Today's view of hereditary thrombophilia.

Venous thromboembolism (VTE) is still a serious medical problem with the non-decreasing incidence of new cases despite prophylaxis in risky situations. It is a multifactorial disease, in which the hereditary component is also significantly involved. The aim of the current research is to search for new polymorphisms that are involved in thrombogenesis in addition to classical thrombophilia (deficiency of natural coagulation inhibitors and FVL and FII prothrombin mutations). The article provides an overview of the results of already performed genome-wide association studies of VTE and their use for the calculation of the so-called polygenic risk score, which could be used for individualized prevention of VTE after standardization of the method.

Multiple thrombophilia mutations as a possible cause of premature myocardial infarction.

The incidence of acute myocardial infarction (AMI) increases with clustering of predisposing risk factors. In younger subjects with a positive family history of AMI occurring in relatives under the age of 60 years without obvious risk factors for atherosclerosis, there is a potential for strong inherited traits contributing to the risk of coronary disease. Among them there is increasing evidence that hereditary thrombophilia may play a major role. We present a unique case of a patient developing AMI at the age of 48 years. In this patient, without traditional risk factors for atherosclerosis, eight mutations and polymorphisms in six different genes were identified: polymorphism of factor V Leiden (1691 GA), factor II prothrombin (20210 GA), methylenetetrahydrofolate reductase (MTHFR, 677 CT and 1298 AC), plasminogen activator inhibitor 1 (PAI-1) polymorphism 4G/5G and glycoprotein VI (GP6, 13254 TC, Ser219Pro). All could be involved in the pathogenesis of the arterial thrombosis. Although such associations are extremely rare, it underlines the importance of thrombophilia assessment in cases with otherwise unexpected coronary disease occurring at young age. According to our experience, in the case of documented hereditary thrombophilia lineal relatives should be examined and/or followed up.

[Prevalence of thrombophilic mutations of FV Leiden, prothrombin G20210A and PAl-1 4G/5G and their combinations in a group of 1450 healthy middle-aged individuals in the Prague and Central Bohemian regions (results of FRET real-time PCR assay)]. / Prevalence trombofilních mutací FV Leiden, protrombinu G20210A a PAI-1 4G/5G a jejich vzájemných kombinací v souboru 1450 zdravých osob stredního veku v regionu Praha a strední Cechy (výsledky real-time PCR analýzy FRET).

BACKGROUND: Factor V Leiden (G1691A) and prothrombin gene (FII G20210A) mutations are independent risk factors of venous thrombosis and this risk is further increased by the combined genotype 4G/4G PAI-1. AIM: The primary objective was to identify the frequency of mutations of minor alleles and genotypes of FVL, FII G20210A and PAI-1 4G/5G in healthy Caucasians in the Prague and Central Bohemia regions. The secondary objective was to identify the occurrence of their mutual combinations. METHOD: Genotyping was performed in 1,450 healthy individuals (blood donors, 981 men and 469 women) using robotic DNA isolation and subsequent PCR and melting curve analysis (Light Cycler 480 System, Roche). RESULTS: The minor allele frequencies in FV Leiden and FII G20210A mutations were 4.5% and 1.3% respectively. The frequency of the 4G PAI-1 allele was 55.9%. The genotype frequencies were as follows: GG 91.10%, GA 8.83% and AA 0.07% for FV Leiden; GG 97.38%, GA 2.55% and AA 0.07% for FII G20210A and 4G/4G 30.69%, 4G/5G 50.34% and 5G/5G 18.97% for PAI-1. No differences in these frequencies were found between the genders. The occurrence of the combined heterozygous FII and heterozygous FV Leiden mutations was 0.14%. The PAI-1 4G/4G genotype was combined with the heterozygous FV leiden mutation in 2.83% of cases and with the heterozygous FII mutation in 0.62% of cases. CONCLUSIONS: The found frequencies of genotypes and alleles confirm a relatively high prevalence of hereditary thrombophilia in the Czech Republic.

Platelet gene polymorphisms and risk of bleeding in patients undergoing elective coronary angiography: a genetic substudy of the PRAGUE-8 trial.

AIM: Utilization of cardiac catheterization has increased dramatically over time. Bleeding is a major prognostic predictor after percutaneous coronary catheterization procedures. This study aimed to assess the impact of eight polymorphisms of genes encoding platelet receptors and enzymes on the risk of bleeding in patients undergoing elective coronary angiography (CAG). METHODS: Polymorphisms of platelet receptors, GP Ia (807C>T, rs1126643), GP VI (13254T>C, rs1613662), GP IIIa (HPA-1, rs5918), PAR-1 (IVS-14A>T, rs168753), P2Y(12) (34C>T, rs6785930 and H1/H2 haplotype, rs2046934), and genetic variations of the gene coding for cyclooxygenase-1 (COX-1) (-842A>G, rs10306114 and 50C>T, rs3842787) were studied. The frequencies of gene polymorphisms carriers were investigated in 696 patients undergoing elective CAG because of suspected or proven stable coronary artery disease. Genotyping was done using PCR, followed by melting curve analysis with specific fluorescent hybridization probes. RESULTS: In patients undergoing elective CAG (without ad hoc percutaneous coronary intervention (PCI) and without clopidogrel pretreatment) a significant association was found between bleeding risk and variations in the gene coding for COX-1 (-842A>G and 50C>T) (both p=0.013). Six other investigated polymorphisms did not show any influence on bleeding complications. After controlling for potential bleeding confounders, the association between COX-1 gene polymorphisms (-842A>G and 50C>T) and bleeding risk remained statistically significant (both odds ratios 12.1, p=0.012). CONCLUSION: Cyclooxygenase-1 -842G and 50T alleles significantly contribute to the risk of bleeding complications in patients undergoing elective CAG. Genetic testing is able to influence the safety of diagnostic cardiac catheterization in large numbers of low risk patients with borderline indications.

Platelet glycoprotein GP VI 13254C allele is an independent risk factor of premature myocardial infarction.

AIM: The purpose of this study was to asses the impact of haemostatic and platelet receptor gene polymorphisms as an inherited risk factor for premature onset of myocardial infarction (MI). METHODS: Polymorphisms of platelet receptors - GP Ia (807C>T, rs1126643), GP VI (13254T>C, rs1613662), GP IIIa (HPA-1, rs5918), PAR -1 (IVS -14A>T; rs168753), P2Y(12) (34C>T, rs6785930 and H1/H2 haplotype, rs2046934), and genetic variations of the gene coding for cyclooxygenase-1 (COX-1) ( -842A>G, rs10306114 and 50C>T, rs3842787) were investigated. Mutations in the genes coding for coagulation factor V (Q506R (Leiden) mutation, rs6025) and factor II (prothrombin G20210A, rs1799963) were also determined. The prevalence of gene polymorphisms was investigated in 105 consecutive patients with premature MI. This was compared with the same gene polymorphism prevalence in a group of 132 patients in which coronary artery disease had been excluded. Genotyping was done using PCR, followed by melting curve analysis with specific fluorescent hybridization probes. RESULTS: A significant association between GP VI 13254C allele carriers and premature MI was found (p=0.025). No other differences in prevalence of the investigated polymorphisms between the compared patient populations reached statistical significance. In a logistic regression, which took other cardiovascular risk factors into account, the significance of the GP VI 13254C allele and vascular risk was suggested (OR 1.888, 95% C.I. 1.029 to 3.464, p=0.040). In a binary logistic regression the positive relationship between the GP VI genotype and female gender was observed (0R 3.676; 95% C.I. 1.159 to 11.628; p=0.027). The frequencies of GP VI and GP Ia gene polymorphisms were independent of one another (p=0.836). CONCLUSION: The presence of the GP VI 13254C allele is an independent predictor of premature MI.