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    Von Willebrand: An underdiagnosed disorder

    Several forms of the disease exist, and women with excessive reproductive tract bleeding should be tested for it.

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Approximately 90% of women being treated at hemophilia centers in the United States carry the diagnosis of VWD.1 Because women experience the hemostatic bleeding challenges of menstruation and childbirth, they are disproportionately affected by VWD.

    Obstetricians and gynecologists may encounter women who have already been diagnosed or who have excessive reproductive tract bleeding and those patients should be evaluated for VWD. In his original 1926 paper, Finnish doctor Erik von Willebrand noted that women were twice as likely to be affected as men but while they are disproportionally affected by VWD, women are no more likely to inherit the condition than are men.2 Indeed, with the exception of type 3 and type 2 N VWD, which are autosomal recessive (homozygous or compound heterozygous), transmission of VWD is autosomal dominant.3

    VWF and types of VWD

    VWD results from a deficiency of normal von Willebrand factor (VWF) due to insufficient or abnormal VWF. VWF is an elongated, multimeric protein (made up of multiple identical subunits) and has binding sites for platelets, collagen (in the subendothelium of blood vessels), and factor VIII (FVIII). Because VWF is required for normal adhesion of platelets to the site of a blood vessel injury and for protection of FVIII in the circulation, deficiency of normal VWF results in a bleeding disorder of varying severity depending on the VWF level, the FVIII level, and other modifying factors.

    Not all VWD is caused by a defect in the von Willebrand gene, but the lower a patient’s VWF level, the more likely she is to have a genetic defect.3 The most common type of VWD, comprising 75% of symptomatic individuals, is type 1, which is characterized by a deficiency of normal VWF and is usually mild. Type 2 VWD is characterized by abnormal VWF. Type 3, which is rare, is characterized by the virtual absence of VWF and is severe.3

    Prevalence

    The reported prevalence of VWD depends on the population and the definition of disease. The prevalence based on the number of symptomatic patients seen at hemophilia treatment centers is 1 in 10,000.4 The prevalence based on the number of women with the diagnosis discharged after childbirth is 1 in 4000.5

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    The prevalence based on identification of individuals with bleeding symptoms, low VWF, and a positive family history has been estimated to be as high as 1% to 2%.3

    Diagnosis, classification

    Several forms of VWD exist and current laboratory assays have limitations, so no single test reliably identifies the condition. The diagnosis is based on clinical features and laboratory tests. The initial laboratory work-up consists of a complete blood count to assess hemoglobin and exclude thrombocytopenia; as well as a prothrombin time (PT), an activated partial thromboplastin time (aPTT), and fibrinogen level (or thrombin clot time) to exclude a clotting factor deficiency.6

    While these tests are useful for excluding clotting factor deficiencies, the aPTT may be normal in patients with VWD. The next series of tests includes specific tests for VWD including von Willebrand ristocetin cofactor activity (VWF:RCo), von Willebrand factor antigen (VWF:Ag) and FVIII.6 While a VWF:Co level of less than 40 IU/dL (international units per deciliter—the percent functional activity compared to an international reference) is highly likely to be associated with a genetic defect in the VWF gene,3 the National Institutes of Health/National Heart, Lung, and Blood Institute (NHLBI) criteria for the diagnosis of VWD requires a level <30 IU/dL. The range of 30–50 IU/dL is classified as “low VWF.”6 A VWF:RCo/VWF:Ag ratio ≤0.7 is indicative of type 2 VWD, a deficiency of normally functioning VWF.

    Undetectable VWF is indicative of type 3 VWD. The inheritance, prevalence and phenotype of VWD by type are summarized in Table 1.

    Results of testing may vary depending on multiple factors, including a patient’s age, stressors, inflammation, hormone levels, pregnancy, the quality of the laboratory, and the timeliness of sample processing. If the sample is not centrifuged promptly to separate the plasma, the plasma proteins may become degraded, yielding an artificially low VWF or FVIII level.6

    Often, repeated analyses over several months are required. In many instances, only one of several tests in the panel may be abnormal. Further testing to determine the type and subtype of VWD includes analysis of von Willebrand multimers among other studies. Analysis for genetic mutations provides important information for research, but is not yet considered part of the diagnostic work-up for VWD.

    NEXT: Heavy menstrual bleeing in women with VWD

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