von Willebrand disease: still an intriguing disorder in the era of molecular medicine

Abstract

von Willebrand disease (vWD) is a single-locus disorder resulting from a deficiency of von Willebrand factor (vWF): a multimeric multifunctional protein involved in platelet adhesion and platelet-to-platelet cohesion in high shear stress vessels, and in protecting from proteolysis and directing circulating factor VIII (FVIII) to the site of injury. vWD is the most frequent bleeding disorder, with an estimated prevalence in the general population of 1%. Almost all these cases are represented by a partial quantitative deficiency of von Willebrand factor (vWF) (type 1 vWD). Type 1 is transmitted as an autosomal dominant trait with an extremely variable penetrance and expressivity. A consensus figure for the prevalence of cases with significant bleeding symptoms, requiring some form of treatment, is approximately 100 cases million-1. Among these cases, more than 70-80% are represented by type 1 and respond to deamino-D-arginine vasopressin (DDAVP; desmopressin) administration. The remaining cases are represented by type 2 vWD (qualitative), some of which require substitutive treatment. Only 3-5 cases million-1 result from a total deficiency of vWF in plasma and platelets because of the recessive inheritance of two defective alleles. These cases may have severe bleeding episodes and may require frequent substitutive treatment. The molecular basis of type 2 (missense mutation in the functional domains of the vWF subunit) and type 3 (nonsense or large deletions) is quite well understood. On the contrary the molecular basis for most type 1 cases remains largely unknown, and many genetic factors (e.g. ABO blood group) and environmental or circumstantial factors (e.g. age, stress, drugs, pregnancy, and inflammation) are superimposed on to the genetic background determined by the vWF gene to produce a continuous spectrum from normality to mild type 1 cases. It is extremely difficult to make a clear distinction between mild type 1 cases and normal people because of the wide 'normal' range of laboratory measurements (e.g. length of bleeding time, and levels of vWF and FVIII) and of bleeding symptoms. Molecular testing is useless in this situation, and only good history-taking and repeated laboratory testing of vWF-related measurements in the propositus and his/her family members can help in clinical diagnosis, albeit imprecisely. This difficult task is the main focus of this review which is aimed at alerting the physician toward a balanced approach that should take into consideration both the risk of over- and under-diagnosis of this frequent disorder and the unavoidable production of a number of false positive and false negative cases.

High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls

“…Considering one patient excluded because of thrombocytopenic type 2B VWD, the prevalence of non-type 1 VWD phenotypes in our population is around 12%, lower than the 20-30% reported elsewhere. 27 A racial factor may explain this difference, since the Aborigine admixture in our Caucasian population borders 30%.…”

Irradiation modulates association of NF-Y with histone-modifying cofactors PCAF and HDAC

“…VWF is a glycosylated protein that functions as a mediator of platelet adhesion to damaged subendothelium and acts as a carrier of coagulation factor VIII. Deficiencies of VWF lead to von Willebrand disease while high-circulating VWF levels constitute an independent risk factor for cardiovascular mortality (Rodeghiero, 2002). Irradiation therapy is a major cause of thrombus formation, which is also associated with increased levels of VWF (Fajardo, 1996).…”

Stress repair mechanism activity explains inflammation and apoptosis

“…Parasympathetic stimulation also releases insulin, which indirectly mobilizes nitric oxide in the capillaries of skeletal muscle and other peripheral tissues where parasympathetic innervation is absent [331,[338][339][340][341][342][343][344][345][346][347][348]. This explains why insulin prolongs bleeding time, reduces systemic vascular resistance, increases cardiac index, aggravates angina, and counteracts "vasopressor" (fibrinogenic) drugs [307,314,315,332,343,[349][350][351][352]; why allostatic load inhibits insulin effects [353] [366][367][368][369][370][371][372][373][374]. Sudden von Willebrand Factor destruction disrupts capillary gate structure, causing anaphylaxis (angioneurotic edema), wherein vascular resistance and blood pressure drop sharply as blood shifts from larger vessels into capillaries, causing lethal airway edema, while coagulation enzymes and cardiac output remain unaffected [375][376][377].…”