Von Willebrand Disease - vWD

Von Willebrand Disease - vWD

 

von Willebrand disease (vWD) is the most common congenital bleeding disorder in humans.

Epidemiology

  • Incidence
    • 1/100 in the general population
    • Occurrence of types
      • Type 1 – 70%
      • Type 2 – 15-30%
      • Type 3 – rare
  • Gender – F>M
  • Ethnicity – Caucasians have highest risk

Genetics

  • Type 1 –  autosomal dominant with incomplete penetrance (60%)
  • Type 2
    • 2A – autosomal dominant with strong penetrance
    • 2B – autosomal dominant with strong penetrance
    • 2M – X-linked recessive
    • 2N – autosomal dominant with strong penetrance
  • Type 3 – autosomal recessive

Pathophysiology

  • von Willebrand factor antigen (vWF:Ag)
    • An immunologic measure of vWF
    • Decreased in patients with vWD
    • Normal in patients with hemophilia A and in carriers of hemophilia A
  • Defective synthesis or function of the von Willebrand factor (vWF) causes von Willebrand disease
    • von Willebrand ristocetin cofactor (vWD:RCo)
      • Essential for the formation of the hemostatic plug
      • Primarily involved in the adhesion of platelets to the injured vessel wall
      • Acts to stabilize factor VIII
  • Characterized by type of defect
    • Quantitative – types 1, 3
    • Qualitative – type 2

Clinical Presentation

  • Mucocutaneous bleeding (mild to moderate)
    • Epistaxis
    • Hematomas
    • Menorrhagia
    • Gingival bleeding
  • Acquired vWD – associated with same symptoms as congenital
    • Rare – associated with lymphoproliferative disease, myeloproliferative disorders and immunologic disorders

Diagnosis

  • Three main criteria
    • Positive history of bleeding since childhood
    • Reduced levels of vWF activity
    • Autosomal dominant or recessive inheritance patterns
  • Laboratory testing
    • Screening tests – platelet count, bleeding time, PT/PTT
    • von Willebrand panel testing
      • von Willebrand factor antigen decreased
      • Factor VIII activity is somewhat decreased (mild)
      • Ristocetin cofactor activity decreased
    • Identification of vWD type (see table below for laboratory diagnostic testing parameters)
vWD Types Laboratory Diagnostic Testing Parameters
Type 1 Mild to moderately reduced level of vWF
Frequently reduced factor VIII activity
No functional abnormalities
Levels of factor VIII, vWf:AG and vWF:RCo are often decreased to the same relative degree
Type 2 Abnormality in the vWF molecule resulting in abnormal structure and function (qualitative defects)
Type 2A Decreased platelet dependent function due to the absence of high molecular weight multimers of vWF
The vWF:RCo result is often disproportionately low compared to the vWF:Ag (low vWD:RCo to vWF:Ag ratio)
Type 2B Increased affinity for platelet glycoprotein GPIb
Demonstrated by an enhanced platelet response to ristocetin and the absence of large vWF multimers
vWF:AG, vWF:RCo and factor VIII are variable and may be within normal limits
Some patients with this defect have chronic thrombocytopenia and circulating platelet aggregates due to spontaneous aggregation
Type 2M Decreased vWF-dependent platelet function is not caused by the absence of high molecular weight multimers
The vWF:RCo level may be disproportionately low compared to the vWF:Ag level
Type 2N Abnormally low affinity of vWF for factor VIII
Most patients described have both type 1 vWD and the factor VIII binding defect resulting in decreased vWF:Ag and vWF:RCo, normal multimers and a disproportionately low factor VIII level compared to the vWF level
Patients with the type 2N defect alone may resemble patients with hemophilia
Type 3 Severe form of vWD in which levels of vWF are severely reduced or absent, factor VIII is markedly decreased and all multimers are absent

Treatment

  • Desmopressin – mild to moderate cases of types 1 and 2 disease
  • Replacement therapy with concentrates (vWF and factor VIII) – type 3 disease and only severe cases of types 1 and 2 disease
  • In acquired vWD – treat underlying disorder

Click here for Flowchart Proposed for the Diagnosis of Different von Willebrand Disease Types


See Also