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

A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis

The aim of this study was to assess the cause of enhanced fibrinolysis in cirrhosis by studying the balance between profibrinolytic and antifibrinolytic proteins in 24 patients with mild or severe cirrhosis. Antigen levels of both tissue-type plasminogen activator and plasminogen-activator inhibitor 1 were increased in mild and severe cirrhosis. Activity levels showed a very wide variability, but median activity levels of both proteins were normal. In most patients, the increase in tissue-type plasminogen activator was counterbalanced by the increased levels of plasminogen-activator inhibitor 1, but in a subgroup of patients the change in balance resulted in extremely high tissue-type plasminogen-activator levels. The specific activity of both proteins (activity/ antigen quotient) was reduced in either mild or severe cirrhosis. This finding indicates either that more enzyme-inhibitor complexes circulate in the blood of patients with cirrhosis than in normal individuals or that dysfunctional molecules circulate. Plasminogen and α2-antiplasmin antigen and activity levels were decreased in both mild and severe cirrhosis. The binding of α2-antiplasmin to fibrin was decreased in severe cirrhosis, making fibrin clots more susceptible to lysis. Clot lysis experiments were performed to see if equal decreases in plasminogen and α2-antiplasmin levels, as found in cirrhosis, result in a change in the rate of fibrinolysis. It was found that the proportionate decreases led to enhancement of fibrinolysis, indicating that the inhibitor depletion is more important than the proenzyme depletion. The authors conclude that enhanced fibrinolysis frequently found in cirrhosis may be attributed to an increased tissuetype plasminogen-activator activity relative to plasminogen-activator-inhibitor activity and decreased levels of α2-antiplasmin, resulting in a reduced binding of α2-antiplasmin to fibrin.</p

A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis

The aim of this study was to assess the cause of enhanced fibrinolysis in cirrhosis by studying the balance between profibrinolytic and antifibrinolytic proteins in 24 patients with mild or severe cirrhosis. Antigen levels of both tissue-type plasminogen activator and plasminogen-activator inhibitor 1 were increased in mild and severe cirrhosis. Activity levels showed a very wide variability, but median activity levels of both proteins were normal. In most patients, the increase in tissue-type plasminogen activator was counterbalanced by the increased levels of plasminogen-activator inhibitor 1, but in a subgroup of patients the change in balance resulted in extremely high tissue-type plasminogen-activator levels. The specific activity of both proteins (activity/ antigen quotient) was reduced in either mild or severe cirrhosis. This finding indicates either that more enzyme-inhibitor complexes circulate in the blood of patients with cirrhosis than in normal individuals or that dysfunctional molecules circulate. Plasminogen and α2-antiplasmin antigen and activity levels were decreased in both mild and severe cirrhosis. The binding of α2-antiplasmin to fibrin was decreased in severe cirrhosis, making fibrin clots more susceptible to lysis. Clot lysis experiments were performed to see if equal decreases in plasminogen and α2-antiplasmin levels, as found in cirrhosis, result in a change in the rate of fibrinolysis. It was found that the proportionate decreases led to enhancement of fibrinolysis, indicating that the inhibitor depletion is more important than the proenzyme depletion. The authors conclude that enhanced fibrinolysis frequently found in cirrhosis may be attributed to an increased tissuetype plasminogen-activator activity relative to plasminogen-activator-inhibitor activity and decreased levels of α2-antiplasmin, resulting in a reduced binding of α2-antiplasmin to fibrin.</p

A case-only approach for assessing gene-sex interaction in human longevity

As one aspect of the complex feature of longevity, gene-sex interaction plays an important role in influencing human life span. With advances in molecular genetics, more studies aimed at assessing gene-sex interaction are expected. New and valid statistical methods are needed. In this paper, we introduce a nontraditional approach, the case-only design, which was originally proposed for assessing gene and disease associations, to detect gene-sex interaction in human longevity. Applications of this method to data collected from centenarian studies show that it can produce consistent results as compared with results obtained from case-control and other approaches. Important features of the application in human longevity studies are highlighted and discussed. Since centenarians constitute a special population representing successful ageing, the easily applicable case-only approach will be an important tool for screening potential major genes that contribute to human longevity. (AUTHORS)

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

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

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