Type 3 VWD is defined by a virtual absence of VWF. The inheritance of type 3 VWD has often been reported as autosomal recessive. However, there is emerging evidence that it can also be inherited in a co-dominant pattern: obligate carriers of type 3 VWD mutations have more mucocutaneous bleeding symptoms than normal individuals, and in approximately 50% of cases may carry a diagnosis of type 1 VWD.21 This condition is characterized by prolongation of the activated partial thromboplastin time (aPTT), undetectable levels of VWF:Ag, and VWF:RCo and FVIII levels less than 10 IU/dL (10%). The majority (~80%) of type 3 VWD patients have 2 null alleles as a result of a variety of mutations, with nonsense mutations accounting for about one-third.10 The remainder of the mutational spectrum is made up of missense mutations predominantly located in the D1-D2 (exons 3–11) and D4-CK (exons 37–52) domains that result in intracellular VWF retention, or large deletions, resulting in frameshift mutations affecting 1 or more exons. Because there is little or no circulating VWF, patients with type 3 VWD may develop alloantibodies to VWF, which can complicate treatment.22
VWD is a congenital bleeding disorder. The increased risk of bleeding is present from birth, but symptoms may only manifest when there is a hemostatic challenge. Bleeding symptoms become more apparent with increasing age and exposure to hemostatic challenges. As a result, the diagnosis is often delayed into adulthood in mild to moderate forms of VWD. On the other hand, with more severe bleeding phenotypes such as type 3 VWD, the diagnosis is often made in childhood. Individuals with VWD primarily complain of excessive mucocutaneous bleeding, which includes spontaneous bruising, recurrent epistaxis, and bleeding from the gums after brushing, dental cleaning, and extractions. In addition, prolonged or excessive bleeding after surgery or trauma is often reported. Females frequently experience menorrhagia, usually beginning at menarche, and can have prolonged or excessive bleeding after childbirth.23 Musculoskeletal bleeding is unusual, except in type 2N or type 3 VWD when the FVIII:C level may be less than 10 IU/dL.
Mucocutaneous bleeding symptoms such as epistaxis, gum bleeding, ecchymosis, and menorrhagia overlap with those experienced by a normal population, and therefore can be easily overlooked by both patients and physicians.11 The use of bleeding assessment tools (BATs) to standardize the bleeding history and interpretation of the severity of the bleeding phenotype is becoming part of routine clinical practice. Three different BATs, each an adaptation of its predecessor, have been created and validated.24 Each of the scores performs well in an undiagnosed population presenting with bleeding symptoms. The negative predictive value is typically greater than 0.99, meaning that a negative bleeding score nearly excludes a clinically significant bleeding disorder. Thus, the main utility of the current BATs is at the time of new patient assessments: a negative bleeding score will help avoid unnecessary laboratory testing and prevent false-positive diagnoses of VWD (borderline low VWF:Ag without a significant bleeding history). However, the currently available BATs have some limitations. When scoring severe bleeding disorders, BATs become saturated as they take into account the worst episode of bleeding within each category but not the frequency of bleeding. BATs need to be administered by an expert and are time consuming to complete. Finally, they are not useful for monitoring bleeding symptoms or response to therapy because of the cumulative nature of the scores. In an attempt to standardize the BAT and bleeding score, the ISTH/Scientific and Standardization Committee (SSC) Joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group has established a revised BAT, known as the ISTH-BAT, specifically designed to extend the utility of the earlier BATS by incorporating information on both symptom frequency and severity.25,26 The ISTH-BAT has been further modified to a patient- or self-administered BAT (SELF-BAT). The SELF-BAT has been shown to be a reliable and effective tool in the assessment of patients who are being evaluated for VWD.27
Screening tests include a complete blood count (CBC), prothrombin time, aPTT, thrombin time, and fibrinogen concentration to exclude the presence of other hemostatic disorders. The CBC may show thrombocytopenia in type 2B VWD. The aPTT is often normal, but will be prolonged if the FVIII level is below 30 IU/dL, as can be seen in severe type 1, type 2N, or type 3 VWD. The platelet function analyzer (PFA-100) is a system for analyzing primary hemostasis under high shear rates, but its role in the diagnosis of VWD is controversial.11
The evaluation of VWD involves quantitative (VWF:Ag) and qualitative measurements of VWF (VWF:RCo, or one of the novel assays: VWF:Act or VWF:GPIbM) and FVIII activity (FVIII:C). Type 2 VWD is suspected when the VWF activity to VWF:Ag ratio is < 0.6, the FVIII:C is more significantly decreased as compared to VWF:Ag, or with the presence of thrombocytopenia. In these cases, further testing (multimer gel electrophoresis, VWF:CB, RIPA, VWF:FVIIIB, and genotyping) is required to discriminate the type 2 VWD subtype, but such testing may be available only in specialized laboratories. If type 1C VWD is suspected, the VWFpp/VWF:ag ratio may confirm the diagnosis. Table 2 summarizes the results seen with each subtype. These assays are described in detail below.