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Von Willebrand's disease (vWD) is the most common hereditary coagulation abnormality described in humans. It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion. It is known to affect humans and, in veterinary medicine, dogs.
Symptoms
The various types of vWD present with varying degrees of bleeding tendency. Severe internal or joint bleeding is rare (only in type 3 vWD); bruising, nosebleeds, heavy menstrual periods (in women) and blood loss during childbirth (rare) may occur.
Diagnosis When suspected, blood plasma of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionallity of vWF with a glycoprotein (GP)Ib binding assay, a collagen binding assay or, a ristocetin cofactor (RiCof) activity assay. Factor VIII levels are also performed as factor VIII is bound to vWF which protects the factor VIII from rapid break down within the blood. Normal levels do not exclude all forms of vWD: particularly type 2 which may only be revealed by investigating platelet interaction with subendothelium under flow (PAF), a highly specialistic coagulation study not routinely performed in most medical laboratories. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A platelet function assay (PFA) will give an abnormal collagen/adrenaline closure time but a normal collagen/ADP time. Type 2N can only be diagnosed by performing a "factor VIII binding" assay. Detection of vWD is complicated by vWF being an acute phase reactant with levels rising in infection, pregnancy and stress.
Other tests performed in any patient with bleeding problems are a full blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time and fibrinogen level. Testing for factor IX may also be performed if hemophilia B is suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen.
Classification and types
Classification There are three described types of vWD - type 1, type 2 and type 3. There are inherited and acquired forms of all types of vWD. Most cases are hereditary, but acquired forms of vWD have been described. A form of vWD (type 2A) occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding (Heyde's syndrome). This form of acquired vWD may be more prevalent than is presently thought.
Type 1 Type 1 vWD (60-80% of all vWD cases) is a quantitative defect (heterozygous for the defective gene) but may not have clearly impaired clotting, most patients usually end up leading a nearly normal life. Trouble may arise in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or menorrhagia (heavy periods). Decreased levels of vWF are detected (10-45% of normal, i.e. 10-45 IU).
Type 2 Type 2 vWD (20-30%) is a qualitative defect and the bleeding tendency can be mild. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent. Five subtypes exist: 2A (most common), 2B, 2C, 2M and 2N.
Type 2N (Normandy) is a deficiency of the binding of vWF to factor VIII. This type gives a normal vWF antigen level and normal functional test results but has a low factor VIII. This has probably lead to some 2N patients being misdiagnosed in the past as having hemophilia A.
Type 3 Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding, no detectable vWF antigen, and may have sufficiently low factor VIII that they have occasional hemarthoses (joint bleeding), as in cases of mild hemophilia.
Pathophysiology See also von Willebrand factor for the normal function of that coagulation factor
vWF is mainly active in conditions of high blood flow and shear stress. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly.
Genetics The vWF gene is located on the twelfth chromosome. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively.
Epidemiology In humans, the incidence of vWD is roughly about 1 in 100 individuals. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation. The actual clotting abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population.
Therapy Patients with vWD normally require no regular treatment. However, they are always at increased risk for bleeding. Prophylactic treatment is sometimes given for patients with vWD who are scheduled for surgery. They can be treated with human derived medium purity Factor VIII concentrates. Mild cases of vWD can be trialled on desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP), which works by raising the patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells.
History vWD is named after Erik Adolf von Willebrand, a Finnish pediatrician (1870-1949). He first described the disease in 1926.
Sources - Harrison's textbook of Internal Medicine, Chapter 177.
- Sadler, J. E. "Biochemistry and Genetics of von Willebrand factor." Annu Rev Biochem 1998; 67:395-424. (fulltext (http://arjournals.annualreviews.org/doi/abs/10.1146%2Fannurev.biochem.67.1.395))
- Mannucci PM. Treatment of von Willebrands disease. N Engl J Med 2004;351:683-94. PMID 15306670
See also
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