von Willebrand disease: Clinical and laboratory lessons learned from the large von Willebrand disease studies (original) (raw)
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Journal of Thrombosis and Haemostasis, 2006
Summary. von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high-molecular-weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.
American Journal of Hematology, 1992
A new family with a bleeding diathesis and FVlll deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor Vlll (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVlll activity: one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVlll concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVlll reached basal level within 60 minutes of the infusion. No FVlll response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVlll level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVlll binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVlll/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.7rk1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling. 6 1992 Wiley-Liss, Inc.
International journal of health sciences
An hereditary bleeding illness is Von Willebrand Disease (vWD). Along with normal or declining factor VIII levels, von Willebrand factor (vWF) levels also fall. Clinical signs include bleeding that looks "platelet-like" and bleeds resemble factor VIII insufficiency. Life-threatening bleeding might result from the strategic position of the bleed, the volume of blood lost, or complications brought on by the significant blood loss. Treatment modalities include desmopressin (DDAVP) and replacement of vWF. The aim of this report is to make health professionals aware of this possibility that could be in operating on bleeding patients.
Platelet-type von Willebrand's disease: characterization of a new bleeding disorder
Blood, 1982
An autosomally transmitted bleeding diathesis sharing some, but not all, features previously described in von Willebrand's disease (vWd) was studied in five patients representing three generations of a single family. Bleeding times in the upper normal range in conjunction with low-normal platelet counts, normal factor VIII coagulant activity and VIII-related antigen, decreased VIII-ristocetin cofactor activity, selective decrease of the higher molecule weight factor VIII/von Willebrand factor (VIII/vWF) multimers, and increased ristocetin- induced platelet agglutination at low ristocetin concentrations were characteristic. Binding of patient VIII/vWF to washed normal platelets was within normal limits, whereas binding of normal VIII/vWF to patient platelets was significantly increased (p less than 0.001 at 0.6 mg/ml ristocetin). This disorder accordingly appears to involve an intrinsic platelet abnormality affecting platelet-VIII/vWF interactions. It is proposed that the concept...
Von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease
Blood, 2015
The ratios between von Willebrand factor propeptide (VWFpp) or FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) reflect synthesis, secretion and clearance of VWF. We aimed to define the pathophysiology of 658 types 1, 2 and 3 von Willebrand disease (VWD) patients with VWF levels ≤30 U/dL from the "Willebrand in the Netherlands" (WiN-)study using the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios. We also evaluated the use of VWFpp in the classification and diagnosis of VWD. Based on the ratios, reduced VWF synthesis was observed in 18% (67/380) of type 1 patients and in only 2% (5/240) of type 2 patients. A significant proportion of type 3 patients had detectable VWFpp (14/37, 41%). These patients had a lower bleeding score than type 3 patients with complete absence of both VWF:Ag and VWFpp: 14.0 vs. 19.5, p=0.025. The majority of these patients had missense mutations with rapid VWF clearance, whereas type 3 patients with absence of VWFpp were homozygous for null allele...