Hemophilia A: A High-Yield USMLE Review
Hemophilia A is the classic inherited bleeding disorder, caused by deficiency of coagulation factor VIII. It is an X-linked recessive defect of secondary hemostasis, so affected patients bleed deep and late rather than into skin and mucosa. On the exam it appears as a boy with recurrent hemarthroses, an isolated prolonged PTT, and a family history through the maternal line.
Pathophysiology
The factor VIII gene lies on the X chromosome, so hemizygous males are affected while females are carriers. Factor VIII is a cofactor that accelerates factor X activation; without it, thrombin generation is severely impaired and secondary hemostasis fails. Because the platelet-driven primary hemostasis remains intact, patients form an initial platelet plug but cannot stabilize it — producing deep bleeding and hemarthrosis rather than petechiae.
Presentation
- Recurrent spontaneous hemarthrosis (the most common feature), leading to chronic arthropathy
- Deep muscle hematomas
- Intracranial hemorrhage — the leading cause of death
- Delayed bleeding after procedures
- NO petechiae, because platelets are normal (this is a secondary hemostasis defect, not a platelet/mucocutaneous problem)
- X-linked recessive inheritance pattern: affected males with carrier mothers (e.g., an affected maternal uncle)
Diagnosis
- PTT is prolonged, while PT and platelet count are normal — an isolated intrinsic pathway defect
- Mixing study corrects the prolonged PTT when mixed with normal plasma, proving a factor deficiency rather than an inhibitor
- Factor VIII activity assay confirms the diagnosis
Management
- Factor VIII replacement (recombinant or plasma-derived), with prophylaxis for severe disease
- DDAVP for mild hemophilia A, which releases stored factor VIII
- Emicizumab, a bispecific antibody that mimics factor VIII, used for prophylaxis
- For patients with inhibitors, use bypassing agents such as factor VIIa or activated prothrombin complex concentrate
High-yield
- Hemophilia A = factor VIII deficiency; the classic "bleeding disease"
- X-linked recessive — affected males through carrier mothers; affected fathers cannot transmit to sons
- Hemarthrosis is the hallmark of hemophilia (A or B); mucocutaneous bleeding/petechiae point elsewhere
- Isolated prolonged PTT that CORRECTS with mixing study distinguishes factor deficiency from an inhibitor
- Inhibitor development (antibodies to factor VIII) occurs in 25–30% of severe hemophilia A
- Hemophilia A is more common than hemophilia B (factor IX, "Christmas disease"), which is clinically identical
Pitfalls
- Do not confuse with von Willebrand disease, which causes mucocutaneous (not deep) bleeding and whose prolonged PTT also corrects with mixing — but the clinical bleeding pattern differs
- Do not mistake it for a lupus anticoagulant/inhibitor: in hemophilia the mixing study corrects, whereas with an inhibitor the PTT remains prolonged
- Factor XII deficiency also prolongs the PTT but causes NO bleeding — do not label it hemophilia
- Remember there are no petechiae: expecting mucocutaneous signs will steer you toward a platelet disorder and away from the correct diagnosis
Don't just memorize Hemophilia A — practice reasoning through it on branching cases where your decisions shape the patient.