Thrombosis and haemostasis
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Clot retraction is an essential step during primary haemostasis, thereby promoting thrombus stability and wound healing. Integrin αIIbβ3 plays a critical role in clot retraction, by inducing acto-myosin interactions that allow platelet cytoskeleton reorganisation. However, the signalling pathways that lead to clot retraction are still misunderstood. ⋯ We found an early phosphorylation peak followed by a second peak. By using specific inhibitors of kinases and small G proteins, we showed that MLC kinase (MLCK), RhoA/ROCK, and Rac-1 were involved in clot retraction and in the early MLC phosphorylation peak. Only Rac-1 and actin polymerisation, controlled by outside-in signalling, were crucial to the second MLC phosphorylation peak.
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The clinical penetrance of venous thromboembolism (VTE) susceptibility genes is variable, being lower in heterozygous carriers of factor V Leiden and prothrombin 20210A (mild thrombophilia), and higher in the rare carriers of deficiencies of antithrombin, protein C or S, and those with multiple or homozygous abnormalities (high-risk thrombophilia). The absolute risk of VTE is low, and the utility of laboratory investigation for inherited thrombophilia in patients with VTE and their asymptomatic relatives has been largely debated, leading to the production of several Guidelines from Scientific Societies and Working Groups. The risk for VTE largely depends on the family history of VTE. ⋯ The identification of the asymptomatic carrier relatives of the probands with VTE and thrombophilia could reduce cases of provoked VTE, offering them primary antithrombotic prophylaxis during risk situations. In most guidelines, this is considered justified only for relatives of probands with a deficiency of natural anticoagulants or multiple abnormalities. Counselling the asymptomatic female relatives of individuals with VTE and/or thrombophilia before pregnancy or the prescription of hormonal treatments should be administered with consideration of the risk driven by the type of thrombophilia and the family history of VTE.
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Multicenter Study
Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study.
Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary hypertension (IPAH) share a similar clinical presentation, and a differential diagnosis requires a thorough workup. Once CTEPH is confirmed, patients who can be safely operated have to be identified. We investigated risk factors associated with CTEPH and IPAH, and the criteria for the selection of operable CTEPH patients. ⋯ Non-operable CTEPH patients tended to be less differentiable from IPAH patients by risk factor analysis than operable patients. This study confirmed the association of CTEPH with history of acute venous thromboembolism and blood groups non-O, and identified diabetes mellitus and higher mean pulmonary artery pressure as factors suggesting an IPAH diagnosis. Non-operable CTEPH is more similar to IPAH than operable CTEPH regarding risk factors.
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Review Practice Guideline
General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease.
Contrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self-inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. "Classical" anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors.