Prothrombin Gene G20210A Polymorphism Research Articles

Thrombophilia genetic mutations and their relation to disease severity among patients with COVID-19.

Patients with COVID-19 infection appear to develop virus-induced hypercoagulability resulting in numerous thrombotic events. The aim of the present study was to determine the relationship between the thrombophilia genes mutations (prothrombin G20210A, factor V Leiden, and methyltetrahydrofolate reductase (MTHFR)) and the severity of COVID-19 patients. Prospective cross-sectional study. One hundred and forty patients (80 adults and 60 children) were included in the current study. They were divided into the severe COVID-19 group and the mild COVID-19 group, with each group comprising 40 adults and 30 children. The patients were assessed for FV R506Q, FV R2H1299R, MTHFR A1298C, MTHFR C677T, and prothrombin gene G20210A polymorphisms. CBC, D-dimer, renal and liver function tests, hs-CRP, ferritin, and LDH were also assessed. Thrombotic events were clinically and radiologically documented. Severe COVID-19 cases were significantly more frequent to have a heterozygous mutation for all the studied genes compared to mild COVID-19 cases (p<0.05 for all). Being mutant to gene FV R506Q carried the highest risk of developing a severe disease course (p<0.0001). Patients with abnormally high D-dimer levels were significantly more frequent to be heterozygous for FV R506Q, FV R2H1299R, and prothrombin gene G20210A (p = 0.006, 0.007, and 0.02, respectively). We concluded that there is an evident relationship between severe COVID-19 and inherited thrombophilia. In the current study, FV R506Q gene mutation carried the highest risk of developing a severe COVID-19 disease course.

Post-viral idiopathic purpura fulminans is associated with inherited thrombophilia and anti-cardiolipin antibodies.

Idiopathic purpura fulminans (IPF) is a rare and severe coagulation disorder, associated with transient anti-protein S (anti-PS) antibodies in the context of post-viral infection such as varicella. Anti-protein S antibodies are frequently found in the context of varicella, in contrast with the rarity of IPF. Other factors such as anti-phospholipid antibodies (APL) and inherited thrombophilia may be associated with severe vascular complication. This is an ancillary study of a French multicenter retrospective series and systematic review of literature. We analyzed patients who were tested for inherited thrombophilia, namely antithrombin, protein C, protein S deficiency; prothrombin gene G20210A polymorphism (FII:G20210A),Factor V R506Q polymorphism (FV:R506Q); and/or for APL (lupus anticoagulant (LA), anti-cardiolipin antibodies (ACL), or anti-beta 2-GPI antibodies (Aβ2GP1). Among the 25 patients tested for inherited thrombophilia, 7 (28%) had positive results. Three had FV R506Q, two FII:G20210A, one compound heterozygote FV:R506Q associated to FII:G20210A, and one protein C deficiency. APL testing was performed in 32 patients. It was positive in 19 patients (59%): 17 ACL (53%), 5 LA (16%), 4 Aβ2GP1 (13%). The risk of severe complications was not associated with presence of inherited thrombophilia or APL presence, with RR: 0.8 [95% CI: 0.37-1.71], p = 1 and RR: 0.7 [95% CI: 0.33-1.51], p = 0.39, respectively. We found a high prevalence of inherited thrombophilia or APL in a population of patients with IPF. However, we do not find an association with the occurrence of severe vascular complications or venous thromboembolism.

Genetic correlation between Prothrombin G20210A polymorphism and retinal vein occlusion risk.

The aim of this study was to perform an updated meta-analysis to quantitatively investigate the association between G20210A polymorphism of Prothrombin gene and the risk of retinal vein occlusion (RVO), based on the available publications with inconsistent results. We utilized the Stata software to perform the heterogeneity test, association test, Begg's and Egger's tests, and sensitivity analysis. We searched three on-line databases (PubMed, Embase, and WOS) and obtained a total of 422 articles. Based on our selection criteria, 24 case-control studies were finally enrolled in this overall meta-analysis; a subgroup analysis by the factors ethnicity, control source, and RVO type was done. Through the association test of overall meta-analysis, we did not observe a significant difference between RVO cases and controls under the A vs G (allele) (z=1.49, P=0.137), A vs G (carrier) (z=1.42, P =0.155), GA vs GG (z=1.50, P=0.135), and GA+AA vs GG (z=1.50, P=0.135). Furthermore, we observed similar negative results in the association test of subgroup analysis (all P>0.05). Heterogeneity, Begg's, and Egger's tests excluded the presence of high heterogeneity and publication bias. Statistically stable results were observed in the sensitivity analyses. Based on integrated analysis of the current evidence, Prothrombin gene G20210A polymorphism is likely unrelated to the risk of RVO.

The association of inherited thrombophilia and intrauterine fetal death

Inherited thrombophilias are probably associated with placenta-mediated pregnancy complications, but the strength of the association between inherited thrombophilias and intrauterine fetal death after 22 gestational weeks varies due to small sample size and different methodologies used across studies. The objective of the present study was to investigate the association of inherited thrombophilia and intrauterine fetal death in a case-control design. We studied 105 women with a history of intrauterine fetal death after 22 gestational weeks and 262 controls with live births. We investigated the prevalence of the factor V Leiden (F5 rs6025) and prothrombin gene G20210A (F2 rs1799963) polymorphisms, and antithrombin, protein C and protein S deficiencies, and their association with intrauterine fetal death. Results were presented as percentages and odds ratios (ORs) with 95% confidence intervals (CIs). A total of 18.4% of cases and 11.8% of controls were positive for at least one inherited thrombophilia (OR 1.7; 95% CI 0.9-3.1). The prothrombin gene G20210A polymorphism (OR 4.0; 95% CI 1.1-14.4), but not the factor V Leiden polymorphism, or antithrombin, protein C or protein S deficiencies, was associated with intrauterine fetal death after 22 weeks of gestation. Compared with women with live births only, women with a history of intrauterine fetal death after 22 gestational weeks were significantly more often carriers of the prothrombin gene G20210A polymorphism.

Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms.

Pregnancy is associated with a 10-fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy-related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms. The study comprised 377,155 women with 613,232 pregnancies at 18 Norwegian hospitals from 1 January 1990 to 31 December 2003. Of a total 559 cases with a validated first lifetime diagnosis of VT in pregnancy or within 14 weeks postpartum, and 1229 controls naive for VT, 313 cases and 353 controls donated biological material. The odds ratios for VT during pregnancy or puerperium were 5.0 [95% confidence interval (CI) 3.1-8.3] and 9.4 (95% CI 2.1-42.4) for heterozygous carriers of the FV Leiden and the prothrombin gene polymorphisms, respectively. All homozygous carriers of the FV Leiden polymorphism (n = 8) and the prothrombin polymorphism (n = 1) developed VT, indicating a very high risk of VT. We estimated that pregnancy-related VT occurred in 1.1/1000 non-carriers, in 5.4/1000 heterozygous carriers of the FV Leiden polymorphism, and in 9.4/1000 heterozygous carriers of the prothrombin polymorphism. To avoid one VT, the number of pregnant women needed to be screened for these two polymorphisms and the number needed to be given thromboprophylaxis were 2015 and 157, respectively. Although the relative risk for VT during pregnancy and after delivery was increased among carriers of the FV Leiden and the prothrombin polymorphisms, the overall probability for pregnancy-related VT was low.

Thrombophilia and the risk of thromboembolic events in women on oral contraceptives and hormone replacement therapy

Thrombophilia contributes to the risk of thrombosis in women using female hormones. The objective of the present study was to evaluate the prevalence of thrombophilia in women with thromboembolic events (TEEs) using oral contraceptives or hormone replacement therapy (HRT) and assess the contribution of a family history and the duration of hormone use in predicting thrombosis. A retrospective analysis was performed of the case records of women who developed a TEE while on oral contraceptives or HRT and were referred for thrombophilia evaluation over a 4-year period. Among 85 women who developed a TEE while on oral contraceptives or HRT, 65 had at least one additional thrombophilia risk factor. Of the 85 cases, 23 tested positive for more than two thrombophilias, 16 had factor V Leiden, five had the prothrombin gene G20210A polymorphism, 26 had antiphospholipid antibodies, 10 had elevated homocysteine, four had protein C deficiency, and seven had protein S deficiency. There were 64 TEE: 16 pulmonary emboli, 17 cerebrovascular events, 11 intra-abdominal thromboses, 13 deep venous thromboses, five cases of superficial thrombophlebitis, and two retinal vein thromboses. Of the 65 women, 37% had a positive family history of thrombosis. Approximately half of the women had been taking oral contraceptives or HRT for more than 1 year. There is a high prevalence of thrombophilia in women who developed a TEE while using oral contraceptives or HRT for more than 1 year. Family and personal history of thrombosis should be carefully evaluated in all women before initiating or continuing oral contraceptives or HRT, and a positive history may warrant a thrombophilia screening.

The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis – a population-based case-control study

In this population-based case-control study we explored the association of antiphospholipid antibodies with pregnancy-related venous thrombosis. From 1990 through 2003 615 pregnant women were identified at 18 hospitals in Norway with a diagnosis of first time VT. In 2006, 531 of 559 eligible cases and 1092 of 1229 eligible controls were invited for further investigations. The final study population comprised 313 cases and 353 controls, who completed a comprehensive questionnaire and donated a single blood sample, 3-16 years after index pregnancy. We report the results on lupus anticoagulant, anticardiolipin antibodies, and anti-ß 2 glycoprotein-1 antibodies alone, in combination, and with the contribution of the factor V Leiden and the prothrombin gene G20210A polymorphisms. Cut-off values for APAs were chosen according to current international consensus. 29 (9.3%) of the cases and 24 (6.8%) of the controls had at least one positive test for APAs (OR 1.4; 95% CI 0.8-2.5). Nine cases (2.8%) and no controls had more than one positive test (multi-positivity) for APAs. After excluding women with factor V Leiden or prothrombin polymorphisms, still 6 cases were multi-positive for APAs. We conclude that multi-positivity, but not single-positivity, for APAs was weakly associated with a history of ante- and postnatal VT.

Henoch–Schonlein purpura: polymorphisms in thrombophilia genes

Henoch-Schonlein purpura (HSP) is a small-sized vasculitis affecting mainly children. Based on the hypothesis that an inherited predilection to hypercoagulability may predispose to HSP or may mark those who develop acute clinical manifestations, we evaluated the possible roles of methylenetetrahydrofolate reductase (MTHFR) gene C677T, factor V (FV) gene G1691A (Leiden), and prothrombin gene G20210A polymorphisms in patients with HSP. Fifty-two HSP patients (32 boys and 20 girls) from different ethnic groups (22 Jews and 30 Arabs) and 104 ethnically matched controls were studied for these three polymorphisms. The frequencies of these mutations for each group, separately and in combinations, are described. The mutation frequencies in the MTHFR, prothrombin and FV genes in HSP patients did not differ from those in controls. In a small number of individuals (n=5) homozygosity for the 677T thermolabile variant of MTHFR was associated with hematuria. To summarise, hypercoagulability does not seem to play a role in HSP. Studies in larger cohorts and possibly inclusion of additional factors may be needed to ascertain whether homozygoty for MTHFR 677T polymorphism can influence disease severity.

Thrombophilic Disorders and the Risk of Thromboembolic Events in Women on Oral Contraceptives and Hormone Replacement Therapy.

Objective: To evaluate the frequency and distribution of thrombophilic conditions in women with thromboembolic events (TEE) while on oral contraceptives (OC) or hormone replacement therapy (HRT). To assess the contribution of the duration of hormone use and a positive family history for TEE in predicting thrombosis.Methods: Retrospective analysis of all case records of women who developed a TEE while on OC or HRT and who were referred for hypercoagulable evaluation to the Thrombosis and Hemostasis Section at a teaching hospital from 1999–2002.Results: 65 women who were taking OC or HRT and developed a TEE were identified with one or more hypercoagulable disorders. 23 women tested positive for two or more hypercoagulable disorders: 16 had Factor V Leiden 3 of them were homozygous and 13 heterozygous, 5 were heterozygous for the prothrombin gene g20210a polymorphism, 26 had positive antiphospholipid antibody tests, 10 had elevated homocysteine levels, 4 had protein C deficiency and 7 had protein S deficiency. There were 65 thromboembolic events: 16 pulmonary emboli, 17 cerebrovascular events, 11 intra-abdominal vascular thromboses, 13 extremity deep venous thrombosis (DVTs), 5 superficial thrombophlebitis, and 2 retinal vein thromboses. Of the 65 women, 37% of patients had a positive family history of thrombosis. 52% had additional risk factors for thrombosis including smoking or obesity. 51% had been taking OC or HRT for > 1 year.Conclusions: In this population, thrombophilic conditions contribute in most cases to TEE in women on OC and HRT. Approximately 50% of TEE occurred in women on OC or HRT for > 1 year. The burden of thrombosis associated with hypercoagulability in women on OC and HRT has been underestimated in prior studies by including only DVT/PE. Family and personal history of thrombosis must be thoroughly explored before initiating or continuing OC or HRT and a positive history of thrombosis may warrant a hypercoagulable evaluation.

Do we need screening for thrombophilia prior to kidney transplantation?

There is increased risk for the occurrence of deep venous thrombosis (DVT) and renovascular thrombosis after kidney transplantation. A disruption of the blood homeostasis caused by surgery and leading to clotting and bleeding malfunctions is widely accepted. However, other causes such as inherited or acquired disorders of the clotting system may further increase the risk of thrombosis. Here, we summarize and review data on possible causes, incidence and ways to prevent the occurrence of DVT and/or renovascular thrombosis after kidney transplantation. The incidence of DVT after kidney transplantation is 6.2-8.3% and approximately 25% of these patients suffer from pulmonary embolism. The DVT occurs primarily on the side of the transplant with an increased risk throughout the first 5 months after transplantation. Thereby, 2-12% of the patients develop renovascular thromboses, most of which are related directly to the surgery. However, inherited or acquired thrombophilia may also play an important role. A severe course is known for prothrombin gene G20210A polymorphism, which can result in graft loss. A great diversity of prophylactic treatments is available but adjustment to the underlying circumstances is crucial for a favourable outcome. Low-dose heparin prophylaxis for at least 2-3 weeks can be used as standard therapy to prevent the occurrence of DVT after kidney transplantation. However, this may not be sufficient for concurrent disorders of the blood homeostasis such as elevated levels of antiphospholipid antibodies, lupus anticoagulant, prothrombin gene G20210A polymorphism or a combined inherited thrombophilia. These patients may need a prophylactic anticoagulation with coumarins starting prior to transplantation and being continued for at least 1 year or even lifelong. Only randomized trials can answer the question concerning optimal duration and safety of coumarins in this setting. DVT and/or renovascular thromboses are severe complications after kidney transplantation. Inherited and acquired thrombophilia, apart from surgery and abnormal anatomy itself, have to be considered and proper prophylactic treatment initiated.

Factor V Leiden and prothrombin gene G20210A mutations in Italian patients with Behçet's disease and deep vein thrombosis

To evaluate the frequency and type of vascular lesions and to study the association of factor V gene G1691A (Leiden) and prothrombin gene G20210A polymorphisms with venous thrombosis in Italian patients with Behçet's disease (BD). Included were 118 consecutive Italian BD patients followed over a 3-year period (1997-1999) who satisfied the International Study Group criteria for BD. The control group consisted of 132 healthy Italian blood donors. All BD patients and controls were genotyped by polymerase chain reaction and allele-specific restriction enzyme techniques for factor V Leiden and prothrombin gene G20210A polymorphisms. Vascular lesions were observed in 37 (31.4%) patients. The 2 most common lesions were subcutaneous thrombophlebitis (10.2%) and deep vein thrombosis (DVT) of the legs (22.8%). No significant demographic and clinical differences between patients with and without DVT were present. The distribution of allele and genotype frequencies of prothrombin gene G20210A and factor V Leiden polymorphisms did not differ significantly between BD patients and healthy controls. The frequencies of carriage rates of prothrombin gene G20210A and factor V Leiden polymorphisms in BD patients with and without DVT were similar. However, the frequency of 20210A allele was significantly higher in BD patients with ocular disease than in those without, particularly in the patients with posterior uveitis/retinal vasculitis. The frequency and types of vascular lesions in Italian BD patients were similar to those reported in studies from other countries. No association between factor V Leiden mutation and G20210A mutation in the 3'-untranslated region of the prothrombin gene with DVT was found. However, a prothrombin gene G20210A mutation may influence the development and severity of ocular involvement in BD.

Thrombophilic mutations in high-risk atrial fibrillation patients: high prevalence of prothrombin gene G20210A polymorphism and lack of correlation with thromboembolism.

Atrial fibrillation (AF) is a common arrhythmia that results in a high risk of cerebral and peripheral embolism. Factor V Leiden and factor II G20210A variant are two leading conditions for venous thrombosis. The aim of our study was to find out whether these two common prothrombotic mutations play a role in the occurrence of embolic events in AF patients. We investigated 336 non-valvular AF patients and 336 healthy control subjects. Factor II G20210A variant was found in 24/336 patients (7.14%) and in 11/336 of control subjects (3.3%). At a multivariate analysis, factor II G20210A variant was independently associated to AF (OR 2.4 95% CI 1.1-5.2; p<0.05). No significant difference was observed in the prevalence of factor V Leiden in the two groups investigated [6/304 (2.0%) in patients vs 13/336 (3.9%) in controls (p=0.24)]. AF patients were separately analyzed in relation to the occurrence or absence of a cerebral or peripheral embolic event (200 with and 136 without embolic event). The prevalence of the two mutations among AF patients with and without an embolic event was similar [factor II G20210A polymorphism (7% and 7.3% respectively) and factor V Leiden (1.2% and 2.9%, respectively)]. No differences were found in relation to the type of embolic event. Our results suggest a possible relationship between the presence of prothrombin gene variant and AF per se.

Prospective study of the G20210A polymorphism in the prothrombin gene, plasma prothrombin concentration, and incidence of venous thromboembolism.

Case-control studies have indicated increased risk of venous thrombosis associated with the prothrombin gene G20210A polymorphism and with elevated plasma prothrombin levels. We sought to confirm these results in a prospective population-based study of 21,690 persons. We measured G20210A and prothrombin antigen on pre-event blood samples of 302 participants who developed venous thromboembolism (VTE) and 626 participants who remained free of VTE. Approximately 4.0% of cases and 2.4% of controls carried the G20210A polymorphism, but only one of 137 African Americans did. The odds ratio in whites was 1.87 (95% CI = 0.85, 4.11)--higher for those who reported a prior history of VTE (OR = 5.44) than those reporting no VTE history (OR = 1.41) and in those with idiopathic VTE (OR = 2.51) than those with secondary VTE (OR = 1.38). There was no association between venous thromboembolism and plasma prothrombin antigen level. We estimated that the G20210A polymorphism may account for approximately 2.5% of venous thromboembolism events in United States whites.

The prothrombin G20210A polymorphism in patients with myocardial infarction.

To investigate a possible association between the human prothrombin gene G20210A polymorphism and coronary artery thrombosis, we screened 172 consecutive patients with ischaemic heart disease admitted for coronary arteriography. The patients were divided into two groups on the basis of their clinical history and examination of their hospital records: 66 patients with a definite previous myocardial infarction, and 106 with angina-like chest pain but no evidence of myocardial infarction. The overall frequency of the G20210A polymorphism was 0.011, four out of the 172 patients being heterozygous for the mutation. The allelic frequency was 0.015 in the group with myocardial infarction and 0.009 in the group without myocardial infarction (P = 0.622). The results of this study suggest that the single nucleotide polymorphism at position 20210 of the prothrombin gene is unlikely to be a risk factor for coronary thrombosis.