(See also Overview of Platelet Dysfunction.)
Von Willebrand factor is synthesized and secreted by vascular endothelium to form part of the perivascular matrix. Von Willebrand factor promotes the platelet adhesion phase of hemostasis by binding with a receptor on the platelet surface membrane (glycoprotein Ib/IX), thus connecting the platelets to the vessel wall. VWF is also required to maintain normal plasma factor VIII levels. Levels of VWF can temporarily increase in response to stress, exercise, pregnancy, inflammation, or infection.
Von Willebrand disease is classified into 3 types:
Type 1: A quantitative deficiency of VWF, which is the most common form and is an autosomal dominant disorder
Type 2: A qualitative impairment in synthesis of VWF that can result from various genetic abnormalities and is an autosomal dominant disorder
Type 3: A rare autosomal recessive disorder in which homozygotes have no detectable VWF
Although VWD, like hemophilia A, is a hereditary disorder that may cause factor VIII deficiency, the factor VIII deficiency in VWD is usually only moderate.
Bleeding manifestations are mild to moderate in von Willebrand disease (VWD) and include easy bruising, mucosal bleeding, bleeding from small skin cuts that may stop and start over hours, sometimes increased menstrual bleeding, and abnormal bleeding after surgical procedures (eg, tooth extraction, tonsillectomy). Platelets function well enough that petechiae and purpura rarely occur.
Von Willebrand disease is suspected in patients with unexplained bleeding, particularly those with a family history of a similar bleeding diathesis. Screening coagulation tests reveal a normal platelet count, normal international normalized ratio (INR), and sometimes a slightly prolonged PTT. Bleeding time testing is unreliable and no longer done.
Diagnosis requires measuring total plasma VWF antigen, VWF function as determined by the ability of plasma to support agglutination of normal platelets by ristocetin (ristocetin cofactor activity), and plasma factor VIII level. Stimuli (such as pregnancy and inflammation) that temporarily increase VWF levels can cause false-negative results in mild VWD; tests may need to be repeated.
In the type 1 form of VWD, results are concordant; ie, VWF antigen, VWF 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. Levels of VWF antigen can also be as low as 40% of normal in healthy people with type O blood.
Type 2 variants are suspected if test results are discordant, ie, VWF antigen is higher than expected for the degree of abnormality in ristocetin cofactor activity. VWF antigen is higher than expected because the VWF defect in type 2 is qualitative (loss of high molecular weight VWF multimers) not quantitative. Diagnosis is confirmed by demonstrating a reduced concentration of large VWF multimers on agarose gel electrophoresis. Four different type 2 variants are recognized, distinguished by different functional abnormalities of the VWF molecule.
Patients with type 3 VWD have no detectable VWF and a marked deficiency of factor VIII.
Patients with von Willebrand disease (VWD) are treated only if they are actively bleeding or are undergoing an invasive procedure (eg, surgery, dental extraction).
For patients with type 1 and some variants of type 2 VWD, desmopressin, an analog of vasopressin (antidiuretic hormone) that stimulates release of VWF into the plasma and may increase levels of factor VIII, can be helpful. Desmopressin is ineffective in other variants of type 2 and in type 3 VWD, and in type 2B can exacerbate thrombocytopenia.
To ensure adequate response to the drug, physicians give patients a test dose and measure the response of VWF antigen. Desmopressin 0.3 mcg/kg given in 50 mL of 0.9% saline solution IV over 15 to 30 minutes may enable patients to undergo minor procedures (eg, tooth extraction, minor surgery) without needing replacement therapy. If a replacement product is needed, desmopressin may reduce the required dose.
One dose of desmopressin is effective for about 4 to 6 hours. About 48 hours must elapse for new stores of VWF to accumulate, permitting a 2nd injection of desmopressin to be as effective as the initial dose. For many patients, intra-nasal desmopressin may be as effective as IV treatment and is often useful to prevent bleeding during minor surgical procedures. Frequent use can lead to hyponatremia.
For patients with variants of type 2 VWD unresponsive to desmopressin, those with type 3 VWD, or patients with type 1 VWD who are undergoing more extensive invasive procedures, treatment involves replacement of VWF by infusion of intermediate-purity factor VIII concentrates, which contain components of VWF. These concentrates are virally inactivated and therefore do not transmit HIV infection or hepatitis. Because they do not cause transfusion-transmitted infections, these concentrates are preferred to the previously used cryoprecipitate. High-purity factor VIII concentrates are prepared by immunoaffinity chromatography and contain no VWF and should not be used.
For women with heavy menstrual bleeding due to von Willebrand disease, a brief period of treatment with tranexamic acid by mouth or intranasal desmopressin may decrease bleeding.
Patients have easy bruising and purpura, usually mucosal, and rarely joint bleeding.
Screening tests reveal a normal platelet count, normal INR, and sometimes a slightly prolonged PTT.
Confirming tests include total plasma von Willebrand factor (VWF) antigen, VWF function (VWF ristocetin cofactor assay), and plasma factor VIII level.
Treatment: Desmopressin or sometimes intermediate-purity factor VIII concentrate, is given for active bleeding and before an invasive procedure.
Oral tranexamic acid may be helpful in women with excessive menstrual bleeding.