab for 30 days past their last exchange and were followed for an additional 28 days versus 38% randomized to placebo. Caplacizumab subjects needed an average of 5.8 days of plasma exchange versus 9.4 days in the placebo arm (N Engl J Med. 2019 Jan 24;380(4):335-46).

Based on the results, the Food and Drug Administration approved the agent for acquired TTP in combination with plasma exchange and immunosuppressives in Feb. 2019 for 30 days beyond the last plasma exchange, with up to 28 additional days if ADAMTS13 activity remains suppressed. Labeling notes a risk of severe bleeding.

“The data on refractory disease and mortality aren’t quite there yet, but there’s a suggestion [caplacizumab] might impact that as well,” Dr. Cataland said. In its recent TTP guidelines, the International Society on Thrombosis and Haemostasis gave the agent only a conditional recommendation, in part because it’s backed up only by HERCULES and a phase 2 trial.

Also, the group noted that in the phase 2 study caplacizumab patients had a clinically and statistically significant increase in the number of relapses at 12 months: 31% versus 8% placebo. “Caplacizumab may leave patients prone to experience a later recurrence owing to the unresolved ADAMTS13 deficiency and inhibitors,” Dr. Cataland said.

“We do see some early recurrence” when caplacizumab is stopped, suggesting that when the agent’s “protective effect is removed, the risk is still there,” said Dr. Cataland, who was also an author on the ISTH guidelines, as well as the phase 2 trial.

It raises the question of how long patients should be kept on caplacizumab. There are few data on the issue, “but the consensus has been to stop caplacizumab when two consecutive ADAMTS13 measurements show 20% or greater activity,” or perhaps with one reading above 20% in a patient trending in the right direction. “With a bleeding complication, you might stop it sooner,” he said.

Dr. Cataland anticipates TTP management will eventually move away from plasma exchange to more directed therapies, including caplacizumab and perhaps recombinant ADAMTS13, which is in development.

There have been a few reports of TTP patients who refuse plasma exchange on religious grounds being successfully treated with caplacizumab. Dr. Cataland also noted a patient of his with relapsing TTP who didn’t want to be admitted yet again for plasma exchange and steroids at the start of a new episode.

“We managed her with caplacizumab and rituximab, and in a couple weeks she had recovered her ADAMTS13 activity and was able to stop the caplacizumab.” She was a motivated, knowledgeable person, “someone I trusted, so I was comfortable with the approach. I think that may be where we are headed in the future, hopefully,” he said.

Dr. Cataland disclosed research funding and consulting fees from Alexion, caplacizumab’s maker, Sanofi Genzyme, and Takeda,. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Men with genetic variants that cause hereditary hemochromatosis have an increased risk of liver cancer and death, according to a large cohort study.

Hereditary hemochromatosis is primarily caused by HFE gene variants. Past research suggested that 81% of patients with hereditary hemochromatosis carry the p.C282Y variant and 5% carry the p.C282Y/p.H63D compound heterozygote genotype.

In a new study, the presence of HFE p.C282Y and p.H63D genotypes was associated with a 10-fold greater risk of developing a hepatic malignancy among men of European ancestry aged 40-70 years. In addition, men with HFE variants were 1.2 times more likely to die of any cause, compared with men who had neither pathogenic variant.

Janice L. Atkins, PhD, of the University of Exeter (England), and colleagues reported these findings in JAMA.

For this study, Dr. Atkins and colleagues used follow-up data from a large genotyped community sample to estimate the incidence of primary hepatic carcinomas and deaths by HFE variant status in participants of European descent.

Data for the two linked coprimary endpoints, incident primary liver carcinoma and all-cause mortality, were derived from hospital and death certificate records. Where available, primary care data was also included.
 

Results: Increased risks for men, not women

The researchers analyzed data from 451,186 men and women, aged 40-70 years, from the UK Biobank. There were 2,890 (0.9%) patients who were p.C282Y homozygous, 1,294 of whom were men.

Among the 1,294 men with HFE p.C282Y homozygosity, 21 were diagnosed with a primary hepatic malignancy. Ten of these patients were not diagnosed with hemochromatosis at baseline.

At a median follow-up of 8.9 years, the risk of primary hepatic malignancy was significantly higher in men with HFE p.C282Y homozygosity, compared with men without HFE pathogenic variants (hazard ratio, 10.5; 95% confidence interval, 6.6-16.7; P < .001).

The risk of all-cause death was significantly higher in men with HFE p.C282Y homozygosity as well (HR, 1.2; 95% CI, 1.0-1.5; P  = .046).

In contrast, female HFE p.C282Y homozygotes had no significant increases in the risk of incident primary hepatic malignancy or all-cause mortality.

Life table projections estimated that 7.2% of men with HFE p.C282Y homozygosity will develop a primary hepatic malignancy by age 75, compared with 0.6% of men without p.C282Y or p.H63D variants.

The researchers acknowledged that a key limitation of this study was the ancestral homogeneity of the cohort. Thus, the findings may not be generalizable to all patient populations.
 

Implications: Earlier diagnosis and treatment

The results of this study underline the importance of early diagnosis and genetic testing, according to the researchers.

“Tragically, men with the hemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare,” study author David Melzer, MBBCh, PhD, of University of Exeter, said in a press release.

“The large scale of the UK Biobank study allowed us to measure cancer risk accurately. We were shocked to find that more than 7% of men with two faulty genes are likely to develop liver cancer by age 75, particularly considering that the U.K. has the second-highest rate of these faulty genes in the world. Fortunately, most of these cancers could be prevented with early treatment,” Dr. Melzer added.

“Physicians and scientists have long acknowledged that iron overload is an important cofactor fueling the development of many serious diseases, including cancer,” said study author Jeremy Shearman, MBChB, DPhil, of Nuffield Health and South Warwickshire NHS Foundation Trust in the United Kingdom.

“This research is a vital step towards quantifying that risk and should raise awareness of the importance of iron in the minds of both clinicians and patients. Measurement of iron stores and recognition of the genetic risk of iron overload needs to become a routine part of health assessment and monitoring in the U.K.,” Dr. Shearman added.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said study author Paul Adams, MD, of the University of Western Ontario in London.

This research was funded by the UK Medical Research Council. Dr. Melzer disclosed financial affiliations with the UK Medical Research Council during the conduct of the study.

SOURCE: Atkins JL et al. JAMA. 2020 Nov 24. doi: 10.1001/jama.2020.21566.

Men with genetic variants that cause hereditary hemochromatosis have an increased risk of liver cancer and death, according to a large cohort study.

Hereditary hemochromatosis is primarily caused by HFE gene variants. Past research suggested that 81% of patients with hereditary hemochromatosis carry the p.C282Y variant and 5% carry the p.C282Y/p.H63D compound heterozygote genotype.

In a new study, the presence of HFE p.C282Y and p.H63D genotypes was associated with a 10-fold greater risk of developing a hepatic malignancy among men of European ancestry aged 40-70 years. In addition, men with HFE variants were 1.2 times more likely to die of any cause, compared with men who had neither pathogenic variant.

Janice L. Atkins, PhD, of the University of Exeter (England), and colleagues reported these findings in JAMA.

For this study, Dr. Atkins and colleagues used follow-up data from a large genotyped community sample to estimate the incidence of primary hepatic carcinomas and deaths by HFE variant status in participants of European descent.

Data for the two linked coprimary endpoints, incident primary liver carcinoma and all-cause mortality, were derived from hospital and death certificate records. Where available, primary care data was also included.
 

Results: Increased risks for men, not women

The researchers analyzed data from 451,186 men and women, aged 40-70 years, from the UK Biobank. There were 2,890 (0.9%) patients who were p.C282Y homozygous, 1,294 of whom were men.

Among the 1,294 men with HFE p.C282Y homozygosity, 21 were diagnosed with a primary hepatic malignancy. Ten of these patients were not diagnosed with hemochromatosis at baseline.

At a median follow-up of 8.9 years, the risk of primary hepatic malignancy was significantly higher in men with HFE p.C282Y homozygosity, compared with men without HFE pathogenic variants (hazard ratio, 10.5; 95% confidence interval, 6.6-16.7; P < .001).

The risk of all-cause death was significantly higher in men with HFE p.C282Y homozygosity as well (HR, 1.2; 95% CI, 1.0-1.5; P  = .046).

In contrast, female HFE p.C282Y homozygotes had no significant increases in the risk of incident primary hepatic malignancy or all-cause mortality.

Life table projections estimated that 7.2% of men with HFE p.C282Y homozygosity will develop a primary hepatic malignancy by age 75, compared with 0.6% of men without p.C282Y or p.H63D variants.

The researchers acknowledged that a key limitation of this study was the ancestral homogeneity of the cohort. Thus, the findings may not be generalizable to all patient populations.
 

Implications: Earlier diagnosis and treatment

The results of this study underline the importance of early diagnosis and genetic testing, according to the researchers.

“Tragically, men with the hemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare,” study author David Melzer, MBBCh, PhD, of University of Exeter, said in a press release.

“The large scale of the UK Biobank study allowed us to measure cancer risk accurately. We were shocked to find that more than 7% of men with two faulty genes are likely to develop liver cancer by age 75, particularly considering that the U.K. has the second-highest rate of these faulty genes in the world. Fortunately, most of these cancers could be prevented with early treatment,” Dr. Melzer added.

“Physicians and scientists have long acknowledged that iron overload is an important cofactor fueling the development of many serious diseases, including cancer,” said study author Jeremy Shearman, MBChB, DPhil, of Nuffield Health and South Warwickshire NHS Foundation Trust in the United Kingdom.

“This research is a vital step towards quantifying that risk and should raise awareness of the importance of iron in the minds of both clinicians and patients. Measurement of iron stores and recognition of the genetic risk of iron overload needs to become a routine part of health assessment and monitoring in the U.K.,” Dr. Shearman added.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said study author Paul Adams, MD, of the University of Western Ontario in London.

This research was funded by the UK Medical Research Council. Dr. Melzer disclosed financial affiliations with the UK Medical Research Council during the conduct of the study.

SOURCE: Atkins JL et al. JAMA. 2020 Nov 24. doi: 10.1001/jama.2020.21566.

Men with genetic variants that cause hereditary hemochromatosis have an increased risk of liver cancer and death, according to a large cohort study.

Hereditary hemochromatosis is primarily caused by HFE gene variants. Past research suggested that 81% of patients with hereditary hemochromatosis carry the p.C282Y variant and 5% carry the p.C282Y/p.H63D compound heterozygote genotype.

In a new study, the presence of HFE p.C282Y and p.H63D genotypes was associated with a 10-fold greater risk of developing a hepatic malignancy among men of European ancestry aged 40-70 years. In addition, men with HFE variants were 1.2 times more likely to die of any cause, compared with men who had neither pathogenic variant.

Janice L. Atkins, PhD, of the University of Exeter (England), and colleagues reported these findings in JAMA.

For this study, Dr. Atkins and colleagues used follow-up data from a large genotyped community sample to estimate the incidence of primary hepatic carcinomas and deaths by HFE variant status in participants of European descent.

Data for the two linked coprimary endpoints, incident primary liver carcinoma and all-cause mortality, were derived from hospital and death certificate records. Where available, primary care data was also included.
 

Results: Increased risks for men, not women

The researchers analyzed data from 451,186 men and women, aged 40-70 years, from the UK Biobank. There were 2,890 (0.9%) patients who were p.C282Y homozygous, 1,294 of whom were men.

Among the 1,294 men with HFE p.C282Y homozygosity, 21 were diagnosed with a primary hepatic malignancy. Ten of these patients were not diagnosed with hemochromatosis at baseline.

At a median follow-up of 8.9 years, the risk of primary hepatic malignancy was significantly higher in men with HFE p.C282Y homozygosity, compared with men without HFE pathogenic variants (hazard ratio, 10.5; 95% confidence interval, 6.6-16.7; P < .001).

The risk of all-cause death was significantly higher in men with HFE p.C282Y homozygosity as well (HR, 1.2; 95% CI, 1.0-1.5; P  = .046).

In contrast, female HFE p.C282Y homozygotes had no significant increases in the risk of incident primary hepatic malignancy or all-cause mortality.

Life table projections estimated that 7.2% of men with HFE p.C282Y homozygosity will develop a primary hepatic malignancy by age 75, compared with 0.6% of men without p.C282Y or p.H63D variants.

The researchers acknowledged that a key limitation of this study was the ancestral homogeneity of the cohort. Thus, the findings may not be generalizable to all patient populations.
 

Implications: Earlier diagnosis and treatment

The results of this study underline the importance of early diagnosis and genetic testing, according to the researchers.

“Tragically, men with the hemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare,” study author David Melzer, MBBCh, PhD, of University of Exeter, said in a press release.

“The large scale of the UK Biobank study allowed us to measure cancer risk accurately. We were shocked to find that more than 7% of men with two faulty genes are likely to develop liver cancer by age 75, particularly considering that the U.K. has the second-highest rate of these faulty genes in the world. Fortunately, most of these cancers could be prevented with early treatment,” Dr. Melzer added.

“Physicians and scientists have long acknowledged that iron overload is an important cofactor fueling the development of many serious diseases, including cancer,” said study author Jeremy Shearman, MBChB, DPhil, of Nuffield Health and South Warwickshire NHS Foundation Trust in the United Kingdom.

“This research is a vital step towards quantifying that risk and should raise awareness of the importance of iron in the minds of both clinicians and patients. Measurement of iron stores and recognition of the genetic risk of iron overload needs to become a routine part of health assessment and monitoring in the U.K.,” Dr. Shearman added.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said study author Paul Adams, MD, of the University of Western Ontario in London.

This research was funded by the UK Medical Research Council. Dr. Melzer disclosed financial affiliations with the UK Medical Research Council during the conduct of the study.

SOURCE: Atkins JL et al. JAMA. 2020 Nov 24. doi: 10.1001/jama.2020.21566.

Patients with hemophilia A or von Willebrand disease undergoing anterior cruciate ligament (ACL) reconstruction had rates of postoperative complications and ACL reinjuries that were not significantly different from those control patients. However, the cost of health care utilization was significantly greater for the hemophilia A and von Willebrand disease patients, according to a large retrospective database study published online in The Knee.

All patients who underwent an ACL reconstruction from 2010 to 2014 in a large commercial database were assessed. Patients with hemophilia A, hemophilia B, and von Willebrand disease were identified. Patient demographics, cost of surgery, blood product use, concomitant injuries, repeat ACL injury, complications, and various operative variables were collected.

A total of 33 patients with hemophilia A, 3 with hemophilia B patients, 63 with von Willebrand disease and 103,478 control patients who had ACL reconstruction were compared, according to Connor Zale, MD, and colleagues at Penn State Hershey (Pa.) Medical Center.
 

Similar outcomes, higher costs

Complications – including length of hospital stay, postoperative hemorrhage within 14 days after surgery, infection rates within 90 days of surgery, lysis of adhesions or manipulation under anesthesia within 90 days of surgery, concomitant injuries to the knee, additional ACL injury within 1 year of surgery, deep-vein thrombosis, and pulmonary embolism – were not statistically different between the hemophilia/von Willebrand cohorts and the control group, according to the researchers.

However, surgery and postoperative care were costlier in the hemophilia A and von Willebrand cohorts. Total health care utilization within 30 days of ACL reconstruction was significantly more expensive for patients with hemophilia A ($25,982) and those with von Willebrand disease ($16,445), compared with those among controls ($12,887). In addition, the total health care utilization costs within 90 days of ACL reconstruction were significantly higher for patients with hemophilia A ($30,310) and those with von Willebrand disease ($20,355), compared with those among controls ($14,564), with all P values less than .001.

None of the patients with hemophilia A or those with von Willebrand received blood products perioperatively, had a known major hemarthrosis, or were readmitted within 30 or 90 days, the authors noted, adding that this finding differs from previous studies. The authors speculated that, since no blood products were administered and there was no significant difference in postoperative hemorrhage, the patients with hemophilia A were preoperatively optimized for an acceptable prothrombin time and international normalized ratio and/or were more effectively managed postoperatively.

“Many surgeons may be fearful of performing an ACL reconstruction on those with hemophilia A, hemophilia B, and von Willebrand disease due to concerns over risk of a major hemarthrosis and other complications postoperatively. This study observed that hemophilia A and von Willebrand disease patients who underwent an ACL reconstruction had rates of postoperative complications that were not statistically different than those who underwent ACL reconstructions and did not have a known hypocoagulable condition,” the researchers concluded.

The authors reported that they had no potential conflicts of interest to disclose.

[email protected]

SOURCE: Zale C et al. Knee. 2020;27(6):1729-34.

Patients with hemophilia A or von Willebrand disease undergoing anterior cruciate ligament (ACL) reconstruction had rates of postoperative complications and ACL reinjuries that were not significantly different from those control patients. However, the cost of health care utilization was significantly greater for the hemophilia A and von Willebrand disease patients, according to a large retrospective database study published online in The Knee.

All patients who underwent an ACL reconstruction from 2010 to 2014 in a large commercial database were assessed. Patients with hemophilia A, hemophilia B, and von Willebrand disease were identified. Patient demographics, cost of surgery, blood product use, concomitant injuries, repeat ACL injury, complications, and various operative variables were collected.

A total of 33 patients with hemophilia A, 3 with hemophilia B patients, 63 with von Willebrand disease and 103,478 control patients who had ACL reconstruction were compared, according to Connor Zale, MD, and colleagues at Penn State Hershey (Pa.) Medical Center.
 

Similar outcomes, higher costs

Complications – including length of hospital stay, postoperative hemorrhage within 14 days after surgery, infection rates within 90 days of surgery, lysis of adhesions or manipulation under anesthesia within 90 days of surgery, concomitant injuries to the knee, additional ACL injury within 1 year of surgery, deep-vein thrombosis, and pulmonary embolism – were not statistically different between the hemophilia/von Willebrand cohorts and the control group, according to the researchers.

However, surgery and postoperative care were costlier in the hemophilia A and von Willebrand cohorts. Total health care utilization within 30 days of ACL reconstruction was significantly more expensive for patients with hemophilia A ($25,982) and those with von Willebrand disease ($16,445), compared with those among controls ($12,887). In addition, the total health care utilization costs within 90 days of ACL reconstruction were significantly higher for patients with hemophilia A ($30,310) and those with von Willebrand disease ($20,355), compared with those among controls ($14,564), with all P values less than .001.

None of the patients with hemophilia A or those with von Willebrand received blood products perioperatively, had a known major hemarthrosis, or were readmitted within 30 or 90 days, the authors noted, adding that this finding differs from previous studies. The authors speculated that, since no blood products were administered and there was no significant difference in postoperative hemorrhage, the patients with hemophilia A were preoperatively optimized for an acceptable prothrombin time and international normalized ratio and/or were more effectively managed postoperatively.

“Many surgeons may be fearful of performing an ACL reconstruction on those with hemophilia A, hemophilia B, and von Willebrand disease due to concerns over risk of a major hemarthrosis and other complications postoperatively. This study observed that hemophilia A and von Willebrand disease patients who underwent an ACL reconstruction had rates of postoperative complications that were not statistically different than those who underwent ACL reconstructions and did not have a known hypocoagulable condition,” the researchers concluded.

The authors reported that they had no potential conflicts of interest to disclose.

[email protected]

SOURCE: Zale C et al. Knee. 2020;27(6):1729-34.

Patients with hemophilia A or von Willebrand disease undergoing anterior cruciate ligament (ACL) reconstruction had rates of postoperative complications and ACL reinjuries that were not significantly different from those control patients. However, the cost of health care utilization was significantly greater for the hemophilia A and von Willebrand disease patients, according to a large retrospective database study published online in The Knee.

All patients who underwent an ACL reconstruction from 2010 to 2014 in a large commercial database were assessed. Patients with hemophilia A, hemophilia B, and von Willebrand disease were identified. Patient demographics, cost of surgery, blood product use, concomitant injuries, repeat ACL injury, complications, and various operative variables were collected.

A total of 33 patients with hemophilia A, 3 with hemophilia B patients, 63 with von Willebrand disease and 103,478 control patients who had ACL reconstruction were compared, according to Connor Zale, MD, and colleagues at Penn State Hershey (Pa.) Medical Center.
 

Similar outcomes, higher costs

Complications – including length of hospital stay, postoperative hemorrhage within 14 days after surgery, infection rates within 90 days of surgery, lysis of adhesions or manipulation under anesthesia within 90 days of surgery, concomitant injuries to the knee, additional ACL injury within 1 year of surgery, deep-vein thrombosis, and pulmonary embolism – were not statistically different between the hemophilia/von Willebrand cohorts and the control group, according to the researchers.

However, surgery and postoperative care were costlier in the hemophilia A and von Willebrand cohorts. Total health care utilization within 30 days of ACL reconstruction was significantly more expensive for patients with hemophilia A ($25,982) and those with von Willebrand disease ($16,445), compared with those among controls ($12,887). In addition, the total health care utilization costs within 90 days of ACL reconstruction were significantly higher for patients with hemophilia A ($30,310) and those with von Willebrand disease ($20,355), compared with those among controls ($14,564), with all P values less than .001.

None of the patients with hemophilia A or those with von Willebrand received blood products perioperatively, had a known major hemarthrosis, or were readmitted within 30 or 90 days, the authors noted, adding that this finding differs from previous studies. The authors speculated that, since no blood products were administered and there was no significant difference in postoperative hemorrhage, the patients with hemophilia A were preoperatively optimized for an acceptable prothrombin time and international normalized ratio and/or were more effectively managed postoperatively.

“Many surgeons may be fearful of performing an ACL reconstruction on those with hemophilia A, hemophilia B, and von Willebrand disease due to concerns over risk of a major hemarthrosis and other complications postoperatively. This study observed that hemophilia A and von Willebrand disease patients who underwent an ACL reconstruction had rates of postoperative complications that were not statistically different than those who underwent ACL reconstructions and did not have a known hypocoagulable condition,” the researchers concluded.

The authors reported that they had no potential conflicts of interest to disclose.

[email protected]

SOURCE: Zale C et al. Knee. 2020;27(6):1729-34.

Dental extractions can cause significant risk of bleeding in hemophilia patients being treated with factor replacements. However, mouth splints significantly decreased the risk of postextraction bleeding in these patients, according to Takahiro Yagyuu, DDS, of the department of oral and maxillofacial surgery, Nara Medical University, Kashihara, Japan, and colleagues.

The researchers performed a retrospective analysis of the medical records of hemophilia patients who underwent tooth extraction(s) between April 2006 and April 2019 at a single university hospital in Japan.

They conducted logistic regression analyses to identify risk/protective factors for postextraction bleeding in procedures involving patients receiving factor replacement therapy. Postextraction bleeding was defined as bleeding that could not be stopped by biting down on gauze and required medical treatment between 30 minutes and 14 days after the extraction, according to the report published online on in the British Journal of Oral & Maxillofacial Surgery.

A total of 130 extractions in 48 patients with hemophilia A and 21 extractions in 7 patients with hemophilia B were performed. Postextraction bleeding events were observed in 9 patients (16.3%) and 12 extractions (7.9%). On average, postextraction bleeding occurred 6 days after intervention and on the fifth postoperative day for extractions, according to the researchers.
 

Benefits of splints

The study found that the use of mouth splints significantly decreased the risk of postextraction bleeding (odds ratio, 0.13; P = .01) in hemophilia patients being treated with clotting factor replacements.

However, other factors in the study cohort, such as age, severity of hemophilia, duration of factor replacement therapy, gingival incision, bone removal, tooth separation, use of absorbable hemostats, wound closure, and the prescription of NSAIDs, were not significantly associated with postextraction bleeding, the researchers added.

“The use of mouth splints significantly decreased the risk of post-extraction bleeding. [In the future], we will conduct a prospective study to investigate the optimal type of splint and splint-wearing period to improve hemostatic management of tooth extraction in hemophilia patients,” the researchers concluded.

One author reported grants and personal fees from Bayer, Bioverativ, Chugai Pharmaceutical, Novo Nordisk, and Shire. A second author teaches a course endowed by Shire Japan. The other authors reported they had no conflicts.

[email protected]

SOURCE: Yagyuu T et al. Br J Oral Maxillofac Surg. 2020 Oct 11. doi: 10.1016/j.bjoms.2020.08.121.

Dental extractions can cause significant risk of bleeding in hemophilia patients being treated with factor replacements. However, mouth splints significantly decreased the risk of postextraction bleeding in these patients, according to Takahiro Yagyuu, DDS, of the department of oral and maxillofacial surgery, Nara Medical University, Kashihara, Japan, and colleagues.

The researchers performed a retrospective analysis of the medical records of hemophilia patients who underwent tooth extraction(s) between April 2006 and April 2019 at a single university hospital in Japan.

They conducted logistic regression analyses to identify risk/protective factors for postextraction bleeding in procedures involving patients receiving factor replacement therapy. Postextraction bleeding was defined as bleeding that could not be stopped by biting down on gauze and required medical treatment between 30 minutes and 14 days after the extraction, according to the report published online on in the British Journal of Oral & Maxillofacial Surgery.

A total of 130 extractions in 48 patients with hemophilia A and 21 extractions in 7 patients with hemophilia B were performed. Postextraction bleeding events were observed in 9 patients (16.3%) and 12 extractions (7.9%). On average, postextraction bleeding occurred 6 days after intervention and on the fifth postoperative day for extractions, according to the researchers.
 

Benefits of splints

The study found that the use of mouth splints significantly decreased the risk of postextraction bleeding (odds ratio, 0.13; P = .01) in hemophilia patients being treated with clotting factor replacements.

However, other factors in the study cohort, such as age, severity of hemophilia, duration of factor replacement therapy, gingival incision, bone removal, tooth separation, use of absorbable hemostats, wound closure, and the prescription of NSAIDs, were not significantly associated with postextraction bleeding, the researchers added.

“The use of mouth splints significantly decreased the risk of post-extraction bleeding. [In the future], we will conduct a prospective study to investigate the optimal type of splint and splint-wearing period to improve hemostatic management of tooth extraction in hemophilia patients,” the researchers concluded.

One author reported grants and personal fees from Bayer, Bioverativ, Chugai Pharmaceutical, Novo Nordisk, and Shire. A second author teaches a course endowed by Shire Japan. The other authors reported they had no conflicts.

[email protected]

SOURCE: Yagyuu T et al. Br J Oral Maxillofac Surg. 2020 Oct 11. doi: 10.1016/j.bjoms.2020.08.121.

Dental extractions can cause significant risk of bleeding in hemophilia patients being treated with factor replacements. However, mouth splints significantly decreased the risk of postextraction bleeding in these patients, according to Takahiro Yagyuu, DDS, of the department of oral and maxillofacial surgery, Nara Medical University, Kashihara, Japan, and colleagues.

The researchers performed a retrospective analysis of the medical records of hemophilia patients who underwent tooth extraction(s) between April 2006 and April 2019 at a single university hospital in Japan.

They conducted logistic regression analyses to identify risk/protective factors for postextraction bleeding in procedures involving patients receiving factor replacement therapy. Postextraction bleeding was defined as bleeding that could not be stopped by biting down on gauze and required medical treatment between 30 minutes and 14 days after the extraction, according to the report published online on in the British Journal of Oral & Maxillofacial Surgery.

A total of 130 extractions in 48 patients with hemophilia A and 21 extractions in 7 patients with hemophilia B were performed. Postextraction bleeding events were observed in 9 patients (16.3%) and 12 extractions (7.9%). On average, postextraction bleeding occurred 6 days after intervention and on the fifth postoperative day for extractions, according to the researchers.
 

Benefits of splints

The study found that the use of mouth splints significantly decreased the risk of postextraction bleeding (odds ratio, 0.13; P = .01) in hemophilia patients being treated with clotting factor replacements.

However, other factors in the study cohort, such as age, severity of hemophilia, duration of factor replacement therapy, gingival incision, bone removal, tooth separation, use of absorbable hemostats, wound closure, and the prescription of NSAIDs, were not significantly associated with postextraction bleeding, the researchers added.

“The use of mouth splints significantly decreased the risk of post-extraction bleeding. [In the future], we will conduct a prospective study to investigate the optimal type of splint and splint-wearing period to improve hemostatic management of tooth extraction in hemophilia patients,” the researchers concluded.

One author reported grants and personal fees from Bayer, Bioverativ, Chugai Pharmaceutical, Novo Nordisk, and Shire. A second author teaches a course endowed by Shire Japan. The other authors reported they had no conflicts.

[email protected]

SOURCE: Yagyuu T et al. Br J Oral Maxillofac Surg. 2020 Oct 11. doi: 10.1016/j.bjoms.2020.08.121.

International normalized ratio (INR) does not predict periprocedural bleeding in patients with cirrhosis, according to a meta-analysis of 29 studies.

This finding should deter the common practice of delivering blood products to cirrhotic patients with an elevated INR, reported lead author Alexander J. Kovalic, MD, of Novant Forsyth Medical Center in Winston Salem, N.C., and colleagues.

“INR measurement among cirrhotic patients is important in MELD [Model for End-Stage Liver Disease] prognostication and assessment of underlying hepatic synthetic function, however the INR alone does not capture the complicated interplay of anticoagulant and procoagulant deficiencies present in cirrhotic coagulopathy,” Dr. Kovalic and colleagues wrote in Alimentary Pharmacology & Therapeutics. “Yet, the ‘correction’ of these aberrancies among peripheral coagulation tests remains common ... even in modern practice, and not uncommonly occurs in the periprocedural setting.”

According to investigators, addressing INR with blood transfusion can have a litany of negative effects. Beyond the risks faced by all patient populations, increasing blood volume in those with cirrhosis can increase portal venous pressure, thereby raising risks of portal gastropathy or variceal hemorrhage. In addition, giving plasma products to patients with cirrhotic coagulopathy may further disrupt the balance between anticoagulants and procoagulants, potentially triggering disseminated intravascular coagulation.

Dr. Kovalic and colleagues noted that the lack of correlation between peripheral coagulation tests and bleeding risk has been a longstanding subject of investigation, citing studies from as early as 1981.

To add further weight to this body of evidence, the investigators conducted a systematic review and meta-analysis involving 13,276 patients with cirrhosis who underwent various procedures between 1999 and 2019. Primary outcomes included periprocedural bleeding events and the association between preprocedural INR and periprocedural bleeding events. Secondary outcomes included mortality, quantity of blood and/or plasma products used, and relationship between preprocedural platelet count and periprocedural bleeding events.

The analysis showed that preprocedural INR was not significantly associated with periprocedural bleeding events (pooled odds ratio, 1.52; 95% confidence interval, 0.99-2.33; P = .06), a finding that held across INR threshold subgroups. Similarly, no significant difference was found between mean INR of patients who had bleeding events versus that of those who did not (pooled mean difference, 0.05; 95% CI, 0.03-0.13; P = .23).

Preprocedural platelet count was also a poor predictor of periprocedural bleeding, with a pooled odds ratio of 1.24 (95% CI, 0.55-2.77; P = .60), although the investigators noted that platelet count thresholds varied widely across studies, from 30 to 150 × 10⁹/L. When studies were stratified by procedural bleeding risk or procedure type, subgroup effects were no longer significant. Other secondary endpoints were incalculable because of insufficient data.

“Hopefully, these findings will spark initiation of more large-scale, higher-quality studies ... to reinforce minimizing administration of fresh frozen plasma for inappropriate correction of INR, which carries a multitude of adverse effects among cirrhotic [patients],” the investigators concluded.

According to Stephen H. Caldwell, MD, of the University of Virginia in Charlottesville, “The present paper augments accumulating literature over the past 15 years that INR should be discarded as a measure of procedure-related bleeding risk.”

Dr. Caldwell pointed out that “bleeding in cirrhosis is usually related to portal hypertension not with impaired hemostasis, with the occasional exception of hyperfibrinolysis, which is very different from a prolonged INR.”

He went on to suggest that the present findings should dissuade clinicians from a practice that, for some, is reflexive rather than evidence based.

“It’s remarkable how many medical practices become entrenched based on hand-me-down teaching during our early training years, and remain so for many years beyond as we disperse into various medical and surgical fields,” Dr. Caldwell said. “These learned approaches to common problems can clearly persist for generations despite overwhelming evidence to the contrary that usually evolve slowly and well-insulated within subspecialties or sub-subspecialties, and hence take several generations of training to diffuse into the wider practice of medical care for common problems. These may become matters of expedience in decision-making, much like the old antibiotic conundrum of ‘no-think-a-cillin,’ as critics referred to over-use of broad spectrum antibiotics. And so it has been with the INR.”The investigators disclosed relationships with AbbVie, Eisai, Gilead, and others. Dr. Caldwell disclosed research support from Daiichi concerning the potential role of anticoagulation therapy in preventing cirrhosis progression.

SOURCE: Kovalic AJ et al. Aliment Pharmacol Ther. 2020 Sep 10. doi: 10.1111/apt.16078.

International normalized ratio (INR) does not predict periprocedural bleeding in patients with cirrhosis, according to a meta-analysis of 29 studies.

This finding should deter the common practice of delivering blood products to cirrhotic patients with an elevated INR, reported lead author Alexander J. Kovalic, MD, of Novant Forsyth Medical Center in Winston Salem, N.C., and colleagues.

“INR measurement among cirrhotic patients is important in MELD [Model for End-Stage Liver Disease] prognostication and assessment of underlying hepatic synthetic function, however the INR alone does not capture the complicated interplay of anticoagulant and procoagulant deficiencies present in cirrhotic coagulopathy,” Dr. Kovalic and colleagues wrote in Alimentary Pharmacology & Therapeutics. “Yet, the ‘correction’ of these aberrancies among peripheral coagulation tests remains common ... even in modern practice, and not uncommonly occurs in the periprocedural setting.”

According to investigators, addressing INR with blood transfusion can have a litany of negative effects. Beyond the risks faced by all patient populations, increasing blood volume in those with cirrhosis can increase portal venous pressure, thereby raising risks of portal gastropathy or variceal hemorrhage. In addition, giving plasma products to patients with cirrhotic coagulopathy may further disrupt the balance between anticoagulants and procoagulants, potentially triggering disseminated intravascular coagulation.

Dr. Kovalic and colleagues noted that the lack of correlation between peripheral coagulation tests and bleeding risk has been a longstanding subject of investigation, citing studies from as early as 1981.

To add further weight to this body of evidence, the investigators conducted a systematic review and meta-analysis involving 13,276 patients with cirrhosis who underwent various procedures between 1999 and 2019. Primary outcomes included periprocedural bleeding events and the association between preprocedural INR and periprocedural bleeding events. Secondary outcomes included mortality, quantity of blood and/or plasma products used, and relationship between preprocedural platelet count and periprocedural bleeding events.

The analysis showed that preprocedural INR was not significantly associated with periprocedural bleeding events (pooled odds ratio, 1.52; 95% confidence interval, 0.99-2.33; P = .06), a finding that held across INR threshold subgroups. Similarly, no significant difference was found between mean INR of patients who had bleeding events versus that of those who did not (pooled mean difference, 0.05; 95% CI, 0.03-0.13; P = .23).

Preprocedural platelet count was also a poor predictor of periprocedural bleeding, with a pooled odds ratio of 1.24 (95% CI, 0.55-2.77; P = .60), although the investigators noted that platelet count thresholds varied widely across studies, from 30 to 150 × 10⁹/L. When studies were stratified by procedural bleeding risk or procedure type, subgroup effects were no longer significant. Other secondary endpoints were incalculable because of insufficient data.

“Hopefully, these findings will spark initiation of more large-scale, higher-quality studies ... to reinforce minimizing administration of fresh frozen plasma for inappropriate correction of INR, which carries a multitude of adverse effects among cirrhotic [patients],” the investigators concluded.

According to Stephen H. Caldwell, MD, of the University of Virginia in Charlottesville, “The present paper augments accumulating literature over the past 15 years that INR should be discarded as a measure of procedure-related bleeding risk.”

Dr. Caldwell pointed out that “bleeding in cirrhosis is usually related to portal hypertension not with impaired hemostasis, with the occasional exception of hyperfibrinolysis, which is very different from a prolonged INR.”

He went on to suggest that the present findings should dissuade clinicians from a practice that, for some, is reflexive rather than evidence based.

“It’s remarkable how many medical practices become entrenched based on hand-me-down teaching during our early training years, and remain so for many years beyond as we disperse into various medical and surgical fields,” Dr. Caldwell said. “These learned approaches to common problems can clearly persist for generations despite overwhelming evidence to the contrary that usually evolve slowly and well-insulated within subspecialties or sub-subspecialties, and hence take several generations of training to diffuse into the wider practice of medical care for common problems. These may become matters of expedience in decision-making, much like the old antibiotic conundrum of ‘no-think-a-cillin,’ as critics referred to over-use of broad spectrum antibiotics. And so it has been with the INR.”The investigators disclosed relationships with AbbVie, Eisai, Gilead, and others. Dr. Caldwell disclosed research support from Daiichi concerning the potential role of anticoagulation therapy in preventing cirrhosis progression.

SOURCE: Kovalic AJ et al. Aliment Pharmacol Ther. 2020 Sep 10. doi: 10.1111/apt.16078.

International normalized ratio (INR) does not predict periprocedural bleeding in patients with cirrhosis, according to a meta-analysis of 29 studies.

This finding should deter the common practice of delivering blood products to cirrhotic patients with an elevated INR, reported lead author Alexander J. Kovalic, MD, of Novant Forsyth Medical Center in Winston Salem, N.C., and colleagues.

“INR measurement among cirrhotic patients is important in MELD [Model for End-Stage Liver Disease] prognostication and assessment of underlying hepatic synthetic function, however the INR alone does not capture the complicated interplay of anticoagulant and procoagulant deficiencies present in cirrhotic coagulopathy,” Dr. Kovalic and colleagues wrote in Alimentary Pharmacology & Therapeutics. “Yet, the ‘correction’ of these aberrancies among peripheral coagulation tests remains common ... even in modern practice, and not uncommonly occurs in the periprocedural setting.”

According to investigators, addressing INR with blood transfusion can have a litany of negative effects. Beyond the risks faced by all patient populations, increasing blood volume in those with cirrhosis can increase portal venous pressure, thereby raising risks of portal gastropathy or variceal hemorrhage. In addition, giving plasma products to patients with cirrhotic coagulopathy may further disrupt the balance between anticoagulants and procoagulants, potentially triggering disseminated intravascular coagulation.

Dr. Kovalic and colleagues noted that the lack of correlation between peripheral coagulation tests and bleeding risk has been a longstanding subject of investigation, citing studies from as early as 1981.

To add further weight to this body of evidence, the investigators conducted a systematic review and meta-analysis involving 13,276 patients with cirrhosis who underwent various procedures between 1999 and 2019. Primary outcomes included periprocedural bleeding events and the association between preprocedural INR and periprocedural bleeding events. Secondary outcomes included mortality, quantity of blood and/or plasma products used, and relationship between preprocedural platelet count and periprocedural bleeding events.

The analysis showed that preprocedural INR was not significantly associated with periprocedural bleeding events (pooled odds ratio, 1.52; 95% confidence interval, 0.99-2.33; P = .06), a finding that held across INR threshold subgroups. Similarly, no significant difference was found between mean INR of patients who had bleeding events versus that of those who did not (pooled mean difference, 0.05; 95% CI, 0.03-0.13; P = .23).

Preprocedural platelet count was also a poor predictor of periprocedural bleeding, with a pooled odds ratio of 1.24 (95% CI, 0.55-2.77; P = .60), although the investigators noted that platelet count thresholds varied widely across studies, from 30 to 150 × 10⁹/L. When studies were stratified by procedural bleeding risk or procedure type, subgroup effects were no longer significant. Other secondary endpoints were incalculable because of insufficient data.

“Hopefully, these findings will spark initiation of more large-scale, higher-quality studies ... to reinforce minimizing administration of fresh frozen plasma for inappropriate correction of INR, which carries a multitude of adverse effects among cirrhotic [patients],” the investigators concluded.

According to Stephen H. Caldwell, MD, of the University of Virginia in Charlottesville, “The present paper augments accumulating literature over the past 15 years that INR should be discarded as a measure of procedure-related bleeding risk.”

Dr. Caldwell pointed out that “bleeding in cirrhosis is usually related to portal hypertension not with impaired hemostasis, with the occasional exception of hyperfibrinolysis, which is very different from a prolonged INR.”

He went on to suggest that the present findings should dissuade clinicians from a practice that, for some, is reflexive rather than evidence based.

“It’s remarkable how many medical practices become entrenched based on hand-me-down teaching during our early training years, and remain so for many years beyond as we disperse into various medical and surgical fields,” Dr. Caldwell said. “These learned approaches to common problems can clearly persist for generations despite overwhelming evidence to the contrary that usually evolve slowly and well-insulated within subspecialties or sub-subspecialties, and hence take several generations of training to diffuse into the wider practice of medical care for common problems. These may become matters of expedience in decision-making, much like the old antibiotic conundrum of ‘no-think-a-cillin,’ as critics referred to over-use of broad spectrum antibiotics. And so it has been with the INR.”The investigators disclosed relationships with AbbVie, Eisai, Gilead, and others. Dr. Caldwell disclosed research support from Daiichi concerning the potential role of anticoagulation therapy in preventing cirrhosis progression.

SOURCE: Kovalic AJ et al. Aliment Pharmacol Ther. 2020 Sep 10. doi: 10.1111/apt.16078.

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

[email protected]

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

[email protected]

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

[email protected]

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.