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The Clinical Manifestations And Treatment Of Von Willebrand’s Disease (Pseudohemophilia)

Updated on February 4, 2014

Von Willebrand’s disease

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Clinical Manifestations

Von Willebrand’s disease (vWD) is a primary vascular hemostatic defect, transmitted as an autosomal dominant, affecting both sexes. Next to hemophilia, this is the most frequent inherited hemostatic defect. The basic defect is reduction of the amount of subendothelial factor VIII: vWF polymers or the presence of abnormal or inadequately polymerized subendothelial factor VIII:vWF. Normal vWF contains multimers of varying molecular sizes ranging from 850,000 to 12 million Daltons. The defective factor VIII:vWF leads to impairment of platelet adhesion to sites of vascular injury. Depending on the genetic defect, the disease has been divided into three types.

  1. Type I (or classic disease): Decreased release of factor VIII:vWF from endothelial cell. This is the common form.
  2. Type II A: Defective endothelial cell polymerization of factor VIII:vWF sub-units.
  3. Type II B: Abnormal synthesis of factor VIII:vWF polymers by endothelial cells.

Clinical features

These are similar to that of ITP, i.e excessive post-traumatic bleeding, menorrhagia and mucosal bleeding, especially from the nose, gums, gastrointestinal tract and genitourinary tract. Bleeding time is prolonged. Platelet counts are norla in Types I and II A, but may be moderately decreased in IIB. In those with factor VIII:C levels below 1% of normal, manifestations of a coagulation defect may also be prominent. Bleeding manifestations are most marked in homozygous type IIA vWD which is rare.

Diagnosis of the specific defect of factor VIII:vWF is made by electrophoresis. Another in vitro test is to determine the capacity of plasma to aggregate platelets in the presence of the antibiotic-ristocetin. Ristocetin partially neutralizes negative charges on platelet surfaces and thus enables the negatively charged factor VIII: vWF polymers to induce platelet aggregation. This phenomenon is called ristocetin cofactor activity. Ristocetin cofactor activity is diminished in types I and II A disease.

In patients with type I and IIA vWD, the diminution of ristocetin cofactor activity correlates with the defective platelet adhesion to subendothelium in vitro. But in type II B disease, this is not so. In type II B, the factor VIII: vWF polymers are abnormally formed and these are incapable of inducing platelets to adhere to vascular endothelium. But even in the presence of small amounts of ristocetin, these abnormal polymers present in platelet poor plasma attach to platelets and induce aggregation in vitro.

In homozygous type II A vWD, patients with severe bleeding tendency, endothelial polymerization of factor VIII: vWF monomers is defective and only small factor VIII: vWF polymers are present in plasma. In these patients, bleeding time is prolonged and plasma levels of factor VIII: vWF antigen, ristocetin cofactor activity, and factor VIII:C are extremely low. The majority of cases of vWD being heterozygous, have only mild bleeding tendency.

Factor VIII:C is also reduced in the plasma of majority of patients with vWD. Unlike hemophilia in which the synthesis of factor VIII:C is diminished, in vWD, though factor VIII:C is synthesized, it is not transported effectively in the systemic circulation without adequate levels of polymerized factor VIII: vWF. Further, factor VIII:C molecules which enter the circulation unbound to VIII”vWF polymers are rapidly removed.

Treating Von Willebrand’s disease

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Treatment

Cryoprecipitate infusions arrest bleeding promptly and these are employed to arrest bleeding episodes and to prepare the patient for surgery. The largest factor VIII:vWF polymers in the cryoprecipitate get deposited on the injured subendothelial surface and this favours platelet adhesion and hemostasis. The therapeutic effect lasts only for 4 hours and hence cryoprecipitate has to be repeated. Lyophilised factor VIII preparations are not as effective as cryoprecipitate as they do not contain the largest plasma factor VIII:vWF polymer forms.

In type I vWD where synthesis of factor VIII:vWF within the endothelial cells is normal, infusion of deamino-8-D arginine vasopression (DDAVP) causes release of VIII:vWF polymers from endothelial cells- DDAVP attaches itself to vasopressin receptors on the endothelial cells and helps in releasing factor VIII:vWF polymers. In heterozygous type IIA and IIB and homozygous type II A vWD, DDAVP is not very effective.

© 2014 Funom Theophilus Makama

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