Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working. If you have hemophilia or VWD type 3, it is important to be tested for inhibitors once a year. People with hemophilia have a better quality of life today than ever before, but medical complications can still occur. Approximately 1 in 5 people with hemophilia A 1 and about 3 in people with hemophilia B 2 will develop an antibody—called an inhibitor—to the treatment product medicine used to treat or prevent their bleeding episodes. People with VWD type 3 may also develop inhibitors. Developing an inhibitor is one of the most serious and costly medical complications of a bleeding disorder because it becomes more difficult to treat bleeds.

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Amplification of the coagulation cascade to generate the thrombin burst that ultimately leads to stable clot formation is mediated by the intrinsic Xase complex. In the single-center phase 1 double-blinded, randomized control trial, pharmacokinetic studies showed an average half-life of In a separate trial of 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous injections of ACE over the course of 12 consecutive weeks at 0.

There were no thromboembolic events observed. Antithrombin is an important negative regulator of excess thrombin formation via thrombin and fXa inhibition. Individuals with inherited or acquired deficiencies of antithrombin have an increased risk for thrombosis.

The siRNA technology allows for targeted interference of post-transcription gene expression at sites of endogenous protein production of specific genes by interfering with mRNA translation. In the multicenter phase 1 trial, no thromboembolic events or significant alterations in thrombotic parameters occurred in healthy adult volunteers or patients with moderate or severe hemophilia A and B after a single subcutaneous dose of ALN-AT3.

Inhibition of natural anticoagulants. Preclinical studies in a rabbit hemophilia A model demonstrated reduced cuticle bleeding after Concizumab administration. All patients remained on their standard on-demand or prophylaxis regimens with factor products during the trial. There were no antidrug antibodies formed or serious adverse events observed.

Aptamers are single-stranded oligonucleotides that bind a specific target protein with high affinity. The aptamer improved whole-blood clotting times, clot formation, and thrombin generation in plasmas of patients with hemophilia A and B.

There have been other bioengineered extended half-life rfVIIa products, including glycopegylated rfVIIa N7-GP and BAY, developed; however, the clinical trials were prematurely stopped because of a lack of a dose-response or development of neutralizing antidrug antibodies with rfVIIa cross-reactivity in a patient with hemophilia with inhibitors. In a phase 2 open-labeled trial, rpfVIII demonstrated hemostatic efficacy and safety in 9 patients with congenital hemophilia A and inhibitors. Conclusions Inhibitors remain a challenging complication of treatment in patients with hemophilia.

The process of inhibitor eradication through immune tolerance therapy is the standard of care and optimal long-term strategy for prevention of future bleeds and restoration of factor efficacy. However, ITI is a time-intensive and costly commitment that can impose substantial psychological and financial stressors on families.

There are currently limited available agents beyond the BPAs to prevent and treat bleeding in inhibitor patients who have frequent bleeding episodes, fail ITI, relapse, or present with poor-risk features at high risk for ITI failure.

Several questions remain regarding the optimal therapeutic approach in poor-risk patients. Nonetheless, there are several novel therapies in development or active clinical trials that may potentially lessen the burden of disease and reduce bleeding risk in patients with hemophilia with or without inhibitors. References 1. Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas. DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention.

Br J Haematol. Increased burden on caregivers of having a child with haemophilia complicated by inhibitors. Pediatr Blood Cancer. Healthcare expenditures for males with haemophilia and employer-sponsored insurance in the United States, Waters B, Lillicrap D.

The molecular mechanisms of immunomodulation and tolerance induction to factor VIII. J Thromb Haemost. Toward optimal therapy for inhibitors in hemophilia. International workshop on immune tolerance induction: consensus recommendations.

Thromb Haemost. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Immune tolerance in hemophilia with factor VIII inhibitors: predictors of success. Challenges in the management of hemophilia B with inhibitor. Semin Thromb Hemost. Management of haemophilia B inhibitor patients with anaphylactic reactions to FIX concentrates.

Desensitization and immune tolerance induction in children with severe factor IX deficiency; inhibitors and adverse reactions to replacement therapy: a case-report and literature review.

Ital J Pediatr. Late immune tolerance induction in haemophilia A patients. US Guidelines for immune tolerance induction in patients with haemophilia A and inhibitors. Abshire T, Kenet G. Ettingshausen CE, Kreuz W. Early long-term FEIBA prophylaxis in haemophilia A patients with inhibitor after failing immune tolerance induction: A prospective clinical case series.

Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors.

Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors. Vox Sang. Factors affecting choice of hemostatic agent for the hemophilia patient with an inhibitor antibody. Am J Hematol. The application of bypassing-agent prophylaxis in haemophilia A patients with inhibitors: a meeting report. Shima M. The potential of bispecific antibodies for treatment of hemophilia A [abstract]. Abstract AS Thrombophilia as a multigenic disease.

Clinical syndromes associated with acquired antithrombin deficiency via microvascular leakage and the related risk of thrombosis.

Thromb Res. Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov. J Am Chem Soc. A subcutaneously administered investigational RNAi therapeutic ALN-AT3 targeting antithrombin for treatment of hemophilia: interim weekly and monthly dosing results in patients with hemophilia A or B.

Antithrombin reduction corrected thrombin generation in samples from hemophilia A and B patients with inhibitors. Safety and pharmacokinetics of anti-TFPI antibody concizumab in healthy volunteers and patients with hemophilia: a randomized first human dose trial.

Inhibition of tissue factor pathway inhibitor by the aptamer BAX improves clotting of hemophilic blood and plasma.


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