Von Willebrand disease

VWD is usually due to a mutation in the von Willebrand factor (VWF) gene, but linkage is not seen in approximately 30% of type 1 cases. In type 1 VWD, the linkage is stronger the lower the level of VWF.[7] Several identified and unidentified genetic and environmental factors affect VWF levels, including age, blood type, thyroid status, inflammation, stress, and hormone levels.[8]

Type 1 VWD may result from mutations that affect gene expression or clearance. Heterozygotes for null mutations are usually asymptomatic. Specific mutations that affect functional epitopes have been identified that result in type 2 disease; many of these mutations are in the 134-amino acid segment encoded by exon 28. Mutations resulting in type 3 VWD are usually nonsense mutations or frameshifts due to small insertions or deletions. Large deletions, splice site mutations, and missense mutations are less common.

Rarely patients may develop acquired von Willebrand syndrome (aVWS).[9] This is often associated with lymphoproliferative disorders, such as monoclonal gammopathy of undetermined significance, multiple myeloma, or Waldenstrom macroglobulinemia.[9] sVWS has also been reported with aortic stenosis, myeloproliferative disorders, and hypothyroidism, as a result of several different mechanisms.

Von Willebrand factor (VWF) protein is synthesized in endothelial cells and megakaryocytes, undergoes complex processing, and is secreted as multimers up to 20 million Daltons in size. The high-molecular-weight multimers mediate platelet adhesion to exposed subendothelium at sites of vascular injury. VWF also stabilizes and carries factor VIII, a function not dependent on multimer size.

Patients with VWD have symptoms characteristic of platelet dysfunction, predominantly mucosal bleeding. They may also experience excessive postoperative bleeding, although mucosal symptoms predominate in all but type 2N and type 3. Symptoms are exacerbated by medications that inhibit platelet function, such as aspirin.

In types 1, 2A, 2B, and 2M VWD there may be a modest decrease in factor VIII, quantitatively similar to the change in VWF antigen level, but factor VIII is often within the normal range.

Type 2B VWD is a gain-of-function mutation that results in increased binding of VWF to the platelet. As a result, VWF is more readily cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) and the platelet-VWF complex is cleared by the reticuloendothelial system. Patients often have mild to moderate thrombocytopenia. A similar syndrome can arise from mutation in platelet glycoprotein Ib, which also results in spontaneous binding to VWF (known as platelet type or pseudo VWD). This can be distinguished by mixing studies combining patient and control platelets with patient and control plasmas. DNA analysis can also provide a definitive classification.

Type 2N VWD is characterized by a marked decrease in the affinity of VWF for factor VIII. Consequently, the patient's factor VIII has a very short half-life, and plasma factor VIII is reduced to 5% to 25% (0.05 to 0.25 international units [IU]/mL). Type 3 VWD is characterized by a complete absence of VWF, which results in factor VIII levels of approximately 1% to 5% (0.01 to 0.05 IU/mL). Patients with severe VWD have factor VIII levels low enough to result in joint bleeding and other symptoms more typical of hemophilia A.

International Society on Thrombosis and Haemostasis Subcommittee on von Willebrand Factor[1]

Type 1: partial quantitative deficiency of von Willebrand factor (VWF)

Type 2: qualitative VWF defects

Type 2A: decreased VWF-dependent platelet adhesion due to a selective deficiency of high-molecular-weight multimers

Type 2B: increased affinity for platelet glycoprotein Ib

Type 2M: decreased VWF-dependent platelet adhesion without a selective deficiency of high-molecular-weight multimers; it has been suggested that rare patients with decreased collagen binding activity without reduction in high-molecular-weight multimers should also be included in this group

Type 2N: markedly decreased binding affinity for factor VIII

Type 3: virtually complete deficiency of VWF.

Pathophysiology

Classification

International Society on Thrombosis and Haemostasis Subcommittee on von Willebrand Factor[1]