Regulation and modulation of the plasma fibrinogen level

Fibrinogen is a soluble plasma glycoprotein that, under normal circumstances, is present in human plasma at a concentration of 2-4 mg/ml (6-12 I'M). The plasma half-life is 3-4 days in humans and about 10-25 % of the total body fibrinogen is extravascularl. Fibrinogen is composed of two sets of three polypeptide chains (AOI, 86 . and 'Y) that are interconnected by disulphide bridges . The aminoterminal segments of all six chains form a central domain from which the AOI and 86 chains protrude. These aminotermini are the target of thrombin and small peptides (FPA and FP8) can be cleaved off

Effect of genetic variation in STXBP5 and STX2 on von willebrand factor and bleeding phenotype in type 1 von willebrand disease patients

Background: In type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients. Methods: In 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score. Results: In STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = -0.04 IU/mL per allele, [95%CI -0.07;-0.001], p = 0.04) and VWF:CB activity (β = -0.12 IU/mL per allele, [95%CI -0.17;-0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = -0.03 IU/mL per allele [95% CI -0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02). Conclusions: Genetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients

FIBTEM clot firmness parameters correlate well with the fibrinogen concentration measured by the Clauss assay in patients and healthy subjects

The Clauss assay is the assay most often used for measuring plasma fibrinogen levels. However, the FIBTEM-assay, determined using thromboelastometry (ROTEM) can also be used to estimate fibrinogen levels. A major advantage of the FIBTEM is that it can provide information about fibrinogen levels within minutes, while the Clauss assay needs 30–60 min before the result is available. The aim of this study was to investigate the correlation between fibrinogen levels measured by the Clauss assay and results from the FIBTEM-assay. We included 111 patients 18 years for whom both ROTEM analyses and a fibrinogen measurement using the Clauss assay were available. In addition, ROTEM and Clauss measurements from 75 healthy subjects were included. Spearman correlation was used to determine the association between the results of both assays. The patients included were mostly patients with major trauma or undergoing large surgery (e.g. cardiac surgery or liver transplantation). Strong correlations were found between FIBTEM clot firmness parameters and fibrinogen levels measured by the Clauss assay in patients (Spearman’s correlation coefficients (rs) above 0.80 (p < .001) for all subgroups) and healthy subjects (rs ¼ 0.66, p < .001). The correlation between early FIBTEM parameters (clot firmness at 5 or 10 min) and the maximum clot firmness was almost perfect (rs above 0.96). Also, the correlation between the a-angle a

A comparative study on changes in hemostasis in orthotopic and auxiliary liver transplantation in pigs

We compared blood loss and hemostasis in pigs which had undergone either orthotopic liver transplantation (OLT) (group A, n=12) or auxiliary heterotopic partial liver transplantation (APLT) (group B, n=11). Blood samples were taken at regular intervals during and after the operations. In both groups, nine animals survived longer than 24 h and data from these animals were used for analysis. Median (range) intraoperative blood loss was 825 ml (250-1500 ml) in OLT and 425 ml (300-750) in APLT (P<0.01). Routine clotting times, as the activated partial thromboplastin time, prothrombin time and thrombin time, showed no major intraoperative changes in either group. Fibrinogen levels decreased in both groups, but no significant difference was found between the two groups. The only significant difference between group A and B was a more sustained increase in fibrinolytic activity after graft recirculation in group A. Post-operatively, restoration of fibrinogen, antithrombin-III and α2-antiplasmin levels was slightly faster in group B, resulting in significantly higher levels during the first day. We conclude that, in this animal model, APLT is associated with significantly lower blood loss and less severe fibrinolytic activity, than OLT. This difference might result from the lack of an anhepatic period and the reduced surgical trauma in auxiliary heterotopic liver transplantation

Antithrombin levels are associated with the risk of first and recurrent arterial thromboembolism at a young age

Background and aims: It is as yet unknown whether antithrombin levels are associated with arterial thromboembolism (ATE) at a young age. To investigate the association between antithrombin levels and premature and recurrent ATE, we performed a case-control study and a subsequent nested cohort study of p

Variation in the C-reactive protein gene is associated with serum levels of CRP in patients with acute ischemic stroke

Background and Purpose: Elevated levels of C-reactive protein (CRP) are found in up to three quarters of patients with acute ischemic stroke and are associated with poor outcome. We investigated whether haplotypes representing common variations in the CRP gene are associated with levels of CRP in patients with acute ischemic stroke. Methods: We included 185 patients with ischemic stroke in whom CRP was measured within 24 h of symptom onset. Common haplotypes within the CRP gene were determined by 3 genotype-tagging single-nucleotide polymorphisms (SNPs). Results: Four haplotypes with frequencies >5% covered 99.2% of the genetic variation. Haplotype 4 (CCG, frequency 8.3%) was associated with a 20.6 mg/l (95% CI, 9.8-30.4) stronger increase in CRP level as compared with haplotype 1 (CTC, frequency 33.7%). Conclusion: Variation in the CRP gene is associated with levels of CRP in acute ischemic stroke. Copyrigh

Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study

Inflammatory mediators and soluble cell adhesion molecules predict cardiovascular events. It is not clear whether they reflect the severity of underlying atherosclerotic disease. Within the Rotterdam Study, we investigated the associations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 with noninvasive measures of atherosclerosis. Levels of CRP were assessed in a random sample of 1317 participants, and levels of IL-6 and soluble cell adhesion molecules were assessed in a subsample of 714 participants. In multivariate analyses, logarithmically transformed CRP (regression coefficient [beta]=-0.023, 95% CI -0.033 to -0.012) and IL-6 (beta=-0.025, 95% CI -0.049 to -0.001) were inversely associated with the ankle-arm index. Only CRP was associated with carotid intima-media thickness (beta=0.018, 95% CI 0.010 to 0.027). Compared with the lowest tertile, the odds ratio for moderate to severe carotid plaques associated with levels of CRP in the highest tertile was 2.0 (95% CI 1.3 to 3.0). Soluble intercellular adhesion molecule-1 levels were strongly associated with carotid plaques (odds ratio 2.5, 95% CI 1.5 to 4.4 [highest versus lowest tertile]). Soluble vascular cell adhesion molecule-1 was not significantly associated with any of the measures of atherosclerosis. This study indicates that CRP is associated with the severity of atherosclerosis measured at various sites. Associations of the other markers with atherosclerosis were less consistent

Evaluation of thromboelastometry, thrombin generation and plasma clot lysis time in patients with bleeding of unknown cause: A prospective cohort study

Introduction: Diagnostic evaluation of patients with a bleeding tendency remains challenging, as no disorder is identified in approximately 50% of patients. An impaired interplay of several haemostatic factors might explain bleeding phenotype in these patients. Objective: To investigate whether global haemostasis assays are able to identify haemostatic abnormalities in patients with a bleeding tendency unexplained by current diagnostic laboratory tests. Materials and methods: Patients of ≥12 years with a bleeding tendency were included from a tertiary outpatient clinic. Bleeding phenotype was assessed with the ISTH-BAT. Patients were classified as having bleeding of unknown cause (BUC) or a mild bleeding disorder (MBD) based on abnormalities assessed by routine haemostatic tests. Global haemostasis tests (rotational thromboelastometry (ROTEM), thrombin generation test (TG) and plasma clot lysis time (CLT)) were measured in all patients. The results were compared with 76 controls. Results: One hundred and eighty-one patients were included, and 60% (109/181) was classified as having BUC. BUC patients demonstrated a significantly prolonged lag time in TG (median 7.7 minutes, IQR 6.7-8.7) and a significantly prolonged CLT (median 60.5 minutes, IQR 54.7-66.1) compared to controls. No differences in ROTEM variables were found. Patients with MBD showed an impaired thrombin generation with a significantly decreased ETP (median 1024 nmol/L*min, IQR 776-1355) and peak height (median 95 nmol/L, IQR 76-138), compared to BUC patients and controls. Conclusion: No major differences were found in ROTEM and TG variables in BUC patients compared to controls. BUC patients did have a significantly prolonged clot lysis time. The underlying mechanism for this finding is unknown