For Factor V Leiden Research Articles

Impact of Thrombophilic Polymorphisms in Antenatal Women on Perinatal Health: A Single-Center Prospective Study.

Despite pregnancy's hypercoagulable state, the correlation between inherited thrombophilia and thrombotic adverse pregnancy outcomes remains uncertain. The objective of this study was to determine the prevalence of inherited thrombophilic polymorphisms among asymptomatic pregnant individuals and to examine their potential correlation with adverse perinatal outcomes. in this single-center prospective study, 105 healthy pregnant women were included. Genotyping was conducted for factor V Leiden (FVL), prothrombin gene mutation, methylenetetrahydrofolate reductase enzyme (MTHFR) C677T, MTHFR A1298C, and plasminogen activator inhibitor-1 (PAI-1), alongside the assessment of protein C (PC), protein S (PS), and antithrombin (AT) levels. The study analyzed the association between inherited thrombophilic polymorphisms and pregnancy complications linked to placental insufficiency, such as gestational hypertension (GH), preeclampsia (PE), intrauterine death (IUD), fetal growth restriction (FGR), and placental abruption. The prevalence of identifiable thrombophilic polymorphism mutations was 61.9% (95% confidence interval-CI 52.4-70.8%), with the most common single mutation being PAI-1 4G/5G (12/105, 11.4%, 95% CI 6.4-18.5). The most frequent combined mutation was heterozygosity for MTHFR C677T and PAI-1 (12/105, 11.4%, 95% CI 6.4-18.5). Notably, no FVL homozygous carriers or single homozygous and heterozygous carriers for prothrombin polymorphisms were found. Additionally, no deficiencies in PC and AT were detected among participants. Except for homozygosity for PAI-1, none of the studied polymorphisms demonstrated a significant association with pregnancy complications linked to placental insufficiency. The asymptomatic carriers of inherited thrombophilic polymorphisms do not have an increased risk of adverse perinatal outcomes.

Risk Factors, Clinical Manifestations, Anticoagulation Duration, and Outcomes in Carriers of Severe Inherited Thrombophilia

Severe Inherited thrombophilia comprises deficiencies of antithrombin (AT), protein C (PC), and protein S (PS), while gain-of-function (GoF) variants include homozygosity for factor V Leiden (FVL) or prothrombin gene G20210A mutation (PGM), or double-heterozygosity. Persons with AT, Protein C, or S deficiencies have a heightened risk of developing thrombosis from a young age. Several family members are usually affected, and thrombosis may occur in unusual locations.Homozygote or double heterozygous of GoF variants may not have a family history of thrombosis, and the first thrombotic event may present later in life. The optimal duration and type of anticoagulation and their long-term outcomes for persons with severe thrombophilia require further investigation. This study aimed to compare risk factors, clinical manifestations, type and duration of anticoagulation and clinical outcomes between persons with AT, protein C, and S deficiencies and homozygote or double heterozygous persons with GoF variants. Retrospective evaluation of electronic medical records of persons with severe inherited thrombophilia referred to the Center for Blood Disorders at Weill Cornell Medicine-New York Presbyterian Hospital between January 2009 and December 2022. Severe deficiencies of AT, PC and PS were defined as (AT ≤ 60%, PC ≤ 50% and PS ≤ 40%). Results needed to be confimed in second testing in one month interval. Statistical analysis was performed using descriptive statistics, and chi-square test and Fisher's exact test were applied to compare variables between persons with AC deficiencies and GoF variants. 795 persons with inherited thrombophilia were identified, of those 671 were excluded as they had mild thrombophilia. Of the remaining 124 persons, 17 were eliminated due to absence of confirmatory results. A total of 107 persons were analyzed. There were 47 (44%) persons with anticoagulant deficiencies (AT, PC, and PS) and 60 (56%) homozygotes for FVL, PGM or double heterozygote. Mean age (SD) was 48 (13.6) and 49 (12.2) for anticoagulation deficiency and GoF mutation, respectively (Table 1). Overall risk factors for thrombosis were similar in both groups. A positive family history of thrombosis in a first-degree family member was higher in the anticoagulant deficient group (68%) compared to the GoF mutation (42%) (p=0.008). In addition, persons with anticoagulant deficiency had higher rates of thrombosis before 40 years of age compared to the GoF mutation group, 68% and 26%, respectively (p=0.031). The most frequent anticoagulant prescribed was a DOAC in both groups, with 38% and 30% used for the anticoagulation deficient group and GoF mutation group, respectively. The duration of anticoagulation was similar in both groups with most patients remaining on anticoagulation for more than one year (79% anticoagulant deficient group, 65% GoF mutation group) (p=0.3). Patients with AC deficiency had more recurrent thrombotic events while on anticoagulation compared to GoF variants (17% vs 6.7%) (Table 2). Our results indicate that patients with severe inherited thrombophilia either due to anticoagulant deficiencies or GoF mutations are likely to remain on anticoagulation for long durations and may have recurrent thrombosis despite therapeutic anticoagulation.

Thrombophilia Screening in Autoimmune Hemolytic Anemia: A Single-Center Cross-Sectional Study

Background Autoimmune hemolytic anemia (AIHA) is characterized by an increased rate of thrombosis, whose predictors are not completely clarified, although an association with active hemolysis (i.e., LDH >1.5 x ULN), anemia severity and previous splenectomy has been reported. Moreover, antithrombotic prophylaxis and its duration are not standardized in this patient-population. The value of thrombophilia screening, including congenital and acquired abnormalities, has not been established yet. Aim To investigate the prevalence of inherited and acquired thrombophilia abnormalities in a cohort of AIHA patients with or without thrombosis. Methods AIHA patients followed from January 2019 until September 2022 at a tertiary hematologic center in Milan, have been systematically tested for Factor V Leiden (FVL) and prothrombin (FII) G20210A mutation, protein C (PC), protein S (PS), antithrombin (AT) levels, and the presence of antiphospholipid antibodies (APLA, i.e., lupus anticoagulant, LAC, anti-cardiolipin and anti-b2-glycoprotein-1). Patients' hematological characteristics, additional thrombotic risk factors, history of venous/arterial thrombosis before and after AIHA diagnosis, and anticoagulant and/or antiplatelet therapies were retrospectively recorded. Results As shown in table 1, 59% of 92 enrolled patients were female with a median age at diagnosis of 70.5 years (range 24-89), and were classified as warm AIHA (50%), cold agglutinin disease (31.5%), mixed/atypical AIHA (9.8%), and Evans syndrome (association of AIHA and other immune cytopenia, 8.7%). Thrombophilia screening resulted positive in 19 patients (20.7%) including FVL (1.1%), F II (1.1%), APLA (10.8%), PC deficiency (1.1%), PS deficiency (2.2%), AT deficiency (2.2%), and more than one abnormality (2.2%). Additional risk factors considered were thrombosis prior to AIHA diagnosis, reported in 6 patients (7%, 3 venous and 3 arterial), and associated conditions (29%), including autoimmune disease (N=17), lymphoproliferative disease (N=7), myeloproliferative neoplasm (N=1), and paroxysmal nocturnal hemoglobinuria (N=1). Furthermore, 97% of subjects presented at least one risk factor (i.e., diabetes, obesity, bed rest, etc.) in addition to AIHA. Twenty-seven patients (28%) received anticoagulant prophylaxis after AIHA diagnosis, mainly short-term for hemolysis (42%) or surgery of lower limb fractures (37%), and long-term for atrial fibrillation in 24%; 22% of patients were on antiplatelet prophylaxis, and 4 patients had been splenectomized. Since AIHA diagnosis, 26 patients (28%) experienced thrombosis (77% venous, 23% arterial), with 33 total events (3 patients had > 1 event). Median hemoglobin and LDH at thrombosis were 8.6 g/dL (2-11.7), and 374 U/L (129-1873) respectively, indicating active hemolysis. No relationship was found with inherited thrombophilia abnormalities (3 patients, 8% experienced thrombosis vs 7, 10.5% who did not), whilst a significant association was noted with APLA positivity (p<0.05). Two patients with APLA experienced more than 1 event, one had 1 venous and 1 arterial event. Conclusions Along with disease activity and Evans syndrome, positivity for APLA appears the main predictor of thrombosis in AIHA and is therefore worth of testing, whilst extensive thrombophilia screening encompassing inherited abnormalities appears less useful.

A Curious Case of Acute STEMI in a Young Patient; Things are Not Always What They Seem

BACKGROUND: Acute myocardial infarction (MI) is a rare occurrence in patients under 40 years of age without positive family history for coronary artery disease (CAD). Genetic conditions as inherited thrombophilia can lead to a hypercoagulable state, resulting in thromboembolic events and arterial thrombosis. CASE SUMMARY: We present a case of a 35-year-old male patient who presented to the emergency room with an inferior MI after a strenuous cycling exercise. An urgent coronary angiography showed thrombotic formations in the right coronary artery without atherosclerotic plaques. Plain old balloon angioplasty and thrombus aspiration were performed, which was followed by GP IIb/IIIa inhibitor infusion and unfractionated heparin for 24 h. From past medical history, the patient had COVID-19 like symptoms 20 days before the event and had his first dose of anti- COVID vaccine 2 weeks prior. After additional testing, molecular genetic analysis results revealed the patient to be heterozygous for factor V Leiden (FVL) and homozygous for methylenetetrahydrofolate reductase C677T gene mutation. The patient was discharged on direct oral anticoagulant and antiplatelet therapy. After 1-year follow-up, he had no symptoms or recurrent cardiovascular events. CONCLUSION: Inherited thrombophilia is а significant risk factor for CAD and performing genetic testing in younger patients with a cardiovascular event and plays an important role for adequate treatment and prophylaxis from recurrent complications. The use of oral anticoagulation for prophylaxis is shown to be effective in these patients. However, further studies are needed to prove their exact role and duration of treatment.

Recommendations from the EGAPP Working Group: Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members

Summary of RecommendationsThe Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found adequate evidence to recommend against routine testing for Factor V Leiden (FVL) and/or prothrombin 20210G>A (PT) in the following circumstances: (1) adults with idiopathic venous thromboembolism (VTE). In such cases, longer term secondary prophylaxis to avoid recurrence offers similar benefits to patients with and without one or more of these mutations. (2) Asymptomatic adult family members of patients with VTE and an FVL or PT mutation, for the purpose of considering primary prophylactic anticoagulation. Potential benefits are unlikely to exceed potential harms. The overall certainty of these findings was deemed “moderate.” The evidence was insufficient to determine whether FVL/PT testing might have clinical utility in some circumstances, such as for identifying FVL homozygosity among asymptomatic family members of adults with idiopathic VTE or counseling patients about the risks and benefits of antithrombotic therapy. Based on the available evidence, the certainty of net health benefit was deemed “low.” The recommendations do not extend to patients with other risk factors for thrombosis, such as contraceptive use, as the evidence review that serves as the basis for the recommendations focused primarily on idiopathic VTE. RationaleIn developing these recommendations the EGAPP Working Group considered evidence in the following three areas. Analytic ValidityThere is adequate evidence that testing accurately and reliably detects the R506Q (FVL) and 20210G>A (PT) variants in the Factor V and PT genes, respectively (a more complete definition of analytic validity, clinical validity, and clinical utility is contained under the “Clinical Considerations” section). Clinical ValidityThe presence of a heterozygous FVL variant seems to be a weak risk factor for recurrence of VTE (odds ratio [OR]: 1.56). Rare homozygous FVL mutations present somewhat greater risks of VTE recurrence (OR: 2.65). The evidence for this increased risk is convincing, but the magnitude of excess risk is not as great as previously thought. The evidence is insufficient to draw conclusions about excess VTE recurrence risk resulting from compound heterozygosity (FVL and PT), but it is likely to be at least as high as with FVL alone. The OR for compound heterozygosity is 6.69. The evidence is insufficient to draw conclusions about VTE recurrence risks associated with PT mutations alone. For family members of index VTE cases, there is convincing evidence that both heterozygosity and homozygosity for FVL are associated with higher risks for VTE occurrence (ORs 3.49 and 17.84, respectively) than for family members without FVL variants. Clinical UtilityThere is convincing evidence that longer term secondary prophylaxis after an initial idiopathic VTE event yields comparable benefits to those with and without a FVL or PT mutation. For asymptomatic family members of index cases, no prophylaxis trials have been reported. Hence, there is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high.

Treatment and secondary prophylaxis of venous thromboembolism with direct oral anticoagulants in patients with severe hereditary thrombophilia

Deficiency of protein C (PC), protein S (PS), antithrombin III (AT III), and homozygosity or combined heterozygosity for Factor V Leiden (FVL) and Factor II (FII) 20210A mutation represent severe hereditary thrombophilia (SHT) and are associated with a higher risk of early-onset venous thromboembolism (VTE). In literature, few papers have described the efficacy and safety of therapy with direct oral anticoagulants (DOACs) in VTE occurring in patients with SHT. In our setting, we identified 8 patients who have suffered from early-onset VTE and underwent therapy with DOACs (6 rivaroxaban, 2 apixaban). Among them, 2 AT III deficiency, 2 PC deficiency, 3 PS deficiency, 1 combined heterozygosity for FVL, and FII 20210A were detected. During the follow-up, neither recurrences of VTE nor hemorrhagic episodes were observed. This report describes the efficacy and safety of therapy with anti-Xa in the treatment and secondary prophylaxis of VTE in patients with SHT.

Impact of double heterozygosity for Factor V Leiden and Prothrombin G20210A on the thrombotic phenotype

IntroductionBecause of the rarity of double heterozygosity for Factor V Leiden (FVL) and Prothrombin (FII) G20210A, little is known about the thrombotic phenotype in double heterozygotes. Material and methodsIn a retrospective cohort study of patients referred for a thrombophilia work-up, we investigated whether double heterozygotes (n = 138) exhibit a more severe thrombotic phenotype compared with single FVL or FIIG20210A heterozygotes, single FVL homozygotes, or wildtype carriers. ResultsThe risk of venous thromboembolism (VTE) was higher for female but not male double heterozygotes compared with single heterozygotes (FVL: 2.51, 95%CI 1.55–4.08, FIIG20210A: 1.75, 95%CI 1.14–2.68) and wildtype carriers (HR 2.53, 95%CI 1.58–4.05) but not compared with FVL homozygotes (HR 1.31, 95%CI 0.94–1.83). Female double heterozygotes developed VTE nearly a decade earlier than wildtype carriers and FVL heterozygotes (mean 44.2 vs. 52.6 and 52.2 years), most often in association with oral contraceptives. Spontaneous VTE and arterial thromboembolic events were not more frequent in double heterozygotes compared with the other genotype groups.Deep vein thrombosis (DVT) of the lower limb was the predominant VTE location in double heterozygotes, atypical vein thrombosis was rare. A phenomenon that has been described as the FVL paradox, a higher proportion of isolated DVT than pulmonary embolism, was also found for double heterozygotes. ConclusionThe thrombotic phenotype in double heterozygotes resembles the appearance of the thrombotic phenotype in FVL carriers but the thrombotic risk is aggravated by women-specific risk factors.

Prothrombotic Factors Have Significant Association with Arterial and Venous Strokes in Indian Tamilians.

Prothrombotic factors have been correlated with vascular events in young patients, with recurrent strokes, and with venous thromboembolisms. However, their prevalence in adult strokes, in healthy populations, and in specific ethnic groups is not well defined. We investigated the association of prothrombotic factors with strokes in a South Indian Tamil population. In this hospital-based cross-sectional study, plasma homocysteine (Hcys), protein C and protein S activity levels, activated protein C resistance (APCR) as a surrogate for factor V Leiden (FVL), fibrinogen, and antithrombin III (ATIII) were determined from 75 consecutive patients with ischemic stroke (IS), 25 with cortical venous thrombosis (CVT), and 75 healthy control participants. The Student t test or Mann-Whitney U test was used for comparing prothrombotic factor levels between the stroke and control groups. The χ2 or Fisher exact test was used for comparisons of proportions of thrombophilia and estimation of odds ratios. Mid-P correction was done for multiple estimations. Hcys levels in patients with IS were significantly higher compared with those in healthy control participants (P = 0.02). Proportions of ATIII deficiency and hyperfibrinogenemia were significantly higher in the IS group, and no healthy control participants had hyperfibrinogenemia. Protein C deficiency was more frequent in those with IS (17%; P < 8 × 10-5) and CVT (P < 10-7) compared with healthy control participants, and protein C activity levels (P = 0.016) were also significantly lower in patients with CVT. Other parameters had no significant associations with IS and CVT. The frequency of protein S deficiency was high in healthy control participants (60%) and in both patients with IS (45%; P = 0.1) and patients with CVT (48%; P = 0.4). No patients or control participants had abnormal APCR. In Tamilian participants, several prothrombotic factors were associated with IS. Protein C deficiency alone was associated with CVT. Replication of the pattern in genetically linked populations around the world may affect management of stroke in those populations.

Risk Factors, Clinical Manifestations, Treatment Duration and Outcomes in Carriers of Severe Inherited Thrombophilias

Background Severe Inherited thrombophilia comprisses deficiencies of natural anticoagulants (antithrombin (AT), protein C (PC), and protein S (PS), and homozygosity for factor V Leiden (FVL) or prothrombin gene mutation (PGM) or double heterozygosity or other combined thrombophilia. Carriers of AT, PC and PS have a high risk of thrombosis starting at a young age, usually several members of the same family are affected and thrombosis may occur at unusual locations. Conversely homozygotes for either FVL, PGM or double heterozygotes may not have a family history of thrombosis and the first thrombotic event may present later on life. It is also unclear what is the duration and type of anticoagulation and long-term outcomes of these carriers. The purpose of this study was to compare risk factors, clinical manifestations, type and duration of anticoagulation and clinical outcomes between carriers of anticoagulant deficiencies and those with gain of function mutations (homozygosity or double heterozygosity for FVL and PGM). Methods Retrospective evaluation of electronic medical records of patients with severe inherited thrombophilia referred to the Center for Blood Disorders at Weill Cornell Medicine-New York Presbyterian Hospital between January 2009 and June 2019. Severe deficiencies of AT, PC and PS were defined and (AT ≤ 60%, PC ≤ 50% and PS ≤ 40% (2). Patients without confirmatory laboratory results for the anticoagulant deficiencies were excluded from the study. We collected demographic data, risk factors for thrombosis, family history, type of thrombotic events, pregnancy complications in females, type and duration of anticoagulant and outcomes. Statistical analysis was performed using descriptive statistics and chi-square test was applied for comparison of variables between anticoagulant deficiency carriers and gain of function mutation carriers. Results Of a total of 107 patients identified,17 were excluded due to absence of confirmatory results. A total of 90 patients were analyzed; 70 (78%) females; mean age and range 44 (22- 82). There were 34 (38%)patients with anticoagulant deficiencies (10 AT, 6 PC and 18 PS) and 56 (62%) homozygotes for FVL, PGM or double heterozygote. Of those, 23 (39%) homozygote for FVL with one also heterozygote for the PGM, 2 (3.6%) homozygote PGM and 31(55.4%) double heterozygote. Overall risk factors for thrombosis were similar in both groups. There were no identified thrombosis risk factors in 12 and 19 patients in the anticoagulant deficiency and gain of function mutation respectively. The most common type of clinical presentation in both groups was deep vein thrombosis and pulmonary embolism. A positive family history of either thrombosis of thrombophilia in a first degree family member was equal in both groups. Likewise age less than 40 at first thrombotic event was similar. The most frequent anticoagulant prescribed in the patients with anticoagulant deficiency was a direct oral anticoagulant in 26.%% and vitamin K antagonists 22.3% in the ones with gain of function mutation. More patients with anticoagulant deficiencies remain on anticoagulation for more than 1 year than the ones with a gain of function mutation (88.5% vs 64%) and had more recurrent thrombotic events (20.6% vs.5.4%). Within the 70 female patients, 5 (7%) had first trimester pregnancy loss and 14 (20%) had multiple pregnancy losses. Conclusions: Our results suggest that patients with severe inherited antithrombin, protein C and S deficiencies have worse outcomes despite longer duration of anticoagulation than patients homozygote or double heterozygote for gain of function mutations. Disclosures De Sancho: Apellis Pharmaceuticals: Other: Advisory Board; BPL: Other: Advisory Board.

Thrombophilia genetic testing in Romanian young women with acute thrombotic events: role of Factor V Leiden, Prothrombin G20210A, MTHFR C677T and A1298C polymorphisms / Evaluarea genetică a trombofiliilor la femei tinere din România cu evenimente acute trombotice: rolul Factorului V Leiden, Protrombinei G20210A, polimorfismelor MTHFR C677T și A1298C

Abstract Objective: The present case-control study aimed at evaluating the contribution of thrombophilic polymorphisms to acute venous (VTE) as well as arterial thrombotic events (ATE) in a population of young women with few traditional thrombotic factors (CVRF). Methods: We consecutively enrolled patients under 45 years of age, with less than 3 CVRF, evaluated for VTE or ATE, women and men as a comparator. The control group consisted of healthy young women. A thrombophilia panel and genetic testing for Factor V Leiden (FVL), G20210A Prothrombin and MTHFR polimorphisms were done. Results: A total of 323 persons were enrolled: 71 women and 121 men with thromboembolic events, and 131 healthy female as controls. Hyperhomocysteinemia was more frequent in ATE (30.4%) than VTE female patients (6.25%), p&lt;0.01. Genetic testing was available in 45 women and 84 men with acute thrombotic events and in all controls. Homozygous FVL was associated with VTE in young women (10.3% vs 0% controls, p&lt;0.01). Prothrombin G20210A polymorphism had the lowest prevalence – 5.4% and only heterozygosity was found. MTHFR C677T heterozygosity showed no significant difference between women patients and controls (62.2 % vs 43.5% respectively, p=0.1). The homozygous status, less frequent (6.6%), was not associated with ATE or VTE. Homozygous MTHFR A1298C was associated with VTE in women (17.2% patients vs 4.5% controls, OR 4.34, p 0.02, CI 1.22-15.3). Conclusion: In young women with few CVRF, mild hyperhomocysteinemia, homozygosity for FVL and for MTHFR A1298C polymorphisms increase the risk for VTE but not ATE. MTHFR polymorphisms are found with increased frequency in both healthy persons and patients therefore, their significance as an important thrombotic risk modifier remains unclear.

VKORC1 -1639 G>A Polymorphism in Romanian Patients With Deep Vein Thrombosis.

The purpose of the research was to study the influence of several genetic factors, especially the -1693 G>A polymorphism of the VKORC1 gene, on the risk of acute unprovoked lower extremity deep vein thrombosis (DVT). The study included 127 patients (median age 63 [53.2; 72] years; 61 [48%] women and 66 [52%] men) who were diagnosed with acute lower extremity DVT and 114 controls (median age 62 [53; 73] years; 64 [56.1%] women and 50 [43.9%] men) without DVT. We recorded data regarding the history of DVT and the presence of varicose veins. We determined the genotypes for factor V Leiden (FVL) mutation, prothrombin G20210A mutation, VKORC1 -1639 G>A mutation, and PAI-1 -675 4G/5G polymorphism. Varicose veins were found in 67 (52.8%) patients and 29 (25.4%) controls (P < .001). FVL was present in 29 (22.8%) patients and 10 (8.8%) controls (P = .005). The VKORC1 (-1693 G>A) GG genotype was found in 42 (33.1%) patients and 41 (36%) controls, the GA genotype in 71 (55.9%) patients and 47 (41.2%) controls, and AA genotype in 14 (11%) patients and 26 (22.8%) controls (P = .020). Multivariate analysis showed that the presence of varicose veins, FVL, and VKORC1 -1639 G>A was independently associated with the risk of DVT. The VKORC1 (-1693 G>A) AA genotype was associated with fewer cases of DVT (odds ratio = 0.435; 95% confidence interval 0.205-0.991; P = .031).

Impact of Prothrombotic Risk Factors in a Cohort of Egyptian Hemophilia A Patients.

Hemophilias are a group of related bleeding disorders that show an X-linked pattern of inheritance. The clinical phenotype of severe hemophilia may vary markedly among patients as a result of many factors, including genetic prothrombotic risk factors. Our objective was to study the incidence of the most common prothrombotic risk factors for additive effects among Egyptian patients with hemophilia A and their impact on clinical phenotype; annual bleeding frequency and severity of hemophilic arthropathy, as well as the effect of a single variation in these patients. This study was carried out in 100 patients with hemophilia A. Genotyping for factor V Leiden (FVL) G1691A, prothrombin G20210A, MTHFR C677T, and A1298C mutations was conducted using a real time-polymerase chain reaction (RT-PCR) assay. Our study revealed mutations in hemophilia patients as follows: prothrombin G20210A (3 %), FVL (14 %), MTHFR C677T (42 %), and A1298C (59 %). Despite a lack of statistical significance when each gene was analysed separately, heterozygosity of prothrombin G20210A or FVL was always associated with either a mild or moderate, but never a severe, clinical presentation. The lowest bleeding frequency (less than once per month) was identified among patients with two heterozygous variants irrespective of the involved genes. In addition, the incidence of hemarthrosis was significantly higher among patients with a wild genotype of the prothrombin gene and FVL, and the average number of affected joints was significantly higher among patients with wild-type prothrombin and FVL genes than among heterozygous patients. These prothrombotic mutations have a cumulative effect in amelioration of the severity of bleeding in hemophiliacs. The most prominent effect is that of prothrombin G20210A and FVL, while MTHFR C677A and A1298C gene mutations are less conclusive.

The Contributions of Thrombophilic Mutations to Genetic Susceptibility to Deep Venous Thrombosis in Iraqi Patients.

There is a paucity of data on the contribution of various thrombophilic mutations to the development of venous thrombosis in Iraqi patients. Therefore we designed a study to assess the frequencies of known thrombophilic mutations in this population. 100 consecutive Iraqi patients with color Doppler confirmed deep venous thrombosis of the lower extremities and 100 age- and sex-matched healthy controls were enrolled in the study. Their DNAs were tested by multiplex polymerase chain reaction (PCR) followed by reverse hybridization for factor V Leiden (FVL), the prothrombin (PT) G20210A SNP, and the MTHFR C677T SNP. The factor V A4070G mutation was assessed by restriction fragment length polymorphism-PCR. The prevalence of FVL was 13% in patients versus 2% in controls (odd ratios [OR] 7.3; p=0.007). Patients with recurrent thrombosis also had a significantly higher frequency of Factor V Leiden (OR 8.4, p=0.0007). The prothrombin G20210A, SNP, the factor V A4070G SNP, and the MTHFR 677 TT genotypes were present among patients at 5%, 9%, and 11%, respectively, and among controls at 2%, 6%, and 6%; none of these single mutation prevalence differences were significant. Interestingly, however, when these polymorphisms were studied in aggregate we found that 24% of patients had two or more thrombophilic alleles, compared to only 8% of the controls (OR 3.6; p=0.002). This subgroup included significantly more patients with proximal (p=0.007) and recurrent thrombosis (p=0.012), as well as younger patients (≤40 years) (p=0.026). Two or more thrombophilic alleles, as well as FVL on its own, were both significantly associated with an increased risk of venous thrombosis and recurrence in Iraqi patients. Single thrombophilic mutations on their own were not associated with an increased risk.

IS ACROMEGALY A HYPERCOAGULABLE CONDITION? CASE REPORTS AND REVIEW OF THE LITERATURE

Introduction: Cardiovascular complications are a major cause of morbidity and mortality in patients with uncontrolled acromegaly. However, there are no published reports of an increased risk of venous thromboembolism (VTE) in such patients. We report three patients with uncontrolled acromegaly who presented with VTE. Clinical Cases: A 52-year-old male with uncontrolled acromegaly despite transsphenoidal (TSP) surgery and medical therapy presented in 2012 with acute chest pain and shortness of breath that was later con rmed as secondary to pulmonary embolism. A 44-year-old male immigrant, previously treated for acromegaly with radiation therapy alone, in 1992, in his native country, was referred to our centre in 2006 for acromegaly which remained uncontrolled despite medical therapy until 2009 when he achieved remission through TSP surgery. He had several episodes of VTE between 2008 and 2010. A 69-year-old male with uncontrolled acromegaly for 28 years despite two surgical resections and radiation therapy in 1986 and 1992, as well as continuous medical therapy, presented with VTE of the right axillary vein and bilateral pulmonary emboli in 2011. A thrombophilia screen in case 1 showed mild protein S de ciency, case 2 was homozygous for factor V Leiden (FVL) mutation and case 3 was heterozygous for FVL. Extensive investigations revealed no evidence of malignancy and echocardiography showed preserved ejection fraction in all three patients. Conclusion: Patients with uncontrolled acromegaly may be at increased risk of VTE. However, larger studies are required to further assess this association and determine the underlying cause. Key words: Acromegaly, pituitary tumours, thromboembolism

The 1691 G > A (factor V Leiden) and 1328 T > C V coagulation factor polymorphisms and recurrent miscarriages

Objectives: Inherited thrombophilia might lead to recurrent pregnancy loss (RPL). The aim of the study was to estimate the prevalence of V coagulation factor polymorphisms related with inherited thrombophilia among women in Malopolska region.Material and methods: Group of 136 women, who experienced at least 2 unexplained, idiopathic pregnancy loss. 106 healthy women having at least one uncomplicated pregnancy and delivered healthy children constituted a control group. Each patient were examined for factor V Leiden (FVL) and mutation 1328 T>C of factor V gene with use of real –time PCR and Taq-Man probes.Results: Among patients with RPL inhabiting region of Malopolska compared to control group occurred higher prevalence of FVL and mutation 1328 T>C. There is coincidence of polymorphism 1328 T>C of factor V gene and FVL in group of early and late RPL.Conclusions: TC genotype of 1328 T>C mutation carriers reveal tendency toward RPL below 7 weeks of pregnancy.Based on results of these findings inherited thrombophilia evaluation in patients after two or more RPL should be recommended.

Biomarkers for post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is a serious condition that occurs in 20%-50% of patients following deep venous thrombosis (DVT). Biomarkers can be of use in further exploring the etiology as well as in developing risk stratification tools for PTS. The relationship between PTS and specific biomarkers may help guide prevention and therapy based on a patient's individual risk profile. This review gives an overview of the current knowledge on biomarkers in relation to PTS. A systematic search was executed in three databases (Pubmed, Embase/Medline, Cochrane) to identify all publications on biomarkers in relation to PTS. Where possible, results of studies were pooled and a meta-analysis was performed using Review Manager 5.1 (The Cochrane Collaboration). Twenty-four papers were included in this review. Inpatients after DVT, increased D-dimer appeared to be associated with the development of PTS (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.02-4.08; P= .04). Neither prothrombin G20210A (OR, 0.95; 95% CI, 0.53-1.69; P= .86, nor increased factor VIII (OR, 1.78; 95% CI, 0.88-3.57; P= .11) were associated with PTS. For factor V Leiden (FVL), conflicting results were found. FVL was not associated with PTS within a population of patients with a history of DVT (OR, 0.98; 95% CI, 0.74-1.29; P= .88), but FVL was positively associated with post-thrombotic ulceration in severe PTS, inpatients compared with healthy individuals without a history of DVT (OR, 11.42; 95% CI, 6.37-20.48; P<.00001). A meta-analysis could not be performed for markers of inflammation and tissue remodelling in relation to PTS. Increased D-dimer levels are associated with a twofold increased risk for PTS. Inherited hypercoagulability, including FVL is not associated with PTS in general. In contrast, FVL is strongly associated with post-thrombotic ulceration in severe PTS. The role of inflammation in the etiology of PTS still has to be elucidated.

Thrombophilic molecular markers in young patients (&lt;40 years) with coronary artery disease

There has been an alarming rise in the incidence of coronary artery disease (CAD) in India especially involving the age group of less than 45 years. In recent past, various studies focused on hemostatic aspects of CAD, but could not determine the significance of thrombophilic molecular marker in combination. The study was undertaken to investigate the association of thrombophilia related molecular markers in young patients with CAD. Thirty diagnosed patients with CAD of either sex under 40 years were included. Thirty healthy age and sex matched control subjects without evidence of CAD formed the control group. Detailed history and clinical examination findings were recorded. In addition to routine investigations, polymerase chain reaction (PCR) based molecular analysis for Factor V Leiden (FVL), methyltetrahydrofolate reductase (MTHFR) gene, tumor necrosis factor receptor 2 (TNFR2) gene, and prothrombin gene mutation were carried out. The mean age (± SD) was 36.86 ± 3.90 years in the patients. Smoking was the most prevalent risk factor. FVL, MTHFR and TNFR2 gene mutation were seen in nine (30%) patient. Three patients had presence of more than one mutation. FVL, MTHFR and TNFR2 gene mutation was found in 4 (13.3%), 3 (10%), and 5 (16.6%) patients respectively. Prothrombin gene mutation was not seen in any of the subjects. There was no significant difference in lipid profile, fibrinogen levels and CRP among the patients with mutation and patients without mutation. Almost one-third of the cases were positive for the various mutations in the study and the presence of at-least one or the other risk factor adds on to the risk of future thrombosis. There is a need to demonstrate or document these mutations in a larger group further based upon ethnicity and geographic distribution.

Recurrent Pregnancy Loss and Its Relation to Combined Parental Thrombophilic Gene Mutations

Recurrent pregnancy loss (RPL) is a heterogeneous disorder that has been associated with antiphospholipid syndrome and other prothrombotic parameters. We aimed to investigate the prevalence of 12 thrombophilic gene mutations in RPL couples in the current results. In a total of 543 Turkish women with RPL and 327 of their male partners (870 individuals with RPL), and a control group of 106 fertile couples (control) were analyzed for factor V leiden (FVL), factor V H1299R, factor II prothrombin G20210A, FXIII V34L, β-fibrinogen -455G>A, plasminogen activator inhibitor-1 (PAI-1), GPIIIa L33P (HPA-1 a/b L33P), methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q, and Apo E genes. The overall, heterozygous and/or homozygous point mutations in FVL-FVR2, ApoE2, PAI-1, MTHFR C677T-A1298C, and ACE genes were associated with RPL. There was no meaningful association between RPL and other studied genes. The homozygosity of 4G in PAI-1 and MTHFR C677T genes in women with RPL, and heterozygosity of FVL, FVR2, ACE, and ApoE2 genes in both parents play crucial role in RPL and should be considered as a risk factor in RPL. Current results showed that RPL is related to combined parental (not only maternal) thrombophilic gene mutations.

Spontaneous obliteration of a dural arteriovenous fistula after treatment of polycythemia in a patient with Factor V Leiden mutation: case report

Dear Sirs, A 62-year-old man experienced sudden shaking and dysesthesia of the right arm that lasted about 5 min. Several hours later, he developed dysesthesia in the right hand that rapidly spread to his shoulder and right side of his face and tongue. After 10 min, these symptoms disappeared completely. Four more similar events occurred in the following 2 weeks. A few months earlier, he had experienced three episodes with visual disturbances in his right hemifield that lasted 10 min and were followed by headache. His past medical history revealed myocardial infarction, renal insufficiency due to longstanding hypertension, hyperlipidemia, and polycythemia that was untreated for several years. Neurological examination was normal. Laboratory investigations showed an increased hemoglobin (11.6 mmol/l, reference values 8.6–10.7 mmol/l), increased hematocrit (0.56, reference values 0.41–0.50), and heterozygosity for Factor V Leiden (FVL). EEG revealed no signs of epilepsy. Subarachnoid hemorrhage was seen on CT (Fig. 1b). DSA showed a DAVF (Fig. 1c) with cortical reflux (Cognard grade 2b; Borden type II) [1, 3] and thrombosis of the superior sagittal sinus. Venesections were initiated resulting in normal hemoglobin (10.2 mmol/l) and hematocrit (0.50). No more attacks occurred afterwards. Fig. 1 T1-enhanced MR image shows multiple dilated intracranial and extracranial vessels (a). Non-enhanced CT scan shows subarachnoid hemorrhage especially in the right hemisphere (b). Diagnostic DSA shows a DAVF with arterial supply from medial meningeal and ... Peroperative embolization using a burr hole directly above the fistula point was planned because tortuous feeders hampered a femoral approach and this combined approach was considered less invasive than neurosurgical occlusion. During the localizing DSA, the DAVF was found occluded with partial recanalization of the sinus (Fig. 1d–e). Follow-up MRI after 1 year showed no signs of recurrence of the fistula, a patent superior sagittal sinus, and obvious reduction of the dilated vessels (Fig. ​(Fig.11f). DAVFs are one or more direct arteriovenous connections without intervening capillary bed. They are associated with trauma, cerebral venous sinus thrombosis (CVST), and thrombophilia [4, 8, 14]. Clinical outcome correlates with angiographic features. The retrograde flow into cortical veins in our patient is associated with a hemorrhage risk of 10% according to the Cognard classification [3]. Borden type II en III fistulas are associated with either progressive neurological deficits or hemorrhage [1]. Our case demonstrates that spontaneous obliteration of a DAVF can occur after treatment of polycythemia by venesections. The combination of polycythemia and heterozygosity for FVL had resulted in a prothrombotic state that probably caused gradual development of CVST and subsequent DAVF formation. CVST commonly occurs in patients with a DAVF [14]. One hypothesis proposes opening of physiological arterial-venous shunts between meningeal arteries and venous sinuses due to increased venous pressure [7, 14]. A rat-model suggests that venous hypertension may decrease cerebral perfusion which induces angiogenesis with subsequent development of a DAVF [9, 14]. In our patient venous pressure probably decreased after normalization of the blood viscosity. Finally, organization of a thrombus in a dural sinus may lead to “growth” of dural arteries that are normally present in sinus walls, which may result in a direct communication between artery and sinus [2]. FVL is a risk factor for CVST [12], but is also implicated in the pathogenesis of DAVFs [4, 8, 15]. Moreover, polycythemia is a risk factor for CVST [12], and these patients are prone to ischemic events probably because increased blood viscosity leads to decreased cerebral blood flow [5, 11]. Venesections may increase flow in patients with polycythemia [6, 13]. Spontaneous obliteration of DAVFs has been described [4, 10]. Possible mechanisms include recanalization of CVST, intracranial bleeding (with mass effect or vasospasm leading to obliteration), or intrinsic compression of the DAVF in the sinus wall [10]. Based on the observation in our patient, we suggest that in patients with polycythemia and DAVFs that have a relatively low risk of hemorrhage, polycythemia should be treated before interventional treatment, because venesections may lead to spontaneous closure of the DAVF.

Risk factors for failure of heparin thromboprophylaxis in patients with acute traumatic spinal cord injury

Venous thromboembolism (VTE) is a well-recognized complication of Acute Traumatic Spinal Cord Injury (ATSCI). Despite prophylaxis by heparins, VTE occurs in a substantial number of ATSCI patients without an obvious explanation. In this matched case-control study we examined whether thrombophilia and other risk factors are associated with failure of thromboprophylaxis. Cases and controls receiving heparin thromboprophylaxis were selected from consecutively admitted ATSCI patients. Patients who developed a new, objectively confirmed, symptomatic VTE despite prophylaxis at hospital were matched by gender, age, level and mechanism of ATSCI with 2-3 controls without VTE. Patients were interviewed about VTE risk factors and tested for factor V Leiden (FVL), prothrombin G20210A (PT), methylenetetrahydrofolate reductase C677T homozygosity (MTHFR), lupus anticoagulant, homocysteine (Hcy) and plasma factor VIII (FVIII) levels. Twenty-two patients with new VTE episodes and 64 controls were ascertained. The total number of gene alterations for MTHFR, FVL and PT or elevated levels of Hcy or FVIII was significantly more common in patients compared to controls (82% vs. 48%, p = 0.006). Multiple logistic regression proved the PT mutation, a positive family history of thrombosis and elevated levels of either FVIII or Hcy to be predictors of thrombosis. Conclusion A positive family history of VTE, carriership of the prothrombin mutation and elevated FVIII or Hcy levels were significantly associated with failure to prevent VTE by heparin therapy following ATSCI. Testing for thrombophilia in patients with ATSCI and possibly a more intense thromboprophylactic regimen seem desirable but need to be verified by a prospective study.