Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders

Abstract

Along with haemophilia A and B, von Willebrand disease (VWD) and rare bleeding disorders (RBDs) cover all inherited bleeding disorders of coagulation. Bleeding tendency, which can range from extremely severe to mild, is the common symptom. VWD, due to a deficiency and/or abnormality of von Willebrand factor (VWF), represents the most frequent bleeding disorder, mostly inherited as an autosomal dominant trait. The diagnosis may be difficult, based on a bleeding history and different diagnostic assays, which evaluate the pleiotropic functions of VWF. Different treatment options are available for optimal management of bleeding and their prevention, and long-term outcomes are generally good. RBDs are autosomal recessive disorders caused by a deficiency of any other clotting factor, apart from factor XII, and cover roughly 5% of all bleeding disorders. The prevalence of the severe forms can range from 1 case in 500,000 up to 1 in 2-3 million, according to the defect. Diagnosis is based on bleeding history, coagulation screening tests and specific factor assays. A crucial problem in RBDs diagnosis is represented by the non-linear relationship between clinical bleeding severity and residual clotting levels; genetic diagnosis may help in understanding the phenotype. Replacement therapies are differently available for patients with RBDs, allowing the successful treatment of the vast majority of bleeding symptoms.

Keywords: bleeding; clotting factor deficiency; desmopressin; inherited disorder; on-demand; prophylaxis; replacement therapy; von Willebrand factor.

Figure 1

The role of von Willebrand factor (VWF) in hemostasis. After vessel injury, subendothelium becomes exposed with collagen and VWF contained in the subendothelial matrix. The interaction of von Willebrand factor with glycoprotein Ibα (GpIbα), naturally exposed on the platelet surface, creates initial adhesion of platelets to the subendothelium and platelet activation. This makes the platelets to expose glycoprotein IIb/IIIa (αIIbβ3) which binds fibrinogen and VWF thus, increasing platelet plug. Factor VIII is bound to VWF and is naturally conveyed to the site of lesion, thus allowing also the generation of adequate amounts of fibrin (modified by courtesy of AB Federici).