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Arg506GIn Factor V Mutation (Factor V Leiden) in Patients with Ischaemic Cerebrovascular Disease and Survivors of Myocardial Infarction
Abstract
The point mutation Arg506- > Gln of factor V was recently shown to be an important and relatively common genetic cause of venous thromboembolism. Using a DNA technique based on polymerase chain reaction, we surveyed the blood samples of 236 patients with ischaemic stroke or a transient ischaemic attack, 122 survivors of myocardial infarction and 137 control subjects for the presence of this mutation. Although the frequency of the factor V mutation in patients with arterial disease (4.5%) was not significantly different from that in healthy blood donors (2.9%), a carrier status for this mutant gene was associated with symptoms of migraine and relatively mild angiographic abnormalities among patients with cerebrovascular disease. A more extensive study addressing the occurrence and significance of the mutant factor V mutation in patients with vasospastic cerebrovascular diseases seems to be warranted.
... The role of APC resistance in arterial infarction, however, is less clear. With respect to stroke, studies yield conflicting results: some found individuals with APC resistance to be more likely to suffer from an ischemic stroke [7][8][9][10], others were not able to demonstrate any association [4,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and yet others only found associations in certain subgroups such as young patients or patients who had a cryptogenic stroke [31][32][33][34][35]. Cryptogenic strokes are strokes with no identifiable cause which account for approximately 30-40% of ischemic strokes [36]. Indications, benefits and drawbacks of testing for inherited thrombophilias within the diagnostic work-up of ischemic stroke patients are therefore controversially discussed [37][38][39][40][41]. Nevertheless, current clinical practice frequently includes testing for FV Leiden in patients with a history of stroke [42], particularly in young patients who have suffered from a cryptogenic stroke. ...
... If APC-resistance is a slight risk factor for a first stroke, risk for recurrence might be minimal in this subgroup. Consistent with our follow-up data, several cross-sectional original studies [4,[11][12][13][14][15][16][17][18] as well as one large-scale meta-analysis [19] examined unselected cohorts of adult stroke patients and found prevalences of APC-resistance comparable to healthy controls. Consequently, as in our study, odds ratios for stroke were not increased by the presence of APC-resistance. ...
Background:
Activated protein C (APC) resistance is the most common inherited prothrombotic disorder. The role of APC resistance in ischemic stroke is controversially discussed.
Objectives:
The aim of this single center follow up study was to investigate the effect of APC resistance on stroke recurrence and survival in stroke patients.
Patients/methods:
We retrospectively identified 966 patients who had had an ischemic stroke or transitory ischemic attack (TIA) and in whom laboratory tests for APC resistance had been conducted. These patients were contacted to determine the primary outcomes of recurrent ischemic stroke or death.
Results:
A total of 858 patients with an average follow up time of 8.48 years were included. APC resistance did not influence cumulative incidence functions for stroke free and total survival. In multivariate analyses, crude and adjusted hazard ratios for recurrent stroke as well as for death where not significantly increased in patients with APC resistance. This also applies to the subgroups of young patients, patients with cryptogenic stroke and patients with atrial fibrillation.
Conclusion:
APC-resistance is not a risk factor for subsequent stroke or death in patients with a first ischemic stroke or TIA. Testing for APC-resistance in stroke patients therefore cannot be routinely recommended.
... Previous studies have investigated the prevalence of activated biological thrombophilia in patients with migraine but results remain controversial. Although some authors [7,8] failed to show a strong association between inherited biological thrombophilia and migraine, other observations showed a high prevalence of genetic thrombophilia, particularly FVL mutation, in migrainous patients [9,10]. ...
... In a Finnish study, Kontula et al suggested an association between APC resistance due to FVL mutation and MA [9]. They identified FVL mutation in 3.8% of 236 survivors of stroke, as compared to 2.9% in a healthy group (the difference was not significant). ...
Introduction
Migraine, particularly migraine with aura (MA), is associated with a higher risk for ischemic stroke (IS). A procoagulant state may predispose to IS. Whether inherited biological thrombophilia are associated with migraine risk remains controversial.
Objective
To assess the risk of migraine without or with aura related to inherited biological thrombophilia adjusted for the main potential confounders.
Material and Methods
A cross-sectional study was conducted in 1456 French women aged 18 to 56 years, referred for biological coagulation check-up because of personal or familial venous thrombosis history. Between April 2007 and December 2008, all women answered a self-administered questionnaire to determine whether they had headache.
Results
There were 294 (20%) migrainous sufferers (including 71 [5%] with MA), 975 (67%) non migrainous women and 187 (13%) non migrainous headache women. Inherited thrombophilia were detected in 576 (40%) women, including 389 (40%) non migrainous women, 90 (40%) migraine without aura (MWA), 33 (46%) MA women and 64 (34%) non migrainous headache women. Factor V Leiden (FVL) i.e. F5rs6025 or Factor II G20210A (FIIL) i.e. F2rs1799963 mutation was detected in 296 (30%) non migrainous women and in 100 (34%) migrainous women of which 27 had MA. There was a significant association between MA and FVL or FIIL mutations (adjusted OR = 1.76 [95% CI 1.02-3.06] p = 0.04) whereas this association in MWA and in non migrainous headache women was not significant. There was no significant association between migraine and other biological thrombophilia.
Conclusion
FVL or FIIL mutations were more likely among patients suffering from MA. Whether biological thrombophilia screening should be systematically performed in women suffering from MA remains to be determined.
... The point mutation causing the Leiden phenotype results in defective lysis of factor V by activated protein C (Bertina et al. 1994, Dalhback 1997. Approximate frequencies of genotypes in the Finnish population are 96.5-97% for GG, 3.0-3.5% for GA and possibly about 0.1% for AA (Hakala et al. 1995, Kontula et al. 1995. The increased risk of the GA genotype for venous thromboembolism seems established (Hakala et al. 1995, Dahlback 1997, Ridker et al. 1999. ...
... The increased risk of the GA genotype for venous thromboembolism seems established (Hakala et al. 1995, Dahlback 1997, Ridker et al. 1999. The possible role of the GA in MI patients has been studied extensively and several studies have shown that the GA genotype is not associated with increased risk for MI (Emmerich et al. 1995, Kontula et al. 1995, Dacosta et al. 1998, Doggen et al. 1998a, Junker et al. 1998, Araujo et al. 1999, Ardissino et al. 1999, Gardemann et al. 1999a, Mangoni et al. 1999, Redondo et al. 1999, Ridker et al. 1999, although it has been suggested to increase the risk of MI in women under 40 with additional risk factors, such as smoking or obesity ). Due to very low incidence of MI in this group and to the low prevalence of the A allele, it does not seem to be an important risk factor for MI on population-basis. ...
... Few studies have investigated the prevalence of prothrombotic genetic risk factors in patients with migraine, and conflicting results have been reported. A Finish study detected a higher frequency of migraine with aura in patients suffering from ischemic stroke who carried the factor V Leiden (67%) than in those who had no mutation (26%) [18]; these findings were subsequently confirmed by Leone et al. [19]. In contrast, a case-control study did not find a significantly higher frequency of several prothrombotic factors (factor V Leiden, G20210A mutation of factor II, decanucleotide insertion/deletion in factor VII promoter, HPA-1 and HPA-2 polymorphisms) in 106 migrainous patients compared to healthy controls [20], even if a particularly high frequency of factor V Leiden, not reaching statistical significance, was found in patients suffering from migraine with aura. ...
... We concluded that platelet hyperaggregation may be considered to be a more specific marker of migraine. Conflicting results have been reported regarding the prevalence of genetic prothrombotic risk factors in migraine [18][19][20][21][22][23]. In our study, in accordance with Corral et al. [20] and Soriani et al. [22], the frequencies of the two main prothrombotic polymorphisms for venous thromboembolism (Leiden, prothrombin) did not differ from those of controls. ...
Growing evidence suggests a possible relationship between
migraine and thrombotic risk factors. The aim of this study was
to analyze the possible relationship between migraine and
acquired and genetic thrombophilia in a young population. We
compared 16 migrainous adolescents, 12 children with
tension-type headache, and controls in terms of frequencies of
prothrombotic polymorphisms (factor V Leiden, C677T mutation of
5,10 methylenetetrahydrofolate reductase, G20210A mutation of
prothrombin), platelet aggregability, anticoagulant antibodies,
blood lipid pattern, serum folate and vitamin B12 levels,
homocysteinemia, coagulation parameters, and family history for
migraine and precocious thrombotic events. This study confirms
the link between migraine and increased platelet responsiveness.
Overall, 62.5% of migrainous patients carried at least three
thrombophilic factors. Our preliminary data suggest that, in
order to assess prevention strategies, it could be appropriate
to perform a complete thrombophilia screening in young patients
suffering from migraine and with a family history of
thrombosis.
... In the current study, none of the 40 women with ischemic strokes had factor V Leiden (95% CI derived from the binomial distribution, 0 to 8.8%). Considering prior reports on series of patients with stroke [11][12][13][14]16,18,19,21,22,25,27,28,33 and the results of this study for ischemic stroke, we calculated that 73 of 1610 stroke patients (4.5%) who have been genotyped carry factor V Leiden, similar to the 3% to 5% reported for the general population. 2 The associa-tion between factor V Leiden and hemmorrhagic stroke was also not statistically significant (OR, 0.4; 95% CI, 0.1 to 3.4). ...
... Unanswered by this study is whether screening would be more useful in select patients, such as those venous strokes. Other investigators have suggested that such select groups may include patients with an ischemic stroke combined with one of the following features: a strong family history of thrombophilia, 17 pregnancy and puerperium, 15,24 childhood, 23,26 an angiographic complication, 31 oral contraceptive use and antiphospholipid syndrome, 22 paradoxical embolus with deep-vein thrombosis and patent foramen ovale, 29 migraine, 13 and young age without any risk factors. 9,10 Given the relative rarity of such ischemic strokes, the utility of screening for these two mutations in these settings will remain difficult to define. ...
Factor V Leiden and a prothrombin gene variant, G20210A, are mutations associated with a thrombotic risk. The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age.
We conducted a case-control study in western Washington state. Case patients were women aged 18 to 44 years with a first stroke (n = 106). Control subjects were women without stroke recruited from the same region by use of random-digit telephone dialing (n = 391). All were interviewed and provided blood specimens, which were genotyped for these mutations.
Factor V Leiden was found in 0.9% of case patients, a single patient with a subarachnoid hemorrhage, and in 4.1% of control subjects. The odds ratio (OR) for any stroke was 0.2 (95% confidence interval [CI], 0.03 to 1.7). The prothrombin variant was found in 1.9% of case patients, 1 with a venous stroke and 1 with an ischemic stroke, and in 1.6% of control subjects. The OR for any stroke was 1.48 (95% CI, 0.14 to 9.17). ORs for stroke types were also not statistically significant.
In this study, neither factor V Leiden nor the prothrombin variant (G20210A) was an important risk factor for stroke in young women. In this setting, screening for these mutations cannot be recommended. Unanswered by this study is whether screening would be useful in select patients, such as those with a strong family history of thrombophilia or those with venous strokes.
... В исследовании Physicians' Health Study, в котором приняли участие почти 15 000 условно здоровых мужчин, FVL был одинаково распространен среди пациентов с инфарктом миокарда (ИМ) и инсультом в качестве контроля [15]. Другие небольшие исследования (<1000 пациентов) также не обнаружили ассоциации FVL и ИМ [18][19][20][21][22]. Однако выполненный в 2006 г. метаанализ выявил увеличение риска развития ишемической болезни сердца при наличии FVL, так же как и метаанализ 2010 г., включающий более 66 000 случаев ИМ у пациентов в возрасте до 45 лет и более 91 000 человек в контрольной группе (соответственно отношение шансов 1,17, 95%-й доверительный интервал (ДИ) 1,08-1,28) [23] и 1,66, 1,15-2,38) [24]. ...
Factor V, encoded by the F5 gene, is a procoagulant blood clotting factor that increases the production of thrombin, the central enzyme that converts fibrinogen to fibrin, which leads to the formation of a blood clot. The F5 gene is localized to 1q24.2 chromosome and consists of 25 exons. There are various mutations in the F5 gene that lead to resistance of activated protein C (APC) (elimination of the APС cleavage site in factor V and factor Va), which can lead to arterial and venous thrombosis. The aim of the present study was to analyze variants of the F5 gene in patients diagnosed with coronary atherosclerosis without acute coronary syndrome with stable functional class II–IV angina pectoris, confirmed by coronary angiography data, using the method of whole exome sequencing.
Material and methods . The study was conducted in the framework of the Program of joint research work IIPM — branch of the ICG SB RAS and the FSBI «Research Institute of Circulation Pathology named after E.N. Meshalkin» Ministry of Health of Russian Federation. The study included 30 men aged 40–70 years with coronary angiography-verified coronary atherosclerosis, without ACS, with stable angina pectoris of the II–IV FC. Patients were admitted for coronary bypass surgery, and endarteriaectomy from the coronary artery (s) was performed during the operation according to intraoperative indications. Whole exome sequencing (SureSelectXT Human All Exon v.6+UTR) was carried out on an Illumina NextSeq 500 instrument (USA).
Results. In 30 patients, 29 single-nucleotide variants were found in the F5 gene. In patients with coronary atherosclerosis, rs9332701 of the F5 gene is 3.33 times more common, and rs6027 is 1.67 times more common than in the population. And rs184663825 was found in 3.33% of cases, while its occurrence in the population is 0.05%. For variants rs6034 and rs144979314, a possible damaging effect on the protein product is shown.
Conclusion . The single-nucleotide variants rs9332701, rs6027, rs184663825, rs6034, rs144979314 of the F5 gene are of interest for inclusion in the genetic panels for the analysis of risk factors for the development of acute coronary syndrome.
... Birçok çalışmada yineleyen baş ağrılarının, kızlarda erkeklerden fazla olduğu ve yaşla birlikte arttığı belirtilmiştir (7,(20)(21)(22)(23). Çalışmamızda kızlarla erkekler arasında baş ağrısının görülme sıklığı açısından fark yoktu. ...
... [81][82][83][84] Multiple studies did not find an increased prevalence of the mutation in patients with myocardial infarction or stroke. 19,[85][86][87][88][89][90][91] Thus, routine anticoagulation is not recommended for FVL carriers with atherosclerotic arterial occlusive disease. However, among carriers with myocardial infarction or stroke, anticoagulation therapy for secondary prevention may be appropriate. ...
Objective.—To review the current state of the art regarding the role of the clinical laboratory in diagnostic testing for the factor V Leiden (FVL) thrombophilic mutation (and other protein C resistance disorders), and to generate, through literature reviews and opinions of recognized thought-leaders, expert consensus recommendations on methodology and diagnostic, prognostic, and management issues pertaining to clinical FVL testing.
Data Sources, Extraction, and Synthesis.—An initial thorough review of the medical literature and of current best clinical practices by a panel of 4 experts followed by a consensus conference review, editing, and ultimate approval by the majority of a panel of 28 additional coagulation laboratory experts.
Conclusions.—Consensus recommendations were generated for topics of direct clinical relevance, including (1) defining those patients (and family members) who should (and should not) be tested for FVL; (2) defining the preferred FVL laboratory testing methods; and (3) defining the therapeutic, prophylactic, and management ramifications of FVL testing in affected individuals and their family members. As FVL is currently the most common recognized familial thrombophilia, it is hoped that these recommendations will assist laboratorians and clinicians caring for patients (and families) with this common mutation.
... Another study found the factor V Leiden polymorphism more often in patients with myocardial infarction (5.7%) than in healthy controls (2.9%). 35 Samani et al 36 and Ardissino et al, 37 however, evaluated young survivors (Ͻ45 years) of myocardial infarction for factor V Leiden and found that the factor V polymorphism was not a factor for the early development of coronary artery disease. The discrepancies among these studies may well be the result of differences in patient populations with respect to sex, since the cause of myocardial infarction may in part differ between men and woman. ...
Background.—Cardiovascular disease remains the leading cause of mortality in the United States, accounting for approximately 33% of all deaths in this country. Of these deaths, most are due to acute myocardial infarctions (AMIs), which are associated with thrombotic coronary artery obstruction and/or occlusion. These events could potentially be due to alterations in genes coding for coagulation factors. Several polymorphisms have been described in the factor II, V, and VII genes, which may predispose one to increased risk for ischemic heart disease (IHD).
Objective.—To determine if mutations in 3 coagulation factor genes could predispose an individual to increased risk for arterial thrombosis as a mechanism for developing unstable angina (UA) or AMI.
Methods.—We examined 125 hospitalized patients (mean age, 53 ± 6 years, 79 men and 46 women), including 32 with AMI, 68 with UA, and 25 noncardiac controls, for a genetic predisposition for increased risk of IHD. EDTA-anticoagulated whole blood was collected at the time of hospital admission. DNA was extracted, and the polymorphisms were detected by polymerase chain reaction amplification of these genes with subsequent restriction enzyme digestion and gel electrophoresis.
Results.—Our results showed that 3 (9.4%), 3 (4.4%), and 1 (4%) individuals were heterozygous for prothrombin G20210A and 3 (9.4%), 5 (7.4%), and 1 (4%) individuals were heterozygous for factor V Leiden in the AMI, UA, and control groups, respectively. The following genotype frequencies for the factor VII R353Q polymorphism were identified: 25 (78.1%), 56 (82.4%), and 18 (72%) with RR and 7 (21.9%), 12 (17.6%), and 7 (28%) with RQ in the AMI, UA, and control groups, respectively. No QQ homozygotes were identified. For the HVR4 size polymorphism, the following genotypes were identified: 3 (9.4%), 4 (5.9%), and 5 (20%) individuals with H7H7; 11 (34.4%), 33 (48.5%), and 12 (48%) with H6H7; and 18 (56.2%), 31 (45.6%), and 8 (32%) with H6H6 genotypes in the AMI, UA, and control groups, respectively. There were no H7H5 and H6H5 genotypes found in this study.
Conclusions.—Although the frequency differences of these polymorphisms in patients with AMI and UA were not statistically significant from those in controls, several trends are consistent with what has been reported in the literature. Although any of these or other undefined genetic abnormalities may result in IHD, it is possible that phenotypic predisposition to IHD initially presents as UA. A larger population study addressing the significance of these polymorphisms in the sequence of events that lead to IHD, including cases of UA, is warranted.
... In contrast, the present study demonstrated a higher frequency of homozygous and heterozygous FVL mutations in stroke patients than in controls. The frequency of this mutation in stroke patients was higher than that reported in previous studies (33)(34)(35)(36)(37)(38)(39). Notably, the frequency of the FVL mutation in healthy individuals was similar to that of the general society. ...
OBJECTIVE: The present study aimed to investigate whether the frequency of factor V, methylenetetrahydrofolate reductase (MTHFR), prothrombin, β-fibrinogen gene mutations, and human platelet alloantigens (HPA), plasminogen activator inhibitor 1 (PAI1), apolipoprotein E (APOE), and angiotensin converting enzyme (ACE) gene polymorphisms in stroke patients is higher than that in normal individuals.
METHODS: Two hundred twelve patients with cerebral infarction and 238 individuals of similar age and gender with no history of stroke were included. Demographics and risk factors for cerebrovascular disease of all individuals were determined. Biochemical parameters were analyzed in serum, and electrocardiography was performed. Factor V, MTHFR, prothrombin, β-fibrinogen mutations and HPA, PAI, APOE, and ACE polymorphisms were investigated. Data were analyzed with SPSS 15.0 software using descriptive statistics, chi-square, independent two-group t-test, and logistic regression tests. Statistically significant differences in independent variables were further analyzed by logistic regression. p < 0.05 was considered statistically significant.
RESULTS: HPA, PAI, APO, and ACE polymorphism frequency was not significantly different between the stroke and control groups. Factor V H1299R, factor V Leiden, and β fibrinogen -455GA mutation frequency was significantly higher in the stroke than the control group by the chi-square test, but not by logistic regression analysis.
CONCLUSION: Stroke etiopathogenesis is multifactorial, and prothrombin gene mutations increase the impact of existing risk factors when other risk factors are considered.
... The prevalence of FV Leiden was 2.2-2.6% in controls of Studies I-IV, and 2.4% in the population sample of 644 blood donors. These numbers are in agreement with other Finnish materials, where the prevalence of FV Leiden has been 2.1-2.9% in controls [141,142]. ...
... New hereditary or acquired thrombophilia was found in 6.4 % of the patients with venous lesions and thromboembolism. This prevalence was comparable to the frequency of thrombophilia in the general Finnish and Western European populations 129,[144][145][146][147] . Of note however, 2 of 5 (40 %) patients with pulmonary embolism had thrombophilia (Table 15). ...
... (31) The prevalence of the FV:Q 506 allele is between 2% and 15% in Western societies, but it varies widely depending on the geographic location and the ethnic background of the population. (21,(32)(33)(34)(35) The highest frequencies of heterozygosity for FV:Q 506 have been observed in certain regions of southern Sweden (36) and in Greece. (35) The FV:Q 506 allele is most probably the result of a founder effect. ...
exposed upon vascular damage. (1,2) In a series of sequential proteolytic reactions, proenzymes are activated, culminating in the formation of thrombin. Several of the reactions are greatly enhanced by non-enzymatic cofactors, which together with the enzymes are assembled into highly efficient and specific proteolytic complexes on the surface of procoagulant phospholipids. (3) The protein C anticoagulant pathway regulates the activity of the procoagulant cofactors, factor Va (FVa) and factor VIIIa (FVIIIa). (4-7) Protein C, which is a zymogen to a serine protease, is activated by thrombin when it is bound to the endothelial cell membrane protein thrombomodulin. (7) In the degradation of FVa and FVIIIa by activated protein C (APC), vitamin K-dependent protein S functions as a non-enzymatic cofactor. (5,6,8) In human plasma the concentration of protein S is approximately 0.3 µM (20-25 mg/l), and it circulates both as free protein (approximately 40%) and bound to C4b-binding protein, a regulator of the complement system. (5) Only the free form of protein S is active as an APC-cofactor. Recently, intact FV was discovered to be a second APC-cofactor. (9,10) Thus, FV appears to function as an anticoagulant protein under normal conditions. It is converted into a potent procoagulant cofactor upon activation of the coagulation system. Just like the transformation that thrombin undergoes upon its binding to thrombomodulin, this dual capacity of FV is an ingenious means of balancing pro- and anti-coagulant forces. Heterozygous deficiency of protein C is associated with thromboembolic diseases. (5,6) In its homozygous form, protein C deficiency manifests very severe, often fatal, thrombosis already in the neonatal period. The association between protein S deficiency and venous thrombosis supports the concept that protein S is a physiologically important natural anticoagulant. Many mutations causing quantitative or qualitative deficiencies of protein C and protein S have been described. (11,12) APC-Resistance as a Basis of Venous Thrombosis Until recently, fewer than 10% of venous thrombosis patients have been found to carry genetic defects of coagulation inhibitors such as antithrombin III, protein S or protein C. (5,13) In 1993, this changed with the description of APC-resistance as a previously unrecognized cause of thrombophilia. (14) In normal plasma, the clotting time increases with increasing concentrations of added APC, whereas a poor anticoagulant response to APC is manifested in APC-resistant plasma. The APC-resistance test is now a standard assay, which is used in the evaluation of thrombosis patients. In its most common form, the assay is a modification of a standard activated partial thromboplastin time (APTT) reaction. Two APTT reactions are performed, one of which includes a carefully standardized amount of added APC, and results are expressed as the ratio of the values obtained with the two APTT tests. (15,16) Among patients suffering from venous
... This study also found several comorbidities and medications could predict dementia. The associations between blood pressure, diabetes and dementia and cognitive impairment have received much attention in studies, but the results are somewhat in conflict2526272829303132. High blood pressure increases the risk of dementia in the elderly [26,30] . ...
Background
Chronic kidney disease (CKD) is more prevalent in Taiwan than in most countries. This population-based cohort study evaluated the dementia risk associated with CKD.
Methods
Using claims data of 1,000,000 insured residents covered in the universal health insurance of Taiwan, we selected 37049 adults with CKD newly diagnosed from 2000–2006 as the CKD cohort. We also randomly selected 74098 persons free from CKD and other kidney diseases, frequency matched with age, sex and the date of CKD diagnosed. Incidence and hazard ratios (HRs) of dementia were evaluated by the end of 2009.
Results
Subjects in the CKD cohort were more prevalent with comorbidities than those in the non-CKD cohort (p <0.0001). The dementia incidence was higher in the CKD cohort than in the non-CKD cohort (9.30 vs. 5.55 per 1,000 person-years), with an overall HR of 1.41 (95% confidence interval (CI), 1.32-1.50), controlling for sex, age, comorbidities and medicaitions. The risk was similar in men and women but increased sharply with age to an HR of 133 (95% CI, 68.9-256) for the elderly. However, the age-specific CKD cohort to non-CKD cohort incidence rate ratio decreased with age, with the highest ratio of 16.0 (95% CI, 2.00-128) in the youngest group. Among comorbidities and medications, alcoholism and taking benzodiazepines were also associated with dementia with elevated adjusted HRs of 3.05 (95% CI 2.17-4.28) and 1.23 (95% CI 1.14-1.32), respectively.
Conclusions
Patients with CKD could have an elevated dementia risk. CKD patients with comorbidity deserve attention to prevent dementia.
... A higher incidence of prothrombotic conditions, such as resistance to activated protein C (ACPR) as well as factor V Leiden G1691A (FVL) and factor II G20210A (PRT) mutations, have been found in migraine patients compared with controls (11,12). ...
... The frequencies of factor V Leiden and the prothrombin variant G20210A have not been consistently shown to be increased among patients with previous MI or stroke (9,10,17). However, increased frequencies of factor V Leiden and prothrombin variant G20210A in younger women with MI have been shown by one group (18,19). ...
Objectives:
We sought to determine the frequencies of factor V Leiden and prothrombin variant G20210A in patients age <50 years with no significant coronary stenoses three to four weeks after myocardial infarction (MI).
Background:
Factor V Leiden and prothrombin variant G20210A occur frequently in patients with venous thromboembolism. However, the contribution of these mutations to the development of MI requires clarification.
Methods:
The frequencies of factor V Leiden and prothrombin variant G20210A were determined in 41 patients age <50 years who had "normal" or "near normal" coronary arteries (no stenosis >50%) at angiography three to four weeks after MI (the study group) and compared with those in 114 patients who had at least one angiographic stenosis >50% after MI (the control group). Patients age > or =50 years with, or without, stenoses were also studied.
Results:
The frequency of factor V Leiden was 14.6% in patients age <50 years in the study group compared with 3.6% in patients in the control group (odds ratio [OR] 4.7 [95% confidence interval (CI) 1.3-17.7], p = 0.02). The frequency of the prothrombin variant G20210A was 7.3% in the study group compared with 1.8% in the control group (OR 4.4 [95% CI 0.7-27.5], p = 0.12). One or both mutations were present in 8 of the 41 patients (19.5%) age <50 years in the study group compared with 6 of the 114 patients (5.5%) in the control group (OR 4.4 [95% CI 1.4-13.5], p = 0.01). In all 271 patients (irrespective of age) with normal arteries, the frequency of factor V Leiden was 11.7% (7/60) compared with 4.3% (9/211) in patients with at least one >50% stenosis (OR 2.9 [95% CI 1.1-8.3], p = 0.04), and the frequency of prothrombin variant G20210A was 6.7% (4/60) compared with 1.4% (3/211) (OR 4.9 [95% CI 1.1-22.8], p = 0.04), respectively.
Conclusions:
The frequencies of factor V Leiden and/or prothrombin variant G20210A are increased in patients age <50 years with normal or near normal coronary arteries after MI.
Arterial thrombosis (AT) is a pivotal event in the natural history of coronary heart disease (CHD), stroke (cerebrovascular ischemic disease), and peripheral vascular disease. CHD represents a continuum of myocardial ischemia ranging from unstable angina to coronary artery disease (CAD), and to myocardial infarction (MI). Although a family history of CAD is a risk factor for cardiovascular ischemic episodes, the overall impact of family history is modest. Common forms of AT segregate in a non-Mendelian inheritance pattern. Over 95% of early CHD cases are not caused by monogenic defects such as familial hypercholesterolemia (FH), but rather by multiple genetic and environmental determinants. The pathogenesis of AT is probably different from that of venous thrombosis (VT). Most forms of AT are multifactorial disorders resulted from many different combinations of genetic prothrombotic polymorphisms and environmental atherogenic factors, even though some by themselves may not be sufficient to cause disease. Environmental risk factors for AT include high fat diets, cigarette smoking, increased salt consumption, and decreased intake of folate.
Several recent studies evaluated a possible effect of the prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C → T, factor V (F V) nt 1691G → A (F V Leiden), and factor II (F II) nt 20210 G → A on the risk of myocardial infarction. In the present study, we analyzed the effect of these prothrombotic polymorphisms, as well as apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, on the risk of myocardial infarction in young males. We conducted a case-control study of 112 young males with first acute myocardial infarction (AMI) before the age of 52 and 187 healthy controls of similar age. The prevalences of heterozygotes for F V G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among cases and controls, respectively). In contrast, the prevalence of MTHFR 677T homozygosity and the allele frequency of Apo E4 were significantly higher among patients (24.1% v 10.7% and 9.4% v5.3% among cases and controls, respectively). Concomitant presence of hypertension, hypercholesterolemia, or diabetes and one or more of the four examined polymorphisms increased the risk by almost ninefold (odds ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5) and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed simultaneously by a logistic model, the combination of prothrombotic and Apo E4 polymorphisms with current smoking increased the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9).The presented data suggest a synergistic effect between atherogenic and thrombogenic risk factors in the pathogenesis of AMI, as was recently found in a similar cohort of women.
Pregnancy can be seen as a positive time for women migraineurs because the elevated estrogen and endogenous opioid levels raise the pain threshold and the stable hormone levels, which no longer fluctuate, eliminate a major trigger factor for the attacks. In a great majority of cases, indeed, migraine symptoms spontaneously improve throughout pregnancy. Generally, migraine without aura (MO) improves better than migraine with aura (MA), which can occur ex novo in pregnancy more frequently than MO. After childbirth, the recurrence rate of migraine attacks increases, especially during the first month; breastfeeding exerts a protective effect against the reappearance of attacks. Migraine and pregnancy share a condition of hypercoagulability; therefore, attention must be paid to the risk of cardiovascular disorders, like venous thromboembolism and ischemic or hemorrhagic strokes. Some of these diseases can be linked to preeclampsia (PE), a serious complication of pregnancy, characterized by hypertension, proteinuria, or other findings of organ failure. This condition is more common in migraineurs compared with non-migraineurs; furthermore, women whose migraines worsen during pregnancy had a 13-fold higher risk of hypertensive disorders than those in which migraine remitted or improved. Pregnancy is generally recognized to exert a beneficial effect on migraine; nonetheless, clinicians should be on the alert for possible cardiovascular complications that appear to be more frequent in this patient population.
Background:
Ischemic stroke is a complex, multifactorial, and polygenic disease. Reports on relationship between Factor V G1691A single nucleotide gene polymorphism and ischemic stroke have revealed inconsistent results. We conducted an updated meta-analysis to determine the role of Factor V single nucleotide gene polymorphism in ischemic stroke.
Methods:
We searched the literature using academic electronic databases that is, PubMed, Trip Data Base, EBSCO, and Google Scholar, last search up to September 2017. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from fixed or random effects models whichever applicable using software STATA version 13 (StataCorp LP, College Station, TX).
Results:
Forty case-control studies met the inclusion criteria, which included 6860 cases and 18,025 controls. Altogether, 19 studies in young adults (age < or = 40 years) and 17 studies were conducted in old stroke (age > 40). Four studies did not report the mean age at recruitment. Significant association between Factor V G1691A gene polymorphism and risk of ischemic stroke were observed under dominant model (OR 1.40; 95% CI: 1.22 to 1.62, P value <.001). Stratified analysis suggested substantial association of Factor V gene polymorphism and risk of ischemic stroke in cases with onset at young age (OR 1.84; 95% CI: 1.47 to 2.30), but was not statistical significant in cases at old age (>40 years).
Conclusions:
Factor V G1691A single nucleotide gene polymorphism was associated with risk of ischemic stroke mainly in young adults. Further research with adequately powered prospective studies in homogenous subjects are required to determine the nature of association in young stroke.
Vascular disease and Alzheimer’s disease are both common disorders, in particularly among elderly subjects. Therefore, it can be expected that the joint occurrence of these two disorders is not a rare phenomenon. In recent years, evidence is increasing that the two may be more closely linked than just by chance. Epidemiological studies have suggested that the risk factors for vascular disease and stroke are associated with cognitive impairment and Alzheimer’s disease, and that the presence of cerebrovascular disease intensifies the presence and severity of the clinical symptoms of Alzheimer’s disease. In this chapter, current knowledge on the relation between vascular risk factors and Alzheimer’s disease is reviewed.
OBJECTIVE: Migraine is an independent risk factor for ischemic stroke, but its pathophysiology is still unclear. Genetic factors that predispose patients to thrombosis have been studied in patients with migraine to highlight the pathogenesis, but the results remain controversial. In this study, the frequencies of factor V Leiden (FVL), prothrombin (Pt) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T mutations were investigated.
METHODS: One hundred and sixty patients aged of 15 to 55 years with no history of systemic disease and who had been diagnosed as migraine according to the International Headache Society (IHS) diagnostic criteria at Baskent University Hospital Neurology Outpatient Clinics were investigated for FVL, Pt G20210A and MTHFR C677T mutations from their genomic DNA, and the results were compared with those of healthy controls.
RESULTS: One hundred and fifty five (96.9%) of 160 migraine patients were homozygote normal, 5 (3.1%) were heterozygote and none of them were homozygote mutant for FVL. The control group had 9.8% heterozygote individuals but the difference between the percentages was not statistically significant (p> 0.05). There were no homozygote mutant individuals in the Turkish population study in normal subjects like our study. Thirty nine (24.4%) of 160 migraine patients were heterozygote and 8 (5%) were homozygote mutant for MTHFR C677T. The control group had 37 (34.9%) heterozygote and 6 (5.6%) homozygote mutant individuals. The difference between the percentages was not statistically significant (p= 0.15). Three (1.9%) of 160 migraine patients were heterozygote and 5 (2.9%) of the control group were heterozygote mutant for Pt G20210A mutation. The control group had 37 (34.9%) heterozygote and 6 (5.6%) homozygote mutant individuals. The difference between the percentages was not statistically significant (p= 0.420).
CONCLUSION: Our study indicates that FVL, Pt G20210A and MTHFR C677T gene mutations, which are considered as risk factors for thrombosis, were not found to be associated with migraine pathogenesis in our population. The differences between populations probably depend on variations in ethnic origin.
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
La trattazione della malattia da decompressione risale al 1841 ed è stata progressivamente arricchita da diversi studi, durante e dopo la prima guerra mondiale. È generalmente la variazione improvvisa della pressione circostante che ne è la causa, il che è stato constatato nelle condizioni seguenti: le immersioni sottomarine, i voli in un aereo depressurizzato o la depressurizzazione in volo, oppure le deflagrazioni e le esplosioni. La malattia da decompressione è causata dalla formazione di bolle di gas nel corpo e il principale agente responsabile è l’azoto, un gas inerte di cui l’organismo è saturo a livello del mare. Durante una discesa rapida la diminuzione della pressione barometrica fa sì che la pressione del gas inerte nei tessuti superi la pressione barometrica esterna. Compaiono allora delle «microbolle» di azoto nei tessuti e nei liquidi organici. Queste bolle sono all’origine della malattia dei cassoni. Delle leggi fisiche regolano la formazione e lo sviluppo delle bolle nell’organismo. Sul piano fisiopatologico, certi incidenti sono «biochimici» e altri sono piuttosto detti «meccanici», poiché legati all’effetto di iperpressione intracavitaria dei gas. I meccanismi biochimici implicano, oltre all’incidente iniziale legato alle bolle, lo scatenamento di fenomeni trombotici, sul versante arterioso, venoso o su entrambi. Gli incidenti meccanici comprendono: i barotraumi dell’orecchio medio e interno, del labirinto, dei seni o altri, l’iperpressione polmonare, gli accidenti cutanei o skin bends e gli episodi osteoarticolari o bends. Gli incidenti neurologici rappresentano gli eventi più gravi e più frequenti in occasione dell’immersione, in particolare durante la risalita. Le lesioni midollari sono in assoluto le più frequenti e danno, talvolta, un quadro clinico detto «ictus midollare», ma spesso il quadro è insidioso e progressivo. Le lesioni cerebrali si presentano con quadri più o meno gravi e possono essere accompagnate da crisi epilettiche. Un altro tipo di incidente avviene per intossicazione da gas: ipossia o iperossia sono dovute rispettivamente alla riduzione della pressione parziale di ossigeno o all’effetto tossico del gas quando la sua pressione parziale aumenta in una miscela. I sintomi neurologici possono manifestarsi nel giro di alcuni minuti o di alcune ore. Diversi gas inerti possono essere responsabili di un effetto narcotico; tra di essi il più potente è lo xenon, ma quello più spesso in causa è l’azoto. Gli incidenti di decompressione rappresentano vere urgenze che mettono in forse la prognosi vitale; il carattere potenzialmente evolutivo del quadro clinico, così come il suo carattere multifunzionale (cardiocircolatorio e sistemico) impongono misure immediate e una grande vigilanza in presenza di un quadro apparentemente «benigno». La ricompressione mira a ridurre il volume dei gas espansi riportandoli in soluzione. L’ossigenazione pura con maschera permette all’infortunato di non inalare più azoto e, dunque, una desaturazione del subacqueo. I trattamenti farmacologici restano, nonostante tutto, empirici, ma l’aspirina è quello più comunemente accettato.
The term 'coronary thrombosis' was derived from clinical and pathological observations
on myocardial infarction made at least 80 years ago' and perhaps even earlier.'·} It was
probably not until the 1930s that clinically manifest ischaemic heart disease in the form
of myocardial infarction became a familiar condition rather than the unusual occurrence
or even the rarity it had hitherto been. When the growing epidemic of clinical ischaemic
heart disease prompted an increasing and concerted research programme after the
Second World War, interest largely centred on the lipid nature of the atheromatous
plaque and the contributions dietary fat intake and blood cholesterol levels make to it.
Introduction
Hematological diseases are seldom found as the etiology of ischemic strokes, but are frequently investigated by expensive laboratory tests after a first cerebral vascular event.
Methods
In the Lausanne Stroke Registry, we retrospectively reviewed the cases of patients hospitalized between 1979 and 2001 for a first ischemic arterial stroke which was attributed to a hematological etiology. Of 4697 patients, 22 (0.47 per cent) had a stroke due to one of the following hematological pathology: polycythemia vera (4), secondary polycythemia (4), essential thrombocytemia (2), secondary thrombocytosis (4), multiple myeloma (1), CIVD (1), protein S deficiency (1), antiphospholipid antibody syndrome (4), moderate homocysteinemia (1). A literature review was undertaken for each hemopathy.
Conclusion
In light of the results of these data, we concluded that a complete blood count provides sufficient hematological screening for the majority of patients hospitalized for an arterial stroke. The antiphospholipid antibody syndrome is a rare cause of cerebral infarction, which needs to be investigated in young patients, in cases of multiple or recurring stroke or in the presence of a typical history. Inherited thrombophilias are not a significant risk factor for arterial cerebral infarction and their investigation is only warranted for a sub-group of young patients with a cryptogenic stroke, in which group the prevalence is slightly increased. Moderate homocysteinemia must be considered as a cerebrovascular risk factor of minor importance, but potentially treatable by a substitution of vitamin B12, B 6 and folates. The efficacy of this substitution in the prevention of cardiovascular events needs yet to be demonstrated.
Activated protein C (APC) proteolytically inactivates factors Va (FVa) and VIIIa (FVIIIa), which in turn control two key steps of the coagulation cascade. The pathophysiological importance of this anticoagulant mechanism is illustrated by the severe prothrombotic diathesis associated with the congenital deficiencies of protein C and its cofactor protein S. A poor anticoagulant response of plasma to APC (APC resistance) was first described in a thrombotic patient in 1993 and soon recognized as the most common risk factor for venous thrombosis. The underlying genetic defect was identified one year later as the FV Arg506Gln mutation (FV Leiden), which abolishes one of the APC-cleavage sites on FVa. These ground-breaking discoveries have stimulated numerous researches into the workings of the proteinC pathway, the molecular mechanisms of APC resistance in carriers and noncarriers of FV Leiden, and the clinical significance of APC resistance. This chapter reviews the most important findings, summarizes the state of the art, and discusses new developments in this rapidly evolving research area.
We do not recommend LMWH in asymptomatic women with FV Leiden in heterozygous form during pregnancy, but coumarin is recommended within 2 months after delivery. In females with personal history of VTE we recommend LMWH in pregnancy. The dosage and time of administration depend on the assessment of personal history of VTE and the assessment of all other risk factors of VTE. Coumarin is also taken 2 months after delivery.
For all women we recommend the physical activity with both legs and elastic compressive stockings. In females with homozygous form LMWH is recommended in all cases and also in this case the dosage and time of introduction depend on personal history of VTE and after careful assessment of all other well known risk factors of VTE in pregnancy (age, obesity, varices etc.). Coumarin is also taken at least within 2 months after delivery.
Introduction
Decompression sickness with cerebral ischemic lesions occurs even in divers who have not committed any technical error. This study sought to determine whether an acquired or inborn thrombophilic factor might be involved.
Methods
44 divers with ischemic medullar lesions (36 men, 8 women, mean age 39.9+/-4.7 yr) were compared with 44 controls (34 men, 10 women, mean age 38.2+/-5.1 yr). Coagulation screening included proteins S, C, and thrombin III and Factor VIII assays and circulating antibodies, Factor V Leiden, and mutation G20210A in Factor II gene research. Total plasma homocysteine (Hcy), an atherosclerosis factor (assayed by FPIA), folate and vitamin B12, (by microbiology), the cofactors of its metabolism, were assayed, and subjects were genotyped for mutation C677T on the MTHFR gene.
Results
Coagulation screening — protein C, protein S, or antithrombin III deficit or mutation G20210A — was negative in all divers. 3/44 divers were heterozygous for Factor V Leiden, 1/44 had IgG antiphospholipid antibodies (9p.cent). While not found in controls, these percentages were not greater than those reported in the general population. 3/44 divers had elevated Factor VIII levels, but repeat assays on Day 2 were much lower. 11/44 divers had a moderate increase in Hcy value (20p.cent): in 7 divers, Hcy values were >15 mol/L, and in 4 others >12, vs. 2.3p.cent of the controls; 2/11 had normal vitamin levels and 11 divers had folate or vitamin B12 deficiency or both, vs 2.3p.cent controls with a vitamin B12 deficit (percentage significantly different). 7/26 divers were homozygous for the C677T mutation, i.e. 27p.cent vs 12p.cent of 98 healthy controls (laboratory technicians).
A high percentage of unexplained diving accident victims had moderate HHC, a folate or vitamin B12 deficiency or both, that are easy to detect, plus a genetic predisposition to HHC or to coagulation abnormality. Easy-to-perform homocysteine, vitamin B12, and folate assays might prove helpful for primary prevention of diving accidents.
The discovery of inherited resistance to activated protein C (APC) as a major risk factor for venous thrombosis has dramatically improved our understanding of the pathogenesis of venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene (FV) that results in substitution of arginine, R, at position 506 by glutamine, Q. (FV:Q506). The mutation renders factor Va partially resistant to degradation by APC. A functional APC resistance test, which includes predilution of the patient plasma with factor V-deficient plasma, is found to be 100% sensitive and specific for the presence of FV:Q506 and is useful as a screening assay. Carriers of the FV:Q506 allele have increased thrombin generation, resulting in hypercoagulability and a lifelong increased risk of venous thrombosis. In Western countries, APC resistance due to the FV mutation is present in 20-60% of thrombosis patients and in 1-15% of healthy controls, whereas the mutation is virtually absent from ethnic groups other than Caucasians. This may explain the high incidence of venous thrombosis in Western countries. The thrombotic risk in APC-resistant individuals may be further increased by other genetic defects, e.g., protein C or protein S deficiency, and by exposure to circumstantial risk factors, e.g., oral contraceptives, pregnancy, immobilization, and surgery. The question is thus raised as to whether general screening for APC resistance before circumstantial risk factors occur is warranted in Western countries. Key Words: Factor V—APC resistance-Protein C-Protein S—Thrombosis—Mutation.
It has been acknowledged that a prothrombotic tendency may result from a specific genetic defect. Resistance to activated protein C (APC) (factor V Leiden) is now recognized as the most prevalent cause of increased thrombogenicity, being found in 2% to 5% of the world population. The APC-resistant phenotype arises from a well-characterized transitional mutation, resulting in an arginine(R)-506-glutamine(Q) amino acid substitution. Much remains to be uncovered concerning the importance of this mutation and how it relates to other conditions on a broader basis. Relevant and accurate detection methods that quickly identify the genetic lesion will play a major part in this strategy. This article details recent advances in identifying the factor V Leiden mutation by modern molecular techniques.
Amaç: Faktör V Leiden mutasyonu, aktif protein C'nin aktivitesine rezistans›n olduu kal›tsal bir p›ht›- laflma bozukluudur. Faktör V Leiden mutasyonu venöz tromboz için en yayg›n risk faktörüdür. Faktör V Leiden mutasyonunun angina pektoris, kalp yetersizlii, reinfarktüs ve kardiyak ölüm gibi miyokard infarktüsü (M‹) sonras› komplikasyonlarla iliflkisi araflt›r›lmam›flt›r. Çal›flmam›zda bu iliflkiyi araflt›rmay› amaçlad›k. Yöntem: Faktör V Leiden mutasyon s›kl›¤› akut M‹ geçiren 122 hastada (yafl ortalamas› 56±11 y›l olan, 82 erkek/40 kad›n) incelendi. Hastalar faktör V Leiden mutasyonu olanlar (Grup I) ve olmayanlar (Grup II) olmak üzere iki gruba ayr›ld›. M‹ sonras› komplikasyonlar 18 ayl›k takip boyunca deerlendirildi. Has- talardan al›nan venöz kan örneklerinden faktör V Leiden mutasyonu polimeraz zincir reaksiyonu (PCR) yöntemiyle analiz edildi. Bulgular: Faktör V Leiden mutasyonu, 122 hastan›n 11 (%)'inde var iken (ortalama yafl; 54±10 y›l, 6 erkek/5 kad›n), 111 (%90)'inde (ortalama yafl; 45±11 y›l, 76 erkek/35 kad›n) tespit edilmedi. Grup I ve II aras›nda s›ras›yla reinfarktüs (% 27 ve % 298; p>0.05), angina pektoris (% 45, % 38; p>0.05), kalp yetersizlii (% 27 ve % 23; p>0.05) ve kardiyak ölüm (% 18 ve % 14; p>0.05) gibi M‹ sonras› kompli- kasyonlar bak›m›ndan anlaml› farkl›l›k yoktu. Sonuç: Faktör V Leiden mutasyonu olan hastalarda reinfarktüs, kalp yetersizlii, angina pektoris ve kar- diyak ölüm gibi M‹ sonras› komplikasyonlarda art›fl görülmedi. (Ana Kar Der, 2001; 1: 242-245). Anahtar kelimeler: Faktör V Leiden, miyokard infarktüsü
Factor V Leiden is the most prevalent genetic thrombophilia in people of European descent. Since its discovery, much clinical information has been gathered regarding the distribution and prevalence of the genetic mutation, the mechanism of thrombophilia, and its association with clinical thromboembolic events. Although its association with venous thromboembolism is clear, the role of Factor V Leiden in other disease states is not clear. A review of the literature regarding the mechanism of hypercoagulability, genetic versus functional diagnostic tests, screening issues, relationship to arterial thromboses, pregnancy and pregnancy complications, and treatment are discussed.
The role of thrombosis in precipitating acute cardiovascular disease (CVD) events has been well known since the early 1970s
[1]. It is now becoming increasingly apparent that thrombosis may also be involved with the chronic development of CVD [2–4]. Clot formation or thrombosis can be conceptualized as a balance between procoagulant and anticoagulant and fibrinolytic
forces C5 (Figure 2-1). Although some factors, such as thrombin, may have more than one role, this “pseudoequilibrium” provides
a schema for assessing the relative coagulant balance.
A recently described coagulation disorder [FV-Arg-506-Gln-mutation-associated resistance to activated protein C (APC-resistance)] leads to a five- to tenfold increased risk for venous thromboembolism. The aim of the study was to determine if this disorder also predisposes to ischemic stroke. Ninety-nine consecutive patients with ischemic stroke of noncardiac origin were screened for APC-resistance and tested for the FV-Arg-506-Gln mutation. The FV-Arg-506-Gln mutation was found in 5 of the 99 stroke patients and in 6% of a pool of blood donors. FV-Arg-506-Gln mutation is not a major cause of ischemic stroke. However, a minor predisposing effect cannot be excluded. Further studies with larger stroke populations and subpopulations are indicated to determine the exact impact of this condition on ischemic stroke.
Activated protein C resistance (APCR) is a recently discovered, medically important cause of venous thrombosis. More than 95% of cases are due to factor V Leiden (FVL), a mutated form of factor V that is resistant to degradation by activated protein C. The prevalence of this disorder, which is inherited in an autosomal dominant fashion, is approximately 5% among asymptomatic people of European heritage. In addition, 20 to 60% of patient cohorts with previous thrombosis demonstrate APCR, making it the most common known genetic cause of abnormal thrombophilia. Current laboratory techniques available for diagnosis include functional assays, such as the APC ratio, as well as DNA-based tests that detect the specific genetic anomaly responsible for FVL. A case report is presented, along with a review of the literature highlighting epidemiology, pathogenesis, clinical features and methods for laboratory diagnosis.
The aim of this study was to determine the prevalence of the prothrombin variant allele 20210A among survivors of myocardial infarction.
The prothrombin gene variant has been identified as a novel genetic risk factor for venous thrombosis. However, the risk of developing arterial thrombosis as a result of the presence of this mutated allele is unknown.
The G-->A transition at position 20210 of the 3'-untranslated region was determined in 220 survivors of myocardial infarction and in 295 individuals from the general population.
The prevalence of heterozygotes for the prothrombin mutated allele was 3% among patients with myocardial infarction and 0.7% in the general population (P = 0.03). No age-related difference in the prevalence of the mutated allele was observed. However, for individuals over 45 years old the prevalence among females was higher than among males (5% vs. 0%).
These data suggest that being heterozygote for the allele variant 20210A of the prothrombin gene could be a genetic risk factor for developing myocardial infarction.
Evidence from twin and family shows that genetic factors contribute to the risk of stroke and that their role may be at least as important in stroke as in coronary heart disease. Additional support for the significance of genetic factors comes from other findings such as epidemiological data showing phenotypic heterogeneity of stroke, genetic influence on many of the risk factors for stroke, and racial and geographic differences in morbidity and mortality in stroke victims. Yet, apart from the reported associations of a small number of cases with Mendelian cerebrovascular diseases, only a few studies have directly investigated gene markers or molecular genetics of stroke. This review presents the existing evidence on the genetic background of stroke and discusses results from the genetic studies of stroke published to date.
The protein C anticoagulant pathway is of major importance in maintaining vascular patency. Resistance to the key enzyme of this system, activated protein C (APC), is a recently discovered congenital defect of the protein C system. This genetic defect is present in 20% to 60% of venous thrombosis patients, making it by far the most common known pathogenetic risk factor of thrombosis. APC resistance is due to a single point mutation in the factor V gene (G to A at nucleotide position 1691) that predicts the replacement of arginine(506) by glutamine. This is associated with the loss of one of three APC cleavage sites in factor Va, one of the substrates for APC, and hypercoagulability. The identification of APC resistance as an additional genetic risk factor in a large proportion of symptomatic protein C- and protein S-deficient families has provided evidence that thrombosis is a polygenetic disease. Thus, several genetic defects act in concert with environmental factors in the pathogenesis of venous thromboembolism.
Ischemic stroke (IS) is a heterogeneous disease in which outcome is influenced by many factors. The hemostatic system is activated in association with cerebral ischemia, and thus, markers measuring coagulation, fibrinolysis, and vasoactivity could be useful tools in clinical practice. We investigated whether repeated measurements of these markers reveal patterns that might help in evaluating IS patients, including the early diagnosis of stroke subtypes, in estimating prognosis and risk of recurrence, and in selecting a treatment for secondary prevention of stroke. Vasoconstrictor peptide endothelin-1 (ET-1), homocysteine (Hcy), indicators of thrombin formation and activation (prothrombin fragment 1+2/F1+2, thrombin-antithrombin complex/TAT), indicators of plasmin formation and fibrinolysis (tissue plasminogen activator/t-PA, plasminogen activator inhibitor-1/PAI-1, and D-dimer), and natural anticoagulants (antithrombin/AT, protein C/PC, and protein S/PS) were measured in 102 consecutive mild to moderate IS patients on four occasions: on admission and at 1 week, 1 month, and 3 months after stroke, and once in controls. All patients underwent neurological examination and blood sampling in the same session. Furthermore, 42 IS patients with heterozygous factor V Leiden mutation (FVLm) were selected from 740 IS patients without an obvious etiology, and evaluated in detail for specific clinical, laboratory, and radiological features. Measurements of ET-1 and Hcy levels did not disclose information that could aid in the diagnostic evaluation of IS patients. F1+2 level at 3 months after IS had a positive correlation with recurrence of thromboembolic events, and thus, may be used as a predictive marker of subsequent cerebral events. The D-dimer and AT levels on admission and 1 week after IS were strongly associated with stroke severity, outcome, and disability. The specific analysis of IS patients with FVLm more often revealed a positive family history of thrombosis, a higher prevalence of peripheral vascular disease, and multiple infarctions in brain images, most of which were `silent infarcts´. Results of this study support the view that IS patients with sustained activation of both the fibrinolytic and the coagulation systems and increased thrombin generation may have an unfavorable prognosis. The level of activation may reflect the ongoing thrombotic process and the extent of thrombosis. Changes in these markers could be useful in predicting prognosis of IS patients. A clear need exists for a randomized prospective study to determine whether a subgroup of IS patients with markers indicating activation of fibrinolytic and coagulation systems might benefit from more aggressive secondary prevention of IS. Valtimokovettumatauti (VK) on iskeemisten aivoverenkierohäiriöiden tavallisin syy. Tiedetään, että veren hyytymisjärjestelmän ja endoteelin toiminta muuttuvat VK yhteydessä. Tällöin veri hyytyy epätarkoituksenmukaisesti suonen sisällä. Tässä tutkimuksessa selvitettiin, voidaanko toistuvien veren hyytymistä, fibrinolyysia ja vasoaktiviteeetia mittaavien merkkiaineiden määritysten perusteella selvittää mahdollisimman varhaisessa vaiheessa AI:n syntymekanismi, arvioida aivoinfarktipotilaiden toipumista ja ennustaa taudin uusiutumisriskiä sekä suunnata oikein ennaltaehkäisevää hoitoa. 102 peräkkäiseltä aivoinfarktipotilaalta mitattiin verisuonten supistusta aiheuttava endoteliini-1 (ET-1), VK:n riskitekijä homokysteiini (Hcy), trombiinin muodostumisen ja aktivoinnin mittarit (protrombiini fragment 1+2/F1+2, trombiini-antitrombiini kompleksi), plasmiinin muodostumisen ja fibrinolyysin mittarit (plasminogeenin kudosaktivaattori, plasminogeenin activaattorin inhibiittori-1 ja D-dimeeri), ja luonnolliset antikoagulantit (antitrombiini/AT, proteiini C ja proteiini S). Mittaus tehtiin 4 kertaa: potilaan tullessa sairaalaan, 1 viikon, 1 kuukauden ja 3 kuukauden kohdalla sairastumisesta. Näytteiden oton yhteydessä potilaille suoritettiin neurologinen tutkimus. Seurannan kesto oli 3 vuotta. Lisäksi 42 potilasta, joiden AI:n taustalta löytyi faktori V Leidenin mutaatio (FVLm), oli poimittu 740 aivoinfarktipotilaasta, joilla ei ollut perinteisiä VK riskitekijöitä. Tarkoituksena oli selvittää, olisiko tällä potilasryhmällä erityisiä kliinisiä tai radiologisia piirteitä. Kohonnut F1+2 taso AI:n kroonisessa vaiheessa ennusti uutta aivotapahtumaa 3 vuoden seurannassa ja näin ollen tätä tekijää voidaan käyttää AI:n uusimisen riskiä arvioitaessa. D-dimeeri ja AT tasot AI:n akuutissa vaiheessa olivat yhteydessä taudin vaikeusasteeseen ja toipumiseen. Potilaat, joilta löytyi FVLm, kärsivät muita aivoinfarktipotilaita useammin alaraajojen VK ja heillä oli suvussa paljon verisuonisairauksia. Lisäksi heillä todettiin aivokuvauksissa runsaasti verisuoniperäisiä muutoksia. Tämän tutkimuksen tulokset viittaavat siihen, että AI:n ennuste on synkempi niillä potilailla, joilla on epätarkoituksenmukainen ja pitkittynyt hyytymisjärjestelmän ja fibrinolyysin aktivaatio. Näin ollen hyytymisjärjestelmän toimintaa mittaavien merkkiaineiden määritys voi olla hyödyksi aivoinfarktipotilaiden arvioinnissa. Tarvitaan laaja satunnaistettu prospektiivinen tutkimus ennen kuin tiedämme, voisivatko aivoinfarktipotilaat, joilla on todettu selkeä hyytymisen ja fibrinolyysin aktivaatio, hyötyä tiukemmasta sekundaaripreventiosta.
Despite a paucity of evidence supporting a true association of ischemic stroke and the inherited thrombophilias, it is common practice for many neurologists to order these tests as part of the work-up of ischemic stroke, especially in young patients. Treatment with oral anticoagulation is often used in patients with positive results for the inherited thrombophilias.
We reviewed the literature focusing on case-control studies of the 5 most commonly inherited disorders of coagulation: protein C deficiency, protein S deficiency, antithrombin deficiency, and the factor V Leiden and prothrombin gene mutations in patients with stroke. We also analyzed the available data on stroke patients with inherited thrombophilia and patent foramen ovale.
Multiple case-control studies have not convincingly shown an association of the inherited thrombophilias with ischemic stroke, even in young patients and patients with patent foramen ovale.
If there is an association between the inherited thrombophilias and arterial stroke, then it is a weak one, likely enhanced by other prothrombotic risk factors. The consequences of ordering these tests and attributing causality to an arterial event can result in significant costs to the health care system and pose a potential risk to patients, because this may lead to inappropriate use of long-term oral anticoagulants, exposing patients to harm without a clearly defined benefit.
Myocardial infarction (MI) can be due to inherited thrombophilia caused by resistance to activated protein C resulting from factor V Leiden (FVL) mutation.
The objectives of this study were to estimate the frequency of FVL mutation among MI cases in various populations and calculate the overall risk related to it.
Subjects comprised 7790 cases with MI and 19,276 healthy controls collected from 41 relevant studies in the search databases. The resulting frequency of FVL mutation among cases and the odds ratio were compared and integrated in a meta-analysis format.
Although there was marked variation of the frequency of FVL mutation among different populations including MI and healthy controls, most studies reported a positive risk related to it. Compilation of analyzed studies resulted in an overall frequency of FVL mutation of 6.791% among MI cases, which was significantly higher than that among controls (1.304%, p = 0.0) with an overall odds ratio of 1.608 (95% confidence interval, 1.98-4.44).
There is a definite risk related to the carriage of FVL mutation among MI cases. This should have a potential impact on the genetic counseling of family members of affected cases for proper prophylaxis.
Stroke is one of the most common causes of death and long term disability throughout the world. It may be the outcome of a number of monogenic disorders or, more commonly, a polygenic multifactorial disease. Numerous studies have investigated the role of genetics in the pathogenesis of ischemic stroke, with varied and often contradictory results. The candidate 'stroke risk' genes affecting haemostasis (F5, F2, FGA/FGB, F7, F13A1, vWF, F12, SERPINE1, ITGB3/ITGA2B, ITGA2, GP1BA, TPA, TAFI, THBD, PZ, ANX5), homocysteine metabolism (MTHFR, CBS, MTR), and lipid metabolism (apo E, LPL, CETP, ABCA1, apo AI, apo CIII, apo AIV, apo AV, apo B, apo H, apo(a), PON1/2/3, LDLR/LOX-1) are evaluated in this review. By examining meta-analyses and case-control studies, we made a classification of gene/gene polymorphisms according to the degree of association with ischemic stroke risk. The data assembled could be very useful for further meta-analysis and for future clinical applications.
Venous lesions, including obstruction and thromboembolism (VTE), are not uncommon after pacemaker implantation. The purpose of this prospective study was to assess the role of various patient and procedure-related risk factors in the development of these complications.
A prospective venography-based study of 150 consecutive pacemaker implantations with a 6-month follow-up was conducted. Current case-control study included all cases (n = 47) with a new venous lesion, and their matched controls. Several surgical and technical factors, i.e. lead burden, choice of venous access, operator experience and procedure duration, as well as patient-related classic risk factors of VTE were assessed. Plasma markers of coagulation and endothelial activation [prothrombin fragment 1 + 2 (F1 + 2), D-dimer (DD), von Willebrand factor (vWF), thrombomodulin (Tm)] were used to evaluate the extent of acute surgical trauma. All cases with venous lesions were also screened for thrombophilia. None of the procedure-related variables were predictive of VTE. Mean levels of vWF, F1 + 2 and DD increased significantly (P < 0.001) and equally in both cases and controls. No single clinical factor predicted venous lesions, but significant (P < 0.05) clustering of classic clinical VTE risk factors was seen among the cases. Thrombophilia was overrepresented in patients with symptomatic pulmonary embolism (2/5, 40%).
Pacemaker implantation induces a transient hypercoagulable state, but its degree does not predict subsequent venous thromboembolism, and neither did the grade of endothelial damage as reflected by plasma markers. The aetiology of these lesions seems to be multifactorial, and clustering of classic thrombotic risk factors plays a role in the pathogenesis.
This report describes the characterization of Swedish families with inherited resistance to activated protein C (APC resistance) and/or protein S deficiency, two genetic disorders associated with functional impairment of the protein C anticoagulant pathway. The APC resistance phenotype was linked to the factor V gene locus in a kindred with independent inheritance of APC resistance and protein S deficiency. A point mutation changing Arg(506) to a Gln (FV:Q(506)) in the factor V gene was the cause of APC resistance. In studies of 50 families with hereditary APC resistance, the FV:Q(506) mutation was identified in 94% (47/50) of the families, and the thrombotic risk was found to be dependent on the factor V genotype. Moreover, 18 families with hereditary deficiency of free protein S were investigated. Type I protein S deficiency (low free and total protein S) and type III deficiency (low free but normal total protein S) coexisted in 78% (14/18) of the families, suggesting the two types to be phenotypic variants of the same genetic disorder. Deficiency of free protein S was caused by equimolar relationship between protein S and beta-chain containing isoforms of C4BP. Though protein S deficiency was a strong risk factor for thrombosis, the FV:Q(506) mutation was identified as an additional genetic risk factor in 39% of the families. Thus, familial thrombophilia is a multiple gene disorder. The thrombophilic tendency associated with APC resistance or protein S deficiency was related to increased levels of prothrombin fragment 1+2, reflecting increased activation of the common coagulation pathway.
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