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Von Willebrand's Disease for USMLE Step 1

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Overview of von Willebrand’s Disease (vWD) for the USMLE Step 1
  • Definition:
    • Von Willebrand’s disease (vWD) is the most common inherited bleeding disorder caused by either quantitative or qualitative defects in von Willebrand factor (vWF).
    • vWF plays a crucial role in platelet adhesion to the subendothelium and stabilizes factor VIII, an important clotting factor.
  • Genetics and Pathophysiology:
    • Inheritance: vWD is usually autosomal dominant but may be autosomal recessive in severe cases (e.g., type 3).
    • Von Willebrand Factor (vWF): vWF is produced by endothelial cells and megakaryocytes. It:
    • Binds to platelets, facilitating their adhesion to the vascular wall.
    • Binds to and stabilizes factor VIII, preventing its degradation.
von Willebrand Factor
    • Pathogenesis: Defective or insufficient vWF impairs primary hemostasis, leading to platelet adhesion issues and reduced levels of factor VIII.
Types of von Willebrand’s Disease
  • Type 1 vWD:
    • Characteristics: Partial quantitative deficiency of vWF, seen in 70-80% of vWD cases.
    • Severity: Generally mild; bleeding often occurs with surgery, trauma, or dental work.
    • Inheritance: Autosomal dominant.
  • Type 2 vWD:
    • Characteristics: Qualitative defects in vWF, affecting its function. Subtypes include:
    • 2A: Reduced high-molecular-weight multimers, impairing platelet binding.
    • 2B: Increased affinity of vWF for platelets, causing abnormal aggregation.
    • 2M: Defective binding of vWF to platelets but normal multimer size.
    • 2N: Reduced binding to factor VIII, mimicking hemophilia A.
    • Severity: Variable by subtype, typically mild to moderate.
    • Inheritance: Mostly autosomal dominant; 2N may be 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: Occurs after minor surgeries or dental procedures.
    • Severe Bleeding (Type 3): Includes joint and muscle bleeds similar to hemophilia.
  • Family History: Frequently positive, particularly in types 1 and 2.
Diagnosis of von Willebrand’s Disease
  • Initial Tests:
    • Complete Blood Count (CBC): Typically normal; anemia may be present if chronic bleeding has occurred.
    • Prothrombin Time (PT): Normal.
    • Activated Partial Thromboplastin Time (aPTT): May be prolonged due to factor VIII deficiency.
  • Specialized Coagulation Tests:
    • vWF Antigen (vWF:Ag): Measures vWF quantity; low in types 1 and 3, variable in type 2.
    • Ristocetin Cofactor Activity (vWF:RCo): Tests vWF’s platelet-binding capacity; reduced in types 1, 2A, 2B, and 3.
    • Factor VIII Activity: Often decreased, especially in type 3.
  • Subtype-Specific Testing:
    • vWF Multimer Analysis: Differentiates between type 1, type 2A, and type 3 by examining vWF multimer patterns.
    • Ristocetin-Induced Platelet Aggregation (RIPA): Diagnoses type 2B, which shows increased platelet aggregation with low-dose ristocetin.
    • Factor VIII Binding Assay: Used to differentiate 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 type 2 cases (2A and 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 most type 3 and some type 2 cases.
    • Products: Plasma-derived concentrates containing both vWF and factor VIII (e.g., Humate-P).
    • Use: Given prophylactically before surgery or for severe bleeding episodes.
  • Antifibrinolytics:
    • Medications: Tranexamic acid, aminocaproic acid.
    • Use: Adjunct for mucosal bleeding and for minor surgeries or dental work in combination with DDAVP or factor concentrates.
    • Contraindications: Avoid in patients with hematuria to prevent obstructive clots.
  • Hormonal Therapy for Menorrhagia:
    • Options: Oral contraceptives, intrauterine devices (IUDs) with levonorgestrel, or antifibrinolytics.
Key Points
  • Von Willebrand’s disease is the most common inherited bleeding disorder, typically autosomal dominant, affecting vWF.
  • There are three main types:
    • Type 1: Partial deficiency of vWF, usually mild.
    • Type 2: Qualitative defect with subtypes based on specific functional issues.
    • Type 3: Complete deficiency or absence of vWF, causing severe bleeding.
  • Diagnosis includes vWF antigen, ristocetin cofactor activity, and factor VIII levels, with additional tests like multimer analysis to confirm subtypes.
  • Treatment includes desmopressin (DDAVP) for mild cases and vWF-containing factor VIII concentrates for severe cases or type 3.
  • Antifibrinolytics are useful for mucosal bleeding, and hormonal therapy is effective for menorrhagia in women with vWD.

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