Platelet type-Von Willebrand disease: a rare, under-diagnosed, inherited bleeding disorder. Studies to improve the diagnosis and to understand the mechanisms of platelet dysfunction and macrothrombocytopenia

Inherited bleeding disorders are genetic diseases that manifest with a tendency to bleed, spontaneously or after trauma, which may be life-threatening and significantly worsen quality of life. Von Willebrand disease (VWD) is the most common hereditary coagulopathy (affecting approximately 1/100) and is due to a reduction in the amount and/or function of von Willebrand factor (VWF), a plasma protein with a pivotal role in blood clotting. Platelet type von Willebrand disease (PT-VWD) is a rare autosomal dominant bleeding disorder caused by a gene mutation of a platelet glycoprotein (GPIbα) that enhances its affinity for VWF and leads to a reduction of platelet number and function with consequent bleeding. PT-VWD resembles, both in clinical and laboratory terms, a subtype of VWD, T2B-VWD. Despite their similarity these two disorders require different treatments, therefore a correct diagnosis is fundamental for the patient wellbeing. Our laboratory has developed a simple test that highlights the increased affinity of VWF for platelets and that can discriminate PT-VWD from T2B-VWD. Our hypothesis is that the application of this method may lead to improved diagnosis of PT-VWD. Moreover, we will investigate the causes of the platelet dysfunction and of thrombocytopenia, and thus of bleeding, of PT-VWD patients as these are currently incompletely understood. The current opinion is that binding of high molecular weight VWF multimers to platelets increases their removal from circulation leading to thrombocytopenia but this does not explain platelet dysfunction. We hypothesize that the hyperactive GPIbα leads to a derangement of the platelet activation mechanisms and, in megakaryocytes, the bone marrow platelet precursors, to impaired platelet production. The unraveling of the mechanisms of platelet dysfunction and thrombocytopenia may set the basis for novel therapies and may improve the understanding of other inherited platelet disorders caused by gain-of-function mutations