Bleeding Disorders

For patients with pediatric immune thrombocytopenia (ITP), treatment with intravenous immunoglobulins (IVIG) is more likely to raise platelet count in the short-term, compared with anti-D immunoglobulins (anti-D), according the authors of a recent systematic review and meta-analysis.

Although findings from the meta-analysis support recommendations for first-line IVIG, not all studies reported bleeding symptoms, so the clinical effects of differing platelet responses remain unknown, reported lead author Bertrand Lioger, MD, of François-Rabelais University in Tours, France, and his colleagues.

“To date, no meta-analysis has compared the efficacy and safety of IVIG vs. anti-D,” the investigators wrote in The Journal of Pediatrics.

Each treatment approach has strengths and weaknesses, the investigators noted. Namely, IVIG is more expensive, while anti-D is more likely to cause adverse drugs reactions (ADRs), such as disseminated intravascular coagulation and hemolysis.

The present review evaluated 11 studies comparing the efficacy of IVIG with that of anti-D in 704 children with ITP. Platelet response and bleeding were the main efficacy outcomes. The investigators used response thresholds defined by each study because several did not use standardized levels. Other outcomes considered were mortality, disease course, splenectomy, and ADRs. The ADRs included serious adverse reactions, infusion reactions, transfusions, hemoglobin loss, and hemolysis.

In alignment with previous guidelines, anti-D therapy was most often given to RhD positive, nonsplenectomized children at a dose of 50-75 mcg/kg, whereas IVIG was dosed at 0.8-1 g/kg for 1 or 2 consecutive days.

Results showed that patients treated with IVIG were 15% more likely to have platelet counts greater than 20 × 10⁹/L within 24-72 hours, compared with those given anti-D. This disparity rose to 25% in favor of IVIG when using a threshold of 50 × 10⁹/L.

Treatment risk was lower and general symptoms were less common after treatment with anti-D infusion, compared with IVIG (24.6% vs. 31.4%), but this was only true for trials foregoing premedication. Anti-D was more often associated with hemolysis, making transfusion necessary for some patients.

Although platelet count is often used as a surrogate measure of bleeding risk, the investigators decided that a lack of bleeding data among the studies precluded an accurate determination of clinical superiority between the treatments.

“Severe hemolysis remains an important issue when using anti-D immunoglobulins and premedication reduces the incidence of general symptoms observed with IVIG,” the investigators wrote. “Our conclusions should, however, be cautiously considered due to the poor overall quality of included studies and to limited data about clinically relevant outcomes.”

The study was not supported by outside funding. The investigators reported financial relationships with Amgen, Novartis, Roche Pharma, Sanofi, and others.

SOURCE: Lioger B et al. J Pediatr. 2019;204:225-33.

For patients with pediatric immune thrombocytopenia (ITP), treatment with intravenous immunoglobulins (IVIG) is more likely to raise platelet count in the short-term, compared with anti-D immunoglobulins (anti-D), according the authors of a recent systematic review and meta-analysis.

Although findings from the meta-analysis support recommendations for first-line IVIG, not all studies reported bleeding symptoms, so the clinical effects of differing platelet responses remain unknown, reported lead author Bertrand Lioger, MD, of François-Rabelais University in Tours, France, and his colleagues.

“To date, no meta-analysis has compared the efficacy and safety of IVIG vs. anti-D,” the investigators wrote in The Journal of Pediatrics.

Each treatment approach has strengths and weaknesses, the investigators noted. Namely, IVIG is more expensive, while anti-D is more likely to cause adverse drugs reactions (ADRs), such as disseminated intravascular coagulation and hemolysis.

The present review evaluated 11 studies comparing the efficacy of IVIG with that of anti-D in 704 children with ITP. Platelet response and bleeding were the main efficacy outcomes. The investigators used response thresholds defined by each study because several did not use standardized levels. Other outcomes considered were mortality, disease course, splenectomy, and ADRs. The ADRs included serious adverse reactions, infusion reactions, transfusions, hemoglobin loss, and hemolysis.

In alignment with previous guidelines, anti-D therapy was most often given to RhD positive, nonsplenectomized children at a dose of 50-75 mcg/kg, whereas IVIG was dosed at 0.8-1 g/kg for 1 or 2 consecutive days.

Results showed that patients treated with IVIG were 15% more likely to have platelet counts greater than 20 × 10⁹/L within 24-72 hours, compared with those given anti-D. This disparity rose to 25% in favor of IVIG when using a threshold of 50 × 10⁹/L.

Treatment risk was lower and general symptoms were less common after treatment with anti-D infusion, compared with IVIG (24.6% vs. 31.4%), but this was only true for trials foregoing premedication. Anti-D was more often associated with hemolysis, making transfusion necessary for some patients.

Although platelet count is often used as a surrogate measure of bleeding risk, the investigators decided that a lack of bleeding data among the studies precluded an accurate determination of clinical superiority between the treatments.

“Severe hemolysis remains an important issue when using anti-D immunoglobulins and premedication reduces the incidence of general symptoms observed with IVIG,” the investigators wrote. “Our conclusions should, however, be cautiously considered due to the poor overall quality of included studies and to limited data about clinically relevant outcomes.”

The study was not supported by outside funding. The investigators reported financial relationships with Amgen, Novartis, Roche Pharma, Sanofi, and others.

SOURCE: Lioger B et al. J Pediatr. 2019;204:225-33.

For patients with pediatric immune thrombocytopenia (ITP), treatment with intravenous immunoglobulins (IVIG) is more likely to raise platelet count in the short-term, compared with anti-D immunoglobulins (anti-D), according the authors of a recent systematic review and meta-analysis.

Although findings from the meta-analysis support recommendations for first-line IVIG, not all studies reported bleeding symptoms, so the clinical effects of differing platelet responses remain unknown, reported lead author Bertrand Lioger, MD, of François-Rabelais University in Tours, France, and his colleagues.

“To date, no meta-analysis has compared the efficacy and safety of IVIG vs. anti-D,” the investigators wrote in The Journal of Pediatrics.

Each treatment approach has strengths and weaknesses, the investigators noted. Namely, IVIG is more expensive, while anti-D is more likely to cause adverse drugs reactions (ADRs), such as disseminated intravascular coagulation and hemolysis.

The present review evaluated 11 studies comparing the efficacy of IVIG with that of anti-D in 704 children with ITP. Platelet response and bleeding were the main efficacy outcomes. The investigators used response thresholds defined by each study because several did not use standardized levels. Other outcomes considered were mortality, disease course, splenectomy, and ADRs. The ADRs included serious adverse reactions, infusion reactions, transfusions, hemoglobin loss, and hemolysis.

In alignment with previous guidelines, anti-D therapy was most often given to RhD positive, nonsplenectomized children at a dose of 50-75 mcg/kg, whereas IVIG was dosed at 0.8-1 g/kg for 1 or 2 consecutive days.

Results showed that patients treated with IVIG were 15% more likely to have platelet counts greater than 20 × 10⁹/L within 24-72 hours, compared with those given anti-D. This disparity rose to 25% in favor of IVIG when using a threshold of 50 × 10⁹/L.

Treatment risk was lower and general symptoms were less common after treatment with anti-D infusion, compared with IVIG (24.6% vs. 31.4%), but this was only true for trials foregoing premedication. Anti-D was more often associated with hemolysis, making transfusion necessary for some patients.

Although platelet count is often used as a surrogate measure of bleeding risk, the investigators decided that a lack of bleeding data among the studies precluded an accurate determination of clinical superiority between the treatments.

“Severe hemolysis remains an important issue when using anti-D immunoglobulins and premedication reduces the incidence of general symptoms observed with IVIG,” the investigators wrote. “Our conclusions should, however, be cautiously considered due to the poor overall quality of included studies and to limited data about clinically relevant outcomes.”

The study was not supported by outside funding. The investigators reported financial relationships with Amgen, Novartis, Roche Pharma, Sanofi, and others.

SOURCE: Lioger B et al. J Pediatr. 2019;204:225-33.

Turoctocog alfa, a recombinant Factor VIII molecule, was effective in preventing bleeding episodes and was well tolerated in more than 200 males with hemophilia A who were part of the Guardian 2 extension trial.

The open label, phase 3b study included patients who had completed the Guardian 1 or Guardian 3 phase 1 pharmacokinetics trials and who chose to continue prophylaxis with turoctocog alfa (Novoeight).

In total, 214 patients were enrolled and 213 were exposed to treatment. Prophylaxis was given as a standard dose level of 20-50 IU/kg once every second day or 20-60 IU/kg three times weekly. Less frequent prophylaxis was available at 40-60 IU/kg twice weekly or once every third day. For on-demand treatment, the recommended dose level was 20-50 IU/kg.

“The final results of guardian 2 are consistent with data from previous interim analyses,” Steven R. Lentz, MD, PhD, of the University of Iowa, Iowa City, and his colleagues wrote in Haemophilia. “Turoctocog alfa was well tolerated, with no unexpected safety signals and no development of FVIII inhibitors.”

Among the 207 patients on prophylaxis, 1,782 bleeds were reported. The overall median annualized bleeding rate (ABR) for this group was 1.37. More than 88% of these bleeds were stopped with one or two injections and the success rate for treatment of bleeds was more than 90%.

The median ABR dropped to zero, with a range of 0.00‐9.91, for the 27 patients who were on the less-frequent prophylaxis regimen. In this group, more than 75% of the 34 bleeds that occurred were stopped with one injection and the success rate for treatment of bleeds was about 94%.

“These data suggest a subset of patients might be well managed with less‐frequent dosing,” the researchers wrote.

For the 19 patients who received on-demand treatment, there were 391 bleeds reported. The overall median ABR was 30.44. Nearly 80% of bleeds were stopped with one injection and more than 15% with two injections. The treatment success rate in this group was more than 96%.

There were no Factor VIII inhibitors reported in the extension trial.

In total, there were 1,260 adverse events reported for 183 patients, corresponding to less than two adverse events per patients per years of exposure to the treatment.

The most common adverse event, seen in 14.6% of patients, was nasopharyngitis. Serious adverse events occurred in 18.3% of patients but all expect one event was deemed unlikely to be related to treatment. The one fatal event in the trial was deemed unlikely to be related to treatment.

The study was funded by Novo Nordisk. Dr. Lentz reported being a paid consultant to Novo Nordisk and receiving research funding from the company.

[email protected]

SOURCE: Lentz SR et al. Haemophilia. 2018 Nov;24(6):e391-4.

Turoctocog alfa, a recombinant Factor VIII molecule, was effective in preventing bleeding episodes and was well tolerated in more than 200 males with hemophilia A who were part of the Guardian 2 extension trial.

The open label, phase 3b study included patients who had completed the Guardian 1 or Guardian 3 phase 1 pharmacokinetics trials and who chose to continue prophylaxis with turoctocog alfa (Novoeight).

In total, 214 patients were enrolled and 213 were exposed to treatment. Prophylaxis was given as a standard dose level of 20-50 IU/kg once every second day or 20-60 IU/kg three times weekly. Less frequent prophylaxis was available at 40-60 IU/kg twice weekly or once every third day. For on-demand treatment, the recommended dose level was 20-50 IU/kg.

“The final results of guardian 2 are consistent with data from previous interim analyses,” Steven R. Lentz, MD, PhD, of the University of Iowa, Iowa City, and his colleagues wrote in Haemophilia. “Turoctocog alfa was well tolerated, with no unexpected safety signals and no development of FVIII inhibitors.”

Among the 207 patients on prophylaxis, 1,782 bleeds were reported. The overall median annualized bleeding rate (ABR) for this group was 1.37. More than 88% of these bleeds were stopped with one or two injections and the success rate for treatment of bleeds was more than 90%.

The median ABR dropped to zero, with a range of 0.00‐9.91, for the 27 patients who were on the less-frequent prophylaxis regimen. In this group, more than 75% of the 34 bleeds that occurred were stopped with one injection and the success rate for treatment of bleeds was about 94%.

“These data suggest a subset of patients might be well managed with less‐frequent dosing,” the researchers wrote.

For the 19 patients who received on-demand treatment, there were 391 bleeds reported. The overall median ABR was 30.44. Nearly 80% of bleeds were stopped with one injection and more than 15% with two injections. The treatment success rate in this group was more than 96%.

There were no Factor VIII inhibitors reported in the extension trial.

In total, there were 1,260 adverse events reported for 183 patients, corresponding to less than two adverse events per patients per years of exposure to the treatment.

The most common adverse event, seen in 14.6% of patients, was nasopharyngitis. Serious adverse events occurred in 18.3% of patients but all expect one event was deemed unlikely to be related to treatment. The one fatal event in the trial was deemed unlikely to be related to treatment.

The study was funded by Novo Nordisk. Dr. Lentz reported being a paid consultant to Novo Nordisk and receiving research funding from the company.

[email protected]

SOURCE: Lentz SR et al. Haemophilia. 2018 Nov;24(6):e391-4.

Turoctocog alfa, a recombinant Factor VIII molecule, was effective in preventing bleeding episodes and was well tolerated in more than 200 males with hemophilia A who were part of the Guardian 2 extension trial.

The open label, phase 3b study included patients who had completed the Guardian 1 or Guardian 3 phase 1 pharmacokinetics trials and who chose to continue prophylaxis with turoctocog alfa (Novoeight).

In total, 214 patients were enrolled and 213 were exposed to treatment. Prophylaxis was given as a standard dose level of 20-50 IU/kg once every second day or 20-60 IU/kg three times weekly. Less frequent prophylaxis was available at 40-60 IU/kg twice weekly or once every third day. For on-demand treatment, the recommended dose level was 20-50 IU/kg.

“The final results of guardian 2 are consistent with data from previous interim analyses,” Steven R. Lentz, MD, PhD, of the University of Iowa, Iowa City, and his colleagues wrote in Haemophilia. “Turoctocog alfa was well tolerated, with no unexpected safety signals and no development of FVIII inhibitors.”

Among the 207 patients on prophylaxis, 1,782 bleeds were reported. The overall median annualized bleeding rate (ABR) for this group was 1.37. More than 88% of these bleeds were stopped with one or two injections and the success rate for treatment of bleeds was more than 90%.

The median ABR dropped to zero, with a range of 0.00‐9.91, for the 27 patients who were on the less-frequent prophylaxis regimen. In this group, more than 75% of the 34 bleeds that occurred were stopped with one injection and the success rate for treatment of bleeds was about 94%.

“These data suggest a subset of patients might be well managed with less‐frequent dosing,” the researchers wrote.

For the 19 patients who received on-demand treatment, there were 391 bleeds reported. The overall median ABR was 30.44. Nearly 80% of bleeds were stopped with one injection and more than 15% with two injections. The treatment success rate in this group was more than 96%.

There were no Factor VIII inhibitors reported in the extension trial.

In total, there were 1,260 adverse events reported for 183 patients, corresponding to less than two adverse events per patients per years of exposure to the treatment.

The most common adverse event, seen in 14.6% of patients, was nasopharyngitis. Serious adverse events occurred in 18.3% of patients but all expect one event was deemed unlikely to be related to treatment. The one fatal event in the trial was deemed unlikely to be related to treatment.

The study was funded by Novo Nordisk. Dr. Lentz reported being a paid consultant to Novo Nordisk and receiving research funding from the company.

[email protected]

SOURCE: Lentz SR et al. Haemophilia. 2018 Nov;24(6):e391-4.

SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.

Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.

Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.

In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.

One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.

Nearly three-quarters of patients in the study had a low bleeding score.

Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.

However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).

“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.

The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.

[email protected]

SOURCE: Nossair F et al. ASH 2018, Poster 3788.

SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.

Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.

Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.

In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.

One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.

Nearly three-quarters of patients in the study had a low bleeding score.

Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.

However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).

“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.

The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.

[email protected]

SOURCE: Nossair F et al. ASH 2018, Poster 3788.

SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.

Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.

Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.

In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.

One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.

Nearly three-quarters of patients in the study had a low bleeding score.

Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.

However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).

“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.

The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.

[email protected]

SOURCE: Nossair F et al. ASH 2018, Poster 3788.

SAN DIEGO – A small study of infants with severe hemophilia A revealed that there are four distinct patient subgroups based on their unique antibody signatures.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Bagirath Gangadharan, PhD, and his colleagues reported the results of HIPS, the Hemophilia Inhibitor Previously Untreated Patient Study, in a poster at the annual meeting of the American Society of Hematology.

The findings included data on 23 infants who had a baseline Factor VIII coagulant activity of less than 0.01 IU/mL at enrollment in the study. All patients received a single type of recombinant FVIII replacement therapy (Advate by Baxalta) with the dose, frequency, and regimen at the discretion of the treating physician.

Patients with prior exposure to clotting factor concentrates or blood products, another clinically significant chronic disease, and those participating in another investigational drug study were excluded.

The researchers discovered that patients fell into four distinct subgroups based on their antibody characteristics after 50 days’ exposure to FVIII infusions:

• Subgroup one, which included seven patients, had no detectable FVIII-specific antibodies and no FVIII inhibitors.
• Subgroup two – also made up of seven patients – had FVIII-specific IgG1, no detectable IgG class–switched antibodies, and no FVIII inhibitors.
• The third subgroup included just two patients. These patients had FVIII-specific IgG1, no detectable IgG class–switched antibodies, but low-titer FVIII inhibitors.
• The final subgroup, which had seven patients, had FVIII-specific IgG1, high-affinity IgG class–switched antibodies (IgG3, IgG4, and IgG2), and FVIII inhibitors.

The researchers concluded that high-affinity FVIII-specific class-switched antibodies precede clinical FVIII inhibitor detection, adding to the evidence of their “potential role as suitable predictive biomarkers for inhibitor development.”

The study is funded by Baxalta, a part of Shire. Dr. Gangadharan is employed by Shire and other authors reported financial disclosures related to the study sponsor.

[email protected]

SOURCE: Gangadharan B et al. ASH 2018, Poster 3774.

SAN DIEGO – A small study of infants with severe hemophilia A revealed that there are four distinct patient subgroups based on their unique antibody signatures.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Bagirath Gangadharan, PhD, and his colleagues reported the results of HIPS, the Hemophilia Inhibitor Previously Untreated Patient Study, in a poster at the annual meeting of the American Society of Hematology.

The findings included data on 23 infants who had a baseline Factor VIII coagulant activity of less than 0.01 IU/mL at enrollment in the study. All patients received a single type of recombinant FVIII replacement therapy (Advate by Baxalta) with the dose, frequency, and regimen at the discretion of the treating physician.

Patients with prior exposure to clotting factor concentrates or blood products, another clinically significant chronic disease, and those participating in another investigational drug study were excluded.

The researchers discovered that patients fell into four distinct subgroups based on their antibody characteristics after 50 days’ exposure to FVIII infusions:

• Subgroup one, which included seven patients, had no detectable FVIII-specific antibodies and no FVIII inhibitors.
• Subgroup two – also made up of seven patients – had FVIII-specific IgG1, no detectable IgG class–switched antibodies, and no FVIII inhibitors.
• The third subgroup included just two patients. These patients had FVIII-specific IgG1, no detectable IgG class–switched antibodies, but low-titer FVIII inhibitors.
• The final subgroup, which had seven patients, had FVIII-specific IgG1, high-affinity IgG class–switched antibodies (IgG3, IgG4, and IgG2), and FVIII inhibitors.

The researchers concluded that high-affinity FVIII-specific class-switched antibodies precede clinical FVIII inhibitor detection, adding to the evidence of their “potential role as suitable predictive biomarkers for inhibitor development.”

The study is funded by Baxalta, a part of Shire. Dr. Gangadharan is employed by Shire and other authors reported financial disclosures related to the study sponsor.

[email protected]

SOURCE: Gangadharan B et al. ASH 2018, Poster 3774.

SAN DIEGO – A small study of infants with severe hemophilia A revealed that there are four distinct patient subgroups based on their unique antibody signatures.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Bagirath Gangadharan, PhD, and his colleagues reported the results of HIPS, the Hemophilia Inhibitor Previously Untreated Patient Study, in a poster at the annual meeting of the American Society of Hematology.

The findings included data on 23 infants who had a baseline Factor VIII coagulant activity of less than 0.01 IU/mL at enrollment in the study. All patients received a single type of recombinant FVIII replacement therapy (Advate by Baxalta) with the dose, frequency, and regimen at the discretion of the treating physician.

Patients with prior exposure to clotting factor concentrates or blood products, another clinically significant chronic disease, and those participating in another investigational drug study were excluded.

The researchers discovered that patients fell into four distinct subgroups based on their antibody characteristics after 50 days’ exposure to FVIII infusions:

• Subgroup one, which included seven patients, had no detectable FVIII-specific antibodies and no FVIII inhibitors.
• Subgroup two – also made up of seven patients – had FVIII-specific IgG1, no detectable IgG class–switched antibodies, and no FVIII inhibitors.
• The third subgroup included just two patients. These patients had FVIII-specific IgG1, no detectable IgG class–switched antibodies, but low-titer FVIII inhibitors.
• The final subgroup, which had seven patients, had FVIII-specific IgG1, high-affinity IgG class–switched antibodies (IgG3, IgG4, and IgG2), and FVIII inhibitors.

The researchers concluded that high-affinity FVIII-specific class-switched antibodies precede clinical FVIII inhibitor detection, adding to the evidence of their “potential role as suitable predictive biomarkers for inhibitor development.”

The study is funded by Baxalta, a part of Shire. Dr. Gangadharan is employed by Shire and other authors reported financial disclosures related to the study sponsor.

[email protected]

SOURCE: Gangadharan B et al. ASH 2018, Poster 3774.

Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.

Svisio/Thinkstock

The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.

“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.

Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.

“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.

After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.

“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”

While this phenomenon gains supporting evidence, it remains poorly understood.

“We have no good explanation for these findings,” the investigators noted.

This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.

SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.

Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.

Svisio/Thinkstock

The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.

“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.

Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.

“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.

After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.

“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”

While this phenomenon gains supporting evidence, it remains poorly understood.

“We have no good explanation for these findings,” the investigators noted.

This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.

SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.

Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.

Svisio/Thinkstock

The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.

“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.

Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.

“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.

After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.

“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”

While this phenomenon gains supporting evidence, it remains poorly understood.

“We have no good explanation for these findings,” the investigators noted.

This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.

SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

[email protected]

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

[email protected]

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

[email protected]

SOURCE: High K et al., ASH 2018, Abstract 487.

A decrease in the expression of two long noncoding RNAs in the factor VIII gene may explain the development of severe hemophilia, according to an analysis recently published in Hematology.

Researchers at the Iranian Comprehensive Hemophilia Care Center in Tehran identified two long noncoding RNAs for investigation – NONHSAT139219.2 and NONHSAT139215.2. They collected 5 mL of venous blood from 50 males with severe hemophilia A and 50 healthy male donors and analyzed the RNA expression.

The mean of the transcript levels of two long noncoding RNAs was significantly lower in the hemophilia A samples, compared with the normal samples – 5.52 for controls versus 1.25 for hemophilia A for NONHSAT139215 and 4.86 for controls versus 2.14 for hemophilia A samples for NONHSAT139219 (P less than .05).

Low expression levels of long noncoding RNAs in severe hemophilia A cases may be linked with the reduction of factor VIII levels, according to the investigators. “It is possible that the transcription of [long noncoding] RNAs leads to gene silencing or activation.”

This provides a potential biomarker with application in both prognosis and therapeutics; long noncoding RNA functional analysis should be performed in future studies, they wrote.

There was no outside funding for the study, and no potential conflict of interest was reported by the authors.

[email protected]

SOURCE: Niloofar N et al. Hematology. 2019;24(1):255-62.

A decrease in the expression of two long noncoding RNAs in the factor VIII gene may explain the development of severe hemophilia, according to an analysis recently published in Hematology.

Researchers at the Iranian Comprehensive Hemophilia Care Center in Tehran identified two long noncoding RNAs for investigation – NONHSAT139219.2 and NONHSAT139215.2. They collected 5 mL of venous blood from 50 males with severe hemophilia A and 50 healthy male donors and analyzed the RNA expression.

The mean of the transcript levels of two long noncoding RNAs was significantly lower in the hemophilia A samples, compared with the normal samples – 5.52 for controls versus 1.25 for hemophilia A for NONHSAT139215 and 4.86 for controls versus 2.14 for hemophilia A samples for NONHSAT139219 (P less than .05).

Low expression levels of long noncoding RNAs in severe hemophilia A cases may be linked with the reduction of factor VIII levels, according to the investigators. “It is possible that the transcription of [long noncoding] RNAs leads to gene silencing or activation.”

This provides a potential biomarker with application in both prognosis and therapeutics; long noncoding RNA functional analysis should be performed in future studies, they wrote.

There was no outside funding for the study, and no potential conflict of interest was reported by the authors.

[email protected]

SOURCE: Niloofar N et al. Hematology. 2019;24(1):255-62.

A decrease in the expression of two long noncoding RNAs in the factor VIII gene may explain the development of severe hemophilia, according to an analysis recently published in Hematology.

Researchers at the Iranian Comprehensive Hemophilia Care Center in Tehran identified two long noncoding RNAs for investigation – NONHSAT139219.2 and NONHSAT139215.2. They collected 5 mL of venous blood from 50 males with severe hemophilia A and 50 healthy male donors and analyzed the RNA expression.

The mean of the transcript levels of two long noncoding RNAs was significantly lower in the hemophilia A samples, compared with the normal samples – 5.52 for controls versus 1.25 for hemophilia A for NONHSAT139215 and 4.86 for controls versus 2.14 for hemophilia A samples for NONHSAT139219 (P less than .05).

Low expression levels of long noncoding RNAs in severe hemophilia A cases may be linked with the reduction of factor VIII levels, according to the investigators. “It is possible that the transcription of [long noncoding] RNAs leads to gene silencing or activation.”

This provides a potential biomarker with application in both prognosis and therapeutics; long noncoding RNA functional analysis should be performed in future studies, they wrote.

There was no outside funding for the study, and no potential conflict of interest was reported by the authors.

[email protected]

SOURCE: Niloofar N et al. Hematology. 2019;24(1):255-62.

The British Society for Haematology has released new recommendations on the clinical management of osteoporosis secondary to glucocorticoid use in patients with immune thrombocytopenia.

The “good practice paper” was published in the British Journal of Haematology.

“Glucocorticoids are a standard first-line treatment for immune thrombocytopenia and are an important risk factor for osteoporosis,” wrote Quentin A. Hill, MBChB, of the University of Leeds (England), and his colleagues.

When given for extended periods of time, glucocorticoids have been shown to trigger substantial reductions in bone mineral density, which has been linked with an increased risk for bone fractures. The researchers reported that fracture risk is not exclusively dependent on steroid use but is also affected by other factors, such as patient age, duration of glucocorticoid use, and treatment dose.

“Some studies have found that fracture risk is not significantly elevated in patients receiving oral glucocorticoids for [less than] 3 months,” the researches wrote. “Most guidelines are for patients with an intended duration of treatment [greater than] 3 months.”

In adult patients treated with glucocorticoids, the authors recommended that appropriate educational information be provided on how to enhance bone health. Additionally, they stated that patients should obtain sufficient calcium and vitamin D, defined as 700-1,200 mg and 800 IU daily, respectively, which can be achieved through diet or supplementation.

“Patients at high risk of fracture should be considered for oral alendronate or risedronate,” they wrote. “If contraindicated or poorly tolerated, zoledronic acid, denosumab, or teriparatide are appropriate alternatives.”

With respect to the use of glucocorticoids for relapse, the experts recommended starting on the lowest effective dose and providing steroid-sparing agents when appropriate. Treatment with bisphosphonates may benefit children and patients aged less than 40 years.

The authors also reported that glucocorticoid cessation may reduce some degree of fracture risk; however, an elevated risk does remain, even after withdrawal of therapy, warranting ongoing clinical assessment and follow-up.

Dr. Hill and several coauthors reported financial affiliations with Amgen, Novartis, Ono Pharmaceuticals, Shire, and others.

SOURCE: Hill QA et al. Br J Haematol. 2019 Jan 4. doi: 10.1111/bjh.15735.

The British Society for Haematology has released new recommendations on the clinical management of osteoporosis secondary to glucocorticoid use in patients with immune thrombocytopenia.

The “good practice paper” was published in the British Journal of Haematology.

“Glucocorticoids are a standard first-line treatment for immune thrombocytopenia and are an important risk factor for osteoporosis,” wrote Quentin A. Hill, MBChB, of the University of Leeds (England), and his colleagues.

When given for extended periods of time, glucocorticoids have been shown to trigger substantial reductions in bone mineral density, which has been linked with an increased risk for bone fractures. The researchers reported that fracture risk is not exclusively dependent on steroid use but is also affected by other factors, such as patient age, duration of glucocorticoid use, and treatment dose.

“Some studies have found that fracture risk is not significantly elevated in patients receiving oral glucocorticoids for [less than] 3 months,” the researches wrote. “Most guidelines are for patients with an intended duration of treatment [greater than] 3 months.”

In adult patients treated with glucocorticoids, the authors recommended that appropriate educational information be provided on how to enhance bone health. Additionally, they stated that patients should obtain sufficient calcium and vitamin D, defined as 700-1,200 mg and 800 IU daily, respectively, which can be achieved through diet or supplementation.

“Patients at high risk of fracture should be considered for oral alendronate or risedronate,” they wrote. “If contraindicated or poorly tolerated, zoledronic acid, denosumab, or teriparatide are appropriate alternatives.”

With respect to the use of glucocorticoids for relapse, the experts recommended starting on the lowest effective dose and providing steroid-sparing agents when appropriate. Treatment with bisphosphonates may benefit children and patients aged less than 40 years.

The authors also reported that glucocorticoid cessation may reduce some degree of fracture risk; however, an elevated risk does remain, even after withdrawal of therapy, warranting ongoing clinical assessment and follow-up.

Dr. Hill and several coauthors reported financial affiliations with Amgen, Novartis, Ono Pharmaceuticals, Shire, and others.

SOURCE: Hill QA et al. Br J Haematol. 2019 Jan 4. doi: 10.1111/bjh.15735.

The British Society for Haematology has released new recommendations on the clinical management of osteoporosis secondary to glucocorticoid use in patients with immune thrombocytopenia.

The “good practice paper” was published in the British Journal of Haematology.

“Glucocorticoids are a standard first-line treatment for immune thrombocytopenia and are an important risk factor for osteoporosis,” wrote Quentin A. Hill, MBChB, of the University of Leeds (England), and his colleagues.

When given for extended periods of time, glucocorticoids have been shown to trigger substantial reductions in bone mineral density, which has been linked with an increased risk for bone fractures. The researchers reported that fracture risk is not exclusively dependent on steroid use but is also affected by other factors, such as patient age, duration of glucocorticoid use, and treatment dose.

“Some studies have found that fracture risk is not significantly elevated in patients receiving oral glucocorticoids for [less than] 3 months,” the researches wrote. “Most guidelines are for patients with an intended duration of treatment [greater than] 3 months.”

In adult patients treated with glucocorticoids, the authors recommended that appropriate educational information be provided on how to enhance bone health. Additionally, they stated that patients should obtain sufficient calcium and vitamin D, defined as 700-1,200 mg and 800 IU daily, respectively, which can be achieved through diet or supplementation.

“Patients at high risk of fracture should be considered for oral alendronate or risedronate,” they wrote. “If contraindicated or poorly tolerated, zoledronic acid, denosumab, or teriparatide are appropriate alternatives.”

With respect to the use of glucocorticoids for relapse, the experts recommended starting on the lowest effective dose and providing steroid-sparing agents when appropriate. Treatment with bisphosphonates may benefit children and patients aged less than 40 years.

The authors also reported that glucocorticoid cessation may reduce some degree of fracture risk; however, an elevated risk does remain, even after withdrawal of therapy, warranting ongoing clinical assessment and follow-up.

Dr. Hill and several coauthors reported financial affiliations with Amgen, Novartis, Ono Pharmaceuticals, Shire, and others.

SOURCE: Hill QA et al. Br J Haematol. 2019 Jan 4. doi: 10.1111/bjh.15735.

Online applications designed to facilitate tailoring of hemophilia A prophylaxis supported a regimen change in nearly half of patients enrolled in a recent study, investigators report.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The development of individualized pharmacokinetic profiles using those online tools may have contributed to improved adherence and decreased bleeding, according to Azusa Nagao, MD, a researcher in the department of blood coagulation at Ogikubo Hospital, Tokyo, and colleagues.

Dr. Nagao and colleagues calculated individual pharmacokinetic profiles for the 39 patients using myPKFiT for those patients receiving antihemophilic factor (recombinant) and the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) for those using other factor concentrates.

Based on profiling results, changes to prophylaxis regimens were warranted for 20 of the 39 patients, Dr. Nagao and coresearchers reported in Thrombosis Research.

Those changes included a higher dosage of factor concentrate in eight patients, a shorter infusion interval in five patients, a change from a standard half-life product to an extended half-life product in five patients, and a reduction in prophylaxis dose for two patients.

Adherence stayed the same in patients who had a dose increase and improved for those who switched to a shorter infusion interval and for those who switched to an extended half-life product, according to the researchers.

Annualized bleeding rate significantly decreased for patients who switched to an extended half-life product (P less than .05), and there was a trend toward decrease in annualized joint bleeding rate in this group, the researchers reported.

The annualized joint bleeding rate did significantly decrease in patients without end-stage arthropathy (P less than .05), with no significant change in this outcome for those with end-stage arthropathy.

“The impact of adopting population pharmacokinetics-based treatment as measured by changes in treatment adherence and bleeding rate was modest, but the study power was limited by the characteristics of the study population,” the researchers wrote.

The myPKFiT and WAPPS-Hemo tools are designed to simplify the development of individual pharmacokinetic profiles to guide prophylaxis dosing in patients with hemophilia A, according to the researchers.

“Full [pharmacokinetic] analysis poses a big burden, especially on children and their families,” they wrote.

A full pharmacokinetic study requires a 72-hour washout period and sample collection at 10 time points over the course of about 48 hours, along with associated hospital admissions or outpatient clinic visits, they noted.

The myPKFiT application, cleared by the Food and Drug Administration for use in hemophilia A patients being treated with antihemophilic factor (recombinant), can generate an individual’s pharmacokinetic profile based on as few as two blood samples, according to a news release from Shire.

Nagao reported receiving a research grant from Shire unrelated to this study. One coauthor also reported disclosures related to Shire, Bayer, Pfizer, Novo Nordisk, CSL Behring, and others.

SOURCE: Nagao A et al. Thromb Res. 2019 Jan;173:79-84.

Online applications designed to facilitate tailoring of hemophilia A prophylaxis supported a regimen change in nearly half of patients enrolled in a recent study, investigators report.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The development of individualized pharmacokinetic profiles using those online tools may have contributed to improved adherence and decreased bleeding, according to Azusa Nagao, MD, a researcher in the department of blood coagulation at Ogikubo Hospital, Tokyo, and colleagues.

Dr. Nagao and colleagues calculated individual pharmacokinetic profiles for the 39 patients using myPKFiT for those patients receiving antihemophilic factor (recombinant) and the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) for those using other factor concentrates.

Based on profiling results, changes to prophylaxis regimens were warranted for 20 of the 39 patients, Dr. Nagao and coresearchers reported in Thrombosis Research.

Those changes included a higher dosage of factor concentrate in eight patients, a shorter infusion interval in five patients, a change from a standard half-life product to an extended half-life product in five patients, and a reduction in prophylaxis dose for two patients.

Adherence stayed the same in patients who had a dose increase and improved for those who switched to a shorter infusion interval and for those who switched to an extended half-life product, according to the researchers.

Annualized bleeding rate significantly decreased for patients who switched to an extended half-life product (P less than .05), and there was a trend toward decrease in annualized joint bleeding rate in this group, the researchers reported.

The annualized joint bleeding rate did significantly decrease in patients without end-stage arthropathy (P less than .05), with no significant change in this outcome for those with end-stage arthropathy.

“The impact of adopting population pharmacokinetics-based treatment as measured by changes in treatment adherence and bleeding rate was modest, but the study power was limited by the characteristics of the study population,” the researchers wrote.

The myPKFiT and WAPPS-Hemo tools are designed to simplify the development of individual pharmacokinetic profiles to guide prophylaxis dosing in patients with hemophilia A, according to the researchers.

“Full [pharmacokinetic] analysis poses a big burden, especially on children and their families,” they wrote.

A full pharmacokinetic study requires a 72-hour washout period and sample collection at 10 time points over the course of about 48 hours, along with associated hospital admissions or outpatient clinic visits, they noted.

The myPKFiT application, cleared by the Food and Drug Administration for use in hemophilia A patients being treated with antihemophilic factor (recombinant), can generate an individual’s pharmacokinetic profile based on as few as two blood samples, according to a news release from Shire.

Nagao reported receiving a research grant from Shire unrelated to this study. One coauthor also reported disclosures related to Shire, Bayer, Pfizer, Novo Nordisk, CSL Behring, and others.

SOURCE: Nagao A et al. Thromb Res. 2019 Jan;173:79-84.

Online applications designed to facilitate tailoring of hemophilia A prophylaxis supported a regimen change in nearly half of patients enrolled in a recent study, investigators report.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The development of individualized pharmacokinetic profiles using those online tools may have contributed to improved adherence and decreased bleeding, according to Azusa Nagao, MD, a researcher in the department of blood coagulation at Ogikubo Hospital, Tokyo, and colleagues.

Dr. Nagao and colleagues calculated individual pharmacokinetic profiles for the 39 patients using myPKFiT for those patients receiving antihemophilic factor (recombinant) and the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) for those using other factor concentrates.

Based on profiling results, changes to prophylaxis regimens were warranted for 20 of the 39 patients, Dr. Nagao and coresearchers reported in Thrombosis Research.

Those changes included a higher dosage of factor concentrate in eight patients, a shorter infusion interval in five patients, a change from a standard half-life product to an extended half-life product in five patients, and a reduction in prophylaxis dose for two patients.

Adherence stayed the same in patients who had a dose increase and improved for those who switched to a shorter infusion interval and for those who switched to an extended half-life product, according to the researchers.

Annualized bleeding rate significantly decreased for patients who switched to an extended half-life product (P less than .05), and there was a trend toward decrease in annualized joint bleeding rate in this group, the researchers reported.

The annualized joint bleeding rate did significantly decrease in patients without end-stage arthropathy (P less than .05), with no significant change in this outcome for those with end-stage arthropathy.

“The impact of adopting population pharmacokinetics-based treatment as measured by changes in treatment adherence and bleeding rate was modest, but the study power was limited by the characteristics of the study population,” the researchers wrote.

The myPKFiT and WAPPS-Hemo tools are designed to simplify the development of individual pharmacokinetic profiles to guide prophylaxis dosing in patients with hemophilia A, according to the researchers.

“Full [pharmacokinetic] analysis poses a big burden, especially on children and their families,” they wrote.

A full pharmacokinetic study requires a 72-hour washout period and sample collection at 10 time points over the course of about 48 hours, along with associated hospital admissions or outpatient clinic visits, they noted.

The myPKFiT application, cleared by the Food and Drug Administration for use in hemophilia A patients being treated with antihemophilic factor (recombinant), can generate an individual’s pharmacokinetic profile based on as few as two blood samples, according to a news release from Shire.

Nagao reported receiving a research grant from Shire unrelated to this study. One coauthor also reported disclosures related to Shire, Bayer, Pfizer, Novo Nordisk, CSL Behring, and others.

SOURCE: Nagao A et al. Thromb Res. 2019 Jan;173:79-84.

Patients with acquired thrombotic thrombocytopenic purpura (TTP) who were treated with caplacizumab had faster time to platelet normalization (2.69 days vs. 2.88 days) and were 1.55 times more likely to achieve platelet normalization, compared with placebo, according to results of the double-blind, controlled HERCULES trial published in the New England Journal of Medicine (2019 Jan 9. doi: 10.1056/NEJMoa1806311).

Patients taking caplacizumab also had a 74% lower incidence of a composite outcome that included TTP-related deaths, recurrence of TTP, or a major thromboembolic event.

We covered this story at the annual meeting of the American Society of Hematology before it was published in the journal. Find our coverage at the link below.

[email protected]

Patients with acquired thrombotic thrombocytopenic purpura (TTP) who were treated with caplacizumab had faster time to platelet normalization (2.69 days vs. 2.88 days) and were 1.55 times more likely to achieve platelet normalization, compared with placebo, according to results of the double-blind, controlled HERCULES trial published in the New England Journal of Medicine (2019 Jan 9. doi: 10.1056/NEJMoa1806311).

Patients taking caplacizumab also had a 74% lower incidence of a composite outcome that included TTP-related deaths, recurrence of TTP, or a major thromboembolic event.

We covered this story at the annual meeting of the American Society of Hematology before it was published in the journal. Find our coverage at the link below.

[email protected]

Patients with acquired thrombotic thrombocytopenic purpura (TTP) who were treated with caplacizumab had faster time to platelet normalization (2.69 days vs. 2.88 days) and were 1.55 times more likely to achieve platelet normalization, compared with placebo, according to results of the double-blind, controlled HERCULES trial published in the New England Journal of Medicine (2019 Jan 9. doi: 10.1056/NEJMoa1806311).

Patients taking caplacizumab also had a 74% lower incidence of a composite outcome that included TTP-related deaths, recurrence of TTP, or a major thromboembolic event.

We covered this story at the annual meeting of the American Society of Hematology before it was published in the journal. Find our coverage at the link below.

[email protected]