摘要:

Plasmin has been reported to activate and inhibit platelet function depending on dose and exposure temperature. The present study examines the induction of fibrinogen-dependent platelet aggregation following prolonged (60 min) platelet exposure to very low doses of plasmin (0.05 CU/ml) at either 22 or 37°C. Maximum aggregation [mean ± SD, 60 ± 19 light transmission units (LTU);n= 43] occurred following platelet exposure to plasmin at 22°C, but significant platelet aggregation (28 ± 4 LTU,n= 3) also occurred following plasmin treatment at 37°C. Plasmin-induced platelet aggregates appeared microscopically larger than aggregates of adenosine diphosphate (ADP)-activated platelets, and were less reversible. Aggregated plasmin-treated platelets also expressed more procoagulant activity than platelets aggregated with ADP, as reflected by shortening of the plasma kaolin recalcification time. Aggregation of platelets exposed to very low doses of plasmin was not accompanied by dense or alpha-granule secretion, and was unaffected by ADP antagonists or aspirin. Partial inhibition of platelet aggregation, however, was achieved with metabolic inhibitors, PGE1, and inhibitors of phosphoinositide 3-kinase or protein kinase C. Although fibrinogen was required for plasmin-treated platelet aggregation, [125I]-fibrinogen binding comprised only 58 ± 3% (n= 3) of fibrinogen binding associated with ADP aggregated platelets. This was consistent with observed decreases in reptilase-induced fibrin clot retraction. Taken together, these data suggest that sustained exposure of platelets to very low plasmin doses leads to platelet activation and thus may contribute to thrombotic complicationsin vivo.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Chronic thromboembolic pulmonary hypertension (CTE-PH) is an infrequent cause of pulmonary hypertension that develops in 0.1–0.2% of patients who survive after an acute venous thromboembolic event. According to the largest series so far reported, 15–30% of patients with diagnosis of CTE-PH have an underlying congenital or acquired hypercoagulable state. To determine the prevalence of thrombophilic factors in our population, we analyzed 24 patients admitted to our institution between November 1992 and March 2000 fulfilling criteria for CTE-PH. Eighteen patients disclosed abnormal results in the screening for thrombophilia. The presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies) was the abnormality most frequently found (12 out of 24 patients). We found hyperhomocysteinaemia in 7/14, true protein S deficiency in 1/10, protein C deficiency in 1/13, activated protein C resistance in 1/22, antithrombin III deficiency in 1/24, and prothrombin gene G20210A mutation in 1/18 patients. Factor V Leiden was normal in all 18 patients studied. Five patients (20.8%) disclosed more than one thrombophilic abnormality. In conclusion, contrary to the largest series of patients with CTE-PH so far reported, we found that 75% of patients with CTE-PH presented at least one thrombophilic risk factor, being antiphospholipid antibodies in 50% of the cases. We recommend a thorough screening for thrombophilia in all patients with diagnosis of CTE-PH.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Hirudin is a small, proteinaceous thrombin inhibitor that clears rapidly from the circulation. A hexahistidine-tagged hirudin–rabbit serum albumin (RSA) fusion protein, HLAH6, was characterized following secretion fromPichia pastoris. HLAH6bound to immobilized nickel, anti-RSA, and anti-hexahistidine antibodies, and contained the expected (ITYTD) N-terminus. Its spectrometric mass was 74 490 (versus the theoretical mass of 74 410 and sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility of 84 kDa). The terminal catabolic half-life in rabbits of HLAH6, recombinantPichia-derived His-tagged RSA, or plasma-derived RSA did not differ. Injection of 2 mg/kg HLAH6into rabbits raised the activated partial thromboplastin time (aPTT) above initial values for 4–24 h, while the equimolar dose of unfused hirudin was without significant effect. A higher dose of HLAH6(3 mg/kg functional HLAH6, equivalent to 37.6 thrombin-inhibitory units/g) raised the aPTT by 2.0- to 2.5-fold; the elevation persisted for > 48 h. Importantly, both HLAH6and unfused hirudin inhibited clot-bound thrombin. Our results suggest that HLAH6exhibits not only delayed clearance, but also prolonged biological activityin vivocompared with unfused hirudin.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The arginine/glutamine (Arg/Gln) polymorphism of the factor VII (FVII) gene is associated with variation in coagulation activity (FVII:C) and antigen concentration (FVII:Ag) of the FVII protein. We estimated frequency distributions of the Arg and Gln alleles and respective genotypes in North Karelia, and evaluated the utility of this polymorphism, serum lipids, and body mass index (BMI) in the prediction of the distributions of FVII:C and FVII:Ag in a cross-sectional study and in a prospective cohort study. The sample comprised 203 males and 262 females (aged 45–64 years) who were seen twice, in 1992 and 1995. The Arg/Arg genotype and the Arg allele frequencies were among the highest reported so far (86 and 93% respectively, in men; and 89 and 94% respectively, in women). Intragenotypic means of both FVII:C and FVII:Ag were significantly higher in the Arg/Arg genotype than in the Arg/Gln genotype in both genders. Also, intragenotypic variances were different in different genotypes in females. Regression relationships between the FVII:C and FVII:Ag and serum triglyceride, and total cholesterol levels and BMI were positive inbothgenotypes in both genders, which has not been found in other populations. In prospective analyses, average changes in the FVII:C and FVII:Ag were genotype specific in both genders, as were also regression relationships between these changes and changes in triglyceride level in females (P= 0.065 for FVII:C andP= 0.061 for FVII:Ag). A consequence of these complex genetic architectures is that predictive utility of the Arg/Gln genotypes depends on population, gender, serum lipid levels, and BMI, and changes in these factors over time.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

In most Westernized societies cardiovascular diseases are the leading cause of death over the age of 45 years and one-quarter of these deaths occur in men below the age of 65 years. The haemostasis system has been identified as an important system in cardiovascular disease (CVD). The European Concerted Action on Prevention from Thrombosis by URokinase Enhancement (ECAPTURE) has focused on the contribution of the urokinase system to CVD. In 2298 patients with angina pectoris the relationship between plasma levels of single-chain urokinase (scu-PA), urokinase antigen (u-PA) and u-PA-inhibitor complex and the risk of cardiovascular events (n= 84) during a 2 year follow-up period was studied. Plasma levels of total u-PA and u-PA-inhibitor complex predicted the risk of cardiovascular events, the adjusted relative risks of the highest quintile versus the lowest were 2.71 [95% confidence interval (CI), 1.34–5.48] and 2.34 (95% CI, 1.08–5.11), respectively. These results suggest that the urokinase system plays a role in cardiovascular disease.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 μg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n= 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

A case–control study was undertaken involving 51 consecutive patients with peripheral artery obstructive disease (PAOD) scheduled for angioplasty. Blood samples of these patients were analysed for plasma homocysteine (tHcy) and levels of vitamin B12and folate, and the MTHFR gene was assessed for mutation. Patients were compared with age- and sex-matched controls who did not present with cardiovascular risk factors. Mean tHcy did not differ between cases and controls (13.3 ± 5.7 and 12.6 ± 4.9 μmol/l,P= 0.49). More patients were above the 95th percentile as determined from the data in the control group with an odds ratio (OR) that almost reached statistical significance [OR, 2.8; 95% confidence interval (CI), 0.9–8.7], but on separate analyses only female patients showed higher tHcy than female controls (15.6 versus 12.0 μmol/l,P= 0.05), with an odds ratio for tHcy above the 95th percentile of 10.5 (95% CI, 1.1–96.6). The TT genotype of the MTHFR gene was found in 24% of the patients and in 12% of the controls (OR, 2.3; 95% CI, 0.8–6.7). Our findings point to a modest association between tHcy and PAOD, with a difference between cases and controls restricted to the highest percentile in female patients. A weak but not significant association was also found for the TT genotype of the MTHFR gene.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

A standardized, quantifiable gunshot trauma to one hind leg of fourteen anaesthetized and sedated pigs was used to investigate the extent to which an isolated gunshot trauma causes activation of blood coagulation. The traumatized pigs were mechanically ventilated in intensive care for 48 h before they were euthanized. Blood samples were drawn at baseline (t= 0), 24, 27 and 48 h after trauma to examine the late effects on haemostasis. The median energy absorption in the pigs was 27.57 (22.6–31.7) J/kg. This gunshot injury caused increased creatine kinase and body temperature and led to a combined metabolic and respiratory alkalosis; the pigs remained circulatory stable. Within the haemostatic system the trauma caused increased activated partial thromboplastin time at 48 h (P< 0.05), prothrombin time at 24 and 27 h (P< 0.05), fibrinogen and soluble fibrin concentration at 48 h (P< 0.05), and 24 h (P< 0.05), respectively. The platelet count, protein C activity, tissue factor concentration and trombin–antithrombin concentration decreased throughout the experiment (P< 0.05); the changes of antithrombin activity did not reach statistical significance. In conclusion, this study in pigs demonstrates that a standardized gunshot trauma to a hind leg activates blood coagulation without signs of organ failure or disseminated intravascular coagulation within 48 h.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We report the case of a 31-year-old woman with protein S deficiency and heterozygosity for the prothrombin 3′ UTR mutation who developed an internal jugular vein thrombosis despite therapeutic anticoagulation with a low molecular weight heparin, following in-vitro fertilization. This case indicates that the stimulus to thrombosis in such women is intense and can occur despite apparent therapeutic anticoagulation. Close attention should, therefore, be paid to any women with a personal or family history of thrombosis and the potential thrombotic risks associated with assisted conception must be discussed.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Anaphylaxis or angioedema in response to recombinant tissue-type plasminogen activator or urokinase have been reported in only a few isolated cases. Both agents are endogenous proteins and thus considered non-antigenic. Activation of fibrinolysis mayper sefacilitate anaphylactoid reactions by pathophysiologic pathways that are not well understood. We report a unique case, review the literature and discuss implication for the clinician. The 25-year-old patient underwent thrombolytic treatment for extensive thrombosis of pelvic and deep lower extremity veins. The patient developed protracted anaphylactoid reactions during recombinant tissue-type plasminogen activator continuous intravenous infusion. After changing treatment to urokinase, the same symptoms recurred with more severe intensity, despite corticosteroid premedication. Symptoms resolved within hours after treatment with histamine receptor blockers. This unique observation, i.e. sequential occurrence of anaphylactoid reactions during recombinant tissue plasminogen activator and urokinase treatments, adds to existing evidence for an unspecific non-antigenic pathomechanism, and for a class effect of thrombolytics. Steroids do not prevent, but histamine receptor blockers seem to be an effective treatment of this unusual complication of thrombolytic therapy.

ISSN:0957-5235    

出版商:OVID    

年代:2001

数据来源: OVID