Pharmacokinetic strategies for achieving precise factor VIII control with susoctocog alfa in acquired hemophilia A.

Background: Recombinant porcine factor (F)VIII (rpFVIII, susoctocog alfa) is used to treat bleeding in patients with acquired hemophilia A (AHA), yet pharmacokinetic (PK) parameters and dosing needs vary widely.

Objectives: To explore the precision of PK-guided bolus dosing and continuous infusion of rpFVIII in AHA.

Methods: We enrolled all AHA patients considered for rpFVIII treatment from 2016 to 2023 at our institution.

Sustained Survival Benefit of Emicizumab and Postponed Immunosuppression in Acquired Hemophilia A.

Acquired hemophilia A (AHA) is a severe bleeding disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII). Standard treatment involves immunosuppressive therapy (IST), which carries a significant risk of serious infections, the leading cause of death in AHA patients. The GTH-AHA-EMI study investigated the use of emicizumab to prevent bleeding during the first 12 weeks of management while postponing IST.

A transposable element prevents severe hemophilia B and provides insights into the evolution of new- and old world primates.

Alu-elements comprise a large part of the human genome and some insertions have been shown to cause diseases. Here, we illuminate the protective role of an Alu-element in the 3'UTR of the human Factor 9 gene and its ability to ameliorate a poly(A) site mutation in a hemophilia B patient, preventing him from developing a severe disease. Using a minigene, we examined the disease-causing mutation and the modifying effect of the transposon in cellulo.

The Importance of Clinical Context and Consistency in Methodology When Using Matching-Adjusted Indirect Comparisons (MAICs) to Compare Outcomes.

Hemophilia A is rare, which makes large, randomized, controlled, statistically driven, head-to-head comparison trials difficult. Matching-adjusted indirect comparisons (MAICs) are validated statistical tools designed to help make the results of non-comparative trials more comparable. The purpose of this commentary is to provide an insight into the MAIC method, in order to assist the hemophilia community with interpretation of MAIC data.

Real-world usage and effectiveness of recombinant factor VIII/factor IX Fc in hemophilia A/B: final data from the 24-month, prospective, noninterventional PREVENT study in Germany.

Background: Real-world experience with efmoroctocog alfa (a recombinant factor [F]VIII Fc fusion protein [rFVIIIFc]) and eftrenonacog alfa (a recombinant factor IX Fc fusion protein [rFIXFc]) is needed to bridge evidence gaps.

Objectives: To describe rFVIIIFc/rFIXFc usage and effectiveness over a 24-month prospective period.

Methods: PREVENT (NCT03055611), a noninterventional study across 25 German hemophilia treatment centers, enrolled previously treated persons with hemophilia A and B (all ages/severities) on individualized rFVIIIFc/rFIXFc prophylaxis before/at enrollment.

Emicizumab versus immunosuppressive therapy for the management of acquired hemophilia A.

Background: Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII. Immunosuppressive therapy (IST) is standard of care to eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST.

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Acquired bleeding disorders can develop in previously healthy people irrespective of age or gender but are particularly common in patients with certain underlying conditions. Here, we review recent advances in the management of acquired haemophilia A (AHA), acquired von Willebrand syndrome (AVWS), and patients with hemostatic abnormalities due to chronic liver disease (CLD). Patients with AHA can now benefit from prophylaxis with emicizumab, a therapeutic antibody that mimics the function of activated coagulation factor VIII.

Rates of venous thromboembolism and use of thromboprophylaxis after major orthopedic surgery in patients with congenital hemophilia A or B: a systematic review.

Background: Venous thromboembolism (VTE) is a well-recognized complication after total joint replacement (TJR). Persons with hemophilia A or B are considered at low postoperative VTE risk due to their coagulation factor deficiencies, and administering pharmacologic thromboprophylaxis is often considered contraindicated. However, using factor replacement therapy could increase the postoperative VTE risk.

Immunotherapy of acquired hemophilia A.

Acquired hemophilia A (AHA) is an autoimmune disorder characterized by the formation of autoantibodies that neutralize the function of coagulation factor VIII. Immunosuppressive therapy (IST) with glucocorticoids, cyclophosphamide, rituximab, or combinations thereof is the standard of care to suppress autoantibody formation and induce remission of AHA. About 80% of patients achieve remission over the course of a few weeks to several months.

Emicizumab for the Treatment of Acquired Hemophilia A: Consensus Recommendations from the GTH-AHA Working Group.

Background:  Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Standard treatment consists of bleeding control with bypassing agents and immunosuppressive therapy. Emicizumab is a bispecific antibody that mimics the function of activated FVIII irrespective of the presence of neutralizing antibodies.

The monosialoganglioside GM1a protects against complement attack.

The complement system is a part of the innate immune system in the fluid phase and efficiently eliminates pathogens. However, its activation requires tight regulation on the host cell surface in order not to compromise cellular viability. Previously, we showed that loss of placental cell surface sialylation in mice in vivo leads to a maternal complement attack at the fetal-maternal interface, ultimately resulting in loss of pregnancy.

Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study.

Background: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis.

von Willebrand factor modulates immune complexes and the recall response against factor VIII in a murine hemophilia A model.

Achieving tolerance toward factor VIII (FVIII) remains an important goal of hemophilia treatment. Up to 40% of patients with severe hemophilia A (HA) develop neutralizing antibodies against FVIII, and the only proven treatment to achieve tolerance is infusion of FVIII over prolonged periods in the context of immune tolerance induction. Here, we addressed the role of von Willebrand factor (VWF) as a modulator of anti-FVIII antibody effector functions and the FVIII-specific recall response in an HA mouse model.

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.

Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series.

von Willebrand factor neutralizing and non-neutralizing alloantibodies in 213 subjects with type 3 von Willebrand disease enrolled in 3WINTERS-IPS.

Background: Type 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions.

Objective: The objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS.

Impact of different factor VIII inhibitor kinetic profiles on the inhibitor titer quantification using the modified Nijmegen-Bethesda assay.

Background: Coagulation factor VIII (FVIII) inhibitor titer quantification is vital for optimizing care in people with hemophilia A.

Objectives: This study analyzed the impact of the different kinetic profiles of four FVIII monoclonal antibodies on inhibitor titer quantification using the modified Nijmegen-Bethesda assay.

Methods: Concentration-related and time-related profiles of FVIII antibodies (4A4, BO2C11, 2-54, ESH-8) were evaluated in vitro.

[Gene therapy of Hemophilia: Recommendations from the German, Austrian, and Swiss Society for Thrombosis and Haemostasis Research (GTH)].

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained.

Gene Therapy for Hemophilia-Opportunities and Risks.

Background: AAV (adeno-associated virus)-based gene therapy is a new treatment for hemophilia and has recently received approval for the treatment of severe hemophilia A. It does not suffer from the limitations of the current standard treatment (regular prophylactic intravenous injections of the missing clotting factor; subcutaneous injection of a bispecific antibody in hemophilia A) and can, it is hoped, raise the concentration of the missing clotting factor over the long term. AAV-based gene therapy can only be performed once, however, because of the generation of antibodies to AAV.

[Use of Thrombopoetin-Receptor-Agonists (TPO-RA) in patients with liver cirrhosis before invasive procedures].

Advanced chronic liver disease is accompanied with relevant changes in the corpuscular and plasmatic coagulation system. Due to thrombocytopenia that is regularly observed in these patients, platelet transfusions are often performed prior invasive procedures to prevent possible bleeding complications. However, platelet transfusions are associated with clinically significant adverse events and economically relevant health care costs.

Microembolic signal monitoring in patients with HeartMate 3 and HeartWare left ventricular assist devices: Association with antithrombotic treatment and cerebrovascular events.

Background: In patients with left ventricular assist devices (LVADs), ischemic and hemorrhagic stroke are dreaded complications. Predictive markers for these events are lacking. This study aimed to investigate the prevalence and predictive value of microembolic signals (MES) for stroke, detected by Transcranial Doppler sonography (TCD) in patients with HeartMate 3 (HM 3) or HeartWare (HW).