Von Willebrand disease (VWD) is a hereditary quantitative deficiency or functional abnormality of von Willebrand factor, which causes platelet dysfunction. Bleeding tendency is usually mild. Screening tests usually show a normal platelet count and, possibly, a slightly prolonged partial thromboplastin time (PTT). Diagnosis is based on low levels of von Willebrand factor antigen and von Willebrand factor activity (ristocetin cofactor activity). Treatment involves control of bleeding with replacement therapy (virally inactivated, intermediate-purity factor VIII concentrate) or desmopressin.
(See also Overview of Platelet Dysfunction.)
Von Willebrand factor (VWF) 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 also binds factor VIII and is 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 main types:
Type 1: A quantitative deficiency of VWF, which is the most common form and is an autosomal dominant disorder. VWD concentration and activity are both reduced proportionally.
Type 2: A qualitative impairment in synthesis and function of VWF that can result from various genetic abnormalities and is an autosomal dominant disorder. VWD activity is reduced more than VWF concentration.
Type 3: A rare autosomal recessive disorder in which patients who are homozygous have no detectable VWF.
Four different type 2 subtypes are recognized, distinguished by different functional abnormalities of the VWF molecule:
In type 2A, VWF fails to bind to platelets and there is a reduction in high molecular weight VWF multimers.
In Type 2B, platelets avidly bind high molecular weight VWF, resulting in increased clearance of platelets and high molecular weight VWF multimers.
In type 2M, there is decreased platelet binding of VWF and VWF levels are reduced. VWF multimer distribution is preserved, but the ratio of VWF activity to concentration is reduced.
In type 2 N, there is impaired binding of VWF to factor VIII and significant reduction in factor VIII levels (ie, to 1 to 5%) similar to that seen in hemophilia A.
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 (ie, to 20 to 40%).
Acquired von Willebrand disease is rare and is characterized by low levels of VWF due to decreased production or increased clearance of VWF from the circulation. It occurs in patients with lymphoproliferative, myeloproliferative, and autoimmune disorders.
Symptoms and Signs of Von Willebrand Disease
Bleeding manifestations in type 1 von Willebrand disease (VWD) include bruising, mucosal bleeding, bleeding from small skin cuts that may stop and start over hours, increased menstrual bleeding, and sometimes bleeding after surgical procedures (eg, tooth extraction, tonsillectomy). Platelets function well enough that petechiae and purpura rarely occur.
Patients with type 3 VWD may additionally experience spontaneous major bleeding under the skin (hematomas) and are at particular risk of life-threatening bleeding with many minor and major surgical procedures.
Diagnosis of Von Willebrand Disease
Total plasma von Willebrand factor (VWF) antigen concentration
VWF function testing
Plasma factor VIII level
Partial thromboplastin time (PTT)
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 (1). 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 the plasma factor VIII level. Stimuli (such as pregnancy and inflammation) that temporarily increase VWF levels can cause false-negative results in type I VWD; tests may need to be repeated after the resolution of such stimuli.
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 subtypes 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. Further specialized functional studies of high molecular VWF binding allow identification of the 4 specific type 2 subtypes.
Patients with type 3 VWD have no detectable VWF and a marked deficiency of factor VIII.
In most women with type 1 VWD, VWF levels commonly return to normal during pregnancy.
Довідковий матеріал щодо діагностики
1. James PD, Connell NT, Ameer B, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021;5(1):280-300. doi:10.1182/bloodadvances.2020003265
Treatment of Von Willebrand Disease
Desmopressin
von Willebrand factor (VWF) replacement when necessary
Tranexamic acid
Patients with von Willebrand disease (VWD) are treated only if they are actively bleeding or are undergoing an invasive procedure (eg, surgery, dental extraction). Treatment guidelines of the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia are available (1).
For patients with type 1 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 usually ineffective in type 2 and in type 3 VWD. In type 2B VWD, desmopressin can exacerbate thrombocytopenia.
To ensure adequate response to desmopressin, 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 second 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 type 2 VWD, those with type 3 VWD, or those 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. Evidence for efficacy of factor VIII concentrates in VWD is mainly from observational studies.
For women with heavy menstrual bleeding due to VWD, a brief period of treatment with tranexamic acid by mouth or intranasal desmopressin may decrease bleeding. Tranexamic acid may also be of use for patients with type 1 and type 2 VWD undergoing minor surgical procedures (eg, dental extraction, skin biopsy, excisional breast biopsy).
Довідковий матеріал щодо лікування
1. Connell NT, Flood VH, Brignardello-Petersen R, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021;5(1):301-325. doi:10.1182/bloodadvances.2020003264
Ключові моменти
Patients with von Willebrand disease 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.
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 or for minor surgical procedures.
