1,721,135 research outputs found
Type 2B von Willebrand Disease : a Matter of Plasma Plus Platelet Abnormality
Full text linkType 2B von Willebrand disease (VWD2B) is a rare, autosomal-dominant inherited bleeding disorder, characterized by an enhanced ristocetin-induced platelet aggregation in platelet-rich plasma and often with variable degree of thrombocytopenia and loss of high-molecular-weight multimers von Willebrand factor (VWF). All these phenomena are caused by a mutant VWF, normally synthesized and assembled by endothelial cells, but with heightened affinity binding to the platelet receptor glycoprotein Ib-α (GpIb-α). When this abnormal VWF is released into the circulation and under specific clinical circumstances, in vivo platelet clumping is observed. Mutations, invariably clustered in exon 28 of the VWF gene encoding for the VWF A1 domain involved in VWF binding to GpIb-α, are responsible for VWD2B phenotype. Clinical and laboratory phenotype appears strongly related to the type of VWF-causative mutations. However, recent evidences suggest that a true platelet defect is also present in this type, with several morphological and functional abnormalities being detected in a subset of VWD2B patients
Association of factor V deficiency with factor V HR2
No full textBackground and Objectives. Factor V HR2 possesses decreased co-factor activity to activated protein C and an increased ratio of factor V1 to factor V2. Factor V HR2 is associated with a mild increase in the risk of venous thromboembolism although not all studies concur on this point. Design and Methods. Inconsistencies in results of the epidemiological studies may stem from a failure to identify other variables in factor V which might contribute to an increased risk of thrombosis in selected HR2 carriers. The aim of this study was to establish whether factor V deficiency increases the risk of venous thromboembolism when associated with HR2. Results. Four hundred and ninety-seven patients with venous thromboembolism and 498 controls were studied. HR2 was present in 12.5% of patients and 10.4% of controls. Factor V deficiency was associated with HR2 in 4.6% of patients and 1.0% of controls. The OR for venous thromboembolism in individual with HR2 alone was 1.2 (95% Cl 0.8-1.8), while it was 4.7 (95% Cl 1.8-12.5) for those with HR2 plus factor V deficiency. Interpretation and Conclusions. Patients with HR2 and factor V deficiency developed a thrombotic event earlier (median age 35 years) than patients with HR2 alone (median age 43 years, p = 0.018). Double heterozygosity for HR2 and a factor V defect, including factor V deficiency, increased the thrombotic risk afforded by HR2
A novel fibrinogen gamma chain mutation (gamma 239 Gln -> His) is the cause of dysfibrinogenemia Vicenza
No full textCongenital hypofibrinogenemia associated with novel heterozygous fibrinogen Bbeta and gamma chain mutations
No full textRecurrence of the “deep-intronic” FGG IVS6-320A>T mutation causing quantitative fibrinogen deficiency in the Italian population of Veneto
No full textQuantitative fibrinogen deficiency is a rare bleeding disorder characterized by abnormally low levels of fibrinogen in plasma, generally due to mutations in one of the three fibrinogen genes: FGA, FGB, and FGG, coding for A[alpha], B[beta], and [gamma] chain, respectively. Although the partial defect (hypofibrinogenemia) is due to mutations occurring in the heterozygous state, homozygosity or compound heterozygosity for the same genetic defects give rise to the more severe afibrinogenemia. Mutations responsible for these conditions are scattered throughout the three fibrinogen genes, with only few sites representing relative mutational hot spots. In this study, we report the identification of the FGG IVS6-320A>T mutation in an Italian hypofibrinogenemic patient from Veneto (a region of North-Eastern Italy). This ‘deep-intronic’ mutation, which would go unnoticed by using conventional mutational screening strategies was previously reported in an afibrinogenemic family from Vicenza (a province of Veneto). The geographic clustering of patients carrying the FGG IVS6-320A>T mutation and the results of haplotype analysis suggest the existence of a common founder. This information will be useful to direct future genetic screenings in patients coming from the same geographic area
Ex vivo experimental thrombosis in variants of von Willebrand disease
No full textIn order to compare quantitative and qualitative abnormalities of von Willebrand factor (vWF) in mediating platelet adhesion and thrombus formation, we performed ex vivo perfusion studies with native blood from patients with various types of von Willebrand disease (vWD). We studied twenty-seven patients having either a quantitative (types I, III) or a qualitative (type II) abnormality of vWF. At high shear rate (2600 s-1) we found that the defect in platelet collagen interactions in type I vWD was at the level of thrombus formation whereas platelet adhesion was normal. In the patients with a qualitative abnormality of vWF (type II), platelet adhesion and thrombus formation were markedly decreased at high shear conditions, indicating that the interaction of normal vWF with the platelet glycoprotein Ib is an essential initial step in platelet collagen interaction
The factor V HR2 haplotype and the risk of venous thrombosis : a meta-analysis.
No full textBackground and Objectives. A complex haplotype of factor V gene (FV HR2) has been recently reported. FVHR2 possesses decreased co-factor activity to APC in the degradation of FVIIIa, and an increased ratio of the more procoagulant isoform FV1 compared to FV2. Contrasting results on whether the haplotype induces a significant risk of venous thromboembolism (VTE) have been reported. Design and Methods. It has been surmised that FVHR2 enhances the risk of VTE carried by FV Leiden. We carried out a meta-analysis of the reported studies on the role of HR2 haplotype in inducing a risk of VTE and the influence of the polymorphism on the risk carried by patients with FV Leiden. Results. Eight studies were analyzed for the estimation of the risk of VTE. A total of 338 out of 2,696 cases (12.5%; range 7.8 to 18.5%) and 885 out of 7,710 controls (11. 5%; range 8.1 to 12.1%) were HR2 positive. The odds ratio for VTE associated with HR2 haplotype was not statistically significant (OR 1.15; 95% C.I. 0.98-1.36). The OR for the association between FV Leiden and FV HR2 and the risk of VTE in cases and controls was largely heterogeneous as to OR and 95% C.I. and no statistical significant difference was observed. Interpretation and Conclusions. The data from the present meta-analysis suggests that FVHR2 could be a very mild prothrombotic factor. The association of FV Leiden and HR2 haplotype seems not to increase significantly the risk of VTE carried by isolated heterozygosity for FV Leiden. However, well-designed clinical studies are needed to clarify this issue definitely
von Willebrand's disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment
Full text linkVon Willebrand's disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency or abnormality of von Willebrand factor (VWF). VWF is a multimeric adhesive protein which plays an important role in primary hemostasis by promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions in high shear-rate conditions. It is also the carrier of factor VIII (FVIII), thus indirectly contributing to the coagulation process. VWD has a prevalence of about 1% in the general population, but the figure for clinically relevant cases is lower (about 100/million inhabitants). Bleeding manifestations are heterogeneous: mucosal bleeding is typical of all VWD cases but hemarthrosis and hematomas may also be present when FVIII levels are low.
Most cases appear to have a partial quantitative deficiency of VWF (type 1 VWD) with variable bleeding tendency, whereas qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous. Type 3 VWD is rare and the patients have a moderate to severe bleeding diathesis because of the virtual absence of VWF, and a recessive pattern of inheritance. The diagnosis of VWD, especially type I, may be difficult, because the laboratory phenotype is highly heterogeneous and is confounded by the fact that factors outside the VWF gene (e.g., blood group) influence VWF levels. An array of tests is usually required to characterize the VWD types of the disorder and establish the best treatment modality.
The aim of treatment is to correct the dual defect of hemostasis, i.e. abnormal coagulation expressed by low levels of FVIII and abnormal platelet adhesion expressed by the prolonged bleeding time (BT). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it corrects the FVIII/VWF levels and the prolonged BT in the majority of cases. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and for these patients plasma virally-inactivated concentrates containing FVIII and VWF are the mainstay of treatment. These concentrates are clinically effective and safe, although they do not always correct the BT
Prevalence of type 2b "Malmo/New York" von Willebrand disease in Italy : the role of von Willebrand factor gene conversion
No full textMutations in the thrombomodulin gene are rare in patients with severe thrombophilia
No full textBecause thrombomodulin plays a key role in the protein C pathway, we evaluated the contribution of thrombomodulin gene mutations to venous thrombosis. We examined 38 patients with recurrent, documented thrombotic events at a young age and a positive family history. Twelve individuals with low levels of soluble thrombomodulin in plasma were also studied. Finally, the allelic frequency of the Ala455Val polymorphism was estimated in 192 patients with at least one thrombotic event and in 369 age- and sex-matched asymptomatic controls. Two mutations were identified; G/A)201, in a severely thrombophilic patient and G/T 1456, in a patient with low soluble thrombomodulin levels. The first mutation has been reported by some, but not others, to be associated with moderately reduced levels of thrombomodulin. The second was identified previously in a patient with low soluble thrombomodulin, but expression studies failed to show functional changes in the mutant. Thrombomodulin gene mutations thus appear to be rare even in highly selected thrombophilic patients, and possibly functionally irrelevant. The allelic frequency of the Ala455Val polymorphism was identical in patients and controls. Considering the lack of a phenotype and the costly screening procedure, we recommend that thrombomodulin defects be sought only for research purposes
- …
