Thrombophilia is a multifactorial disorder, involving both genetic and acquired risk factors that affect the balance between procoagulant and anticoagulant factors and lead to increased thrombotic tendency. The severe forms of thrombophilia are caused by a deficiency of natural anticoagulants: antithrombin, protein C and protein S. The advances in DNA technology played an important role in the identification of the exact nature of these deficiencies and opened up new possibilities in genetic research and molecular diagnostics of thrombophilia. The major breakthrough came with the discovery of activated protein C resistance and the Factor V Leiden gene mutation. Shortly afterwards, a variant in the 3’ untranslated region of the Factor II gene (FII G20210A) associated with an increased concentration of Factor II in plasma was described. These two gene variants represent the most common thrombophilic genetic risk factors. Recently, a novel prothrombin mutation (c.1787G>T) was identified in a Japanese family with juvenile thrombosis. This mutation leads to impaired inhibition of mutant thrombin by antithrombin, proposing a new mechanism of thrombophilia named resistance to antithrombin. In the last decade, several prothrombotic genetic risk factors have been described, including gene variants associated with defects of natural coagulation inhibitors, increased levels of coagulation factors or their impaired inhibition and defects of the fibrinolytic system. However, most of them are not of diagnostic value, due to their minor or unknown impact on the thrombotic risk. Large-scale DNA analysis systems are now becoming available, opening a new era in the genetic studies of the molecular basis of thrombophilia.
Parfrey PS. Cardiac disease in dialysis patients: diagnosis, burden of disease, prognosis, risk factors and management. Nephrol Dial Transplant 2000; 15 (Suppl 5): 5868.
Zoccali C. Traditional and emerging cardiovascular and renal risk factors: An epidemiologic perspective. Kidney Int 2006; 70 (1): 26-33.
Petrović D, Stojimirović B. Prevalencija faktora rizika za razvoj kardiovaskularnih komplikacija kod bolesnika na hemodijalizi. U: Kardionefrologija 3. Radenković S, (ed
Evaluation of Coronary Risk Score Applications in 10-Year Coronary Heart Risk Estimation
Atherosclerosis is a multifactorial disease with risk factors that have multiple effects. In the identification and treatment of asymptomatic individuals at high risk for developing coronary heart disease (CHD) different risk scoring schemes are used in everyday routine. The aim of this study was to compare SCORE recommended for our country with two other most frequently used risk schemes for 10-year CHD risk evaluation: Framingham and PROCAM as well as their modifications. From 220 examined subjects of both sexes, who were treated mainly for lipid metabolism disorder at the Dispensary for Atherosclerosis Prevention, Centre for Laboratory Medicine, Clinical Centre of Vojvodina, 110 subjects were included in our study and agreed to a one-year follow-up. At first check-up, 15% had low risk according to Framingham Weibull and 78% according to PROCAM, intermediate 12% according to PROCAM NS up to 45% according to Framingham Weibull, and high 8% according to PROCAM up to 40% according to Framingham Weibull. After a one-year treatment 30% were in the low risk category according to Framingham Weibull and 88% according to PROCAM. Intermediate from 10% according to PROCAM to 36% according to Framingham Weibull, and high from 2% according to PROCAM to 25% according to Framingham Weibull. There is a significantly lower percentage of high risk individuals and a higher percentage of low risk individuals after one year of lipid disorder treatment.
Laboratory investigation of thrombophilia is aimed at detecting the well-established hereditary and acquired causes of venous thromboembolism, including activated protein C resistance/factor V Leiden mutation, prothrombin G20210A mutation, deficiencies of the physio - logical anticoagulants antithrombin, protein C and protein S, the presence of antiphospholipid antibodies and increased plasma levels of homocysteine and coagulation factor VIII. In contrast, investigation of dysfibrinogenemia, a very rare thrombophilic risk factor, should only be considered in a patient with evidence of familial or recurrent thrombosis in the absence of all evaluated risk factors mentioned above. At this time, thrombophilia investigation is not recommended for other potential hereditary or acquired risk factors whose association with increased risk for thrombosis has not been proven sufficiently to date. In order to ensure clinical relevance of testing and to avoid any misinterpretation of results, laboratory investigation of thrombophilia should always be performed in accordance with the recommended guidelines on testing regarding the careful selection of patients, time of testing and assays and assay methods used. The aim of this review is to summarize the most important aspects on thrombophilia testing, including whom and when to test, what assays and assay methods to use and all other variables that should be considered when performing laboratory investigation of thrombophilia.
Vidosava B. Đorđević, Ivana Stojanović, Slavica Kundalić, Tatjana Ristić, Radmila Pavlović, Vladan Ćosić and Tatjana Cvetković
Nitric oxide (NO) is produced by many cells in the body; however, its production by vascular endothelium is particularly important in the regulation of blood flow. Vascular actions of NO include the following: direct vasodilation, indirect vasodilation by inhibiting the vasoconstrictor influences, anti-thrombotic, anti-inflammatory and anti-proliferative effects. Due to its importance in vascular function, abnormal production of NO, occurring in different diseases can adversely affect blood flow and other vascular functions. It has been suggested that alterations in NO generation are a critical cause of injury in the ischemic heart. A biologic link between the endothelial damage and atherosclerotic coronary arterial disease has been presumably related to de - creased arterial bioavailability of NO through the increased leucocyte and platelet adhesions, vasoconstriction and smooth muscle cell proliferation. However, the precise me - chanism of the impaired NO generation is not known, and there is a considerable controversy regarding whether myo - cardial ischemia results in increased or decreased NO for - mation. Asymmetric dimethylarginine (ADMA) is a natural, com petitive inhibitor, and one of the primary factors controlling the nitric oxide production. ADMA was found to be elevated and closely correlated with the impaired vasodilator function in conditions associated with the endothelial dysfunction, such as hypercholesterolemia, hypertension, insulin resistance and type 2 diabetes, and renal failure. But ADMA also seems to be involved in myocardial ischemia, since its plasma levels predict future coronary events in patients with the elevated cardiovascular risk. It has been recently reported that the elevated plasma ADMA concentrations in the acute coronary events are an independent cardiovascular risk factor.
Vesna Ćorić, Marija Plješa-Ercegovac, Marija Matić, Biljana Krivić, Sonja Šuvakov, Cane Tulić, Jasmina Mimić-Oka and Tatjana Simić
The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell Carcinoma
Members of the glutathione S-transferase (GST) superfamily exhibit polymorphic expression. GSTs are investigated as biomarkers of risk for various cancers, including renal cell carcinoma (RCC). The aim of this study was to test the association between GSTM1 and GSTT1 polymorphism and susceptibility to RCC, independently or in conjunction with known risk factors. Genomic DNA was isolated from 182 controls and 76 patients with RCC. GSTM1 and GSTT1 genotypes were determined by multiplex PCR. Data obtained were analyzed with respect to RCC risk factors including smoking and occupational exposure. The frequency of GSTM1-null genotype was higher in patients with RCC (60.5%) compared to controls (47.2%). GSTT1-null genotype was found in 28.6% controls and 27.6% of cases. GSTM1-null individuals exhibit 1.9-fold increased risk of RCC (95% CI: 1.06-3.33). The presence of GSTT1 active genotype was associated with increased risk of RCC in occupationally exposed subjects when unexposed GSTT1-null subjects were used as a comparison group (OR: 2.48; 95% CI: 1.05-5.86). No association was found between the inactive form of GSTM1 and GSTT1 and smoking in RCC patients. In a Serbian cohort of patients, the presence of a GSTM1 active genotype is protective against RCC, whereas a GSTT1 active genotype increases RCC risk in occupationally exposed subjects.
Milos Maksimovic, Hristina Vlajinac, Djordje Radak, Jelena Marinkovic, Jadranka Maksimovic and Jagoda Jorga
The aim of this study was to compare demographic, clinical and biochemical characteristics, including inflammatory markers, according to the nutritional status of patients with verified atherosclerotic disease.
This cross-sectional study involved 1045 consecutive patients with verified carotid disease or peripheral arterial disease (PAD). Anthropometric parameters and data on cardiovascular risk factors and therapy for hypertension and hyperlipidemia were collected for all participants.
Carotid disease was positively and PAD was negatively associated with body mass index (BMI). Negative association between obesity and PAD was significant only in former smokers, not in current smokers or in patients who never smoked. Overweight and general obesity were significantly related to metabolic syndrome (p < 0.001), lower values of high – density lipoprotein cholesterol (p < 0.001), increased triglycerides (p < 0.001), hyperglycemia (p < 0.001), self-reported diabetes (p < 0.001), hypertension (p < 0.001), high serum uric acid (p < 0.001), increased high sensitivity C-reactive protein (p = 0.020) and former smoking (p = 0.005) after adjustment for age, gender and type of disease. Antihypertensive therapy seems to be less effective in patients who are overweight and obese.
In conclusion, overweight and general obesity were significantly related to several cardiovascular risk factors.
Mirjana Bećarević, Duško Mirković and Nada Majkić-Singh
Hyperhomocysteinemia and Smoking in Primary Antiphospholipid Syndrome
The thrombotic tendency in antiphospholipid syndrome (APS) shares several pathways with atherosclerosis. Atherothrombosis (atherosclerosis superimposed with thromboses) is influenced by nonmodifiable and some modifiable risk factors (smoking, obesity, physical inactivity, alcohol abuse, hyperhomocysteinemia). Therefore, we investigated the association among clinical and serological features of patients with primary APS and potentially modifiable risk factors for the development of atherothrombosis. Also, we compared the analyzed parameters with those in control subjects. Homocysteine concentrations were detected by HPLC (high performance liquid chromatography), while antiphospholipid antibodies were detected by ELISA. Smokers had elevated levels of homocysteine (χ2 = 6.22, p < 0.05). Independently of patients' age, the association between increased levels of homocysteine and history of myocardial infarctions was found (χ2 = 4.61, p < 0.05). Hyperhomocysteinemia and smoking are the most important modifiable risk factors for atherothrombosis in primary APS.
Snežana Jovičić, Svetlana Ignjatović and Nada Majkić-Singh
Comparison of Two Different Methods for Cardiovascular Risk Assessment: Framingham Risk Score and Score System
Numerous studies have shown that the major risk factors for coronary heart disease (cigarette smoking, hypertension, elevated serum total cholesterol and low-density lipoprotein cholesterol - LDL, low serum high-density lipoprotein cholesterol - HDL, diabetes mellitus and advancing age), are additive in predictive power. Accordingly, the total risk of a person can be estimated by summing up the risk imparted by each of the major risk factors. Using data obtained from population studies, various risk assessment algorithms have been developed. The aim of this study was to compare the two most common risk scores. Risk assessment for determining 10-year risk in 185 healthy, asymptomatic individuals of both sexes, 30-85 years old, was carried out according to both Framingham (FRS) and SCORE risk scoring. The risk factors included in the calculation of 10-year risk are gender, age, total cholesterol, HDL-cholesterol, systolic blood pressure, treatment for hypertension and cigarette smoking. The determinations of total cholesterol and HDL-cholesterol were made in sera collected after a 12h fasting period using an Olympus AU2700 automated analyzer. The Framingham risk score was determined using an electronic calculator - ATP III Risk Estimator, and the risk status according to SCORE was obtained using charts for the 10-year risk in populations at high risk. Among 185 participants, in 152 (82%) 10-year risk for Coronary Heart Disease (CHD) death was <10%, 24 (13%) had intermediate and 9 (5%) had high risk (⩾20%) according to FRS. According to SCORE, 110 (60%) participants had <1%, 56 (30%) had 1-5% and 19 (10%) had ⩾5% of 10-year risk for cardiovascular death. Different categories of risk were assigned to ~30% of individuals according to different risk assessment models. Differences in risk classification when using two different risk assessment algorithms can be explained with several important issues, including different endpoints, consideration of interactions and incorporation of antihypertensive use. It is important to note that neither FRS nor SCORE have been appropriately adjusted for our population, according to the national cardiovascular mortality rate.
Venous thromboembolism (VTE) is a multifactorial disease that results from a conjunction of several risk factors, both inherited and acquired. The younger the person, the more risk factors are required to cause the disease. Since 1937, when the term thrombophilia was coined by Nygaard and Brown, and 1965 when it was used for the first time by Egeberg, a substantial increase in the percentage of patients with VTE and underlying thrombophilia has been reported, particularly after the discovery of the most common thrombophilic mutations, FV Leiden and FII G20210A. Presence of thrombophilia could be detected in as many as 50% of all patients with VTE. Thrombophilia testing has increased lately not only in patients with thromboses but also for other indications, however, whether the results will help in the clinical management of the patients is still unclear. Thrombo philia testing is most commonly performed in young patients with VTE, patients with recurrent episodes of VTE or with thromboses at unusual sites and in persons with positive family history. Whether the presence of thrombophilia influences the clinical management of the patient remains controversial. Patients with VTE and the recognized risk factors such are surgery, trauma, immobilization, pregnancy and the puerperium are at very low risk for recurrence, but prediction of the recurrence of VTE based on the presence of thrombophilia has not been sufficiently explored. Presence of clinical risk factors should be integrated in the strategy of VTE risk assessment. Since many risk factors, such as obesity, hypertension, dyslipidemia, diabetes and smoking are common for both arterial and venous thromboses, it has been suggested that VTE should be considered as part of a pancardiovascular syndrome, along with coronary artery disease, peripheral artery disease and cerebrovascular disease. Positive family history for VTE in a first-degree relative increases the risk for VTE occurrence by 2-fold, regardless of the presence of inherited thrombophilia. Pregnancy-related risk of VTE is sixfold in creased compared to nonpregnant age-matched women. Women with thrombophilia have been shown to be at an increased risk not only of pregnancy-associated thromboembolism, but also of other vascular complications, including recurrent fetal loss and intrauterine fetal death. Risk for antepartal pregnancy-related VTE is considerably increased in obese women confined to bed for longer than one week, in women who underwent assisted reproduction, in multiple pregnancies, gestational diabetes and maternal age over 35 years. Postpartal risk factors differ, with eclampsia, emergency cesarian section and placenta praevia being the most important. Testing for thrombophilia generally does not alter the management of a patient with VTE, except for selected groups of patients. Women of fertile age with positive family history and presence of thrombophilia may benefit from thromboprophylaxis implementation during pregnancy, or can make the decision not to use oral contraceptives. In the future, the use of global coagulation tests that could detect a hypercoagulable state, along with other clinical risk factors, might improve VTE risk assessment and optimize the duration of treatment of VTE disease.