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The Journal of Emergency Medicine May 2020
Topics: Blood Coagulation Factors; Humans; International Normalized Ratio; Prothrombin; Warfarin
PubMed: 32546335
DOI: 10.1016/j.jemermed.2019.07.024 -
PloS One 2016To compare the prevalence of prothrombin G20210A in patients with objectively confirmed cerebral vein or cortical vein thrombosis against healthy controls, and evaluate... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To compare the prevalence of prothrombin G20210A in patients with objectively confirmed cerebral vein or cortical vein thrombosis against healthy controls, and evaluate geographical variations.
DESIGN
Systematic review and meta-analysis of case control studies.
METHODS
We conducted a systematic review of electronic databases including MEDLINE and EMBASE. The main outcome was the prevalence of prothrombin G20210A in patients with objectively confirmed cerebral vein or cortical vein thrombosis; we also analyzed individual country variations in the prevalence. The random-effects model OR was used as the primary outcome measure.
RESULTS
In total 19 studies evaluated 868 cases of cerebral venous thrombosis and 3981 controls. Prothrombin G20210A was found in 103/868 of the patients with cerebral venous thrombosis and 105/3999 of the healthy controls [random effects pooled OR 5.838, 95% CI 3.96 to 8.58; I217.9%]. The prevalence of prothrombin G20210A was significantly elevated in Italian studies (OR 9.69), in Brazilian studies (OR 7.02), and in German studies (OR 3.77), but not in Iranian studies (OR 0.98).
CONCLUSION
Prothrombin G20210A is significantly associated with cerebral venous thrombosis when compared to healthy controls, although this association is highly dependent on the country of origin.
Topics: Brazil; Case-Control Studies; Cerebral Veins; Gene Frequency; Germany; Humans; Iran; Italy; Linkage Disequilibrium; Odds Ratio; Point Mutation; Prevalence; Prothrombin; Venous Thrombosis
PubMed: 27031503
DOI: 10.1371/journal.pone.0151607 -
Scientific Reports Mar 2018Trypsin-like proteases are synthesized as zymogens and activated through a mechanism that folds the active site for efficient binding and catalysis. Ligand binding to...
Trypsin-like proteases are synthesized as zymogens and activated through a mechanism that folds the active site for efficient binding and catalysis. Ligand binding to the active site is therefore a valuable source of information on the changes that accompany zymogen activation. Using the physiologically relevant transition of the clotting zymogen prothrombin to the mature protease thrombin, we show that the mechanism of ligand recognition follows selection within a pre-existing ensemble of conformations with the active site accessible (E) or inaccessible (E*) to binding. Prothrombin exists mainly in the E* conformational ensemble and conversion to thrombin produces two dominant changes: a progressive shift toward the E conformational ensemble triggered by removal of the auxiliary domains upon cleavage at R271 and a drastic drop of the rate of ligand dissociation from the active site triggered by cleavage at R320. Together, these effects produce a significant (700-fold) increase in binding affinity. Limited proteolysis reveals how the E*-E equilibrium shifts during prothrombin activation and influences exposure of the sites of cleavage at R271 and R320. These new findings on the molecular underpinnings of prothrombin activation are relevant to other zymogens with modular assembly involved in blood coagulation, complement and fibrinolysis.
Topics: Catalytic Domain; Enzyme Precursors; Kinetics; Protein Binding; Protein Conformation; Proteolysis; Prothrombin; Thrombin
PubMed: 29511224
DOI: 10.1038/s41598-018-21728-9 -
Zhonghua Gan Zang Bing Za Zhi =... Nov 2022To investigate the related risk factors in patients with decompensated cirrhosis complicated with sepsis. 1 098 cases with decompensated cirrhosis were collected from...
To investigate the related risk factors in patients with decompensated cirrhosis complicated with sepsis. 1 098 cases with decompensated cirrhosis were collected from January 2018 to December 2020. A total of 492 cases with complete data meeting the inclusion criteria were included. Among them, the sepsis group (240 cases) was complicated with sepsis and the non-sepsis group (252 cases) was not complicated with sepsis. Albumin, cholinesterase, total bilirubin, prothrombin activity, urea, creatinine, international normalized ratio and other indicators of the two groups of patients were collected. Child-Pugh classification and MELD score were performed on two groups of patients. Mann-Whitney U test was used for non-normally distributed measurement data, and rank sum test for grade data. Logistic regression analysis was performed on sepsis-related factors that may affect patients with decompensated cirrhosis complicated with sepsis. 162 cases of gram negative bacteria, 76 cases of gram positive bacteria and 2 cases of Candida were detected. Child-Pugh grade C was mainly in the sepsis group, and Child- Pugh grade A and B was mainly in the non-sepsis group (=-13.01, <0.05). MELD score was significantly higher in patients with sepsis than that of patients without sepsis (=-12.30, <0.05). Neutrophils percentage, C-reactive protein, procalcitonin, and total bilirubin in patients with decompensated cirrhosis complicated with sepsis were 86.90% (79.00%, 91.05%), 48.48 (17.63, 97.55) mg/l,1.34 (0.40, 4.52) ng/l, and 78.50 (32.75149.80) μmol/L, which were significantly higher than that of patients without sepsis [69.55% (58.58%, 75.90%), 5.34 (5.00, 14.94) mg/l, 0.11(0.06,0.24) ng/l, 22.50(15.10,37.55) respectively] μmol/L, <0.05], while the albumin level, prothrombin activity level, and the cholinesterase level in sepsis patients were 27.30 (24.45, 30.60) g/L, 46.00% (33.50%, 59.00%), and 1.87 (1.29, 2.66) kU/L, respectively, which was significantly lower than the non-sepsis group [32.65 (28.95, 37.23) g/l, 73.00(59.75~84.85)%, 3.13(2.23~4.59) kU/L, <0.05]. Logistic regression analysis showed that serum total bilirubin, albumin, prothrombin activity level and diabetes mellitus were the independent risk factors for complicated sepsis. Patients with decompensated cirrhosis with poor liver function and higher MELD scores are more likely to be complicated with sepsis. Therefore, during the clinical diagnosis and treatment course, patients with decompensated cirrhosis with poor liver reserve function should be actively and dynamically monitored for infection-related indicators such as neutrophil percentage, procalcitonin, C-reactive protein, in an attempt to detect possible potential infections and sepsis, and improve early treatment and prognosis.
Topics: Humans; Liver Cirrhosis; Procalcitonin; C-Reactive Protein; Prothrombin; Risk Factors; Prognosis; Bilirubin
PubMed: 36891692
DOI: 10.3760/cma.j.cn501113-20210913-00469 -
Scientific Reports Apr 2019Prothrombin, or coagulation factor II, is a multidomain zymogen precursor of thrombin that undergoes an allosteric equilibrium between two alternative conformations,...
Prothrombin, or coagulation factor II, is a multidomain zymogen precursor of thrombin that undergoes an allosteric equilibrium between two alternative conformations, open and closed, that react differently with the physiological activator prothrombinase. Specifically, the dominant closed form promotes cleavage at R320 and initiates activation along the meizothrombin pathway, whilst the open form promotes cleavage at R271 and initiates activation along the alternative prethrombin-2 pathway. Here we report how key structural features of prothrombin can be monitored by limited proteolysis with chymotrypsin that attacks W468 in the flexible autolysis loop of the protease domain in the open but not the closed form. Perturbation of prothrombin by selective removal of its constituent Gla domain, kringles and linkers reveals their long-range communication and supports a scenario where stabilization of the open form switches the pathway of activation from meizothrombin to prethrombin-2. We also identify R296 in the A chain of the protease domain as a critical link between the allosteric open-closed equilibrium and exposure of the sites of cleavage at R271 and R320. These findings reveal important new details on the molecular basis of prothrombin function.
Topics: Allosteric Regulation; Chymotrypsin; Crystallography, X-Ray; Enzyme Precursors; Factor Xa; Protein Domains; Protein Stability; Proteolysis; Prothrombin; Structure-Activity Relationship; Thrombin
PubMed: 30992526
DOI: 10.1038/s41598-019-42524-z -
Thrombosis Research Feb 2015Thrombophilia is reported to be a candidate etiology of recurrent pregnancy loss (RPL). No conclusive results on the association between prothrombin G20210A mutation and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thrombophilia is reported to be a candidate etiology of recurrent pregnancy loss (RPL). No conclusive results on the association between prothrombin G20210A mutation and RPL have been reported.
METHODS
We undertook a systematic review and meta-analysis of 37 case-control studies using a comprehensive electronic search on papers published by May 2014. We studied 5400 cases and 4640 controls to investigate the potential association between G20210A and RPL. In this review, we define RPL as more than 2 miscarriages.
RESULTS
A significant association was found between G20210A and RPL, with a combined odds ratio (OR) of 1.81 (95% confidence interval [CI]: 1.26-2.60). However, the risks differed in the subgroup analyses, categorized by study sites, maternal age, and type of miscarriages. The pooled OR remained significant in European studies (OR: 1.80, 95% CI: 1.35-2.41), whereas in the Middle-Eastern studies, it was not significant (OR: 2.39, 95% CI: 0.96-5.92). The risk of RPL was significantly higher in women older than 29 years (OR: 1.91, 95% CI: 1.61-6.11), and a positive relationship was only observed between prothrombin G20210A mutation and fetal loss, but not embryonic loss. There was no evidence of publication bias in any of the analyses. The sensitivity analyses showed that the findings were quite stable.
CONCLUSION
This meta-analysis suggests that the G20210A prothrombin mutation increases the risk of RPL (fetal loss, primary RPL, or secondary RPL), particularly in Europeans and women older than 29 years. We recommend further screening in more specific groups among women.
Topics: Abortion, Habitual; Adult; Female; Humans; Mutation; Pregnancy; Prothrombin; Thrombophilia
PubMed: 25528068
DOI: 10.1016/j.thromres.2014.12.001 -
Arteriosclerosis, Thrombosis, and... Jul 2023
Topics: Protein C; Protein S; Prothrombin; Blood Coagulation
PubMed: 37199157
DOI: 10.1161/ATVBAHA.123.319442 -
Der Anaesthesist Sep 2017The introduction of nonvitamin K antagonistic, direct oral anticoagulants (DOAC) made thromboembolic prophylaxis easier for patients. For many physicians, however,... (Review)
Review
The introduction of nonvitamin K antagonistic, direct oral anticoagulants (DOAC) made thromboembolic prophylaxis easier for patients. For many physicians, however, there is still uncertainty about monitoring, preoperative discontinuation, and restarting of DOAC therapy. Guidelines for the management of bleeding are provided, but require specific therapeutic skills in the management of diagnostics and therapy of acute hemorrhage. Small clinical studies and case reports indicate that unspecific therapy with prothrombin complex concentrates (PCC) and activated PCC (aPCC) concentrate may reverse DOAC-induced anticoagulation. However, PCC or aPCC at higher doses potentially provoke thromboembolic complications. However, idarucizumab, a specific, fast-acting, antidote for dabigatran, provides immediate and sustained reversal with no intrinsic or prohemostatic activity. This review article provides an overview of the pharmacology and potential risk of DOAC and the management in the perioperative period with a focus of current concepts in the treatment of DOAC-associated bleeding.
Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Dabigatran; Hemorrhage; Humans; Prothrombin; Thromboembolism
PubMed: 28455651
DOI: 10.1007/s00101-017-0313-5 -
International Angiology : a Journal of... Feb 2015Deep vein thrombosis (DVT) is a manifestation of venous thromboembolism (VTE) and accounts for most venous thromboembolic events. Although DVT is not directly... (Review)
Review
Deep vein thrombosis (DVT) is a manifestation of venous thromboembolism (VTE) and accounts for most venous thromboembolic events. Although DVT is not directly life-threatening, thrombi in the proximal veins of the leg can embolize to the lungs to form a pulmonary embolism, which may prove rapidly fatal. If untreated, DVT can also lead to significant morbidity, including development of post-thrombotic syndrome. Among many risk factors, surgery, hospitalization, older age and active cancer increase the risk of VTE, and a previous event increases the risk of recurrence. Early detection and effective clot resolution are vital in managing DVT. Conventional approaches to acute treatment of VTE involve initial fast-acting parenteral heparin overlapping with and followed by vitamin K antagonist therapy. However, vitamin K antagonists have a narrow therapeutic window, require regular monitoring, and have multiple food and drug interactions. Results from phase III clinical studies involving direct Factor Xa and IIa inhibitors suggest that these agents provide an alternative therapeutic option that overcomes some of the complications associated with conventional treatment with predictable pharmacological properties and convenient dosing schedules. Analysis of data from the rivaroxaban EINSTEIN studies also suggests that these agents have the potential to improve patient-reported treatment satisfaction and reduce the length of hospital stay compared with conventional therapy. This review considers these treatment options, suitable treatment durations to prevent recurrence, and the management of DVT treatment in challenging patient groups.
Topics: Administration, Oral; Antithrombins; Blood Coagulation; Factor Xa Inhibitors; Hemorrhage; Humans; Patient Selection; Prothrombin; Recurrence; Risk Assessment; Risk Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis
PubMed: 24927023
DOI: No ID Found -
Journal of Thrombosis and Haemostasis :... Jul 2023Current assays that monitor thrombin generation in plasma rely on fluorogenic substrates to follow the kinetics of zymogen activation, which may be complicated by...
BACKGROUND
Current assays that monitor thrombin generation in plasma rely on fluorogenic substrates to follow the kinetics of zymogen activation, which may be complicated by substrate cleavage from other proteases. In addition, these assays depend on activation following cleavage at the prothrombin R320 site and fail to report the cleavage at the alternative R271 site, leading to the shedding of the auxiliary Gla and kringle domains of prothrombin.
OBJECTIVES
To develop a plasma assay that directly monitors prothrombin activation independent of fluorogenic substrate hydrolysis.
METHODS
Cleavage at the R271 site of prothrombin is monitored through loss of Förster resonance energy transfer in plasma coagulated along the extrinsic or intrinsic pathway.
RESULTS
The availability of factor (F)V in plasma strongly influences the rate of prothrombin activation. The rate of thrombin formation is equally perturbed in FV or prothrombin-depleted plasma, implicating that the thrombin-catalyzed feedback reactions that amplify the coagulation response play an important role in generating sufficient amounts of FVa required for the assembly of prothrombinase. Congenital deficiencies in FVIII and FIX significantly slow down cleavage at R271 in plasma coagulated along the extrinsic and intrinsic pathways. Prothrombin activation in FXI-deficient plasma is only perturbed when coagulation is triggered along the intrinsic pathway.
CONCLUSION
The Förster resonance energy transfer assay enables direct monitoring of prothrombin activation through cleavage at R271 without the need for fluorogenic substrates. The assay is sensitive enough to assess how deficiencies in coagulation factors affect thrombin formation.
Topics: Humans; Prothrombin; Thrombin; Fluorescence Resonance Energy Transfer; Fluorescent Dyes; Blood Coagulation Factors; Factor Xa
PubMed: 36931601
DOI: 10.1016/j.jtha.2023.03.008