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At a glance

A hereditary family of blood-clotting disorders caused by a deficiency of the von Willebrand factor protein and factor VIII protein, and characterized by prolonged bleeding.

Synonyms

Pseudohemophilia; Angiohemophilia; Constitutional Thrombopathy; Minot-Von Willebrand Disease; Vascular Hemophilia; Willebrand-Jürgens Disease.

Incidence

Prevalence worldwide is estimated at 1%. Acquired forms are much rarer.

Genetic inheritance

Autosomal dominant or recessive inheritance. Mutation of the von Willebrand Factor gene on 12p13.3 located on chromosome 12. Although a rare, acquired form exists.

Pathophysiology

von Willebrand disease is the most common inherited bleeding disorder in humans, and is secondary to abnormalities of von Willebrand factor (vWF). There are three main types and several subtypes.

Diagnosis

Mucocutaneous bleeding with normal platelet count, elevated bleeding time, decreased ristocetin cofactor activity (ristocetin is an antibiotic that alters normal vWF structure, causing platelet aggregation), decreased vWF antigen (can be normal in Type II), decreased factor VIII activity; gel electrophoresis to determine vWF structure.

Clinical aspects

There are several subtypes.

  • Type I: Characterized by a partial quantitative defect with normal structure, comprises 70% of cases, and has mild to moderate bleeding; it is autosomal dominant.

  • Type II: Affected individuals present both qualitative and quantitative defects.

    • Type IIA: Accounts for 10% of cases. Characterized by mild to moderate bleeding and a poor response to desmopressin acetate.

    • Type IIB: Represents less then 5% of cases. Characterized by mild to moderate bleeding, thrombocytopenia, and a contraindication to desmopressin acetate.

    • Type IIM: Reportable only. Clinically caused by a variable bleeding disorder and associated with decreased vWF:Ag, vWF activity, and factor VII:C.

    • Type IIN: Reportable only. Autosomal recessive trait. Characterized by variable bleeding disorder that may resemble hemophilia A.

  • Type III: Severe and rare form. Possibly transmitted as autosomal recessive trait. Affected individuals present a complete deficiency of vWF. Acquired von Willebrand Disease is associated with myeloproliferative disease, hypothyroidism, B-cell disorders, and cardiovascular defects, resembles Type I or II, and has decreased plasma vWF antigen and normal platelet vWF antigen.

Treatment: The treatment options are either to increase circulating concentrations or the activity of vWF (Types I, IIa; contraindicated in case of Type IIb) or to replace vWF (IIb, IIm, IIn, and III types) in addition to decrease fibrinolysis.

Desmopressin acetate, which increases the release of vWF, has a favorable response in 80% of Type I patients. The response in Type II diseases is variable, because an increased release of qualitatively poor vWF is not useful for platelet binding. Desmopressin acetate may be contraindicated in Type IIB, because platelet aggregation may exacerbate thrombocytopenia, but this is controversial. Estrogen may also increase production of vWF. Replacement therapy, for failures or contraindications to desmopressin acetate, was formerly with cryoprecipitate. ...

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