The Factor V Leiden, Prothrombin Gene 20210GA, Methylenetetrahydrofolate Reductase 677CT and Platelet Glycoprotein IIIa 1565TC Mutations in Patients With Acute Ischemic Stroke and Atrial Fibrillation

SummaryObjective: To investigate if the factor V Leiden mutation (F-V-LM) and/or the prothrombin gene G 20210 A variant (P-G20210A-V) are risk factors for acute stroke in Austrian children. Patients: 33 children with acute ischemic stroke documented by computer tomography and/or magnetic resonance imaging of the brain were enrolled in an open multicenter survey. Results: 6/33 children had F-V-LM (5 heterozygous, 1 homozygous). This represents 18% (95% CI: 6.7-39.9%) of our pediatric stroke population and thus exceeds the expected prevalence in the Austrian population of 4,6% (Fischer’s exact test, p = 0.01). F-V-LM was not found in 11 children with neonatal stroke but in 6/22 children with stroke after the neonatal period. 5/6 children with F-V-LM had an underlying disorder that is a risk factor for stroke in children. The P-G20210A-V was detected in 1/26 (3.85%; 95% CI: 0.1-21.4%) patients. Comparison of the prevalence of P-G20210A-V in our study with that in the general population of Austria of 1% revealed no statistical significance (Fischer’s exact test, p = 0.38). Conclusion: Our data suggest that the F-V-LM is a risk factor for acute stroke in Austrian children beyond the neonatal period. The P-G20210A-V apparently does not represent a risk factor for stroke in Austrian children.

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Abstract 29: Common Thrombophilias are not Associated With Specific Perinatal Stroke Diseases

Stroke ◽

10.1161/str.47.suppl_1.29 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Colleen Curtis ◽

Michael Leaker ◽

Patti Massicotte ◽

Amalia Floer ◽

Aleksandra Mineyko ◽

...

Keyword(s):

Ischemic Stroke ◽

Factor V Leiden ◽

Population Based ◽

Factor V ◽

Arterial Ischemic Stroke ◽

Chi Square ◽

Perinatal Stroke ◽

Potential Contributor ◽

Prothrombin Gene ◽

Disease Specific

Background: Perinatal stroke causes cerebral palsy and lifelong disability. Specific diseases are definable, including arterial and venous ischemic injuries, but pathophysiological mechanisms are poorly understood. Thrombophilia has long been considered a potential contributor but population-based, controlled, disease-specific studies are limited. Hypothesis: Thrombophilia is uncommon in children with perinatal stroke. Methods: Subjects were recruited from the Alberta Perinatal Stroke Project, a population-based cohort with MRI-classified perinatal strokes: neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), and fetal periventricular venous infarction (PVI). Standardized thrombophilia evaluations were performed prospectively (2008-2015) after 12 months of age on stroke cases and matched controls. Measures included protein C and S, antithrombin III, factors VIII/IX/XI, fibrinogen, lipoprotein a, lupus anticoagulant, and antiphospholipid antibodies. Groups were compared (ANOVA, chi-square), corrected for multiple comparisons. Results: A total of 252 children were studied (58 NAIS, 48 APPIS, 69 PVI, 77 controls). Of 14 parameters, no differences were observed in 12 including all common thrombophilias. Prothrombin times were shorter in arterial strokes compared to controls (p<0.001). Factor XI levels were higher in arterial and PVI strokes compared to controls (p=0.004). Rates of genetic thrombophilias including factor V Leiden, prothrombin gene, and MTHFR were low and comparable to population rates. Conclusion: Our prospective, population-based, controlled, disease-specific study suggests minimal association between perinatal stroke and thrombophilia. This does not exclude the possibility of disordered coagulation at the time of stroke but suggests testing in childhood is not indicated.

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The Influence of Hemostasis Genetic Features on Thrombosis Rates in Patients with Polycythemia Vera

Blood ◽

10.1182/blood.v126.23.5180.5180 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5180-5180

Author(s):

Dzhariyat Shikhbabaeva ◽

Vasily Shuvaev ◽

Sergey Kapustin ◽

Irina Martynkevich ◽

Vera Udaleva ◽

...

Keyword(s):

Polycythemia Vera ◽

Methylenetetrahydrofolate Reductase ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Hereditary Thrombophilia ◽

Fibrinogen Receptor ◽

Thrombotic Complications ◽

Prothrombin Gene ◽

Pai 1

Abstract Background. Thrombotic complications are the main cause of disability and mortality in Polycythemia Vera (PV) patients. Thrombosis in PV is a result of both inherited (genetic) and acquired predisposition under the external factors influence. Effective personalized prophylactic antithrombotic therapy is a key factor to save quantity and quality of life in PV patients. Objective. The objective of study was to assess the prevalence of hereditary thrombophilia genetic markers in PV patients in overall and groups with or without thrombotic complications. Materials and methods. 104 PV patients (60 females, 44 males, median age 58 years, range 31-82) were researched. Blood probes were examined by PCR for the presence of nucleotide polymorphisms in the following genes: FV (Leiden mutation), FII (prothrombin), methylenetetrahydrofolate reductase (MTHFR), fibrinogen (FI), plasminogen activator inhibitor (PAI-1), and platelet fibrinogen receptor type IIIA (GPIIIA). We studed the overall hereditary thrombophilia markers rate and the statistical significance between PV patients groups with (Thr+) or without thrombosis (Thr+). We used the next statistical methods: descriptive statistics, the significances of differences by gender and genes frequencies in the groups were evaluates with Fisher exact test, differences in age at the time of diagnosis were assessed with Mann-Whitney U test. Results. Thrombotic complications occurred in 20 (19.2%) of patients (16 arterial and 5 venous thrombotic episodes, 1 patient had both arterial and venous thrombotic episodes). Myocardial infarction was found in 7 (6.7%), cerebrovascular accident in 9 (8.7%) patients. The general PV population thrombophilia markers frequencies were: heterozygous (G/A) Leiden mutation in 4 (3,8%) patients; heterozygous mutation in prothrombin gene (G20210-A) in 4 (3,8%) patients; homozygous (T/T) mutation in MTHFR in 8 (7,7%) patients, heterozygous (C/T) mutation in 43 (41,3%) patients; homozygous (A/A) mutation in FI gene in 4 (3,8%) patients, heterozygous (G/A) mutation in FI gene in 43 (41,3%) patients; combination of mutations in FI and MTHFR was registered in 23 (22,1%) patients; homozygous (4G/4G) mutation in PAI-1 gene was revealed in 35 (33,7%) patients, heterozygous (4G/5G) mutation in 49 (47,1%) patients; mutation frequencies in GPIIIA gene were as follows: homozygous (A2/A2) in 5 (4,8%) patients, heterozygous (A1/A2) in 26 (25%) patients. The markers of hereditary thrombophilia was not identified only in one patient (1%).Characteristics and difference significances in the frequency of detection of thrombophilia genes between groups of patients with thrombosis (Thr+) and without their presence in history (Thr-) are shown in table 1. Table 1. Characteristics of PV patients with (Thr+) or without (Thr-) thrombotic complications. Thr+ (n=20) Thr- (n=84) p Age, median (range) 63 (36-73) 58 (32-82) 0.75 Gender, male/female 9/11 35/49 0.81 Factor V Leiden mutation, GA/GG 2/18 2/82 0.17 Prothrombin gene (G20210A) mutation, GA/GG 1/19 3/81 0.58 MTHFR mutation, (TT+CT)/CC 14/6 37/47 0.05 FI mutation, (AA+GA)/GG 6/14 41/43 0.14 PAI-1 mutation, (4G/4G+4G/5G)/(5G/5G) 17/3 67/17 0.76 GPIIIA mutation, (A2A2+A1A2)/A1A1 1/19 30/54 0.01 Conclusions. Various hereditary thrombophilia gene mutations were present in almost all PV patients. PV patients with and without thrombotic complications were significantly (p≤0.05) differed in frequencies of mutations in methylenetetrahydrofolate reductase gene (MTHR) and platelet fibrinogen receptor type IIIA (GPIIIA). We also observed statistical trends (p≤0.30) in differences of mutations frequencies in fibrinogen (FI) gene and Factor V Leiden mutation, for the confirmation of which the further research is required. Disclosures No relevant conflicts of interest to declare.

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Interaction of Heritable and Estrogen-induced Thrombophilia: Possible Etiologies for Ischemic Optic Neuropathy and Ischemic Stroke

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615698 ◽

2001 ◽

Vol 85 (02) ◽

pp. 256-259 ◽

Cited By ~ 15

Author(s):

Robert Fontaine ◽

Ping Wang ◽

Charles Glueck

Keyword(s):

Ischemic Stroke ◽

Optic Neuropathy ◽

Gene Mutations ◽

Platelet Glycoprotein ◽

Ischemic Optic Neuropathy ◽

C677t Mthfr ◽

Glycoprotein Iiia ◽

Prothrombin Gene Mutation ◽

Mthfr Mutation ◽

Prothrombin Gene

SummaryOur specific aim was to assess how thrombophilic exogenous estrogens interacted with heritable thrombophilias leading to nonarteritic ischemic optic neuropathy (NAION) and ischemic stroke. Coagulation measures were performed in a 74 year old patient and her immediate family. The proband had a 47 year history of 9 previous thrombotic episodes, and developed unilateral NAION 4 years after starting estrogen replacement therapy (ERT). The proband was heterozygous for two thrombophilic gene mutations (G20210A prothrombin gene, platelet glycoprotein IIIa PlA1/A2 polymorphism), and homozygous for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Of 238 normal controls, none had these 3 gene mutations together. The proband’s mother and brother had deep venous thrombosis (DVT). The proband’s brother, sister, nephew, daughter, and two granddaughters were homozygous for the C677T MTHFR mutation. The proband’s brother was heterozygous for the G20210A prothrombin gene mutation. The proband’s niece was heterozygous for the G20210A prothrombin gene mutation, homozygous for the C677T MTHFR mutation, homozygous for the hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene, and heterozygous for the platelet glycoprotein IIIa PlA1/A2 polymorphism. Of 238 normal controls, none had the niece’s combination of 4 gene mutations. When ERT-mediated thrombophilia was superimposed on the proband’s heritable thrombophilias, unilateral ischemic optic neuropathy developed, her tenth thrombotic event over a 5 decade period. When estrogenprogestin oral contraceptives were given to the proband’s niece, she had an ischemic stroke at age 22. Exogenous estrogen-mediated thrombophilia superimposed on heritable thrombophilia and hypofibrinolysis is associated with arterial and venous thrombi, and appears to be a preventable, and potentially reversible etiology for ischemic optic neuropathy and ischemic stroke.

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

Thrombosis and Haemostasis ◽

10.1160/th03-04-0240 ◽

2003 ◽

Vol 90 (12) ◽

pp. 1158-1162 ◽

Cited By ~ 11

Author(s):

Daniela Poli ◽

Emilia Antonucci ◽

Emanuele Cecchi ◽

Irene Betti ◽

Lelia Valdrè ◽

...

Keyword(s):

Atrial Fibrillation ◽

High Risk ◽

Factor V Leiden ◽

Factor V ◽

Embolic Event ◽

Control Subjects ◽

Factor Ii ◽

Significant Difference ◽

Prothrombin Gene ◽

G20210a Polymorphism

SummaryAtrial 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.

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Ramifications of Four Concurrent Thrombophilic Mutations and One Hypofibrinolytic Mutation

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602960401000409 ◽

2004 ◽

Vol 10 (4) ◽

pp. 365-371 ◽

Cited By ~ 3

Author(s):

Charles J. Glueck ◽

Naila Goldenberg ◽

Ping Wang ◽

Dawit Aregawi

Keyword(s):

Plasminogen Activator ◽

Anticoagulation Therapy ◽

Factor V Leiden ◽

Plasminogen Activator Inhibitor ◽

Platelet Glycoprotein ◽

Compound Heterozygous ◽

Factor V ◽

Prothrombin Gene ◽

Activator Inhibitor ◽

Thrombophilic Mutations

A kindred was examined in which the 48-year-old white female proband with three deep venous thrombosis-pulmonary emboli events had four thrombophilic and one hypofibrinolytic mutations, and in which her 14-year-old asymptomatic daughter had four thrombophilic mutations. The proband was heterozygous for the G1691A factor V Leiden, G20210A prothrombin, and platelet glycoprotein IIIa PL A1/A2 mutations, had high factor VIII (221%), and was homozygous for the 4G4G plasminogen activator inhibitor-1 gene mutation, with high plasminogen activator inhibitor activity (23.7 U/mL). Her 14-year-old daughter was homozygous for the G1691A factor V Leiden and platelet glycoprotein IIb-IIIa PL A2/A2 mutations, compound heterozygous for the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations, and heterozygous for the G20210A prothrombin mutation, a combination with an estimated likelihood of 1.6 × 10-7. In 247 white healthy controls, there was no V Leiden homozygosity and no V Leiden-prothrombin gene compound heterozygosity. Heterozygosity for the V Leiden and prothrombin gene mutations was 3.2% and 4.1%, respectively. Homozygosity for the platelet glycoprotein IIb-IIIa PL A2A2, PAI-1 gene 4G4G, and C677T MTHFR mutations was 3.2%, 22.7%, and 12%, respectively. The proband will receive anticoagulation therapy for life. Beyond aspirin, avoidance of exogenous estrogens, and enoxaparin prophylaxis during pregnancy, it is not known whether the proband’s daughter should have lifelong anticoagulation therapy, or only after her first thrombotic event.

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Association of the Factor V Leiden Mutation (1691G>A, Arg534Gln) with Ischemic Stroke in Nonvalvular Atrial Fibrillation in Turkish Population

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2013.08.419 ◽

2013 ◽

Vol 62 (18) ◽

pp. C140

Author(s):

Atilla İçli ◽

Nilgün Erten ◽

Yasin Türker ◽

Salaheddin Akçay ◽

Habil Yücel ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Factor V Leiden ◽

Turkish Population ◽

Factor V ◽

Nonvalvular Atrial Fibrillation ◽

Factor V Leiden Mutation

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Factor V Leiden, Prothrombin Gene G20210A Variant, and Methylenetetrahydrofolate Reductase C677T Genotype in Young Adults With Ischemic Stroke

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602960100700418 ◽

2001 ◽

Vol 7 (4) ◽

pp. 346-350 ◽

Cited By ~ 43

Author(s):

Stanislaw Lopaciuk ◽

Ksenia Bykowska ◽

Hubert Kwiecinski ◽

Anatol Mickielewicz ◽

Anna Czlcankawska ◽

...

Keyword(s):

Young Adults ◽

Ischemic Stroke ◽

Methylenetetrahydrofolate Reductase ◽

Factor V Leiden ◽

Mthfr Gene ◽

Prothrombin G20210a ◽

Factor V ◽

Control Subjects ◽

Stroke In Young Adults ◽

C677t Mutation

Ischemic stroke in young adults is a well-known disease, but despite extensive clinical and laboratory investigations, its etiology remains unclear in approximately half of the cases. We examined the prevalence of factor V Leiden, the prothrombin G20210A genotype, and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in 100 patients (51 males and 49 females) who survived an ischemic stroke without a cardiac embolic source at an age ≤45 years, and in 238 healthy control subjects from the same geographic area. The patients were selected for study only if the diagnosis of stroke was documented by computed tomography scan or nuclear magnetic resonance (NMR) of the brain, or both. Heterozygosity for the FV Leiden mutation was found in 3 patients (3.0%) and in 10 control subjects (4.2%). Two patients (2.0%) and five control subjects (2.1%) were heterozygous for the prothrombin G20210A mutation. The frequencies of the MTHFR 677TT, CT, and CC genotypes in the patient group were 12%, 37%, and 51%, respectively, and were not significantly different from those in control subjects (11%, 40%, and 49%, respectively). In conclusion, our results indicate that FV Leiden mutation, prothrombin G20210A genotype, and homozygosity for the C677T mutation in the MTHFR gene are not associated with an increased risk for ischemic stroke in young adults.

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Predisposition to Thrombophilia and Hypofibrinolysis in Pulmonary Embolism: Analysis of Inherited Factors

Journal of Biomedical and Clinical Research ◽

10.1515/jbcr-2015-0105 ◽

2013 ◽

Vol 6 (2) ◽

pp. 73-81

Author(s):

Regina Komsa-Penkova ◽

Pencho T. Tonchev ◽

Katya S. Kovacheva ◽

Galya B. Georgieva ◽

Yavor Y. Ivanov ◽

...

Keyword(s):

Risk Factors ◽

Pulmonary Embolism ◽

Gene Mutation ◽

Factor V Leiden ◽

Mthfr C677t ◽

Platelet Glycoprotein ◽

Factor V ◽

Prevention Policy ◽

Prothrombin Gene Mutation ◽

Prothrombin Gene

Summary Pulmonary embolism (PE) is a relatively common cardiovascular emergency, though its exact incidence is difficult to assess. Accurate diagnosis is critical because of the high 30-day mortality in patients in whom the diagnosis is missed on admission. Doubt for PE is often raised by the presence of risk factors for venous thromboembolism (VTE), which are categorized into inherited and acquired. Among these, the importance of inherited/genetic thrombophilic factors is increasingly recognized. The most frequent markers of inherited thrombophilia are Factor V Leiden (FVL) and G2021OA prothrombin gene mutation. Among the inherited factors causal to thrombophilia, the C677T variant in methylentetrahydrofolate reductase (MTHFR) gene as well as factors like P1A1/P1A2 polymorphism in platelet glycoprotein Ilb/IIIa (P1A2) and hypofibrinolytic polymorphism 4G/4G in PAI-1 gene are discussed with controversial results. In our study, thrombophilic and hypofibrinolytic genetic variants were identified in 54.2% of 115 patients with PE. The most common significant genetic defects were FVL- 16.5% in patients versus 6.2% in controls (OR=3.102; p=0.05), G20210A PT 5.7% versus 2.1% (OR=2.983; p>0.05). P1A2 was found in 27.3% patients versus 19.9% in controls (OR= 1.523, p>0.05) and PAM 27.8% versus 22.6% (OR =1.501 p>0.05). MTHFR C677T carriage was inverse: 6.7% in patients versus 13.4% in controls. (OR=0.461 p=0.05). Of all the patients studied, 15.65% had a history of recurrent embolic incidents. The risk of recurrence was higher for the carriers of FVL and G20210A prothrombin gene mutation. The association between carriage of thrombophilic genetic factor and the early onset of the first embolic episode was found in the patients with PE. The awareness of risk factors and risk stratification is a critical issue in treatment and prevention policy. Preventive measures should be taken in particular medical conditions.

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Etiological factors in young patients with Retinal Vein Occlusion

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.35.5.546 ◽

2019 ◽

Vol 35 (5) ◽

Author(s):

Serhad Nalcaci ◽

Cumali Degirmenci ◽

Cezmi Akkin ◽

Jale Mentes

Keyword(s):

Gene Mutation ◽

Methylenetetrahydrofolate Reductase ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Etiological Factors ◽

Reductase Gene ◽

Prothrombin Gene Mutation ◽

Prothrombin Gene ◽

Methylenetetrahydrofolate Reductase Gene

Objective: To present the etiological factors of patients with Retinal Vein Occlusion (RVO) under the age of 50 years. Methods: The study was conducted at Ege University Medicine Faculty Department of Ophthalmology. The clinical records of patients with RVO under the age of 50 seen between January 2014 and March 2018 were analyzed retrospectively. Forty patients comprised the study. Detailed ophthalmologic examination was performed. Past medical history, drug use, thrombophilic features, hyperviscosity syndromes and pathologies that may cause vasculitis were noted. Results: Forty patients, 22 (55%) male and 18 (45%) female, were included. Mean age was 41.6 ± 10.01 years. Mean intraocular pressure and best-corrected visual acuity were 16.8 ± 5.47mmHg and 0.76 ± 0.64 logMAR, respectively. Hyperhomocystenemia (15 patients, 37.5%), Behçet’s disease (three patients, 7.5%), diabetes and/or hypertension (16 patients, 40%), methylenetetrahydrofolate reductase gene mutation (11 patients, 27.5%), prothrombin gene mutation (four patients, 10%) and factor V Leiden mutation (five patients, 12.5%) were present among the patients as etiological factor. Multiple etiological factors were detected in 11 (27.5%) patients. Factor V Leiden mutation and methylenetetrahydrofolate reductase gene mutation were detected in one patient (2.5%) with Behçet’s disease. Four patients with diabetes and/or hypertension also had hyperhomocystenemia and one of them had additionally prothrombin gene mutation. Two patients with methylenetetrahydrofolate reductase gene mutation also had a factor V Leiden mutation and one of them had additionally a prothrombin gene mutation. Three patients with methylenetetrahydrofolate reductase gene mutation also had hyperhomocystenemia and one patient with prothrombin gene mutation also had methylenetetrahydrofolate reductase gene mutation. Conclusions: Etiological factors that might result in RVO in young individuals should be investigated in detail. Targeted therapies may help to prevent development of new RVOs and potential vascular problems in other organs. doi: https://doi.org/10.12669/pjms.35.5.546 How to cite this:Nalcaci S, Degirmenci C, Akkin C, Mentes J. Etiological factors in young patients with Retinal Vein Occlusion. Pak J Med Sci. 2019;35(5):---------. doi: https://doi.org/10.12669/pjms.35.5.546 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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