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Von Willebrand's Disease for the ABIM

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Overview of von Willebrand’s Disease (vWD)
  • Definition:
    • Von Willebrand’s disease (vWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (vWF), a glycoprotein essential for platelet adhesion and stabilization of factor VIII.
    • vWD presents with mucocutaneous bleeding and varies in severity.
  • Genetics and Pathophysiology:
    • Inheritance: vWD is usually autosomal dominant, though some subtypes are autosomal recessive.
    • Von Willebrand Factor (vWF): vWF is produced by endothelial cells and megakaryocytes. It plays two primary roles:
    • Mediates platelet adhesion to subendothelial collagen at the site of vascular injury.
    • Stabilizes and protects factor VIII from degradation.
von Willebrand Factor
    • Pathogenesis: Deficiency or dysfunction of vWF impairs platelet adhesion and aggregation and reduces factor VIII levels, leading to prolonged bleeding.
Classification of von Willebrand’s Disease
  • Type 1 vWD:
    • Description: Partial quantitative deficiency of vWF, accounting for 70-80% of cases.
    • Pathophysiology: Reduced production of vWF with normal function.
    • Severity: Usually mild to moderate bleeding tendency.
    • Inheritance: Autosomal dominant.
  • Type 2 vWD:
    • Description: Qualitative defect in vWF, with several subtypes (2A, 2B, 2M, and 2N) based on specific functional abnormalities.
    • Pathophysiology:
    • Type 2A: Decreased high-molecular-weight vWF multimers, reducing platelet binding.
    • Type 2B: Increased affinity of vWF for platelet GPIb, leading to abnormal platelet aggregation and clearance.
    • Type 2M: Defective binding of vWF to platelets but normal multimer distribution.
    • Type 2N: Reduced binding of vWF to factor VIII, resembling hemophilia A.
    • Severity: Varies by subtype, often mild to moderate.
    • Inheritance: Primarily autosomal dominant, but 2N can be autosomal recessive.
  • Type 3 vWD:
    • Description: Severe quantitative deficiency or absence of vWF, the rarest and most severe type.
    • Pathophysiology: Minimal or undetectable levels of vWF and factor VIII.
    • Severity: Severe bleeding similar to hemophilia A, including joint and muscle bleeds.
    • Inheritance: Autosomal recessive.
Clinical Presentation
  • Symptoms:
    • Mucocutaneous Bleeding: Epistaxis, easy bruising, gingival bleeding, and menorrhagia are common in mild to moderate vWD.
    • Prolonged Bleeding: Bleeding after surgery, dental procedures, or trauma.
    • Severe Bleeding (Type 3): Similar to hemophilia, with hemarthrosis and deep muscle bleeding in the absence of trauma.
  • Family History: Often positive for bleeding disorders, especially in Type 1 and Type 2 vWD due to autosomal dominant inheritance.
Diagnosis of von Willebrand’s Disease
  • Initial Laboratory Tests:
    • Complete Blood Count (CBC): Usually normal; may show mild anemia if chronic bleeding is present.
    • Prothrombin Time (PT): Normal.
    • Activated Partial Thromboplastin Time (aPTT): Often prolonged in severe vWD due to low factor VIII.
  • Specialized Coagulation Tests:
    • vWF Antigen (vWF:Ag): Measures the quantity of vWF; low in types 1 and 3, variably reduced in type 2.
    • Ristocetin Cofactor Activity (vWF:RCo): Measures vWF function by assessing its ability to bind platelets in the presence of ristocetin; decreased in types 1, 2A, 2B, and 3.
    • Factor VIII Activity: Reduced in all types of vWD, particularly in type 3.
  • Additional Tests for Subtype Differentiation:
    • vWF Multimer Analysis: Identifies patterns of vWF multimers to distinguish between type 1, type 2A, and type 3.
    • Ristocetin-Induced Platelet Aggregation (RIPA): Used to diagnose type 2B, which shows enhanced platelet aggregation at low ristocetin concentrations.
    • vWF:Factor VIII Binding Assay: Differentiates type 2N from hemophilia A by measuring vWF’s binding capacity to factor VIII.
Management of von Willebrand’s Disease
  • General Management:
    • Avoid antiplatelet medications (e.g., aspirin, NSAIDs) that can exacerbate bleeding.
    • Ensure close monitoring during surgical or dental procedures and consider prophylactic therapy.
  • Desmopressin (DDAVP):
    • Mechanism: Stimulates endothelial release of vWF and factor VIII.
    • Indications: Effective for mild to moderate bleeding in type 1 and some type 2 (2A, 2M) vWD cases.
    • Administration: Intravenous, subcutaneous, or intranasal routes.
    • Limitations: Not effective in type 3 or type 2B; may cause hyponatremia with repeated doses, especially in young children and the elderly.
  • vWF-Containing Factor VIII Concentrates:
    • Indications: For patients unresponsive to DDAVP, including most type 3 and some type 2 vWD cases.
    • Products: Plasma-derived vWF/factor VIII concentrates (e.g., Humate-P, Alphanate) provide both vWF and factor VIII.
    • Dosing: Based on the type and severity of bleeding; prophylaxis may be necessary for major surgery or severe bleeding episodes.
  • Antifibrinolytics:
    • Medications: Tranexamic acid and aminocaproic acid inhibit fibrinolysis, stabilizing clots.
    • Use: Adjunct therapy for mucosal bleeding or in conjunction with DDAVP or factor concentrates for surgery and dental procedures.
    • Contraindications: Avoid in patients with hematuria due to risk of obstructive clots in the urinary tract.
  • Hormonal Therapy:
    • Indication: Menorrhagia in women with vWD can be managed with oral contraceptives, intrauterine devices (IUDs) releasing levonorgestrel, or tranexamic acid during menstruation.
  • Gene Therapy (Investigational):
    • Experimental approaches are under investigation for severe vWD, though not yet available in clinical practice.
Prognosis and Complications
  • Prognosis:
    • Patients with mild to moderate vWD generally have a good prognosis with appropriate management.
    • Severe vWD (type 3) may require ongoing prophylaxis to prevent severe bleeding, similar to hemophilia.
  • Complications:
    • Bleeding Complications: Potential for significant bleeding with trauma, surgery, or in severe types.
    • Hyponatremia: Risk with repeated DDAVP administration due to water retention.
    • Development of Inhibitors: Rarely, patients receiving vWF concentrates may develop antibodies against vWF, complicating management.
Key Points
  • von Willebrand’s disease is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in vWF.
  • vWD is classified into three main types:
    • Type 1: Partial quantitative deficiency of vWF, with generally mild symptoms.
    • Type 2: Qualitative defects in vWF, with subtypes (2A, 2B, 2M, 2N) based on functional abnormalities.
    • Type 3: Severe deficiency or absence of vWF, associated with severe bleeding.
  • Diagnostic tests include vWF antigen, ristocetin cofactor activity, factor VIII levels, and multimer analysis to differentiate subtypes.
  • Treatment options include DDAVP for mild cases, vWF-containing factor VIII concentrates for severe cases, and antifibrinolytics as adjunct therapy.
  • Monitoring and prophylaxis are essential in major surgical or high-risk bleeding scenarios, especially in severe cases.

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