Prothrombin G20210A Research Articles

The association between thrombophilic genes alterations and poor ovarian response in infertile women: a retrospective case-control study

This research aimed to retrospectively investigate the possible association between poor ovarian stimulation and selected thrombophilia markers in Iranian women with infertility. For this study 100 Iranian infertile women, with a history of at least three Assisted Reproduction Technology (ART) failures (50 with a poor ovarian response and 50 with a normal response), referred to Royan Institute were selected. Targeted genetic variation evaluation for Factor V G1691A, F II Prothrombin G20210A, MTHFR C677T, MTHFR A1298C was performed by PCR-RFLP followed by Sanger Sequencing. The association between these variants and the ovarian response was examined. The results showed an association between Factor V G1691A mutation and poor ovarian response. The heterozygosity rate of the FVL was significantly different between poor responders compared with the normal response group (p-value ≤ 0.05). In conclusion screening of this polymorphism can be used as a genetic determinant of ovarian response functioning through a vascular mechanism. A larger study with bigger sample size is recommended. Impact statement What is already known on this subject? Thrombophilia is a multi-genetic disease that is associated with changes in homeostatic mechanisms. Some studies have suggested that thrombophilia has no relationship with poor ovarian response and reduced ovarian reserve in general infertile population undergoing ART. What do the results of this study add? Our results showed a significant association between the FVL heterozygote mutation and poor ovarian response. What are the implications of these findings for clinical practice and/or further research? Screening of FVL polymorphism may be suggested as a predictive test for ovarian stimulation response in infertile women undergoing ART. Further prospective studies with bigger sample size evaluating other thrombophilia markers and ovarian response, as well as further in-vitro studies may help clarify the biological mechanisms behind the effect of the FVL polymorphism on ovarian response, oocyte quality and embryo quality.

Genetic Mutations Pai-1 4G/4G and ACE D/D that Reduce Fibrinolysis are responsible for most Serious Pregnancy Complications and Abortions and are Best treated with S/C LMW Heparin and Aspirin

Background: Abortions, stillbirths, PET and other serious pregnancy complications cause more than 3-4 million pregnancy failures annually worldwide. Hypofibrinolytic and thrombophilia mutations are responsible for a large number of these events. Methods: A study of 11 such genetic mutations (Table 5) in 26 Cypriot ladies after failed pregnancies from serious complications, stillbirths and abortions was carried out between 2006 and 2020. All 26 ladies had significant hypo fibrinolysis and thrombophilia mutations. Hypofibrinolytic mutation PAI-1 4G/4G, was the commonest (X2 p=0.0052) with 11 ladies, 9 of them also ACE D/D positive. Factor V Leiden was present in 5 ladies (X2 p=ns). Clinical results: After the diagnosis of hypo fibrinolysis ± thrombophilia, 19 of these 26 ladies proceeded with 1-2 more pregnancies using LMW s/c heparin and oral aspirin, all with healthy babies. The remaining 7 ladies were too stressed for another pregnancy. 12 ladies were referred after PET, 2 with stillbirths and 9 after caesareans with birthweights at 700, 900, 950, 1050+1080, 1200, 1250, 2050, 2080 and 2200g. One baby developed mental retardation. The 12th lady with PET at 20 weeks, was immediately treated with LMW s/c heparin and had a healthy baby at 32 weeks. The remaining 14 ladies had other earlier pregnancy complications, 9 of them ending as abortions. Three ladies had their pregnancies saved with an instant mutational study and therapy with LMW heparin, leading to healthy babies. Conclusion: Hypofrinolytic mutations PAI-1 4G/4G and ACE D/D are serious mutations leading to abortions and pregnancy complications and should always be taken seriously in pregnancy. Thrombophilia mutations Factor V Leiden, Factor VR2, prothrombin G20210A, and MTHFR also lead to complicated pregnancies but less frequently. LMW s/c heparin in pregnancies with such mutations saves lives. It would be ideal if these mutations were always studied prior to every first pregnancy. Keywords: Mutations PAI-1 4G/4G; ACE D/d In Pregnancy

Prevalence of Thrombophilia in Women with Recurrent Early Miscarriage, and a Systematic Review of the Literature

Background: There are many studies reporting a disproportionally high prevalence of thrombophilia in women with a history of recurrent miscarriage, which has led to over diagnosis and treatment, without an improvement in clinical outcomes. Methods: This is a retrospective cohort study of 1155 women between 2012 and 2017. All patients had three or more first trimester miscarriages and a full thrombophilia screen. We reviewed all the available literature related to causes of recurrent miscarriages. We ascertained the prevalence of thrombophilia in the study population and compared it with historical and published prevalence in the general population. Findings: The overall prevalence of thrombophilia in our study population is 9.2% (106/1155) with the majority of cases positive for inherited thrombophilia, 8.1% (94/1155) which is similar to the general population; Factor V Leiden (FVL) (4.9%; 57/1155) and Prothrombin Gene Mutation (PGM) (2.9%; 34/1155) were the most common thrombophilias. Only 1% (12/1155) tested positive for acquired thrombophilia. Persistent positive lupus anticoagulant (LA) was found in 0.5% (6/1155) and persistent positive anticardiolipin (ACL) antibodies with a value ≥40 U/ml 0.5% (6/1155) of patients. Both tests were performed a minimum of 12 weeks apart; meeting the revised Sapporo criteria for a diagnosis of antiphospholipid syndrome. Interpretation: Women with recurrent miscarriage have a low prevalence of acquired thrombophilia, albeit higher than the general population, and a similar prevalence of inherited thrombophilia to the general population. Our findings of inherited thrombophilia are in agreement with the literature and we therefore do not recommend testing or treatment. When we applied the revised Sapporo criteria, we found a lower prevalence of acquired thrombophilia among miscarriage patients than what has previously been published. However, despite the low percentage, the prevalence is higher among the miscarriage population when compared to the general population. We therefore recommend screening for antiphospholipid antibodies and lupus anticoagulant, but it is important to adhere to the revised Sapporo criteria to define a diagnosis of antiphospholipid syndrome. Trial Registration: This study is registered with International Prospective Register of systematic Reviews PROSPERO 2020 CRD42020223554. Funding: None Declaration of Interest: None Ethical Approval: This study has been approved by NHS Health Research Authority (HRA) (IRAS ID: 281484, REC reference 20/HRA/6376)

Splanchnic vein thrombosis: Clinical manifestations, risk factors, management, and outcomes

BackgroundClinical manifestations and optimal management strategies in patients with splanchnic vein thrombosis (SVT) are not well characterized. MethodsWe conducted a retrospective cohort study including all newly diagnosed SVT evaluated between January 2007 and December 2018. Efficacy outcome was thrombosis resolution, and safety outcomes included death and occurrence of bleeding. ResultsWe included 155 patients with a mean age of 56.2 (18–87). Local risk factors were present in 118 (76.1%) patients and 30 (19.4%) had only systemic/thrombophilia. Local risk factors included abdominal cancers (31%), surgery (20.6%) and liver cirrhosis (19.4%). Thrombophilia screening was conducted in approximately 50% of patients. Factor V Leiden or Prothrombin G20210A mutations were observed in 7.1% of patients whereas 14.4% were JAK2V617F mutation positive. Most common manifestations at onset were abdominal pain (56.1%), whereas 44.6% were incidentally found. Portal vein thrombosis was observed more in primary cases (91.9% vs. 69.5%, p = 0.012). Anticoagulation was used in 93.5% cases. Indefinite anticoagulation was used more frequently in primary SVT (62.2% vs. 41.5%, p = 0.045). Thrombosis resolution and bleeding complications among primary (without local risk factors) and secondary (with local risk factors) SVT were observed in 48.5%, 65%, 8.1%, and 11.9%, respectively with no difference when comparing patients treated with direct oral anticoagulants or warfarin and/or low molecular weight heparin (58% vs. 62%, p = 0.326, 9% vs. 12%, p = 0.518). ConclusionsIn this cohort anticoagulation resulted in partial or complete thrombosis resolution in a significant proportion of patients with an acceptable bleeding risk regardless local risk factors or type of anticoagulant.

Evaluation of pai-1 polymorphisms in central and peripheral thromboembolies

Thromboembolism is a clinical finding that occurs due to thrombus; formed in the vascular system and has various etiological factors. It can be classified as central and peripheral thromboembolism. Our objective in this study is to explore genetic risk factors in central and peripheral thromboembolism and reveal the differences. 342 thromboembolism patients were retrospectively included to the study between January 2016 and December 2019. Demographic characteristics, risk factors for thromboembolism and genetic mutations in central and peripheral thromboembolism groups were overviewed. The genetic mutations evaluated in patients were Factor V Leiden G1691A, Factor V HR1299R, Factor II (Prothrombin) G20210A, MTHFR (Methylenetetrahydrofolate reductase) C677T, MTHFR A1298C, PAI 4G/5G. Within the scope of the study, genetic analyzes of 106 patients were reached and included in the study. Seventy-two central thromboembolism (69.8%), 34 (31.2%) peripheral thromboembolisms were detected. Sixty-three of the central thromboembolisms were from arterial and nine were from venous origin. There was no significant difference between age, gender and risk factors of central thromboembolism and peripheral thromboembolism patients (p˃0.05), but smoking was more common in central thromboembolism patients (p: 0.041). 4G/5G polymorphism was observed more frequently in patients with central thromboembolism (p: 0.039). Thromboembolism is a multifactorial disease, PAI-1 4G/5G polymorphism is a medium risk factor for thromboembolism. We conclude that PAI-1 4G/5G polymorphism is more frequent in central thromboembolism than peripheral thromboembolism and its evaluation can give more information about the thromboembolic risk analyze.

Association of Factor V Leiden G1691A and Prothrombin gene G20210A mutations with adverse pregnancy outcomes.

To determine the association of Factor V Leiden / prothrombin gene mutation in Pakistani women with adverse pregnancy outcomes. The prospective study was conducted at the Aga Khan University Hospital, Karachi, from January 1 to December 31, 2016, and comprised females > 40 years having history of two or more foetal losses with no apparent aetiology. Restriction fragment length polymorphism- Polymerase chain reaction was performed using MnlI and HindIII restriction enzymes for factor V Leiden G1691A and prothrombin gene mutation G20210A. Females with two or more consecutive normal pregnancies were enrolled as the control group. Data was analysed using SPSS 19. Of the 172 participants with a mean age of 29.3±5.9 years (range: 19-38 years). 86(50%) each were healthy controls and those with recurrent pregnancy loss. There were 238 livebirths among the controls compared to 13 in the other group. Factor V Leiden G1691A was identified in 2(2.3%) women, and prothrombin gene mutation G20210A in 1(1.2%) woman in the patient group, while no mutation was identified in the control group. The prevalence of Factor V Leiden / prothrombin gene mutation in women with recurrent pregnancy loss was found to be very low.

Livedoid vasculopathy and its association with genetic variants: A systematic review.

Livedoid vasculopathy (LV) is considered a disease of hypercoagulability. Association of LV with genetic variants is poorly characterised and large‐scale genetic association studies have not been performed. The aim of the study was to systematically review variants in LV patients and to analyse the available clinical data. A systematic search of the literature in PubMed and Embase databases was performed to identify articles investigating genetic variation in LV patients. Thirty studies or case reports were identified that reported 265 LV patients tested for at least one out of six genetic variations. Among them, PAI‐1 ‐675 4G/5G was the most common, accounting for 85.26% (81/95). Heterozygous 4G/5G was the major genotype. PAI‐1 A844G, MTHFR C677T, and MTHFR A1298C were the second, third, and fourth most common variants in LV patients. Prothrombin G20210A and Factor V G1691A were mainly present in LV patients from Europe, North America, and South America. This review highlights the associations between LV and genetic variants. The distribution of variants may be geographically or ethnicity dependent; however, large sample case‐control studies are needed to clarify associations.

Maxillofacial and oral surgery in patients with thrombophilia: safe territory for the oral surgeon? A single-center retrospective study

The aim of this study was to analyze patients with thrombophilia who underwent oral and/or maxillofacial surgery at our center. We performed a retrospective analysis of patients with hereditary or acquired thrombophilia who had undergone oral/maxillofacial surgery between January 1, 2000 and December 31, 2019. Data regarding demographic and patient characteristics, surgical treatment modalities, antithrombotic therapies, and complications were analyzed. A total of 76 eligible patients (26 male, 50 female) were included in this study, with a mean follow-up period of 3.8 months (range, 0-51 months). The mean age at time of surgery was 44.7 ± 19.4 years. Seven different hereditary and acquired thrombophilia were identified: factor V Leiden (n=31; 40.8%), prothrombin G20210A mutation (n=5; 6.6%), protein C deficiency (n=4; 5.3%), protein S deficiency (n=11; 14.5%), antiphospholipid syndrome (n=10; 13.2%), hyperhomocysteinemia (n=8; 10.5%), and elevated factor VIII (n=2; 2.6%). Complications occurred in 9 patients (11.8%) and included postoperative infections (n=6; 7.9%) and postoperative bleeding (n=3; 3.9%). Our data suggest that oral and/or maxillofacial surgery in patients with a confirmed diagnosis of thrombophilia is not associated with a burden of thrombosis or high complication rates. Furthermore, we formulated a guideline for preoperative antithrombotic therapy for patients with thrombophilia undergoing oral and/or maxillofacial surgery.

Thrombophilia, Inflammation, and Recurrent Pregnancy Loss: A Case-Based Review

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies and is often multifactorial with the majority of miscarriages being due to aneuploidy and anatomic or physiological abnormalities. However, inherited or acquired thrombophilias have also been associated with RPL, albeit inconsistently. While inherited thrombophilias, such as factor V Leiden and prothrombin gene mutation, are relatively prevalent in women with RPL compared with the general population, a causal link has yet to be definitively established. Recently, systemic inflammation, as measured by high-sensitivity C-reactive protein, has also been hypothesized to play a role in infertility. Based on limited prospective trial data, antithrombotic therapy and antiplatelet agents have been proposed as possible tools for the prevention of RPL. Because of the multifactorial nature of RPL and infertility, various clinicians, as obstetricians and gynecologists, endocrinologists, hematologists, or vascular medicine specialists, may be requested to counsel these women. This, together with evidence gaps, frequently leads to distinctly different diagnostic and therapeutic recommendations, especially regarding thrombophilia testing and treatment. Using four case vignettes in this review, we critically appraise the literature and highlight how two clinicians from different subspecialties approach the relationship between RPL, inflammation, and thrombophilia.

Basophil Blood Cell Count Is Associated With Enhanced Factor II Plasma Coagulant Activity and Increased Risk of Mortality in Patients With Stable Coronary Artery Disease: Not Only Neutrophils as Prognostic Marker in Ischemic Heart Disease.

BackgroundWhite blood cell count, which is inexpensive and widely available in clinical practice, has been proposed to provide prognostic information in coronary artery disease (CAD). Elevated levels of white blood cell subtypes may play different roles in atherothrombosis and predict cardiovascular outcomes.Methods and ResultsThe association between white blood cell counts and mortality was evaluated in 823 subjects with angiographically demonstrated and clinically stable CAD in an observational–longitudinal study. The correlation among white blood cell counts and factor II plasma coagulant activity was analyzed in 750 subjects (554 CAD and 196 CAD‐free) not taking anticoagulant drugs. Subjects with overt leukocytosis or leukopenia were excluded. In the longitudinal study after a median follow‐up of 61 months, 160 (19.4%) subjects died, 107 (13.0%) of whom from cardiovascular causes. High levels of neutrophils, monocytes, eosinophils, and basophils were associated with an increased mortality rate. In multiadjusted Cox regression models, only neutrophils and basophils remained predictors of total and cardiovascular mortality. The associations remained significant after adjustment for traditional cardiovascular risk factors and by including D‐dimer and the chemokine CXCL12 in the regression models. Neutrophils and basophils were also significant predictors of factor II plasma coagulant activity variability after adjustment for blood cell counts, age, sex, inflammatory markers, CAD diagnosis, and prothrombin G20210A polymorphism. Factor II plasma coagulant activity was similarly increased in subjects with high neutrophil and basophil counts and in carriers of the prothrombin 20210A allele.ConclusionsBoth high neutrophil and basophil blood counts may predict mortality in patients with clinically stable CAD and are associated with enhanced factor II plasma coagulant activity, thereby suggesting underlying prothrombotic mechanisms.

Patent Foramen Ovale Closure among Patients with Hypercoagulable States Maintained on Antithrombotic Therapy

Background: Percutaneous device closure was shown to effectively prevent recurrent strokes in patients with patent foramen ovale (PFO). Whether this protective effect is relevant for patients with hypercoagulable states (HCSs) is unknown as they were not represented in prior studies. Methods: Data on 136 consecutive patients with a PFO and clinically significant HCS were retrospectively collected. PFO closure and antithrombotic regimen were decided on an individual basis by the treating physicians, and adherence to therapy was routinely evaluated. The outcome was the occurrence of cerebrovascular accident (CVA) or transient ischemic attack (TIA). Results: HCS types consisted of antiphospholipid syndrome (31%), factor-5 Leiden mutation (22%), prothrombin mutation (18%), protein S deficiency (15%), protein C deficiency (7%), methyl-tetra-hydro folate reductase mutation (5%), and essential thrombocytosis (2%). 102 patients (75%) were maintained on anticoagulants and the remaining on antiplatelet therapy. PFO closure was undertaken in 85 (63%); antithrombotic therapy was not interrupted prior to or after the procedures. At a mean follow-up of 46 ± 8 months, 23 patients (17%; 95% confidence interval, 9.3–22%) experienced an outcome event, mainly in the form of CVAs (n = 15, 65%). In multivariable analysis, PFO closure was associated with a 5-fold decrease in the risk of CVA/TIA (p = 0.02). This effect was independent of the type of HCS or antithrombotic therapy. Conclusions: Among patients with HCSs maintained on anticoagulant or antiplatelet therapies, PFO closure was associated with a significantly lower risk of CVA or TIA.

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.

MTHFR (C677T, A1298C), FV Leiden polymorphisms, and the prothrombin G20210A mutation in arterial ischemic stroke among young tunisian adults.

Arterial ischemic stroke (AIS) in young adults is less common in older adults, but the underlying pathogenesis and risk factors are more multi-faceted. The role of inherited thrombophilia such as 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, (C677T and A1298C), factor V of Leiden (FVL) polymorphism, and the prothrombin G20210A mutations remains unclear. This study aims to evaluate the role of prothrombin genetic factor in AIS among young adults in Tunisia and to assess the synergistic effect between thrombogenic mutations in the pathogenesis of AIS. In this case-control study, blood samples were collected from patients and healthy controls, all matched for age and gender. The difference between them is evaluated by using the chi-square test. The odds ratio (OR) was carried out to evaluate the associations between each polymorphism and AIS risk using a binary logistic regression model. Values were considered statistically significant when p < 0.05. Patients carrying simultaneously the MTHFR polymorphisms (677T and 1298C) have a higher risk to develop AIS compared to controls. The heterozygous variants FVL increased the risk of AIS only when it is associated with MTHFR C677T or MTHFR A1298C polymorphisms. In conclusion, our study confirmed the involvement of MTHFR polymorphisms as AIS's important risk factors. The existence of FVL polymorphism or prothrombin G20210A mutation alone doesn't correlate with the occurrence of stroke. We assume that the presence of both MTHFR and FVL polymorphisms has a synergistic effect and increased the risk of the AIS.

Wybrane genetyczne przyczyny poronień

Streszczenie Około 15–25% ciąż kończy się poronieniem samoistnym, czyli wydaleniem z organizmu matki zarodka bądź płodu o masie poniżej 500 g lub przed 20. tygodniem trwania ciąży. Ustalenie etiologii poronień jest trudne ze względu na jej heterogenny charakter. Przyczyną 38,6–80% poronień są zmiany stwierdzane w chromosomach. Największą grupą (93%) aberracji chromosomowych w kariotypie poronionych płodów są zmiany liczbowe – aneuploidie i poliploidie. 7% stanowią niezrównoważone zmiany strukturalne chromosomów, powstałe de novo lub odziedziczone od rodzica nosiciela. U par z poronieniami najczęściej stwierdza się translokacje chromosomowe wzajemne (TCW), rzadziej translokacje robertsonowskie oraz inwersje. Bardziej złożone nieprawidłowości chromosomowe, np. podwójne aneuploidie, stwierdza się u 3,8% płodów. Inną grupą przyczyn poronień, są choroby monogenowe zarodka lub płodu, powstające w wyniku mutacji autosomalnych dominujących lub recesywnych albo mutacji sprzężonych z chromosomem X. Wśród mutacji mogących się przyczynić do utraty ciąży znajdują się m.in. mutacja typu Leiden (c.1601G&gt;A, dawniej 1691G&gt;A) w genie czynnika V krzepnięcia osoczowego i mutacja w genie protrombiny (c.97G&gt;A, dawniej 20210G&gt;A). Nadal prowadzone są badania nad mutacjami genów kandydujących, m.in.: ALOX15, CR1, CYP1A1, CYP17, CYP2D6, FOXP3, HLA-G, IL-6, KHDC3L, NLRP7, NOS3, PLK4, SYCP3, TLR3, TNF, TP35 i VEGFA.

Genetic and Clinical Predictors of Left Atrial Thrombus: A Single Center Case-Control Study.

Left atrial (LA) thrombus formation is the presumed origin of thromboembolic complications in patients with atrial fibrillation (AF). Beyond clinical risk factors, the factors causing formation of LA thrombi are not well known. In this case-control study, we analyzed clinical characteristics and genetic thrombophilia markers (factor V Leiden (FVL), prothrombin G20210A (FIIV), Tyr2561 variant of von Willebrand factor (VWF-V)) in 42 patients with AF and LA thrombus (LAT) and in 68 control patients with AF without LAT (CTR). Patients with LAT had more clinical conditions predisposing to stroke (mean CHA2DS2-VASc-score 3.4 ± 1.5 vs. 1.9 ± 1.4; P < 0.001), a higher LA volume (96 ± 32 vs. 76 ± 21 ml, P = 0.002) and lower LA appendage emptying velocity (0.21 ± 0.11vs. 0.43 ± 0.19 m/s, P < 0.001). Prevalence of FVL, FIIV and VWF-V mutations was not different, but in the subgroup of patients <65 years (y) there was a tendency for a higher incidence of VWF-V with a prevalence of 27% (LAT <65 y) vs. 7% (CTR <65 y, P = 0.066). These findings warrant further investigation of the VWF-V as a risk factor for LA thrombogenesis in younger patients.

Carrier frequencies for thrombophilia-related genetic variants in a Romanian cohort

Genetic testing for hereditary thrombophilia, an inherited predisposition to thrombotic events, is increasingly available. To evaluate the rate of positive thrombophilia tests in our laboratory we analyzed the carrier status for common thrombophilia-related gene variants in a consecutive unselected cohort of 360 Romanian patients. Genetic tests were performed on a Real-Time PCR platform. Majority of patients (98.6%) carried at least one thrombophilic variant. The carrier frequencies for classical prothrombotic mutations in F5 (Factor V Leiden) and F2 genes (prothrombin G20210A mutation) were 11.67% (10.27% heterozygous, 1.4% homozygous) and 6.95% (6.39% heterozygous, 0.56% homozygous), respectively. Concurrently, high carrier frequencies for MTHFR c.677C&gt;T, MTHFR c.1298A&gt;C, and PAI-1 4G/5G variants, that are controversially associated with thrombophilia, were observed: 65.28% (52.5% heterozygous, 12.78% homozygous), 53.61% (45% heterozygous, 8.61% homozygous), and 78.61% (49.44% heterozygous, 29.17% homozygous), respectively. The impact of MTHFR genotypes on plasma homocysteine levels was also determined. Male carriers of TT homozygous genotype and CT heterozygous genotype of MTHFR C677T polymorphism had significantly higher levels of plasma homocysteine unrelated to age, compared to those harboring CC homozygous genotype (P=0.028). In unselected patients a high rate of positive thrombophilia tests was observed and the clinical implications of such results need to be carefully examined.

Association of venous thromboembolism and myocardial infarction with Factor V Leiden and Factor II gene mutations among Libyan patients

ABSTRACT Factor V Leiden G1691A (FVL) and Factor II prothrombin G20210A (PGM) mutations are the leading causes of thrombophilia. In this study, we have investigated the prevalence of the FVL G1691A and PGM G20210A single nucleotide polymorphisms (SNPs) among Libyan deep vein thrombosis (DVT) and myocardial infarction (MI) patients. SNP genotyping was performed using high-resolution melt analysis (HRM) and DNA sequencing. Biochemical parameters conducted on 112 males and 93 females showed no significant difference in means between the control group and the deep vein thrombosis and myocardial infarction groups. For Factor V Leiden, 40 samples were genotyped. Of the 40 samples, 6 (15.0%) of them were heterozygous and no one was homozygous. As for Factor II SNP, 59 samples were genotyped and only 2 (3.3%) were heterozygous. All the heterozygous samples showed 100% concordance between the HRM-PCR and DNA sequence analysis. Our study showed, for the first time, that both the FVL and PGM mutations are present among Libyan DVT and MI patients and that the FVL mutation is significantly associated with DVT but not with MI. However, our results do not support the association of PGM G20210A mutation with DVT or MI.

Janus Kinase-2 Mutation Associated Portal Vein Thrombosis Complicating Liver Cirrhosis and Hepatocellular Carcinoma

Background:Portal vein thrombosis (PVT) might be a catastrophic event complicating liver cirrhosis and hepatocellular carcinoma (HCC). Aim:role of JAK2 RS V617F mutation as a risk factor for PVT development in liver cirrhosis and HCC. Methods:A case control study conducted on 100 PVT patients (76 HCC and 24 liver cirrhosis) additionally, 100 healthy individuals used as a control group. PVT was diagnosed incidentally by Doppler ultrasound during routine follow-up HCC screening. Prothrombin G20210A mutation, MTHFR mutation, Factor V Leiden mutation (VFL), antithrombin III (ATIII), protein C, S, and antiphospholipid antibodies, along with JAK2 RS V617F mutation by real-time polymerase chain reaction all were analyzed.Results:Patients with PVT were significantly older (p<0.001), thrombocytopenic (p<0.001), with high alkaline phosphatase (p<0.001). JAK2 RS V617F mutation was found in 28/100 (28%) in idiopathic PVT complicating liver cirrhosis and hepatocellular carcinoma. Cases with positive JAK2 rs V617F mutation were significantly accompanied by protein S deficiency (P 0.03), LA absence (p 0.06), and high frequency of ascites (P 0.03). While, the MTHFR heterozygous mutation (p0.001), ATIII (P 0.02), and VFL (P 0.01) were more frequent with negative JAK2 rs V617F mutation. The comparison between demographic data and thrombophilic parameters in PVT cases revealed that no significant differences were recorded except for male gender, Diabetes Mellitus, splenomegaly significantly increased among HCC cases (p<0.05). Conclusions: JAK2 rs V617F mutation must be considered in any case of PVT with liver cirrhosis and hepatocellular carcinoma without identified thrombophilic risk factors, with potential considerations of evolving myeloproliferative disorders. New diagnostic and therapeutic implications are still awaited.

MTHFR Gene Polymorphisms and Cardiovascular Risk Factors, Clinical-Imagistic Features and Outcome in Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) as a severe neurological emergency, is represented by variable conditions in its clinic presentation, onset, risk factors, neuroimagistic features and outcome. The genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C was associated with CVST. We aimed to characterize the prevalence of MTHFR gene polymorphisms associated with cardiovascular risk factors in the group of patients with CVST. Also, we studied additional causes associated with CVST including local infections, general infections, obstetric causes (pregnancy, puerperium) and head injury. This is a retrospective study including 114 patients which referred to our hospital between February 2012–February 2020. The protocol included demographic (age, sex), clinical, neuroimagistic features, paraclinic (genetic polymorphism of MTHFR, factor V G1691A—Leiden, prothrombin G20210A, PAI-1 675 4G/5G; Homocysteine level, the lipid profile, blood glucose and Glycohemoglobin HbA1c, high- sensitive C- reactive protein- hsCRP) data, as well as treatment and outcome. The mean age was 37.55 years with a female predominance (65.79%). In the first group of patients with inherited thrombophilia (60 cases; 52.63%) we found genetic mutation includes MTHFR C677T (38.59%) and A1298C (14.03%), factor V G1691A- Leiden (15.78%), prothrombin G20210A (2.63%), PAI-1 675 4G/5G (42.98%), and hyperhomocysteinemia (35.08%). At the second group with other etiology of CVST, except thrombophilia, we included 54 patients (47.36%). The most common sites of thrombosis were the superior sagittal sinus (52.63%). Headache was the most common symptom (91.22%) and seizures were the main clinical presentation (54.38%). The MTHFR polymorphism was significantly correlated with higher total cholesterol (TC) (p = 0.023), low- density lipoprotein cholesterol (LDL) (p = 0.008), homocysteine level (tHcy) (p < 0.001). Inside the first group with MTHFR polymorphism we have found a significant difference between the levels of homocysteine at the patients with MTHFR C677T versus MTHFR A1298C polymorphism (p < 0.001). The high-sensitive C-reactive protein (hsCRP) was increased in both groups of patients, but the level was much higher in the second group (p = 0.046). Mortality rate was of 2.63%. Demographic, clinical and neuroimagistic presentation of CVST in our study was similar with other studies on the matter, with a high frequency of thrombophilia causes. MTHFR gene polymorphisms (C677T and A1298C) are increased in prevalence in CVST. PAI-1 675 4G/5G gene mutation seems to be involved in CVST etiology. Plasma C-reactive protein level and hyperhomocysteinemia should be considered as a prognostic factor in CVST.

Role of thrombophilia testing in retinal vein occlusion: single centre experience from Oman

Thrombophilia is a known predisposition to venous thromboembolism however there was no significant relationship with retinal vein occlusion (RVO). Herein, we aimed to study the prevalence of thrombophilia among Omani patients presented with RVO. In a retrospective study, 11 consecutive patients diagnosed by the ophthalmologists at Armed Forces Hospital with RVO (central RVO, n=7; branch RVO, n=4) were included. Thrombophilia testing including factor V Leiden, Prothrombin gene mutation (G20210A) and Janus Kinase-2 (JAK2 V617F) mutation analysis; presence of autoantibodies including Anti-nuclear antibody(ANA), Anti-neutrophil cytoplasmic antibody (ANCA), Lupus anticoagulant (LA), Anti-cardiolipin antibody (ACA), Anti-B2 glycoprotein positivity; abnormal coagulation protein levels including protein S, Protein C, Anti-thrombin and Factor VIII as well as biochemical parameters like elevated serum lipoprotein 1a, triglycerides, total cholesterol and homocysteine levels were performed. Patient’s ages ranged between 25 to 75 years (mean + SD; 48.8 + 13.6) with a mild male preponderance (54.5%). None of them gave history of smoking. However, 27.3% and 45.5% had history of diabetes and hypertension, respectively. Amongst the thrombophilia tests evaluated, only one patient was positive for an underlying Prothrombin gene (G20210A) heterozygosity, another patient was positive for Anti-beta2 glycoprotein antibody and one patient with high serum homocystine. Our study demonstrated that thrombophilia is not prevalent in omani patients diagnosed with RVO in the armed forces hospital. Furthermore, 27.3% and 45.5% of those patients were suffering from diabetes and hypertension, respectively which are known risk factors for RVO.