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Von Willebrand's Disease for USMLE Step 3

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Overview of von Willebrand’s Disease (vWD) for the USMLE Step 3 Exam
  • Definition:
    • Von Willebrand’s disease (vWD) is the most common inherited bleeding disorder, due to a quantitative or qualitative defect in von Willebrand factor (vWF).
    • vWF is essential for platelet adhesion at injury sites and stabilizes factor VIII, a critical clotting factor.
  • Genetics and Pathophysiology:
    • Inheritance: Primarily autosomal dominant, with autosomal recessive inheritance in severe cases (e.g., type 3).
    • Von Willebrand Factor (vWF):
    • Produced by endothelial cells and megakaryocytes.
    • Binds to platelets and subendothelial collagen at sites of injury, facilitating platelet adhesion.
    • Binds and stabilizes factor VIII, preventing degradation and ensuring clot formation.
von Willebrand Factor
    • Pathogenesis: Defective or insufficient vWF disrupts platelet adhesion and reduces factor VIII stability, causing prolonged bleeding times.
Types of von Willebrand’s Disease
  • Type 1 vWD:
    • Characteristics: Partial quantitative deficiency of vWF, representing 70-80% of cases.
    • Severity: Generally mild, with bleeding typically occurring with surgery or trauma.
    • Inheritance: Autosomal dominant.
  • Type 2 vWD:
    • Characteristics: Qualitative defect with functional abnormalities, classified into subtypes:
    • 2A: Loss of high-molecular-weight multimers, impairing platelet binding.
    • 2B: Increased affinity for platelets, causing abnormal platelet aggregation and clearance.
    • 2M: Reduced platelet binding with normal multimer distribution.
    • 2N: Reduced binding to factor VIII, clinically resembling hemophilia A.
    • Severity: Variable, from mild to moderate depending on subtype.
    • Inheritance: Mostly autosomal dominant, except for 2N (autosomal recessive).
  • Type 3 vWD:
    • Characteristics: Severe quantitative deficiency or absence of vWF.
    • Severity: Severe, with bleeding manifestations similar to hemophilia, including joint and muscle bleeding.
    • Inheritance: Autosomal recessive.
Clinical Presentation
  • Symptoms:
    • Mucocutaneous Bleeding: Common in types 1 and 2, with epistaxis, gingival bleeding, easy bruising, and menorrhagia.
    • Prolonged Bleeding: After surgical procedures or dental work.
    • Severe Bleeding (Type 3): Similar to hemophilia, including spontaneous joint and muscle bleeds.
  • Family History: Often positive, particularly in types 1 and 2.
Diagnosis of von Willebrand’s Disease
  • Initial Tests:
    • Complete Blood Count (CBC): Usually normal, though anemia may be present if bleeding is chronic.
    • Prothrombin Time (PT): Normal.
    • Activated Partial Thromboplastin Time (aPTT): May be prolonged, especially in type 3, due to low factor VIII levels.
  • Specialized Coagulation Tests:
    • vWF Antigen (vWF:Ag): Measures the amount of vWF; reduced in types 1 and 3, variably reduced in type 2.
    • Ristocetin Cofactor Activity (vWF:RCo): Assesses vWF function by evaluating platelet binding; decreased in types 1, 2A, 2B, and 3.
    • Factor VIII Activity: Reduced in all types of vWD, particularly low in type 3.
  • Additional Testing for Subtype Differentiation:
    • vWF Multimer Analysis: Identifies patterns of vWF multimers, useful in distinguishing type 1, type 2A, and type 3.
    • Ristocetin-Induced Platelet Aggregation (RIPA): Enhanced aggregation at low-dose ristocetin suggests type 2B.
    • Factor VIII Binding Assay: Differentiates type 2N from hemophilia A by testing vWF’s ability to bind factor VIII.
Treatment
  • Desmopressin (DDAVP):
    • Mechanism: Stimulates endothelial release of stored vWF and factor VIII.
    • Indications: Effective in mild to moderate type 1 and certain type 2 (2A, 2M) cases.
    • Administration: Intravenous, subcutaneous, or intranasal.
    • Limitations: Not effective in type 3 or type 2B; may cause hyponatremia if used repeatedly.
  • vWF-Containing Factor VIII Concentrates:
    • Indications: For patients unresponsive to DDAVP, including type 3 and some cases of type 2.
    • Products: Plasma-derived concentrates (e.g., Humate-P) containing both vWF and factor VIII.
    • Use: Given prophylactically before surgery or for severe bleeding episodes.
  • Antifibrinolytics:
    • Medications: Tranexamic acid, aminocaproic acid.
    • Use: Adjunct treatment for mucosal bleeding and minor surgical procedures.
  • Hormonal Therapy for Menorrhagia:
    • Options: Oral contraceptives, levonorgestrel-releasing IUDs, or tranexamic acid.
Key Points
  • Von Willebrand’s disease is the most common inherited bleeding disorder, typically autosomal dominant, caused by quantitative or qualitative defects in vWF.
  • vWD has three types:
    • Type 1: Partial deficiency of vWF, generally mild.
    • Type 2: Functional defect with subtypes affecting platelet adhesion and multimer size.
    • Type 3: Complete deficiency or absence of vWF, leading to severe bleeding.
  • Diagnosis includes vWF antigen levels, ristocetin cofactor activity, factor VIII, and multimer analysis to distinguish subtypes.
  • Treatment includes DDAVP for mild cases, with vWF-containing factor VIII concentrates for severe cases or type 3.
  • Antifibrinolytics and hormonal therapy are adjunct options for managing mucosal bleeding and menorrhagia.

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