von Willebrand Factor (vWF) Multimers

Plasma, frozen

2 mL

1 mL

Blue-top (sodium citrate) tube

Do not draw from an arm with a heparin lock or heparinized catheter.

Aid in the determination of von Willebrand factor (vWF) deficiency subtype^6-9

Western blot (WB)

vWF is produced by megakaryocytes and endothelial cells.⁶ The vWF protein polymerizes in plasma into multimers of up to 100 subunits that range in size from 0.5 to 20 million daltons.^6,7 The plasma half-life of vWF is about 24 hours. vWF performs two major functions in hemostasis.^6,8 vWF acts as a cross-linking protein that connects platelets to each other and to subendothelial material at the site of vascular damage. This functionality is dependent on the presence of high molecular weight multimers of vWF. vWF also serves as an obligate carrier of factor VIII in plasma. Functional vWF serves to protect factor VIII from proteolytic degradation and effectively increases its half-life.⁹ Effective factor VIII binding is not dependent on the presence of large multimeric vWF complexes.⁸

The assessment of these two distinct vWF functions requires the performance of multiple assays in the laboratory. The vWf activity (ristocetin cofactor) assay reflects the effectiveness of the patient vWF in supporting platelet adhesion. A measure of factor VIII activity helps to determine if the vWF can bind factor VIII and increase its circulating half-life. Factor VIII levels can be diminished due to low vWF levels or due to ineffective factor VIII binding by a defective vWF. Of course, factor VIII levels can be low due to inherited or acquired factor VIII deficiency (hemophilia A).

von Willebrand disease (vWF) should be considered in the differential diagnosis of any case where a patient with bleeding history has a normal protime (PT) and activated partial thromboplastin time (aPTT). The aPTT can be prolonged in severe vWD due to diminished levels of factor VIII that result from inadequate vWF binding.⁷ vWD is the most common congenital bleeding disorder known with an estimated incidence of 1 in 100 individuals.^6,8 However, the clinical incidence of vWD is much lower because many of these individuals remain asymptomatic and are never diagnosed.^8-10

The severity of bleeding for patients with vWD can vary, even among family members with the same defect.^6,9 Bleeding symptoms are usually similar to those seen with platelet disorders and other defects in primary hemostasis.⁸ Many individuals with the less severe forms of vWD are first identified because of a history of recurrent nosebleeds (epistaxis) or menorrhagia.⁶ vWD patients generally present with mucocutaneous bleeding characterized by epistaxis, easy bruising, gingival bleeding, menorrhagia, or genitourinary bleeding.^6,11 Three different types of vWD can be distinguished based on the results of laboratory tests and the severity of symptoms.⁶

• Type 1: A genetic defect causing diminished production of functional vWF. Laboratory tests typically reveal correspondingly low levels of both vWF antigen and activity.⁶ This is the most common form of vWD, representing approximately 75% of cases.⁹ Type 1 vWD is usually inherited as an autosomal dominant mutation.⁶ Individuals with heterozygous type 1 vWD usually suffer a mild bleeding disorder. Bleeding can often occur during childhood with improvement after adolescence.⁹ The risk of bleeding in women with vWD is increased in the postpartum period when vWF levels drop precipitously from the elevated levels achieved during pregnancy.⁸

• Type 2: A number of forms of type 2 vWD are characterized by the presence of dysfunctional vWF protein. These individuals represent approximately 25% of cases of vWD.⁹ Individuals with type 2 vWD often have normal or slightly low levels of vWF antigen with relatively lower levels of vWF activity.⁶ Type 2 vWD can be inherited as either dominant or recessive mutations.⁶ Individuals with heterozygous type 2 vWD generally suffer from more severe bleeding than those with type 1 vWD.

• Type 3: This relatively rare form of vWD occurs as the result of homozygous or compound heterozygous defects producing undetectable levels of vWF antigen and activity. These patients generally have the worst bleeding symptoms. They can present with spontaneous bleeding, significant postsurgical bleeding, or gastrointestinal hemorrhage.⁶ Factor VIII levels can be low or absent in type 3 patients resulting in bleeding similar to that seen in hemophilia A.⁸ It is important to distinguish between these two conditions because the methods of treatment are very different.

Acquired vWD is rare, although is likely an under-reported and underevaluated condition.¹² The majority of cases have been reported in association with autoimmune or clonal proliferative conditions.¹² Acquired vWD had been reported in patients with systemic lupus erythematosus, antiphospholipid syndrome, and hypothyroidism. Other conditions associated with acquired vWD are Wilms tumor and congenital cardiovascular disease.^6,12 Autoantibodies to vWF can sometimes cause vWD in elderly individuals with multiple myeloma, lymphoproliferative disorders, or collagen vascular disease.⁶