An 18-year-old man with a history of recurrent hemarthroses and severe mucosal bleeding due to hemophilia A comes to the office for follow-up. He has had occasional breakthrough bleeding despite receiving prophylactic factor VIII infusions. Testing reveals the patient now has inhibitor alloantibodies against factor VIII, and factor replacement products can no longer be used. Treatment with a novel medication that prevents bleeding by mimicking the function of factor VIII is initiated. This medication most likely works by which of the following mechanisms?

Question

An 18-year-old man with a history of recurrent hemarthroses and severe mucosal bleeding due to hemophilia A comes to the office for follow-up.  He has had occasional breakthrough bleeding despite receiving prophylactic factor VIII infusions.  Testing reveals the patient now has inhibitor alloantibodies against factor VIII, and factor replacement products can no longer be used.  Treatment with a novel medication that prevents bleeding by mimicking the function of factor VIII is initiated.  This medication most likely works by which of the following mechanisms?

Quizplus · Accepted Answer

Hemophilia A is an X-linked, recessive bleeding disorder caused by mutations to the gene that encodes clotting factor VIII. Factor VIII is part of the intrinsic coagulation cascade; it acts as a bridging protein that brings together the catalytic component of factor IXa (the protease) with factor X (the substrate), thereby amplifying formation of factor Xa, which promotes fibrin clots. Patients with hemophilia A have severe reductions in factor VIII and are unable to form fibrin clots at sites of minor trauma, leading to potentially life-threatening hemarthroses and mucosal bleeding. Treatment with factor VIII replacement products (eg, factor VIII concentrate from plasma) can prevent or treat bleeding in these patients. However, long-term efficacy is often limited by the formation of neutralizing antibodies (factor VIII inhibitors). Emicizumab, a bispecific monoclonal antibody, mimics the normal physiologic function of factor VIII and can be used to prevent or treat bleeding in patients who have factor VIII inhibitors. This antibody has 2 binding sites; one site binds to factor IXa and the other binds to factor X, which brings them into close proximity and allows factor IXa to cleave factor X into its active form (Xa). (Choice A) Von Willebrand factor, a large glycoprotein produced by the endothelium, aids platelet clot formation by binding platelets to subendothelial collagen at sites of injury. It is also a carrier protein for factor VIII; therefore, patients with Von Willebrand factor deficiency often have mild or moderate reductions in factor VIII. However, serious bleeding (eg, hemarthroses) is very uncommon. (Choice B) Activation of factor X to Xa can also occur via the extrinsic (tissue factor pathway) in response to tissue trauma. In this case, factor VIIa in combination with tissue factor activates factor X. This pathway does not require factor VIII and is unaffected in those with hemophilia A. (Choice C) Ultra-large von Willebrand factor multimers produced by the endothelium are cleaved to smaller subunits by the metalloprotease ADAMTS13. Loss of ADAMTS13 activity leads to thrombotic thrombocytopenic purpura. (Choice D) Factor XIIIa cross-links loose fibrin molecules into a dense network, thereby forming stable fibrin clots. Factor XIIIa is unaffected in those with hemophilia A. Educational objective: Hemophilia A is an X-linked disorder associated with a deficiency of factor VIII. Emicizumab-a bispecific, monoclonal antibody-mimics the activity of factor VIII by binding to both factor IXa and factor X, bringing them into close proximity to allow for factor X activation. __________ References: Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. (http://www.ncbi.nlm.nih.gov/pubmed/30157389)

An 18-Year-Old Man with a History of Recurrent Hemarthroses and Severe