Back
ditki Logo
medical & biological sciences

Hemophilia for the USMLE Step 3

Start your One-Week Free Trial
Already subscribed? Log in »
Hemophilia for the USMLE Step 3 Exam
  • Definition:
    • Hemophilia is an X-linked recessive bleeding disorder due to deficiencies in specific clotting factors, leading to impaired blood coagulation.
    • Hemophilia predominantly affects males, while females are typically carriers, though some may experience mild symptoms due to X-chromosome inactivation.
  • Types:
    • Hemophilia A: Caused by a deficiency in factor VIII, accounting for approximately 80% of cases.
    • Hemophilia B (Christmas Disease): Caused by a deficiency in factor IX, representing around 20% of cases.
Genetics and Pathophysiology
  • Inheritance:
    • Hemophilia A and B are X-linked recessive, primarily affecting males. Carrier females have a 50% chance of passing the affected gene to sons (affected) or daughters (carriers).
  • Pathogenesis:
    • Factor VIII (Hemophilia A) and factor IX (Hemophilia B) are intrinsic coagulation factors essential for the activation of factor X, leading to thrombin generation and fibrin clot formation.
    • Deficiency in these factors disrupts the clotting cascade, resulting in impaired clot stability and prolonged bleeding.
Hemophilia pathophysiology
  • Severity:
    • Severe: Factor level <1% of normal, often associated with spontaneous bleeding episodes.
    • Moderate: Factor level 1–5% of normal, with bleeding following mild trauma.
    • Mild: Factor level 5–40% of normal, with bleeding typically only after significant trauma or surgery.
Clinical Presentation
  • Bleeding Sites:
    • Hemarthrosis: Repeated bleeding into joints (e.g., knees, elbows, ankles) is a hallmark of severe hemophilia and leads to joint deformity and hemophilic arthropathy if untreated.
    • Muscle Bleeding: Deep muscle bleeds, especially in the thigh or iliopsoas, may lead to compartment syndrome if left untreated.
    • Mucocutaneous Bleeding: Less common than in von Willebrand disease; may occur in dental procedures or minor nasal trauma.
    • Intracranial Hemorrhage: Rare but life-threatening, often following head trauma.
  • Postoperative or Post-Traumatic Bleeding:
    • Prolonged bleeding after procedures or trauma is common, particularly in mild or moderate cases where hemophilia diagnosis may be delayed.
Diagnosis
  • Laboratory Tests:
    • Complete Blood Count (CBC): Usually normal but may show anemia if there is significant blood loss.
    • Prothrombin Time (PT): Normal, as PT assesses the extrinsic pathway, which is unaffected by factor VIII or IX deficiencies.
    • Activated Partial Thromboplastin Time (aPTT): Prolonged due to deficiency in the intrinsic pathway.
    • Factor Assays: Measurement of factor VIII and IX levels confirms diagnosis and determines disease severity.
  • Genetic Testing:
    • Useful for carrier detection and prenatal diagnosis, especially in families with known hemophilia.
  • Inhibitor Testing:
    • Antibodies (inhibitors) against factor VIII or IX can develop in some patients, particularly those with severe hemophilia A, complicating treatment.
Treatment
  • Factor Replacement Therapy:
    • Factor VIII Concentrate (Hemophilia A) and Factor IX Concentrate (Hemophilia B):
    • On-Demand Therapy: For active bleeding episodes.
    • Prophylactic Therapy: Regular infusions to maintain target factor levels and prevent spontaneous bleeding, especially in severe hemophilia.
    • Dosing: Based on factor deficiency, weight, and specific bleeding situation.
  • Bypassing Agents for Inhibitors:
    • Recombinant Factor VIIa (rFVIIa) and Activated Prothrombin Complex Concentrate (aPCC): Used in patients with high-titer inhibitors to factor VIII or IX.
  • Emicizumab:
    • Mechanism: A bispecific antibody that mimics factor VIII function by bridging factors IXa and X, used for prophylaxis in hemophilia A patients with or without inhibitors.
    • Administration: Subcutaneous injection, generally given weekly or biweekly.
  • Adjunct Therapies:
    • Antifibrinolytics (e.g., tranexamic acid, aminocaproic acid): Useful for mucosal bleeding and dental procedures.
    • Pain Management: Acetaminophen preferred over NSAIDs to avoid platelet inhibition.
Key Points
  • Hemophilia is an X-linked recessive disorder caused by deficiencies in factor VIII (hemophilia A) or factor IX (hemophilia B), primarily affecting males.
  • Disease severity (severe, moderate, mild) is based on factor levels, with severe cases often presenting with spontaneous joint and muscle bleeds.
  • Diagnosis includes prolonged aPTT, specific factor assays, and genetic testing to identify carriers.
  • Management includes on-demand and prophylactic factor replacement, bypassing agents for inhibitor patients, and emicizumab for prophylaxis in hemophilia A.
  • Complications include joint deformities from recurrent hemarthrosis, inhibitor development, and increased bleeding risk with trauma or surgery.

Related Tutorials