Von Willebrand Disease

Epidemiology

  • Prevalence: occurs in 1 in 800-1000 persons

Etiology

Inherited Von Willebrand Disease

  • Type 1 (75% of all Von Willebrand Disease cases): autosomal dominant (with incomplete penetrance)
  • Type 2A (10-15% of all Von Willebrand Disease cases): autosomal dominant (usually)
  • Type 2B: autosomal dominant
  • Type 2M: autosomal dominant (usually)
  • Type 2N: autosomal recessive (usually)
  • Type 3: autosomal recessive or dominant
  • Platelet-Type: autosomal dominant

Acquired Von Willebrand Disease

Autoimmune Disease

  • Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome): antibodies against VWF
  • Scleroderma (see Scleroderma): antibodies against VWF
  • Systemic Lupus Erythematosus (SLE)s (see Systemic Lupus Erythematosus): antibodies against VWF (higher MW multimers appear to be more susceptible to degradation by this mechanism)
  • Other Autoimmune Disease: antibodies against VWF

Drugs

  • Ciprofloxacin (see Ciprofloxacin)
  • Dextran (see Dextran): branched polysaccharides of 40 or 70 kDa which inhibit platelet factor-3 availability, adsorb to platelets, and decrease plasma factor VIII-VWF -> inhibit platelet aggregation + secretion
  • Griseofulvin (see Griseofulvin)
  • Hydroxyethyl Starch (Hetastarch) (see Hydroxyethyl Starch)
  • Thrombolytics (see Thrombolytics): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
  • Valproic Acid (see Valproic Acid)

High Intravascular Shear Forces

  • Aortic Stenosis (AS) (see Aortic Stenosis): high intravascular shear forces -> increased clearance of high MW multimers
    • Heyde’s Syndrome (Constellation of Aortic Stenosis and Gastrointestinal Angiodysplasia): high intravascular shear forces across stenotic aortic valve leads to increased clearance of high MW multimers, possibly due to increased susceptibility to serum proteases
    • Resolves with Aortic Valve Replacement
  • Extracorporeal Membrane Oxygenation (ECMO)
  • Hypertrophic Cardiomyopathy (see Hypertrophic Cardiomyopathy): high intravascular shear forces -> increased clearance of high MW multimers
  • Mitral Valve Replacement: high intravascular shear forces (due to paravalvular leak) -> increased clearance of high MW multimers
  • Mitral Valve Prolapse (see Mitral Valve Prolapse): high intravascular shear forces -> increased clearance of high MW multimers
  • Ventricular Assist Device (VAD) (see Cardiac Assist Devices): high intravascular shear forces -> increased clearance of high MW multimers
  • Ventricular Septal Defect (VSD) (see Ventricular Septal Defect): high intravascular shear forces -> increased clearance of high MW multimers

Malignant/Hematologic Disease

Other

  • Acute Pancreatitis (see Acute Pancreatitis)
    • Physiology: due to hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
  • End-Stage Liver Disease (ESLD) (see End-Stage Liver Disease)
    • Physiology: due to hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
  • Gastrointestinal Angiodysplasia (see Gastrointestinal Angiodysplasia)
    • Heyde’s Syndrome (constellation of aortic stenosis + gastrointestinal angiodysplasia): high intravascular shear forces across stenotic aortic valve leads to increased clearance of high MW multimers, possibly due to increased susceptibility to serum proteases
  • Hemoglobinopathies
  • Hypothyroidism (see Hypothyroidism)
    • Physiology: due to decreased synthesis of VWF
  • Post-Multiple Transfusions
    • Physiology: due to development of antibodies against VWF
  • Uremia

Physiology

Background

  • Von Willebrand Factor (vWF) are Long Stringlike Molecules Synthesized by Vascular Endothelial Cells and Megakaryocytes
    • vWF is Synthesized as a Single VWF Precursor: cleavage and assembly into disulfide-linked multimers occurs in plasma
    • VWF Activity is Distributed Among a Series of Plasma Multimers: ranging in size from MW 400k-20 million
    • Modest Reduction in Plasma VWF Concentration OR Selective Loss of One of the High Molecular Weight Multimers Results in Decreased Platelet Adhesion and Clinical Bleeding
  • Locations of Von Willebrand Factor
    • VWF Circulates as a Series of Multimers Formed from a Basic Dimer Subunit
    • Ultralarge Von Willebrand Factor Multimers Attach to the Endothelial Surface
  • Von Willebrand Factor Binds to the Platelet GP1b Receptor
    • Platelet Shape Change (with Increased Platelet Surface Area)
    • Platelet Granule Release of Procoagulant Molecules (from Alpha Granules) and Cofactors (from Dense Granules)
    • Receptor Activation and Expression
  • Functions of Von Willebrand Factor in Primary Hemostasis
    • VWF Forms an Adhesive Bridge Between Platelets and Exposed Vascular Subendothelial Basement Membrane
    • VWF Forms an Adhesive Bridge Between Adjacent Platelets at Sites of Endothelial Injury
    • VWF is the Plasma Carrier Protein for Factor VIII While it is Inactive in the Circulation: factor VIII degrades rapidly when not bound to vWF

Diagnosis

  • INR: prolonged with deficiency of factor VII and common pathway factors (fibrinogen, II, V, and X)
  • PTT: prolonged with deficiency/inhbitors of factors VIII, IX, XI, XII, as well as common pathway factors
    • However, PTT is less sensitive for deficiency/inhbitors of common pathway factors -> this is why vitamin K deficiency (with decreased factors II, VII, IX, X) prolongs INR more than PTT
  • Thrombin Time: measures how fast given amount of thrombin turns fibrinogen into fibrin -> therefore, is designed to detect quantitative or qualitative problems with fibrin
    • Can be prolonged by high levels of fibrin degradation products
    • Very sensitive to heparin
  • Reptilase Time: used to determine if prolonged thrombin time is due to heparin
    • Insensitive to heparin
  • 1:1 Mix: mix control plasma (with 100% activity of each factor) + patient plasma to determine if a factor deficiency vs inhibitor is present
    • As factor levels of 50% or higher are sufficient for a normal INR/PTT, 1:1 mix will correct INR/PTT in presence of a factor deficiences, but not in presence of a factor inhibitor
  • PTT with Polybrene or Heparinase:used to neutralize heparin in the sample to determine if prolonged PTT is due to heparin
  • PTT with Excess Phospholipid: used to detect presence of anti-phospholipid antibody (lupus anticoagulant, etc)
  • Bleeding Time: assesses for platelets defects (relatively insensitive for factor deficiencies or inhibitors)
  • Platelet Function Analysis (PFA): essentially an in vitro bleeding time assay which assesses different components of platelet activation (in response to ADP, epinephrine, collagen)
  • Von Willebrand Factor Antigen: quanitifies the amount of Von Willebrand factor -> decreased in Von Willebrand Disease
    • Normal Level of VWF: 10 mg/L
  • Ristocetin Cofactor Test: evaluates function of Von Willebrand factor by testing ristocetin-induced platelet aggregation of normal platelets in presence of patient’s plasma
    • Most sensitive and specific test for Von Willebrand disease -> decreased in all types of Von Willebrand disease
    • Assesses the binding of Von Willebrand factor to platelet GP1b
  • Ristocetin-Induced Platelet Aggregation (RIPA): evaluates function of Von Willebrand factor by testing ristocetin-induced platelet aggregation of patient’s platelets in presence of patient’s plasma
    • Less sensitive and specific than ristocetin cofactor test
    • Usually decreased in Von Willebrand disease, but may be normal in some cases
    • In type IIB Von Willebrand disease: platelets are hyperresponive to ristocetin (platelets aggregate in response to abnormally low ristocetin concentration)
  • Factor VIII Activity/Level (factor VIII activity assay is performed -> level is inferred from activity): decreased in factor VIII deficiency and Von Willebrand disease
    • Von Willebrand factor normally carries factor VIII (this prolongs factor VIII half-life) -> therefore, if Von Willebrand factor binding of factor VIII is impaired or Von Willebrand factor is low, then, factor VIII level is low
  • Stepwise Evaluation of Coagulopathy
    • Step 1 (assessment for platelet problem): platelet count, PFA
    • Step 2 (assessment for single factor deficiency): INR/PTT, factor assays
    • Step 3 (assessment for multiple factor deficiency): INR/PTT, thrombin time, factor assays
    • Step 4 (assessment for circulating anticoagulant): PTT with polybrene or heparinase, PTT with 1:1 mix, PTT with excess phospholipid, thrombin time

Clinical Features


Treatment

Inherited Von Willebrand Disease

  • Desmopressin (DDAVP) (see Desmopressin
    • Indications:
    • Contraindications: type 2B (may cause thrombocytopenia)
    • Administration: IV
    • Adverse Effects:
  • Cryoprecipitate (see Cryoprecipitate): contains concentrated fibrinogen, vWF, factor VIII, and factor XIII
    • Administration: IV
    • Adverse Effects: transmission of infection
  • Factor VIII + VWF Factor Complex (Humate-P) (see Factor VIII + Von Willebrand Factor Complex)
    • Indications:
    • Administration:
    • Adverse Effects:
  • Premarin (see Estrogen)
    • Administration:
    • Adverse Effects:
  • Anti-Fibrinolytic Agents (see Anti-Fibrinolytics)

Acquired Von Willebrand Disease

  • DDAVP and Plasma Derivatives are Often Not Effective: therapy should focus on treating the primary etiology

References

  • High dose of tranexamic acid for treatment of severe menorrhagia in patients with von Willebrand disease. J Thromb Thrombolysis. 2002 Dec;14(3):255-7
  • Acquired and Reversible von Willebrand Disease With High Shear Stress Aortic Valve Stenosis. Ann Thorac Surg 2006;81:490-494
  • Acquired von Willebrand Syndrome After Continuous-Flow Mechanical Device Support Contributes to a High Prevalence of Bleeding During Long-Term Support and at the Time of Transplantation. J Am Coll Cardiol, 2010; 56:1207-1213