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Blood Jun 2024The factor V Leiden (FVL; rs6025) and prothrombin G20210A (PTGM; rs1799963) polymorphisms are 2 of the most well-studied genetic risk factors for venous thromboembolism...
The factor V Leiden (FVL; rs6025) and prothrombin G20210A (PTGM; rs1799963) polymorphisms are 2 of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with previous studies showing marked disagreement regarding thrombosis risk conferred by the DH genotype. Using multidimensional data from the UK Biobank (UKB) and FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937 939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared with wild-type individuals (odds ratio [OR] = 5.24; 95% confidence interval [CI], 4.01-6.84; P = 4.8 × 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N = 445 144) found that effect size estimates for the DH genotype remained largely unchanged (OR = 4.53; 95% CI, 3.42-5.90; P < 1 × 10-16) after adjustment for commonly cited VTE risk factors, such as body mass index, blood type, and markers of inflammation. In contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic data sets to conduct, to our knowledge, the largest study to date on the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and may confer a similarly increased risk of VTE.
Topics: Humans; Prothrombin; Factor V; Female; Male; Heterozygote; Middle Aged; United Kingdom; Biological Specimen Banks; Aged; Risk Factors; Venous Thromboembolism; Adult; Thrombosis; Genetic Predisposition to Disease; Genotype; Polymorphism, Single Nucleotide; UK Biobank
PubMed: 38498041
DOI: 10.1182/blood.2023023326 -
Scientific Reports Jan 2020The equilibrium between active E and inactive E* forms of thrombin is assumed to be governed by the allosteric binding of a Na ion. Here we use molecular dynamics...
The equilibrium between active E and inactive E* forms of thrombin is assumed to be governed by the allosteric binding of a Na ion. Here we use molecular dynamics simulations and Markov state models to sample transitions between active and inactive states. With these calculations we are able to compare thermodynamic and kinetic properties depending on the presence of Na. For the first time, we directly observe sodium-induced conformational changes in long-timescale computer simulations. Thereby, we are able to explain the resulting change in activity. We observe a stabilization of the active form in presence of Na and a shift towards the inactive form in Na-free simulations. We identify key structural features to quantify and monitor this conformational shift. These include the accessibility of the S1 pocket and the reorientation of W215, of R221a and of the Na loop. The structural characteristics exhibit dynamics at various timescales: Conformational changes in the Na binding loop constitute the slowest observed movement. Depending on its orientation, it induces conformational shifts in the nearby substrate binding site. Only after this shift, residue W215 is able to move freely, allowing thrombin to adopt a binding-competent conformation.
Topics: Amino Acid Motifs; Humans; Kinetics; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Prothrombin; Sodium; Thrombin
PubMed: 31974511
DOI: 10.1038/s41598-020-57822-0 -
Reviews on Recent Clinical Trials 2022Alterations in erythrocyte morphology parameters have been identified and associated with hematological disorders and other chronic and cardiovascular diseases....
BACKGROUND
Alterations in erythrocyte morphology parameters have been identified and associated with hematological disorders and other chronic and cardiovascular diseases. Erythrocytes are abundant in thrombus content. Their hemoglobin density and differences in the ratio of macrocytic and microcytic cells may be associated with hypercoagulopathy in those with a history of thrombosis.
OBJECTIVE
This cross-sectional study aimed to investigate the relationship between hemogram parameters and thrombophilia genetic parameters.
METHODS
A total of 55 patients whose thrombophilia panel was reviewed due to the diagnosis of thrombosis were included in the study. % MIC, % MAC, % HPO, % HPR and all hemogram parameters were measured using Abbott Alinity HQ. Prothrombin G20210A, MTHFR C677T, MTHFR A1298C, Factor V Leiden G169A and PAI-1 4G/5G mutations were studied using Real Time- PCR.
RESULTS
The MTHFR C677T mutation was detected in 58.2% of the patients. The Factor V Leiden mutation was detected in 5.5% of the patients. The MTHFR A1298C mutation was detected in 58.2%, The PAI mutation was detected in 74.5%, and the Factor 13 mutation was detected in 29% of the patients. Prothrombin G20210A mutation was not detected in any of the patients. Red blood cell (RBC) and hematocrit (Hct) values were higher in Factor 13 mutant group; the Hgb and Htc values were higher in the MTHFR C677T mutant group. The plateletcrit (PCT) and platelet (PLT) values were lower in MTHFR C677T mutant group.
CONCLUSION
The MTHFR C677T and Factor 13 mutations may be associated with high Hct and Hgb, RBC, Hgb, and Htc values, respectively and coagulation tendency in patients with a history of thrombosis.
Topics: Cross-Sectional Studies; Erythrocytes; Factor XIII; Humans; Mutation; Prothrombin; Thrombophilia; Thrombosis
PubMed: 34814821
DOI: 10.2174/1574887116666211123092603 -
Casopis Lekaru Ceskych 2019Thrombotic states are inherited or acquired predisposition for thrombosis in the human vascular system. Nowadays Leiden mutation and mutation in prothrombin G20210A...
Thrombotic states are inherited or acquired predisposition for thrombosis in the human vascular system. Nowadays Leiden mutation and mutation in prothrombin G20210A contributing to congenital thrombophilia are routinely tested. These mutations have a high prevalence in the population. Congenital deficiencies of protein S, protein C and antithrombin III are rare thrombophilia with lower population frequency, but higher risk of thromboembolic event. The genetic causes are mutations in the genes, which encode these proteins. The choice of proper molecular genetic testing depends on the difference in the detection of well-known single nucleotide polymorphism or unknown/rare variant. For the detection of causative variant FV Leiden and prothrombin G20210A are mostly used PCR-RFLP, reverse Strip Assay®, allele-specific PCR, TaqMan real-time PCR and SNaPshot®. Precise patient selection should precede the genetic testing of rare variants in anticoagulant proteins. It is appropriate to use methodology of massive parallel sequencing supplemented by a methodology for the detection of larger gene rearrangements - MLPA. We are successfully employing this approach in our institute. This methodology is faster with larger analytic capacity compared to commonly used direct sequencing by Sanger method.
Topics: Genetic Predisposition to Disease; Humans; Mutation; Prevalence; Prothrombin; Risk Factors; Thrombophilia
PubMed: 31046389
DOI: No ID Found -
SARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition.Nature Communications Oct 2023Severe COVID-associated lung injury is a major confounding factor of hospitalizations and death with no effective treatments. Here, we describe a non-classical fibrin...
Severe COVID-associated lung injury is a major confounding factor of hospitalizations and death with no effective treatments. Here, we describe a non-classical fibrin clotting mechanism mediated by SARS-CoV-2 infected primary lung but not other susceptible epithelial cells. This infection-induced fibrin formation is observed in all variants of SARS-CoV-2 infections, and requires thrombin but is independent of tissue factor and other classical plasma coagulation factors. While prothrombin and fibrinogen levels are elevated in acute COVID BALF samples, fibrin clotting occurs only with the presence of viral infected but not uninfected lung epithelial cells. We suggest a viral-induced coagulation mechanism, in which prothrombin is activated by infection-induced transmembrane serine proteases, such as ST14 and TMPRSS11D, on NHBE cells. Our finding reveals the inefficiency of current plasma targeted anticoagulation therapy and suggests the need to develop a viral-induced ARDS animal model for treating respiratory airways with thrombin inhibitors.
Topics: Animals; Humans; COVID-19; SARS-CoV-2; Thrombin; Prothrombin; Lung; Epithelial Cells; Fibrin
PubMed: 37821447
DOI: 10.1038/s41467-023-42140-6 -
Blood Coagulation & Fibrinolysis : An... Jul 2016Distribution of hereditary thrombophilic gene mutations differs globally. Prothrombin gene mutation G20210A is a common prothrombotic single-nucleotide polymorphism. In... (Review)
Review
Distribution of hereditary thrombophilic gene mutations differs globally. Prothrombin gene mutation G20210A is a common prothrombotic single-nucleotide polymorphism. In this systematic review, we provide a comprehensive report of the prevalence of prothrombin G20210A across the globe. Databases [Pubmed, Web of Science, Embase] were interrogated from their inception through December 2015 for articles reporting prothrombin G20210A prevalence rates and ethnicity. Prevalence rates were organized by continent and ethnoracial ancestry. A total of 113 articles were included with a total 61 876 participants tested for prothrombin G20210A. Reported prevalence rates varied from 0 to 15.9% among ethnic groups, with higher rates seen in the thromboembolism affected cohort compared with the unaffected cohort. Carrier rate distribution is supported by known historical migration patterns of global populations. This review of prothrombin G20210A prevalence may guide resourceful screening for identification of hereditary thrombophilia in female populations of interest with hypercoagulable states.
Topics: Asian People; Black People; Female; Gene Expression; Global Health; Heterozygote; Humans; Mutation Rate; Polymorphism, Single Nucleotide; Prevalence; Prothrombin; Thrombophilia; Venous Thromboembolism; White People; Women's Health
PubMed: 27058219
DOI: 10.1097/MBC.0000000000000562 -
Medizinische Klinik, Intensivmedizin... Oct 2015More and more patients are being treated with direct oral anticoagulants (DOAC). Under treatment with DOACs gastrointestinal bleeding appears to occur more frequently,... (Review)
Review
BACKGROUND
More and more patients are being treated with direct oral anticoagulants (DOAC). Under treatment with DOACs gastrointestinal bleeding appears to occur more frequently, particularly in the lower gastrointestinal tract, compared to treatment with vitamin K antagonists (e.g. warfarin).
OBJECTIVE
A possible approach should now be elaborated in a joint effort by gastroenterologists and cardiologists.
MATERIAL AND METHODS
A selective literatue search was carried out and own experiences were also included.
RESULTS
The decision to perform procoagulant therapy by slowly injecting 30-50 IU prothrombin complex concentrate (PPSB) per kg body weight intravenously depends on various factors and should be assessed critically. Specific antidotes are awaiting approval. After a bleeding episode potentially controllable and reversible triggers must be excluded (e.g. drug interactions and renal impairment). The risk of recurrent bleeding and the risk of thromboembolic events have to be weighed against each other before deciding to readminister an anticoagulant and its form. Dose reduction and changing to apixaban (in reduced dosage) are options for risk reduction and vitamin K antagonists can also be considered.
DISCUSSION
It is still unclear what role specific antidotes will play.
Topics: Administration, Oral; Anticoagulants; Critical Care; Drug Substitution; Gastrointestinal Hemorrhage; Humans; Injections, Intravenous; Prothrombin; Pyrazoles; Pyridones; Recurrence; Risk Factors; Thromboembolism; Vitamin K
PubMed: 26420063
DOI: 10.1007/s00063-015-0082-3 -
Animal Models and Experimental Medicine Feb 2023Knowing the variability of blood coagulation responses to liver damage of different origins can provide a key to curing liver tissues or to mitigating treatment side...
BACKGROUND
Knowing the variability of blood coagulation responses to liver damage of different origins can provide a key to curing liver tissues or to mitigating treatment side effects. The aim of the present work was to compare the changes in the main components of hemostasis under experimental drug-induced hepatosis and hepatitis in rats.
METHODS
We modeled diclofenac-induced hepatitis and tetracycline-induced hepatosis. Hemostasis response was gauged by measuring fibrinogen, factor X, protein C (PC), and prothrombin in plasma. The decarboxylated form of prothrombin was detected by measuring prothrombin index and ecamulin index. Platelet reactivity was studied using aggregometry.
RESULTS
Both hepatitis and hepatosis decreased the synthesis of fibrinogen, factor X, and prothrombin. However, protein carboxylation was not disrupted in hepatosis but was much impaired in hepatitis. PC decreased in both models as a consequence of its consumption possibly during inflammatory response. Platelet aggregation rate was lower in hepatosis but higher in hepatitis.
CONCLUSIONS
Our findings imply the need for a thorough monitoring of the hemostasis system in liver diseases to avoid possible thrombotic complications. Its state indicates the disorder's rate and character.
Topics: Rats; Animals; Prothrombin; Factor X; Blood Coagulation Factors; Fibrinogen; Liver Diseases; Hemostatics; Chemical and Drug Induced Liver Injury
PubMed: 36574273
DOI: 10.1002/ame2.12301 -
Thrombosis Research Sep 2023Cancer-associated thrombosis (CAT) is common and associated with mortality. We estimated CAT rate by cancer sites and inherited factors among cancer patients from the UK...
Cancer-associated thrombosis (CAT) is common and associated with mortality. We estimated CAT rate by cancer sites and inherited factors among cancer patients from the UK Biobank (N =70,406). The 12-month CAT rate after cancer diagnosis was 2.37% overall but varied considerably among cancer sites. Among the 10 cancer sites classified as 'high-risk' of CAT by the National Comprehensive Cancer Network guidelines, 6 had CAT rate <5%. In contrast, 5 cancer sites classified as 'average-risk' by the guidelines had CAT rate >5%. For inherited risk factors, both known mutation carriers in two genes (F5/F2) and polygenic score for venous thromboembolism (VTE) (PGS) were independently associated with increased CAT risk. While F5/F2 identified 6% patients with high genetic-risk for CAT, adding PGS identified 13 % patients at equivalent/higher genetic-risk to CAT than that of F5/F2 mutations. Findings from this large prospective study, if confirmed, provide critical data to update guidelines for CAT risk assessment.
Topics: Humans; Venous Thromboembolism; Prospective Studies; Thrombosis; Risk Factors; Mutation; Neoplasms; Factor V; Prothrombin
PubMed: 37419004
DOI: 10.1016/j.thromres.2023.06.023 -
Medicina (Kaunas, Lithuania) Jul 2022Background and Objectives: We aim to compare the diagnostic performance of Protein induced by vitamin K absence-II (PIVKA-II), a biomarker for hepatocellular carcinoma...
Background and Objectives: We aim to compare the diagnostic performance of Protein induced by vitamin K absence-II (PIVKA-II), a biomarker for hepatocellular carcinoma (HCC), and alpha-fetoprotein (AFP) in differentiating HCC and non-malignant high-risk (NMHR) groups and to determine their cut-off values. Materials and Methods: A total of 163 patients, including 40 with HCC and 123 with NMHR (100 with liver cirrhosis and 23 with non-cirrhotic high-risk patients) were prospectively enrolled. The levels of AFP and PIVKA-II were measured, and their cut-off values were determined. We calculated and compared the areas under the receiver operating characteristic (AUROC) curves of PIVKA-II, AFP, and their combination. Results: The levels of PIVKA-II and AFP were found to be significantly higher in the HCC compared to NMHR patients (p < 0.0001). For the differentiation of HCC from NMHR, the optimal cutoff values for PIVKA-II and AFP were 36.7 mAU/mL (90% sensitivity; 82.1% specificity) and 14.2 ng/mL (75% sensitivity; 93.5% specificity), respectively. The AUROC of PIVKA-II (0.905, p < 0.0001) was higher compared to AFP (0.869, p < 0.0001), but the combination of PIVKA−II and AFP gave the highest AUROC value (0.911, p < 0.0001). However, their differences were not statistically significant (AFP vs. PIVKA; p = 0.4775, AFP vs. Combination; p = 0.3808, PIVKA vs. Combination; p = 0.2268). Conclusions: PIVKA-II and AFP showed equal performance in detecting HCC in high-risk patients. AFP as a screening marker for HCC may be adequate, and replacing or adding the PIVKA-II test in current clinical practice may be of little value.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Protein Precursors; Prothrombin; alpha-Fetoproteins
PubMed: 36013482
DOI: 10.3390/medicina58081015