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Von Willebrand's Disease for USMLE Step 2

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Overview of von Willebrand’s Disease (vWD) for the USMLE Step 2 Exam
  • Definition:
    • Von Willebrand’s disease (vWD) is the most common inherited bleeding disorder, resulting from quantitative or qualitative defects in von Willebrand factor (vWF).
    • vWF is essential for platelet adhesion at injury sites and for stabilizing factor VIII, a critical clotting factor.
  • Genetics and Pathophysiology:
    • Inheritance: Generally autosomal dominant, with autosomal recessive patterns in more severe forms (e.g., type 3).
    • Von Willebrand Factor (vWF):
    • Produced by endothelial cells and megakaryocytes.
    • Binds to subendothelial collagen and platelets at injury sites, facilitating platelet adhesion.
    • Binds and stabilizes factor VIII to prevent its degradation.
von Willebrand Factor
    • Pathogenesis: Low or dysfunctional vWF disrupts platelet adhesion and reduces factor VIII stability, leading to prolonged bleeding.
Types of von Willebrand’s Disease
  • Type 1 vWD:
    • Characteristics: Partial quantitative deficiency of vWF, affecting 70-80% of patients.
    • Severity: Mild; bleeding occurs with surgery or trauma.
    • Inheritance: Autosomal dominant.
  • Type 2 vWD:
    • Characteristics: Qualitative defect with four subtypes:
    • 2A: Reduced high-molecular-weight multimers, impairing platelet binding.
    • 2B: Enhanced platelet binding and aggregation, leading to platelet clearance.
    • 2M: Reduced platelet binding but normal multimer pattern.
    • 2N: Reduced binding to factor VIII, mimicking hemophilia A.
    • Severity: Mild to moderate, varies by subtype.
    • Inheritance: Mostly autosomal dominant, but 2N is autosomal recessive.
  • Type 3 vWD:
    • Characteristics: Severe quantitative deficiency or absence of vWF.
    • Severity: Severe, with symptoms similar to hemophilia, including joint and muscle bleeding.
    • Inheritance: Autosomal recessive.
Clinical Presentation
  • Symptoms:
    • Mucocutaneous Bleeding: Epistaxis, easy bruising, gingival bleeding, and menorrhagia are common, especially in types 1 and 2.
    • Prolonged Bleeding: After surgeries or dental procedures.
    • Severe Bleeding (Type 3): Includes joint and muscle bleeding.
  • Family History: Frequently positive, especially in type 1 and type 2 patients.
Diagnosis of von Willebrand’s Disease
  • Initial Tests:
    • Complete Blood Count (CBC): Usually normal; anemia may be present if there is significant chronic bleeding.
    • Prothrombin Time (PT): Normal.
    • Activated Partial Thromboplastin Time (aPTT): Often prolonged due to reduced factor VIII.
  • Specialized Coagulation Tests:
    • vWF Antigen (vWF:Ag): Measures vWF quantity; decreased in types 1 and 3, variably reduced in type 2.
    • Ristocetin Cofactor Activity (vWF:RCo): Assesses vWF’s ability to bind platelets; decreased in types 1, 2A, 2B, and 3.
    • Factor VIII Activity: Often low, particularly in type 3.
  • Additional Testing for Subtype Differentiation:
    • vWF Multimer Analysis: Determines the distribution of vWF multimers to help differentiate type 1 from 2A and type 3.
    • Ristocetin-Induced Platelet Aggregation (RIPA): Enhanced aggregation with low-dose ristocetin is specific to type 2B.
    • Factor VIII Binding Assay: Distinguishes type 2N from hemophilia A.
Treatment
  • Desmopressin (DDAVP):
    • Mechanism: Stimulates release of vWF and factor VIII from endothelial stores.
    • Indications: Effective for mild to moderate bleeding in type 1 and some cases of type 2 (2A, 2M).
    • Administration: Intravenous, subcutaneous, or intranasal.
    • Limitations: Not effective in type 3 or type 2B; can cause hyponatremia with repeated doses.
  • vWF-Containing Factor VIII Concentrates:
    • Indications: For patients unresponsive to DDAVP, including type 3 and some type 2 cases.
    • Products: Plasma-derived concentrates (e.g., Humate-P) containing both vWF and factor VIII.
    • Use: Given prophylactically before surgery or during severe bleeding episodes.
  • Antifibrinolytics:
    • Medications: Tranexamic acid and aminocaproic acid, which inhibit clot breakdown.
    • Use: Adjunct for mucosal bleeding and minor surgeries or dental procedures.
  • Hormonal Therapy:
    • Indications: Menorrhagia in women with vWD can be managed with oral contraceptives, intrauterine devices (IUDs) releasing levonorgestrel, or tranexamic acid.
Key Points
  • von Willebrand’s disease is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in vWF.
  • vWD is categorized into three types:
    • Type 1: Partial deficiency of vWF, usually mild.
    • Type 2: Functional defect with specific subtype variations in binding properties and multimer size.
    • Type 3: Severe deficiency or absence of vWF, leading to severe bleeding.
  • Diagnosis includes measuring vWF antigen, ristocetin cofactor activity, and factor VIII levels, with additional tests to differentiate subtypes.
  • Treatment includes DDAVP for mild cases and vWF-containing factor VIII concentrates for severe cases or type 3.
  • Antifibrinolytics and hormonal therapy are adjunct options for mucosal bleeding and menorrhagia.

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