Clinical Information

von Willebrand factor (VWF) is synthesized by the endothelial cell and megakaryocyte and is present in these cells, as well as in platelets, subendothelial tissue, and plasma.

VWF serves as an adhesive protein important in adhering platelets to subendothelial tissue at the site of vascular injury and for adhering platelets to each other (aggregation). Platelet adhesion and aggregation are essential to form a mechanical hemostatic "plug" and as the focus for interaction of clotting factors and phospholipid required for the formation of the fibrin platelet clot. VWF also stabilizes plasma factor VIII by binding it and protecting it from proteolysis and serves as a carrier protein for that clotting factor.

VWF circulates in the blood in 2 distinct compartments. Plasma VWF mainly reflects VWF synthesis and release from vascular endothelial cells. Platelet VWF (about 10% of the blood VWF) reflects VWF synthesis by bone marrow megakaryocytes with storage primarily in the alpha granules of circulating platelets.

Plasma VWF circulates normally in multimeric forms with molecular weights ranging from 500,000 to as much as 20,000,000. The high-molecular-weight (HMW) forms of VWF are the most effective components for interaction with platelets. This primary activity of plasma VWF is measured in the laboratory with the VWF activity assay, whereas VWF antigen testing measures the amount of VWF protein, and factor VIII coagulant activity indirectly reflects VWF interaction with factor VIII. VWF multimer analysis visualizes the distribution of VWF multimers and is useful as a reflexive test for subtyping von Willebrand disease (VWD).

Levels of factor VIII, VWF antigen, and VWF activity may vary greatly within an individual over time and also with blood type (normal blood type O individuals may have VWF lower than normals of other blood groups). VWF levels (and factor VIII) can be elevated in liver disease, pregnancy, estrogen therapy, inflammation, and after exercise (acute-phase reactant). VWF levels in hemophilia are normal.

VWF antigen measurement assesses the mass of plasma VWF protein but does not reflect VWF functions or platelet VWF. The function of VWF (mediating platelet-platelet or platelet-vessel interaction) is most commonly assessed by measurement of plasma VWF activity.

VWD is the most common inherited bleeding disorder, affecting up to 1% of the population. It can also occur as an acquired bleeding disorder. Bleeding symptoms in all types of VWD are primarily mucosal, including epistaxis, menorrhagia, gastrointestinal bleeding, and ease of bruising, but surgical or posttraumatic bleeding can also occur.

Subtypes of inherited VWD are:

Type 1 VWD:

VWF plasma levels (antigen and activity) typically are concordantly reduced in type 1 VWD. Because of this reduction, the level of coagulation factor VIII is often secondarily reduced. Type 1 VWD is the most common VWD variation, representing 70% to 80% of clinical VWD. It is typically inherited in autosomal dominance fashion, although recessively inherited VWD also occurs (eg, type 3 VWD). Clinical severity ranges from mild or minimal to a moderately severe bleeding diathesis and tends to correlate most closely with VWF activity. Severe type 1 disease is also called type 3 VWD, but the distinction between the two may sometimes be difficult.

Type 2 VWD:

Type 2 VWD variants represent 20% to 30% of clinical VWD, typically autosomal dominant in inheritance. There are 4 subtypes of type 2 VWD: 2A, 2B, 2M, and 2N. Abnormal plasma HMW VWF function and multimeric structure with decreased or absent HMW multimers are characteristic of types 2A and 2B but are normal in type 2M or 2N.

VWF activity is decreased in types 2A, 2B, and 2M and typically is discordantly lower than VWF antigen. Type 2N (Normandy) has substantially decreased factor VIII coagulant activity (usually 5%-30% of mean normal), with normal VWF antigen and activity and normal VWF multimers with clinical manifestation as autosomally inherited mild hemophilia (in contrast to classical X chromosome-linked hemophilia A).

Type 2A is the most common of the 4. Type 2B manifests thrombocytopenia, either persistent or transient, and is distinguished from type 2A by abnormally heightened aggregation response of patient platelets and plasma to low dose ristocetin stimulation. Type 2M typically demonstrates hypofunctional VWF with decreased VWF activity discordantly lower than VWF antigen not due to loss of HMW multimers. One variant of type 2M, Vicenza variant VWD, has ultralarge VWF multimers in plasma.

Type 3 VWD:

VWF is absent or markedly decreased in type 3 VWD (VWF antigen and activity either undetectably low or below 5% to 10% of mean normal), with secondary decrease of factor VIII coagulant activity (5%-30%). VWF multimers may be undetectable or, if present, have a normal distribution. Platelet VWF may also be absent.

Acquired VWD:

VWD can also occur on an acquired basis by a variety of mechanisms not well understood. Disorders associated with acquired VWD include certain myeloproliferative or lymphoproliferative disorders, plasma cell dyscrasias including monoclonal gammopathy of undetermined significance, autoimmune disorders (eg, rheumatoid arthritis, systemic lupus erythematosus), and a variety of other diseases. In some cases, no associated disorder is detected. Laboratory testing currently cannot distinguish between congenital and acquired VWD; clinical correlation is required.