Von Willebrand disease (VWD) is a family of bleeding disorders caused by an abnormality of the von Willebrand factor (VWF). VWD is the most common hereditary bleeding disorder.
First described by Erik Adolf von Willebrand in 1926, VWD is a congenital bleeding disorder characterized by a lifelong tendency toward easy bruising, frequent epistaxis, and menorrhagia.
VWD is due to an abnormality, either quantitative or qualitative, of the VWF, which is a large multimeric glycoprotein that functions as the carrier protein for factor VIII (FVIII). VWF also is required for normal platelet adhesion. VWF functions in both primary (involving platelet adhesion) and secondary (involving FVIII) haemostasis. In primary haemostasis, VWF attaches to platelets by its specific receptor to glycoprotein Ib on the platelet surface and acts as an adhesive bridge between the platelets and damaged subendothelium at the site of vascular injury. In secondary haemostasis, VWF protects FVIII from degradation and delivers it to the site of injury.
VWF is composed of dimeric subunits that are linked by disulfide bonds to form complex multimers of low, intermediate, and high molecular weights. The small multimers function mainly as carriers for FVIII.
High molecular weight multimers have higher numbers of platelet-binding sites and greater adhesive properties. Each multimeric subunit has binding sites for the receptor glycoprotein Ib on non-activated platelets and the receptor glycoprotein IIb/IIIa on activated platelets. This facilitates both platelet adhesion and platelet aggregation, making high molecular weight multimers most important for normal platelet function.
Classification of VWd
Type 1 VWD is characterized by a partial quantitative decrease of qualitatively normal VWF and FVIII. An individual with type 1 VWD generally has mild clinical symptoms, and this type usually is inherited as an autosomal dominant trait.. In addition, clinical and laboratory findings may vary in the same patient on different occasions. Typically, a proportional reduction in VWF activity, VWF antigen, and FVIII exists with type 1 VWD.
15-20% of patients have type 2 disease. VWD type 2 is a variant of the disease with primarily qualitative defects of VWF. Type 2 VWD can be either autosomal dominant or recessive. Of the 5 known type 2 VWD subtypes (ie, 2A, 2B, 2C, 2M, 2N), type 2A VWD is by far the most common.
Type 2A VWD is inherited as an autosomal dominant trait and is characterized by normal-to-reduced plasma levels of factor VIIIc (FVIIIc) and VWF.
Type 2B VWD also is inherited as an autosomal dominant trait. Patients with type 2B VWD have a haemostatic defect caused by a qualitatively abnormal VWF and intermittent thrombocytopenia. The abnormal VWF has an increased affinity for platelet glycoprotein Ib. The platelet count may fall further during pregnancy, in association with surgical procedures, or after the administration of desmopressin acetate (DDAVP). Although some investigators found DDAVP to be clinically useful in persons with type 2B VWD, studies directed at excluding the 2B variant should be completed before DDAVP is used therapeutically. Measurements of FVIIIc and VWF in plasma are variable; however, studies involving the use of titered doses of ristocetin reveal that aggregation of normal platelets is enhanced and induced by unusually small amounts of the drug.
In patients with the rare type 2M VWD, laboratory results are similar to those of certain patients with type 2A VWD. Type 2M VWD is characterized by a decreased platelet-directed function that is not due to a decrease of high–molecular weight multimers. Laboratory findings show decreased VWF activity, but VWF antigen, FVIII, and multimer analysis are found to be within reference range.
Type 2N VWD is also rare and is characterized by a markedly decreased affinity of VWF for FVIII, resulting in FVIII levels reduced to usually around 5% of the reference range. Other VWF laboratory parameters (ie, VWF antigen [VWF:Ag], ristocetin cofactor activity) are usually normal. The FVIII-binding defect in these patients is inherited in an autosomal recessive manner.
Type 3 is the most severe form of VWD. In the homozygous patient, type 3 VWD is characterized by marked deficiencies of both VWF and FVIIIc in the plasma, the absence of VWF from both platelets and endothelial cells, and a lack of response to DDAVP. Type 3 VWD is characterized by severe clinical bleeding and is inherited as an autosomal recessive trait. Less severe clinical abnormalities and laboratory abnormalities may be identified in occasional heterozygotes; however, such cases are difficult to identify.
Prevalence worldwide is estimated at 0.9-1.3%.
The morbidity in individuals with VWD is variable. Many children with VWD are asymptomatic. Some of these children have cutaneous and/or mucus membrane bleeding.
Menorrhagia is a common symptom in females with VWD. It occurs in more than 50% of women with VWD and may be the only clinical manifestation of the disease.
The rare type 3 VWD can manifest with severe bleeding symptoms similar to severe haemophilia
No influence of ethnicity on the prevalence of VWD exists.
VWD affects males and females in equal numbers.
VWD is a congenital bleeding disorder and can be diagnosed at any age.
VWD is caused by an inherited defect that results in a deficiency or dysfunction of von Willebrand factor (VWF). The gene for VWF is on the short arm of chromosome 12. Various point mutations, insertions, and deletions at the VWF locus have been described.
In some cases, VWD is believed to result from other pathological processes; however, because of the relatively high prevalence of VWD, its concomitant occurrence with other disease states may be coincidental.
Acquired forms of VWD can be observed in the following conditions:
o Wilms tumour
o Congenital heart disease
o Systemic lupus erythematosus
o Seizure disorders treated with valproic acid
Minor bleeding problems, such as bruising or a brief nosebleed, may not require specific treatment. For more serious bleeding, medications that can raise the von Willebrand factor (VWF) level and, thereby, limit bleeding are available. The goal of therapy is to correct the defect in platelet adhesiveness (by raising the level of effective VWF) and the defect in blood coagulation (by raising the FVIII level). In recent years, desmopressin (1-deamine-8-D-arginine vasopressin, DDAVP) has become a mainstay of therapy for most patients with mild von Willebrand disease (VWD). At appropriate doses, DDAVP causes a 2- to 5-fold increase in plasma VWF and FVIII concentrations in individuals who are healthy and patients who are responsive. DDAVP can be used to treat bleeding complications or to prepare patients with VWD for surgery.
In general, a patient's responsiveness to DDAVP prior to its use for these purposes can be determined. Once determined, such responsiveness generally is consistent in patients over time and within families. In patients with serious bleeding, prompt treatment is important in order to decrease the possibility of complications.
Desmopressin is a synthetic analogue of antidiuretic hormone. It is considered the primary treatment for bleeding in individuals with mild von Willebrand disease (VWD). It works by causing release of von Willebrand factor (VWF) from endothelial storage sites.
The higher concentration intranasal preparation allows home treatment for bleeding symptoms; however, experience with its use in the surgical setting is limited. Most experience in treating individuals with VWD is with intravenous infusion, with which the response is rapid (ie, peak VWF levels in approximately 45-90 min of infusion). Doses may be repeated at intervals of 12-24 hours for continued bleeding or for postoperative use. Desmopressin has also been administered subcutaneously with a favourable response.
Desmopressin increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys.
A 2-5-fold increase in VWF and FVIII commonly is obtained after treatment.
Haemophilia Society-'Key facts: what is Von Willebrands?'