Higher Fibrinogen Levels Research Articles

ROTEM and multiplate – a suitable tool for POC?

The early recognition of perioperative coagulation disorders is essential to identify non-surgical reasons of bleeding, to initiate appropriate haemostatic treatment and finally to reduce perioperative blood loss. Conventional laboratory coagulation tests include prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels and platelet counts. Although these parameters are frequently assessed, their value has been challenged at least in the setting of acute perioperative bleeding [1]. PT and aPTT are performed in an artificial ‘in vitro’ system, i.e. in plasma separated from whole blood, which is then warmed to 37 C and buffered to a pH of 7AE4. These standardized conditions often do not reflect the patient’s situation [2]. Plasmatic ‘in vitro’ tests merely reflect the time elapsing until the activation of thrombin, but provide only marginal information about the functional state of the coagulation system (e.g. platelet function, interaction of plasmatic coagulation factors with platelets and red blood cells, clot firmness, fibrinolysis). Routine coagulation tests are mostly performed in the central laboratory, i.e. remote from the operating theatre. As a consequence, test results are often not available in time or with a considerable delay [3]. Current devices designed for point-of-care (POC) monitoring of coagulation have been designed for the assessment of coagulation directly at the bedside, so that results could be available earlier. Moreover, POC tests are usually performed in whole blood, thereby comprising interactions between cellular components (i.e. platelets and red blood cells) and plasmatic coagulation factors. Commonly used POC devices for assessment of plasmatic coagulation and platelet function are listed in Table 1. This review focuses on rotation thrombelastography (ROTEM ) as a global coagulation test and multiple electrode aggregometry (MEA, Multiplate ) for assessment of platelet function. Rotation thrombelastometry (ROTEM )

Insulin resistance and acute coronary syndrome

Background Insulin resistance (IR), which can be quantified by HOMA index (fasting glucose X fasting insulin/22.5), is considered the “primum movens” for the development of Metabolic Syndrome. Many authors have suggested that insulin resistance could raise both incidence and mortality of coronary heart disease (CHD). IR is also associated with important predictors of cardiovascular disease, as increased concentration of LDL or triglyceride, decreased concentration of HDL, high systolic blood pressure, visceral obesity. There is accumulating evidence that chronic sub-clinical inflammation, as measured by inflammatory markers as C-reactive protein (CRP) and fibrinogen, is related with insulin resistance. Aim of the study To clarify if insulin resistance would predict cardiovascular disease independently of the other risk factors, such as hypertension, visceral obesity or dyslipidemia, by focusing our attention on the relation between Acute Coronary Syndrome (ACS) and high HOMA index. Methods We evaluated glucose and insulin levels at baseline and post-prandial phase, in order to estimate HOMA index in both the conditions; we related the data obtained with the incidence of cardiovascular events, also investigating traditional cardiovascular risk factors. The cohort included 118 patients with a clinical diagnosis of ACS and excluded those with type 1 diabetes, acute inflammatory diseases, hepatic or renal failure, disreactive disorders, autoimmunity and cancer. Subjects Subjects were followed-up for a period of 1 year, being subdivided in three groups: (1) subjects at elevated HOMA (HOMA ≥6); (2) subjects at intermediate HOMA (HOMA <6 and ≥2); (3) subjects at low HOMA (HOMA ≤2). We considered as end points new cardiovascular events, cerebrovascular events (both TIA and stroke), procedures of revascularization with angioplasty or surgery, cardiovascular death, sudden death. Results Patients with elevated HOMA have a higher incidence of previous cardio- and cerebrovascular events ( p = 0.03), myocardial infarction without ST elevation ( p = 0.005), unstable angina ( p = 0.01), asymptomatic carotid plaques ( p = 0.05), depressed systolic function ( p = 0.05); we found, also, a significant statistic correlation between HOMA index and high levels of CRP, fibrinogen, serum creatinine and TnI. Cardiovascular and cerebrovascular events were registered in 61% of patients with elevated HOMA during the follow up, despite of 25% registered in the control group: so we could consider HOMA index as a negative prognostic variable, also in virtue by the statistic correlation with the inflammatory markers, whose power of prediction is already known. Conclusions Beyond traditional cardiovascular risk factors, insulin resistance quantified by HOMA index seems to significantly have an important prognostic role, both in primary and secondary prevention in patients with Acute Coronary Syndrome.

Comparison of Plasma With Whole Blood Prothrombin Time and Fibrinogen on the Same Instrument

We compared plasma with whole blood (WB) international normalized ratio (INR) and fibrinogen using the same instrument and reagents. WBINRs were 50% higher than plasma INRs. After increasing the WB sample volume 40% and adjusting the International Sensitivity Index, WBINRs were similar to plasma INRs [adjusted WBINR = 0.99(plasma INR) - 0.02; r(2) = 0.98; n = 155], but the average difference in WB vs plasma INR was 4-fold higher than duplicate plasma INRs. Variation in hematocrit was a major determinant of the accuracy of the WBINR, with increased error at high INRs. The WB fibrinogen assay was highly dependent on the sample hematocrit (r(2) = 0.83), even after the sample volume was adjusted. Accurate WB fibrinogen measurements required a mathematical hematocrit correction. We conclude that WBINR and fibrinogen assays can be performed on point-of-care or automated analyzers, but sample volume must be adjusted to account for hematocrit. Accuracy is limited by variations in hematocrit with worsening accuracy for samples with high INRs or low fibrinogen levels.

Fibrinogen and the Risk of Thrombosis

Fibrinogen contributes to thrombosis risk in different ways. Indeed, various mutations in the fibrinogen genes predispose to thrombosis. At the same time, high levels of fibrinogen are also associated with thrombotic complications. Although the underlying causative mechanisms are not clear, this most likely involves the associated inflammatory and hypercoagulable states. In the last few years, particular attention has focused on the polymorphisms of fibrinogen genes involved in increased fibrinogen levels or fibrinogen qualitative changes. The association between dysfibrinogenemia and risk of thrombosis is well known, and some mechanisms have been clearly identified. Paradoxically, some patients with either hypofibrinogenemia or afibrinogenemia may also suffer from severe thromboembolic complications. The management of these patients is particularly challenging because they are not only at risk of thrombosis but also of bleeding. This review discusses the various quantitative and qualitative defects of fibrinogen associated with thrombosis, the tests that may predict the thrombotic risk, as well as some preventive or therapeutic approaches.

Coagulation Abnormalities in Legg-Calvé-Perthes Disease

Legg-Calvé-Perthes disease is a pediatric disorder characterized by osteonecrosis of the proximal femoral epiphysis. The etiology probably involves successive vascular occlusions, in which hypercoagulable disorders may play a role. We evaluated the etiologic role of thrombophilia in Legg-Calvé-Perthes disease in a pediatric population. One hundred and sixty-nine consecutive patients who had been diagnosed with Legg-Calvé-Perthes disease at two centers in Rotterdam, the Netherlands, when they were between 1.5 and 13.5 years of age were identified between 2000 and 2003. The study also included two control groups: 474 subjects (16.3 to 73.1 years of age) from a population-based case-control study on the etiology of venous thrombosis as well as thirty-eight children (1.8 to 18.8 years of age) who were treated for asthma at one of the centers. We determined levels of protein C, protein S, factor VIII, and fibrinogen and tested for the factor V Leiden and prothrombin G20210A mutations. We calculated age and sex-adjusted odds ratios as measures of the relative risk of the development of Legg-Calvé-Perthes disease. The incidence of Legg-Calvé-Perthes disease was increased in the presence of the factor V Leiden mutation (odds ratio, 3.3; 95% confidence interval, 1.6 to 6.7), in the presence of the prothrombin G20210A mutation (odds ratio, 2.6; 95% confidence interval, 1.0 to 6.3), in association with elevated levels of factor VIII (>150 IU/dL) (odds ratio, 7.5; 95% confidence interval, 2.2 to 25.2), and in association with protein S deficiency (<67 U/dL) (odds ratio, 2.8; 95% confidence interval, 0.7 to 10.8). Neither high levels of fibrinogen (>4.0 g/L) nor protein C deficiency (< or =55 U/dL) had an apparent effect on the risk of Legg-Calvé-Perthes disease. (Odds ratios were adjusted for age and sex.) Overall, males had a 2.4 times higher risk of Legg-Calvé-Perthes disease developing than did females. The effect of the factor V Leiden mutation, high levels of fibrinogen, and increasing levels of factor VIII was stronger in males than in females. The risk of Legg-Calvé-Perthes disease increased with an increasing number of coagulation abnormalities in males but not in females. There appears to be a thrombotic component in the etiology of Legg-Calvé-Perthes disease.

Concentration-dependent effect of fibrinogen on IgG-specific antigen binding and phagocytosis

In this paper, we aim to characterize fibrinogen–IgG interactions, and explore how fibrinogen alters IgG-mediated phagocytosis. Using enzyme-linked binding assays, we found that fibrinogen binding to IgG is optimized for surfaces coated with high levels of IgG. Using a similar method, we have shown that for an antigen unable to specifically bind fibrinogen, fibrinogen enhances binding of antibodies towards that antigen. For binding of IgG antibodies to cells expressing Fc receptors, we found a bimodal binding response, where low levels of fibrinogen enhance binding of antibody to Fc receptors and high levels reduce it. This corresponds to a bimodal effect on phagocytosis of IgG-coated particles, which is inhibited in the presence of excess IgG during coating of the particles with antibodies and fibrinogen. We conclude that fibrinogen can modulate phagocytosis of IgG-coated particles in vitro by changing IgG binding behavior, and that high fibrinogen levels could negatively affect phagocytosis.

In vitro factor XIII supplementation increases clot firmness in Rotation Thromboelastometry (ROTEM®)

Factor XIII (F XIII) is an essential parameter for final clot stability. The purpose of this study was to determine the impact of the addition of factor (F)XIII on clot stability as assessed by Rotation Thromboelastometry (ROTEM). In 90 intensive care patients ROTEM measurements were performed after in vitro addition of F XIII 0.32 IU, 0.63 IU, 1.25 IU and compared to diluent controls (DC; aqua injectabile) resulting in approximate F XIII concentrations of 150, 300 and 600%. Baseline measurements without any additions were also performed. The following ROTEM parameters were measured in FIBTEM and EXTEM tests: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), maximum lysis (ML), maximum clot elasticity (MCE) and alpha-angle (alphaA). Additionally, laboratory values for FXIII, fibrinogen (FBG), platelets and haematocrit were contemporaneously determined. In the perioperative patient population mean FBG concentration was elevated at 5.2 g/l and mean FXIII concentration was low at 62%. The addition of FXIII led to a FBG concentration-dependent increase in MCF both in FIBTEM and EXTEM. Mean increases in MCF (FXIII vs. DC) of approximately 7 mm and 6 mm were observed in FIBTEM and EXTEM, respectively. F XIII addition also led to decreased CFT, increased alphaA, and reduced ML in FIBTEM and EXTEM. In vitro supplementation of FXIII to supraphysiologic levels increases maximum clot firmness, accelerates clot formation and increases clot stability in EXTEM and FIBTEM as assayed by ROTEM in perioperative patients with high fibrinogen and low FXIII levels.

The Relationship between the Levels of Lipoprotein (a) and Fibrinogen and Clinical Outcome in Patients with Acute Myocardial Infarction

The aim of this study was to evaluate clinical outcomes in patients with acute myocardial infarction (AMI) on the basis of serum levels of lipoprotein (a) [Lp(a)] and fibrinogen. A total of 537 consecutive patients (62.4±12.3 years) diagnosed with AMI between January 2006 and December 2007 were divided into four groups according to serum levels of Lp(a) and fibrinogen on admission [group I: normal Lp(a) and normal fibrinogen levels (n=235); group II: elevated Lp(a) and normal fibrinogen levels (n=100); group III: normal Lp(a) and elevated fibrinogen levels (n=105); group IV: elevated Lp(a) and elevated fibrinogen levels (n=95)]. The baseline clinical characteristics showed significant differences between the four groups in age (p<0.001), body mass index (p=0.025), N-terminal pro-brain natriuretic peptide levels (p<0.001), left ventricular ejection fraction (p<0.001), and echocardiographic wall motion scores (p<0.001). In the coronary angiographic findings, the number of diseased vessels was higher?and involvement of the left anterior descending artery was more common in group IV than in group I (1.8±0.9 vs. 1.5±0.8, p=0.001, and 65% vs. 51%, p=0.042, respectively). Likewise, in-hospital and 1-month major adverse cardiac events were more frequent in group IV than in group I (4.2% vs. 1.3%, p=0.037, and 14.1% vs. 3.1%, p<0.001, respectively). In conclusion, AMI patients with high Lp(a) or fibrinogen levels had worse clinical outcomes than did patients with normal levels of Lp(a) and fibrinogen.

Longitudinal assessment of fibrinogen in relation to subclinical cardiovascular disease: the CARDIA study.

To examine the strength of the associations of fibrinogen with subclinical atherosclerosis in healthy persons. A population-based, prospective, observational study of black and white men and women (Coronary Artery Risk Development in Young Adults [CARDIA]). Fibrinogen levels were measured at year 7 (ages 25-37, n = 2969), and again at year 20 (ages 38-50, n = 2832). Measures of subclinical atherosclerosis (coronary artery calcification [CAC] and carotid intimal-medial thickness [CIMT]) were recorded at year 20. Over the 13-year study interval (1992-1993 to 2005-2006), fibrinogen rose from a mean of 3.32 to 4.05 g L(-1). After adjusting for age, gender and race, fibrinogen was positively associated with greater incidence of CAC and increased CIMT cross-sectionally as well as after 13 years of follow-up (all P-trend < 0.001). After further adjustment for field center, BMI, smoking, education, systolic blood pressure, diabetes, antihypertensive medication use, total and HDL cholesterol, and CRP, significant positive relationships between fibrinogen and incidence of CAC remained for the total cohort longitudinally (P-trend = 0.037), but not cross-sectionally (P-trend = 0.147). This 13-year study demonstrates that higher levels of fibrinogen during young adulthood are positively associated with incidence of CAC and increased CIMT in middle-age, but the strength of the association declines with increasing age.

Association of Fibrinogen with Parkinson Disease in Elderly Japanese-American Men: A Prospective Study

Background: The purpose of this prospective study was to examine whether fibrinogen level is associated with Parkinson disease (PD) for both prevalent and incident cases. Methods: The Honolulu Asia-Aging Study is a longitudinal study of Japanese-American men based on the Honolulu Heart Study birth cohort. The original cohort consisted of 8,006 participants with selective service records who were living on the island of Oahu, Hawaii, in 1965. For this analysis, baseline was defined as the 1991–1993 examination (n = 3,845) when men were aged 71–93 years old. Multivariate logistic regression and Cox proportional hazards models were used, adjusting for potential confounders. Results: We identified 61 prevalent cases and 61 incident cases of PD during the follow-up. High fibrinogen level (presence in the top quintile) was associated with higher frequency of PD for both prevalent (OR = 2.07, 95% CI = 1.10–3.88, p = 0.024) and incident cases (HR = 3.05, 95% CI = 1.34–6.97, p = 0.008) among men aged 76–93 years, after adjusting for age, smoking, and low-density lipoprotein cholesterol. Conclusions: These results suggest high fibrinogen level is associated with increased risk of PD among men over 75 years.

Analysis of relative factors of restenosis after artificially grafting bypasses on chronic ischemia of lower extremities

To analyze the relative factors of early-term restenosis after artificially grafting bypasses on chronic ischemia of lower extremities. From January 2006 to September 2007, 40 cases suffered from chronic ischemia of lower extremities were treated by single side femoropopliteal bypass were followed up during 6 months after operation. There were 36 male and 4 case female with a mean age of (66 +/- 9) years old. Lipid, fibrinogen (FIB) and hypersensitive C reactive protein (hsCRP) were chemical examined during peri-operation. Basing on the degree of restenosis in vascular anastomosis by Color Doppler graft scan, all the patients were divided into light, moderate and severe groups, respectively. Biochemical indicators and cytokines were investigated such as lipid, FIB, hsCRP, IL-6, transforming growing factor beta1 (TGF-beta1). Possible risk factors resulting in restenosis were compared statistically among three groups with SPSS 15.0. Restenosis were more severe among the patients with concomitance disease such as diabetes mellitus and smoking after operation. Relative risk were 6.47 and 7.92, respectively. There are significant difference in total cholesterin, low density lipoprotein, FIB, hsCRP, IL-6 and TGF-beta1 among three groups during six months after operation (P < 0.05). Multiple linear regression showed that FIB and TGF-beta1 may be the risk factors to intimal hyperplasia. Diabetes mellitus, smoking and higher levels of FIB may be the major high risk factors resulting in neointima hyperplasia and anastomosis restenosis.

Thromboelastography as a Better Indicator of Hypercoagulable State After Injury Than Prothrombin Time or Activated Partial Thromboplastin Time

To investigate the hemostatic status of critically ill, nonbleeding trauma patients. We hypothesized that a hypercoagulable state exists in patients early after severe injury and that the pattern of clotting and fibrinolysis are similar between burned and nonburn trauma patients. Patients admitted to the surgical or burn intensive care unit within 24 hours after injury were enrolled. Blood samples were drawn on days 0 through 7. Laboratory tests included prothrombin time (PT), activated partial thromboplastin time (aPTT), levels of activated factor XI, D-dimer, protein C percent activity, antithrombin III percent activity, and thromboelastography (TEG). Study subjects were enrolled from April 1, 2004, to May 31, 2005, and included nonburn trauma patients (n = 33), burned patients (n = 25), and healthy (control) subjects (n = 20). Despite aggressive thromboprophylaxis, three subjects (2 burned and 1 nonburn trauma patients [6%]) had pulmonary embolism during hospitalization. Compared with controls, all patients had prolonged PT and aPTT (p < 0.05). The rate of clot formation (alpha angle) and maximal clot strength were higher for patients compared with those of controls (p < 0.05), indicating a hypercoagulable state. Injured patients also had lower protein C and antithrombin III percent activities and higher fibrinogen levels (p < 0.05 for all). Activated factor XI was elevated in 38% of patients (control subjects had undetectable levels). Thromboelastography analysis of whole blood showed that patients were in a hypercoagulable state; this was not detected by plasma PT or aPTT. The high incidence of pulmonary embolism indicated that our current prophylaxis regimen could be improved.

Enhanced erythrocyte aggregation in type 2 diabetes with late complications.

We investigated whether erythrocyte aggregation (EA) is enhanced in type 2 diabetic patients who have developed microvascular or macrovascular complications. EA rates at high and low shear rates were analysed in 141 patients with type 2 diabetes who were further divided into 4 subgroups according to the status of diabetic complications and degree of metabolic control. Groups 1 (n = 43) and 2 (n = 23) consisted of well-controlled patients without and with clinically evident late complications, while groups 3 (n = 33) and 4 (n = 42) represented poorly controlled patients without and with these complications, respectively. 124 healthy subjects served as the control group. Mean EA rate was comparable between control subjects and group 1 both at high (2.05 +/- 0.03 vs. 2.14 +/- 0.07, respectively) and low (6.96 +/- 0.02 vs. 7.04 +/- 0.06, respectively) shear rates. Mean EA rate was also comparable between groups 2 and 4 at high (2.76 +/- 0.09 vs. 2.94 +/- 0.07, respectively) and low (8.18 +/- 0.13 vs. 8.41 +/- 0.1, respectively) shear rates. However, EA at both shear rates in groups 2 and 4 were significantly higher than control subjects, group 1 (p < 0.0001) and group 3 (high shear rate EA: 2.76 +/- 0.09 and low shear rate EA: 7.48 +/- 0.07 (p < 0.01). In group 3, EA rates were significantly higher than control subjects and group 1 (p < 0.05) at both shear rates. No significant correlation was found between EA at high and low shear rates and fibrinogen levels in diabetic subgroups and control subjects. The data suggest that patients with type 2 diabetes who had developed clinically evident late complications have enhanced EA regardless of the degree of metabolic control. Whether enhanced EA is a primary phenomenon contributing to the development of these complications or it occurs secondary to their development remains to be clarified.

Antihypertensive pharmacogenetic effect of fibrinogen-beta variant −455G&gt;A on cardiovascular disease, end-stage renal disease, and mortality: the GenHAT study

The FGB gene codes for fibrinogen-beta, a polypeptide of the coagulation factor fibrinogen, which is positively associated with cardiovascular diseases. Studies show that angiotensin-converting enzyme (ACE) inhibitors lower plasma fibrinogen concentrations, whereas diuretics and calcium-channel blockers do not. As carriers of the FGB-455 minor 'A' allele have higher levels of fibrinogen while ACE inhibitors lower it, we hypothesize that 'A' allele carriers benefit more from antihypertensive treatment with ACE inhibitors than calcium-channel blockers or diuretics, relative to 'GG' genotype individuals. The Genetics of Hypertension Associated Treatment (GenHAT) study [ancillary to Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)] genotyped hypertensive participants for several hypertension-related candidate genes, making this a post-hoc analysis of a randomized trial. In total, 90.1% of the ALLHAT population was successfully genotyped for FGB-455. We included participants (n=30 076) randomized to one of three antihypertensive medications (lisinopril, amlodipine, chlorthalidone), with two treatment comparisons: lisinopril versus chlorthalidone and lisinopril versus amlodipine. The primary outcome of ALLHAT/GenHAT was coronary heart disease, defined as fatal coronary heart disease or non-fatal myocardial infarction, and secondary outcomes included stroke, heart failure, all-cause mortality, and end-stage renal disease (ESRD) with mean follow-up time of 4.9 years. Genotype-by-treatment interactions (pharmacogenetic effects) were tested with the Cox regression. Stroke: common 'GG' homozygotes had higher risk on lisinopril versus amlodipine [hazard ratio (HR)=1.38, P<0.001], whereas minor 'A' allele carriers had slightly lower risk (HR=0.96, P=0.76; P value for interaction=0.03). Mortality: 'GG' homozygotes had higher risk on lisinopril versus amlodipine (HR=1.12, P=0.02) or chlorthalidone (1.05, P=0.23), whereas 'A' allele carriers had slightly lower risk (HR=0.92, P=0.33 for lisinopril versus amlodipine; HR=0.88, P=0.08 for lisinopril versus chlorthalidone; P value for interactions 0.04 and 0.03, respectively). ESRD: 'GG' homozygotes had higher risk on lisinopril versus chlorthalidone (HR=1.27, P=0.08), whereas 'A' allele carriers had lower risk (HR=0.64, P=0.12; P value for interaction=0.03). There was evidence of pharmacogenetic effects of FGB-455 on stroke, ESRD, and mortality, suggesting that relative to those homozygous for the common allele, variant allele carriers of the FGB gene at position -455 have a better outcome if randomized to lisinopril than chlorthalidone (for mortality and ESRD) or amlodipine (for mortality and stroke). For the models in which a pharmacogenetic effect was observed, the outcome rates among 'GG' homozygotes were higher in those randomized to lisinopril versus amlodipine or chlorthalidone, whereas minor 'A' allele carriers had lower event rates when randomized to lisinopril versus the other medications.

221 OUTCOME OF CIRRHOTIC PATIENTS ADMITTED TO THE LIVER ICU AND PREDICTIVE FACTORS OF MORTALITY: RESULTS OF A RECENT COHORT OF 308 PATIENTS

(p = 0.006), inotropic support (p = 0.006) and the absence of transplantation (p = 0.002) were significantly predictive of mortality. In the multivariate analysis, MELD score and need for inotropic support were major significant predictors of death while transplant free survival was significantly related to a MELD score <40 (OR:7.6; 95%CI: 2.2−26.2; p = 0.001), high fibrinogen level (OR: 3.2; 95%CI: 1.3−8.2; p = 0.01) and 3 MARS® treatments (OR: 6.3; 95%CI: 1.4−27.4; p = 0.01). Conclusion: In patients with fulminant hepatic failure awaiting liver transplantation, MELD score, inotropic support, fibrinogen and subsequent albumin dialysis therapy, outweighing liver transplantation, are major predictors of survival.

Elevated Levels of Plasma Fibrinogen in Patients With Pancreatic Cancer

Although changes of plasma fibrinogen have been documented in limited pancreatic malignant tumors, a relationship between plasma fibrinogen and pancreatic cancer in a large-scale clinical study has not been shown. Preoperative plasma levels of fibrinogen were retrospectively analyzed in 133 pancreatic cancer and 38 pancreatic benign tumor patients. Plasma fibrinogen in pancreatic cancer patients were significantly higher than those with benign pancreatic tumor (3.99 +/- 1.01 vs 2.62 +/- 0.65; P < 0.001). The percentage of hyperfibrinogenemia (>4.20 g/L) in pancreatic cancer was 41.1%, and no positive results were obtained in benign pancreatic disease. Plasma fibrinogen levels were increased in pancreatic cancer with advanced tumor stage. Accompanied with the progression of tumor stage, there was an increase in the percentage of positivity of hyperfibrinogenemia in pancreatic cancer. There were markedly higher levels of plasma fibrinogen in the distant-metastasis group than in the no-distant-metastasis group (4.41 +/- 0.84 vs 3.76 +/- 1.04; P < 0.01). Univariate and multivariate analysis revealed that high plasma fibrinogen levels (>4.20 g/L) were positively associated with distant metastasis of pancreatic cancer. Plasma fibrinogen levels had a positive relationship with tumor stage of pancreatic cancer. Increased preoperative plasma fibrinogen levels might be a useful predictor for distant metastasis in human pancreatic cancer.

Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers

Risk of venous thrombosis is increased after long-distance travel. Identifying high-risk groups may provide a basis for targeted prevention. We assessed the effect of increased levels of coagulation factors and combinations of risk factors in travelers in a large case-control study. We calculated odds ratios (ORs) for 334 travelers (200 cases and 134 controls) with coagulation factors II (prothrombin), VII, VIII, and IX; fibrinogen, and von Willebrand factor (VWF) above the 80th percentile; for increasing numbers of risk factors; and for specific combinations. The risk was increased in travelers with high FII (OR, 2.2: 95% CI, 1.3-3.7) and FVIII (OR, 6.2, (95% CI, 3.6-10.5) compared with travelers with normal levels. High FIX and fibrinogen levels increased the risk in air travelers (FIX: OR, 3.2; 95% CI, 0.9-11.0; fibrinogen: OR, 2.0; 95% CI, 0.7-5.5) but not in other travelers. The ORs increased with the number of risk factors, and the risk was increased most in women with the combination of oral contraceptives and high FVIII (OR, 51.7; 95% CI, 5.4-498). We conclude that increased levels of FII and FVIII increase the risk of venous thrombosis in travelers. Furthermore, the risk is greatly increased if other risk factors are present as well.

Increased concentration of plasminogen activator inhibitor-1 and fibrinogen in individuals with metabolic syndrome

Metabolic syndrome (MS) is closely linked to a generalized metabolic disorder referred to as insulin resistance. Disturbances in the hemostasis and fibrinolytic systems are a feature of MS. The aim of this study was to determine the concentration levels of fibrinogen and plasminogen activator inhibitor-1 (PAI-1) in a group of patients with MS with respect to a non-MS group, and to evaluate their possible relation with other risk factors in MS. The study was carried out in a total of 186 male and female non-smoking individuals aged 45-64 years, 93 with MS (ATP III criteria) and 93 without MS. Plasmatic levels of PAI-1 were measured by ELISA, and those of fibrinogen by the Claus method. The plasmatic levels of PAI-1 (men 49.2±19.8 vs. 35.0±12.2 ng/ml and women 42.0±19.7 vs. 31.6±14.6 ng/ml; p=0.0026) and fibrinogen (274.0±82.1 vs. 232.7±66.6 ng/ml; p=0.0002) were significantly higher in the MS group than in the non-MS group. PAI-1 was significantly associated with diastolic blood pressure, triglycerides and waist circumference. Fibrinogen was negatively associated with HDL-c. High plasmatic levels of PAI-1 and fibrinogen contribute to the cardiovascular risk that characterizes individuals with MS.

Erythrocyte aggregability and AB0 blood groups.

It is not established whether there is an association between erythrocyte aggregation and AB0 blood type, as glycophorins carry sialic acid which is responsible for the negative erythrocyte surface charge and the antigenicity for AB0 blood groups. We have determined erythrocyte aggregation by means of the Myrenne aggregometer in 114 healthy volunteers, along with plasma lipids, fibrinogen and AB0 blood groups. No differences in erythrocyte aggregation (EA0 and EA1) were observed when subjects with 0 (n = 45) and non-0 (n=69) blood group were compared (P = 0.624 and P = 0.838, respectively). Fibrinogen was statistically lower in 0 group compared with non-0 group (P = 0.012). Erythrocyte aggregation (EA0 and EA1) correlated significantly with both lipids and fibrinogen (P < 0.01). When erythrocyte aggregation was dichotomized as EA1 > or = 8, no association was found with 0 and non-0 blood groups (P > 0.05) but it was associated with high lipid levels: T-Chol > 220 mg/dl, TG > 175 mg/dl and high fibrinogen levels > 300 mg/dl (P = 0.035; P = 0.030; P = 0.010, respectively). Erythrocyte aggregation does not seem to be associated with blood groups, but rather with plasma lipids and fibrinogen.

The Functional Effects of the −455G/A Polymorphism on the IL-6-Induced Expression of the β-fibrinogen Gene may be due to Linkage Disequilibrium with Other Functional Polymorphisms

Elevated plasma fibrinogen levels have been identified as an independent risk factor for coronary heart diseases, stroke and peripheral artery disease. The −455G/A polymorphism in the promoter region of the β-fibrinogen gene has been associated with increased plasma fibrinogen levels. However, the functional effect of this polymorphism has been controversial and other polymorphisms in the fibrinogen gene have also been implicated in higher fibrinogen levels. In this study, we evaluated the transcriptional activity of 4 natural haplotypes and 6 artificial haplotypes in the promoter region of the β-fibrinogen gene. Significantly lower IL-6-induced activity was observed in the −1420A and −148T alleles. In contrast, the −854A allele had significantly higher activity. Artificial haplotypes containing the −1420A, −854A and −148T alleles were also analyzed to confirm individual functional effects. The −1420A and −148T alleles significantly lowered the activities, while the −854A allele significantly raised the activity. From this study we conclude that the −1420G/A, −854G/A and −148C/T polymorphisms in the β-fibrinogen promoter region are functional polymorphisms while the −455G/A polymorphism may not be a functional one, and that the association of the −455G/A polymorphism with higher fibrinogen levels may actually be due to linkage disequilibrium between the −455G/A polymorphism and other truly functional polymorphisms.