Willebrand's disease in adults

Von Willebrand disease is a congenital deficiency of von Willebrand factor (VWF) that results in platelet dysfunction.

Typically characterized by mild bleeding. Screening shows prolonged bleeding time, normal platelet count, and possibly a slight increase in partial thromboplastin time. Diagnosis is based on low von Willebrand factor antigen levels and abnormal ristocetin cofactor activity. Treatment involves control of bleeding with replacement therapy (cryoprecipitate or intermediate-purity factor VIII concentrate) or desmopressin.

Causes of von Willebrand disease

Von Willebrand factor (VWF) is synthesized and secreted by the vascular endothelium in the perivascular matrix. VWF facilitates the adhesive phase of hemostasis by binding to a receptor on the platelet surface (glycoprotein Ib-IX) that binds platelets to the vascular wall. VWF is also necessary to maintain normal plasma levels of factor VIII. VWF levels may temporarily increase in response to stress, physical activity, pregnancy, inflammation, or infection.

Von Willebrand disease (VWD) involves a quantitative (types 1 and 3) or qualitative (type 2) defect in the synthesis of von Willebrand factor. Type 2 VWD may result from a variety of genetic abnormalities. VWD is inherited in an autosomal dominant pattern. Although VWD, like hemophilia A, is an inherited disorder and can cause factor VIII deficiency, the deficiency is usually mild.

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Symptoms of von Willebrand disease

Bleeding manifestations in von Willebrand disease are mild to moderate and include a tendency to bleed under the skin; persistent bleeding from small cuts in the skin that may stop and then resume after a few hours; occasional prolonged menstrual bleeding; and abnormal bleeding after surgical procedures (eg, tooth extraction, tonsillectomy).

Diagnosis of von Willebrand disease

Von Willebrand disease is suspected in patients with bleeding disorders, especially those with a family history of the disease. Screening tests of the hemostatic system reveal normal platelet counts, normal INR, increased bleeding time, and in some cases a slight increase in partial thromboplastin time. However, stimulation may temporarily increase von Willebrand factor levels, which may cause false-negative results in mild von Willebrand disease, so screening tests should be repeated. The diagnosis requires determination of plasma total von Willebrand factor antigen levels, von Willebrand factor function, determined by the ability of plasma to support ristocetin-induced agglutination of normal platelets (ristocetin cofactor activity); and plasma factor VIII levels.

In general, in the first type of von Willebrand disease, the results of the studies are concordant, i.e. the von Willebrand factor antigen, the von Willebrand factor function, and the plasma level of von Willebrand factor are equally reduced. The degree of depression varies from approximately 15 to 60% of the norm, which determines the severity of bleeding in patients. It should be borne in mind that in healthy people with blood group 0 (I), a decrease in the von Willebrand factor antigen below 40% is observed.

In type 2 von Willebrand disease, the test results are discordant, i.e. the von Willebrand factor antigen is higher than the ristocetin cofactor activity (the von Willebrand factor antigen is higher than expected because the von Willebrand factor abnormality in type 2 is qualitative, not quantitative). The diagnosis is confirmed by detecting a decrease in the concentration of large von Willebrand factor multimers during agarose gel electrophoresis. There are four variants of type 2 von Willebrand disease, differing in the functional abnormalities of the von Willebrand factor molecule.

Type 3 von Willebrand disease is a rare autosomal recessive disorder in which homozygotes have no detectable von Willebrand factor with a significant reduction in factor VIII. They have a combined platelet adhesion and coagulation abnormality.

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Treatment of von Willebrand disease

Treatment of von Willebrand disease is necessary only in the presence of active bleeding or invasive procedures (eg, surgery, dental extractions). Treatment consists of replacing von Willebrand factor with infusion of intermediate-purity factor VIII concentrate, which contains von Willebrand factor. These concentrates are virally inactivated and do not transmit HIV or hepatitis, so they are preferred over the previously widely used cryoprecipitate. Highly purified factor VIII concentrates are prepared by immunoaffinity chromatography and do not contain von Willebrand factor.

Desmopressin is a vasopressin analog that stimulates the release of von Willebrand factor into the blood plasma and can increase factor VIII levels. Desmopressin may be effective in type 1 von Willebrand disease, but is ineffective in other types and may even be harmful in some. To ensure an adequate response to the drug, the physician should give a test dose and measure the response by the level of von Willebrand factor antigen. Desmopressin 0.3 mcg/kg in 50 ml of 0.9% NaCl solution intravenously for 15 to 30 minutes can provide hemostasis for minor procedures (eg, tooth extraction, minor surgery) without the need for replacement therapy. If replacement therapy is still necessary, desmopressin can reduce the required dose. A single dose of desmopressin is effective for 8 to 10 hours. It takes about 48 hours for VF reserves to be replenished, allowing a second injection of desmopressin to be as effective as the initial dose of the drug.