von Willebrand Disease Reflexive Profile

vWF is produced by megakaryocytes and endothelial cells.² The vWF protein polymerizes in plasma into multimers of up to 100 subunits that range in size from 0.5 to 20 million daltons.^1,2 vWF's plasma half-life is about 24 hours. vWF performs two major functions in hemostasis.^1,2 vWF acts a cross-linking protein that connects platelets to each other and to subendothelial cells 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 fivefold.⁴ Effective factor VIII binding is not dependent on the presence of large multimeric vWF complexes.³ The assessment of vWF activity requires two tests to evaluate these two functions. The vWF activity (ristocetin cofactor) assay reflects the effectiveness of the patient vWF in supporting platelet adhesion. Factor VIII levels can be diminished due to low vWF levels or due to ineffective factor VIII binding by a defective vWF.

von Willebrand disease (vWD) 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 extended in severe vWD due to diminished levels of factor VIII that result from inadequate vWF binding.¹

vWD is the most common congenital bleeding disorder known with an estimated incidence of 1 in 100 individuals.^2,3 However, the clinical incidence of vWD is much lower because many of these individuals remain asymptomatic and are never diagnosed.^3,4 The severity of bleeding for patients with vWD can vary, even among family members with the same defect.^2,4 Bleeding symptoms are usually similar to those seen with platelet disorders and other defects in primary hemostasis.³ A typical symptom of an individual with a defect in primary hemostasis would be profuse bleeding from small cuts with the need for prolonged application of pressure to stop the bleeding.⁵ Many individuals with less severe forms of vWD are first identified because of a history of recurrent nosebleeds (epistaxis).² vWD patients generally present with mucocutaneous bleeding characterized by epistaxis, ecchymosis, easy bruising, gingival bleeding, menorrhagia, or genitourinary bleeding.^2,5 Three different types of vWD can be distinguished based on the results of laboratory tests and the severity of symptoms.²

Type 1: A genetic defect causing diminished production of functional vWF. Laboratory tests typically reveal correspondingly low levels of both vWF antigen and activity.² This is the most common form, representing approximately 75% of cases.⁴ Type 1 vWD is usually inherited as an autosomal dominant mutation.² The risk of bleeding in women with vWD is increased in the postpartum period when vWF levels drop precipitously from the elevated levels developed during pregnancy.³

Note: While individuals with very low vWF levels (ie, <30%) are more likely to have an identifiable genetic basis for the condition, individuals with moderately diminished levels (30% to 50%) may be classified simply as having low vWF, not Type I vWF disease.⁶ It is often difficult to directly attribute increased bleeding to low vWF in these patients because bleeding associated with moderately diminished vWF is generally mild, and complaints of mild bleeding tendency are common.⁶

Type 2: A number of forms of type 2 vWD are characterized by the presence of dysfunctional vWF protein. Individuals with these forms represent approximately 25% of cases of vWD.⁴ Individuals with type 2 vWD often have normal or slightly low levels of vWF antigen with relatively lower levels vWF activity.² Type 2 vWD can be inherited as either dominant or recessive mutations.² 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. Patients with this form of vWD generally have the worst bleeding symptoms. These individuals can present with spontaneous bleeding, significant postsurgical bleeding, or gastrointestinal hemorrhage.² Factor VIII levels can be low or absent in type 3 patients, resulting in bleeding similar to that seen in hemophilia A.³ It is important to distinguish between these two conditions, because the methods of treatment are very different.

Acquired vWD is very rare with less than 100 cases documented in the literature.⁷ The majority of cases have been reported in association with autoimmune or clonal proliferative conditions.⁷ Acquired vWD has 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.^2,7 Autoantibodies to vWF can sometimes cause vWD in elderly individuals with multiple myeloma, lymphoproliferative disorders, or collagen vascular disease.²

The profile contains these base tests: von Willebrand Factor Activity (Ristocetin Cofactor) [500670], von Willebrand Factor Antigen (Factor VIII Related Antigen) [500667], von Willebrand Activity/von Willebrand Antigen Ratio [504809], Factor VIII Activity [500659], and Pathologist Interpretation [500683]. The reflexed tests are: vWF Collagen Binding Act. [502666], and von Willebrand Factor Multimers [500148].

If reflex test is performed, additional charges/CPT code(s) may apply.

FVIII Activity and VW Activity are FDA approved; CBA is RUO, VW Antigen and VW Multimeric Analysis are LDT.

Clotting, Turbidometric, ELISA, Western Blot