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Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.

ABSTRACT: BACKGROUND:Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE. OBJECTIVES:To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE. PATIENTS/METHODS:Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes. RESULTS:The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed. CONCLUSIONS:The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results.

SUBMITTER: Martin-Fernandez L

PROVIDER: S-EPMC4718515 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.

Martin-Fernandez Laura L Ziyatdinov Andrey A Carrasco Marina M Millon Juan Antonio JA Martinez-Perez Angel A Vilalta Noelia N Brunel Helena H Font Montserrat M Hamsten Anders A Souto Juan Carlos JC Soria José Manuel JM

PloS one 20160119 1

<h4>Background</h4>Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE.<h4>Objectives</h4>To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE.<h4>Patients/methods</h4>Lag time, thr ...[more]

PMID: 26784699

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Project description:Antiphospholipid syndrome (APS) is associated with arterial and venous thrombosis. The unfavorable fibrin clot phenotype, including formation of dense and poorly lysable clots, has been reported both in thrombotic APS and venous thromboembolism (VTE). The presence and amount of different proteins within a plasma clot, not only associated with the coagulation system, may influence clot properties. To our knowledge, there is a lack of data on plasma fibrin-clot bound proteins in patients with thrombotic APS or VTE. The aim of our study was to perform a quantitative proteomic analysis of fibrin clots prepared from citrated plasma from subjects with thrombotic APS and prior VTE, along with fibrin clot permeability (Ks) and clot lysis time (CLT) assessed ex vivo. We investigated 23 consecutive patients with APS, 18 with a history of first-ever VTE, and 20 age and sex matched healthy subjects. A multiple enzyme digestion filter aided sample preparation and a multienzyme digestion (MED) FASP method combined with LC-MS/MS analysis performed on a Proxeon Easy-nLC System coupled to the Q Exactive HF mass spectrometer were used. The proteomic analysis revealed that clot composition regarding 117 proteins in APS patients and 48 proteins in VTE patients was changed as compared to healthy controls, while 72 clot-bounded proteins differed between APS and VTE subjects. In healthy controls, Ks was associated with fibrinogen alpha and gamma chains (r=0.46 and r=0.46, both p<0.05, respectively) or apolipoprotein B-100 (r=-0.53, p<0.05), while CLT correlated with annexin A2 (r=-0.58, p<0.05), apolipoportein(a) (r=0.47, p<0.05), or platelet glycoprotein 4 (r=0.59, p<0.05). In VTE patients correlations of Ks with complement C1q and histone H2B, as factors closely linked with thrombosis, were observed (r=-0.52 and r=-0.47, both p<0.05, respectively). In patients with thrombotic APS all above-mentioned associations were not found. This study is the first to show that different proteins are able to influence the clot formation, structure, and properties. Since, prothrombotic conditions abolished associations observed in healthy subjects fibrin clots, differences in protein clot components might explain the links between prothrombotic fibrin clot phenotype and thromboembolic events.

Project description:IntroductionVenous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, is a common and potentially fatal post-surgery complication. Research has shown that 50% of VTE causes are intraoperative, with the risk of occurrence highest during and immediately post-surgery. Therefore, strategies for early assessment and prevention should be established.ObjectiveTo identify optimal equipment selection, compression protocols, and strategies for complication prevention and management during intraoperative intermittent pneumatic compression (IPC), this study aims to synthesize the best available evidence. The objective is to inform accurate risk assessment and facilitate early mechanical prophylaxis against venous thrombosis.MethodsThe Practical Application to Clinical Evidence model proposed by the Joanna Briggs Institute was utilized. Indicators were identified using the available best evidence from January 2023 to October 2023, and a baseline review was conducted. Negative factors were identified based on clinical evidence-based practice. The implementation rates of different indicators before (n = 372) and after (n = 405) evidence-based practice, the incidence rates of intraoperative IPC-related adverse events and VTE, and the risk of venous thrombosis before (n = 50) and after (n = 50) practice were identified and compared. Furthermore, medical staff's knowledge of best practices for intraoperative IPC was assessed through pre- and post-intervention surveys involving 109 operating room personnel.ResultsAll review indicators significantly improved (P < 0.01) after the evidence-based practice, and 9 reached 100%. Two intraoperative venous thrombosis events occurred before the evidence-based practice, with an incidence rate of 0.53%; no intraoperative venous thrombosis event occurred after the evidence-based practice, with no significant difference (X2 = 2.171, P = 0.141 > 0.05). However, there were significant differences in intraoperative venous blood hemodynamics before and after the practice (P < 0.05). Moreover, 9 IPC-related adverse events, including 4 cases of skin pressure, 3 cases of skin allergy, and 2 cases of lower limb circulation disorders, were reported before the evidence-based practice, with an incidence rate of 2.4%. Notably, no intraoperative IPC-associated adverse events occurred after the evidence-based practice(X2 = 9.913, P < 0.01). Meanwhile, the score of comprehension of the standard utilization of IPC for preventing venous thrombosis by medical staff in the operating room was 93.34 ± 3.64 after the evidence-based practice, which was higher than that (67.55 ± 5.45) before the evidence-based practice. Overall, the clinical practice was significantly improved the evidence-based practice.ConclusionsApplying intraoperative IPC utilization standards based on the best evidence in clinical practice effectively reduces the intraoperative IPC-associated adverse event rate and the risks of intraoperative venous thrombosis. It also improves the execution rates and compliance with mechanical prevention standards in the operating room by medical staff. Future research should prioritize the development and refinement of best clinical practices for intraoperative venous thrombosis prevention, with a particular emphasis on the integration of mechanical prophylaxis strategies.

Project description:Essentials The role of statins in hemostasis and venous thromboembolism (VTE) prophylaxis is not clear. This trial assessed whether rosuvastatin use affects thrombin generation in patients with VTE. Endogenous thrombin potential and peak were decreased by 10% and 5% with rosuvastatin therapy. These results provide basis for trials on the efficacy of statins in reducing recurrent VTE risk. SUMMARY: Background Statin therapy could form an alternative prophylactic treatment for venous thromboembolism (VTE) if statins are proven to downregulate hemostasis and prevent recurrent VTE, without increasing bleeding risk. Objectives The STAtins Reduce Thrombophilia (START) trial investigated whether statin affects coagulation in patients with prior VTE. Patients/methods After anticoagulation withdrawal, patients were randomized to rosuvastatin 20 mg day-1 for 4 weeks or no intervention. Plasma samples taken at baseline and at the end of the study were analyzed employing thrombin generation assay. Results and conclusions The study comprised 126 rosuvastatin users and 119 non-users. Mean age was 58 years, 61% were men, 49% had unprovoked VTE and 75% had cardiovascular (CV) risk factors. Endogenous thrombin potential (ETP) increased from baseline to end of study in non-statin users (mean 97.22 nm*min; 95% CI, 40.92-153.53) and decreased in rosuvastatin users (mean -24.94 nm*min; 95% CI, -71.81 to 21.93). The mean difference in ETP change between treatments was -120.24 nm*min (95% CI, -192.97 to -47.51), yielding a 10.4% ETP reduction by rosuvastatin. The thrombin peak increased in both non-statin (mean 20.69 nm; 95% CI, 9.80-31.58) and rosuvastatin users (mean 8.41 nm; 95% CI -0.86 to 17.69). The mean difference in peak change between treatments was -11.88 nm (95% CI, -26.11 to 2.35), yielding a 5% peak reduction by rosuvastatin. Other thrombin generation parameters did not change substantially. The reduction in ETP and peak by rosuvastatin was more pronounced in the subgroups of participants with CV risk factors and with unprovoked VTE. We conclude that rosuvastatin reduces thrombin generation potential in patients who had VTE.

Dataset Information

Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.

Publications

Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.

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