Von Willebrand’s Disease – Symptoms, Diagnosis And Treatment

Von Willebrand’s Disease

Von Willebrand’s disease is an autosomal dominant bleeding disorder, resulting from a quantitative (Von Willebrand’s disease type 1 and Von Willebrand’s Disease type 3) or qualitative (Von Willebrand’s disease type 2) abnormality of von Willebrand factor, a plasma protein secreted by endothelial cells that circulates in plasma in multimers of up to 20 million daltons.

Von Willebrand factor has two hemostatic functions:

• Very large von Willebrand factor multimers are required for platelets to adhere normally to subendothelium  at sites of vessel wall injury.
• Multimers of all sizes form complexes in plasma with factor VIII of coagulation, which are required to maintain normal plasma factor VIII levels.

Therefore, two hereditary disorders  may cause  factor VIII deficiency:

1. Hemophilia A, in which the factor VIII molecule is not synthesized in normal amounts or is synthesized abnormally.
2. Von Willebrand’s Disease, in which von Willbrand factor molecule is not synthesized in normal amounts or is synthesized abnormally.

Von Willebrand’s Disease

Von Willebrand’s Disease Symptoms

Von Willebrand’s disease affects both sexes, patients typically have a positive maternal or paternal history. Bleeding manifestations are mild to moderate and include easy bruising, bleeding from small skin cuts that may stop and start over hours, increased menstrual bleeding (in women) and some abnormal bleeding after surgical procedures (tooth extraction, tonsillectomy). Screening coagulation tests reveal a long bleeding time and sometimes a slightly prolonged partial thromboplastin time, reflecting a moderately reduced plasma factor VIII level.

Vasoactive stimuli induced by stress or exercise may temporarily elevate plasma von Willebrand factor through release of endothelial store.  Hormonal changes associated with stress or pregnancy and an acute phase response to inflammation  or infection increase synthesis of von Willebrand factor, thus elevating von Willebrand factor in plasma. In persons with mild Von Willebrand’s disease, plasma level varation may cause screening tests to be normal on some occasion and abnormal on other occasions, making diagnosis difficult.

Von Willebrand’s Disease Diagnosis

Definitive diagnosis requires:

• Total plasma von Willebrand factor antigen.
• Von Willebrand factor function, as determined by the ability of plasma to support agglutination of normal plates by ristocetin (ristocetin cofactor activity)
• Plasma factor VIII level.

In patients with common type 1 form of Von Wiellebrand’s disease results are concordant, von Wiellbeand factor antigen, von Wiellebrand factor function and plasma factor VIII level are equally depressed. The degree of depression varies from about 15% to 60%  of normal and determines the severity of a patient’s abnormal bleeding. Healthy persons with blood grup 0 also have reduced von Wiellebrand factor antigens levels (normal values from 60% down to 40%).

Von Willebrand’s Disease

Patients with type 2 Von Wiellebrand’s disease, synthesize abnormal von Wiellebrand factor molecules, resulting in selective deficiency  of vary large multimers of von Wiellebrand factor (types 2A and 2B) or in molecules that cannot bind coagulation factor VIII (type 2N). The type 2A and 2B variants are suspected when the rsults of test for von Wiellebrand factor antigen do not correspond with those of a screening test of agglutination of the patient’s plasma with different  concentrations of ristocetin.  Diagnosis is confirmed by demonstrating a reduced concentration of large von Wiellebrand factor multimers on agarose gel electrophoresis. The type 2N variant is clinically similar to mild hemophilia A , but the inheritance is autosomal recessive.

Von Willebrand’s Disease Treatment

Replacement of von Wiellebrand factor by infusion of cryoprecipitate controls or prevents bleeding in type 1 or type 2 Von Wiellebrand’s disease.

A pasteurized intermediate – purity factor VIII concentrate contain large multimers of von Wiellebrand factor and has not been found to transmit HIV infection or hepatitis. Therefore, it is a safe alternative to cryoprecipitate. Other intermediate – purity factor VIII concentrates are a less reliable source of von Wiellebrand factor when Humate – P, a pasteurized product, is unavailable.

Desmopressin is a analog of vasopressin that stimulates release into the plasma of von Wiellebrand factor stored within the Weibel – Palade bodies of endothelial cells. Desmopressin is important in type 1 of Von Wiellebrand’s disease but is usally of no value for type 2 Von Wiellebrand’s disease.

Epsilon – Aminocaproic acid or tranexamic acid should be also be given to suppress fibrinolysis.