Von Willebrands disease vWD and vWFrelated bleeding

Autosomal inherited bleeding disorder due to reduced production of von Willebrand factor (vWF) or production of defective protein, affects both sexes with estimated incidence of 1 per few hundred. First described in 1926 in the Aland Islands in the Baltic, it has a worldwide distribution.

Pathophysiology vWF, produced in endothelial cells and megakaryocytes, is a protein of 250kDa molecular weight. Initial dimerisation and subsequent removal of propeptide allows polymerisation and secretion of large multimers. The higher molecular weight (HMW) multimers, up to 20 x 103 kDa, are particularly haemostatically active. vWF has two main functions:

1. Its primary haemostatic function is to act as a ligand for platelet adhesion and it is this reduced activity that causes bleeding.

2. It has a secondary function as a carrier protein for factor VIII protecting it from degradation. In most patients with vWD the associated mild reduction in factor VIII level is not the cause of the haemostatic defect.

Many cases of heritable/congenital vWD are currently thought to be caused by genetic mutations at the vWF locus but some may be due to defects in other genes, which affect vWF levels. Increasingly vWF is considered a continuous variable with low levels associated with an increased bleeding tendency.

Many subtypes but for simplicity the disease is classified into 3 main types:

• Type 1—quantitative deficiency of vWF (autosomal dominant).

• Type 2—qualitative deficiency of vWF (autosomal dominant/recessive).

• Type 3—complete deficiency of vWF (autosomal recessive).

Clinical features

The clinical picture varies markedly. Symptoms may be intermittent, due to dysfunction of platelet adhesion e.g. mucocutaneous bleeding, easy bruising, nose bleeds, prolonged bleeding from cuts, dental extractions, trauma, surgery and menorrhagia.

Type 2B causes thrombocytopenia which may present in pregnancy. Usually the picture is consistent within a family. Laboratory diagnosis

• vWF is an acute phase protein—increasing with stress, oestrogens, pregnancy, neoplasm, thyrotoxicosis, etc. vWF levels are dependent on ABO blood group being lower in group O than non-O.

• In type 1 APTT usually normal as are PT and platelets. VIII may be normal or 5. vWF level and function typically mildly or moderately 5. Bleeding time is often normal and is no longer used in many haemophilia centres. It has been largely replaced by automated in vitro platelet function analysis at high shear rate (PFA-100). When mild, the condition may be difficult to diagnose as many of the tests are normal, including the VIII and variably the vWF level. Repeat testing is necessary. Family testing is useful.

Classification of von Willebrand's disease

Type

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