摘要:

Behcet's disease is a chronic systemic vasculitis with particular systemic features including thrombotic events. The present study was designed to analyse the role of the factor V Leiden and the prothrombin G20210A mutations and plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk of patients with Behcet's disease. A total of 50 unrelated patients with Behcet's disease (34 male, 16 female) were the subjects of the study. Twenty-seven of 50 patients with a history of thrombosis comprised group 1, and 23 patients with no thrombosis comprised group 2. In group 1, nine of the 27 patients (33%) were found to have the factor V Leiden mutation (7.1% in healthy population), and the 4G/4G genotype was found in 23% of the patients (26% in control). No patient had the prothrombin G20210A mutation (2.2% in healthy control). In group 2, two patients (9%) had the factor V Leiden and one patient (4%) had the prothrombin G20210A mutations. The 4G/4G polymorphism was found in 30.5% of the patients. The differences in the frequencies of factor V Leiden mutation between group 1 and group 2 (odds ratio, 5.3; 95% confidence interval, 1.0–27.5) and between group 1 and the healthy population were statistically significant (P<0.05). No statistically significant association was found for the prothrombin G20210A mutation and the 4G/5G genotype between the two groups or between each group and the healthy population, indicating that the prothrombin G20210A mutation and the 4G/4G polymorphism do not play a role in the development of thrombosis in Behcet's disease. These data suggested that the factor V Leiden mutation might be a risk factor for the development of thrombosis in Behcet's disease patients.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The investigation of many hemostatic defects in newborns is restricted by the lack of normal reference values. The coagulation system of the neonate differs in many ways from that of the adult. The present study was designed to compare the concentrations of tissue factor (TF), tissue factor pathway inhibitor (TFPI) and D-dimer (DD) in the umbilical cord blood of healthy newborns and in adult plasma. TF antigen was quantified using an in-house enzyme-linked immunosorbent assay, whereas TFPI and DD levels were measured with commercial kits. The mean TF level in cord blood (mean±standard deviation, 183.94±103.63 pg/ml) was significantly higher (P= 0.008) than that in adults (136.64±65.09 pg/ml). Cord blood exhibited enhanced fibrinolysis, as was reflected by a significantly higher level of DD (924.57±733.87 ng/ml,P<0.001) than that in adults (45.57±17.21 ng/ml). Conversely, cord blood (30.88±10.16 ng/ml) demonstrated significantly lower (P<0.001) TFPI levels than that in adults (55.77±21.16 ng/ml). However, no significant differences of these three hemostatic markers were noted between both gender groups in newborns and adults. Our findings indicate that an active and dynamic state of hemostasis exists in cord blood, as the fluidity of cord blood remains preserved in the presence of birth injury.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We examined the influence of 3,5-diisopropylsalicylic acid (3,5-DIPS) and calcium(II)3(3,5-diisopropylsalicylate)6(H2O)6[Ca(II)3(3,5-DIPS)6], a new activator of calcium-dependent calmodulin-triggered nitric oxide synthase, on thrombin-induced platelet P-selectin expression. Citrated whole blood samples were incubated with either ethanol vehicle, 3,5-DIPS, or Ca(II)3(3,5-DIPS)6. These whole blood samples were also co-incubated with thrombin receptor activating peptide (TRAP) or adenosine diphosphate (ADP), to up-regulate P-selectin (CD62P) on platelets. Both TRAP and ADP up-regulated P-selectin on platelets compared with platelets in whole blood samples that were not incubated with either platelet activator. Co-incubation of whole blood samples with TRAP, ADP together with 3,5-DIPS, or Ca(II)3(3,5-DIPS)6revealed that Ca(II)3(3,5-DIPS)6caused a decrease in platelet P-selectin expression for TRAP, ADP, and no-activator co-incubated samples of whole blood. Incubation of platelets with 3,5-DIPS also caused a decrease in ADP-induced up-regulation of P-selectin but failed to affect TRAP or no-activator-treated platelets. Incubation of whole blood with Ca(II)3(3,5-DIPS)6induced some hemolysis. We found that hemolysis increases basal P-selectin expression on platelets. We therefore conclude that Ca(II)3(3,5-DIPS)6decreased not only basal, but also hemolysis-induced P-selectin expression on platelets. In contrast, incubation of haemolysed whole blood with SIN-1 (standard nitric oxide-releasing drug) had no effect on P-selectin expression. In summary, Ca(II)3(3,5-DIPS)6, a new calmodulin-dependent nitric oxide synthase activator, decreases P-selectin expression of human platelets in response to thrombin receptor activation. Improved calcium-dependent calmodulin activators may become useful drugs for the treatment of disorders associated with platelet activation, and P-selectin may decrease expression due to hemolysis.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The present study investigated the effect of the thrombin inhibitors antithrombin (AT) (with and without unfractionated heparin or low molecular weight heparin), hirudin, inogatran and melagatran on thrombin–thrombomodulin-mediated generation of activated protein C (APC), in solution and on endothelial cells. Sequential incubation with thrombin, thrombin inhibitors and protein C was followed by measurement of APC by an amidolytic assay. The approximate concentrations resulting in 50% inhibition of endothelial cell-mediated APC generation for AT, AT-unfractionated heparin, AT-low molecular weight heparin, hirudin, melagatran and inogatran were 200, 4, 9, 1, 8 and 60 nmol/l, respectively. The normal plasma level of AT is 2800 nmol/l and relevant therapeutic concentrations from clinical trials are 200 nmol/l for hirudin, 500 nmol/l for melagatran and 1000 nmol/l for inogatran. The present study indicates that clinically relevant concentrations of the tested thrombin inhibitors interfere with endothelial-mediated APC generation, which may offer an explanation for the lack of a dose–response effect in clinical trials with thrombin inhibitors.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Low-dose aprotinin inhibits hyperfibrinolysis in cardiac surgery. However, excessive postoperative bleeding and increased fibrinolysis may occur despite low dose-aprotinin administration. We investigated (i) whether fibrinolytic activity significantly rises under low-dose aprotinin administration, and (ii) whether this is associated with excessive postoperative bleeding (⩾ 1000 ml/24 h). In a prospective single-blind trial, 120 consecutive patients were randomized to receive 280 mg aprotinin or no aprotinin before skin incision. D-dimer levels increased significantly to the end of surgery, reaching higher levels in the control group. The risk for excessive bleeding was lower in the aprotinin group (12 versus 37%,P= 0.001). Fifteen minutes after heparin reversal, patients were at risk for excessive bleeding, when enhanced fibrinolysis was documented (aprotinin group, D-dimer ⩾ 1.0 μg/ml, odds ratio = 9.1,P= 0.047; control group, D-dimer ⩾ 3.0 μg/ml, odds ratio = 4.6,P= 0.014). Ninety-seven per cent of the aprotinin group and 81% of control group patients had no excessive bleeding when the D-dimer plasma level was below these values. We conclude that (i) fibrinolytic activity significantly rises under low-dose aprotinin administration, and (ii) plasma D-dimer levels at end of surgery may help to identify patients who are unlikely to develop excessive postoperative bleeding.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

A G-to-T point mutation in exon 2 of the FXIII A-subunit gene results in a leucine rather than valine at amino acid position 34 of the factor XIII molecule. The presence of leucine has been associated with a reduced risk of both arterial and venous thrombosis. We examined the prevalence of this point mutation in 102 cases of pre-eclampsia and 208 matched control subjects, as inherited and acquired risk factors for arterial and venous thrombosis are associated with an increased risk of pre-eclampsia. The GT genotype was observed in 38% of controls and 29.4% of cases and the TT genotype was observed in 6.7% of controls and 5.9% of cases. In subjects heterozygous for the T genotype (GT) the relative risk of pre-eclampsia was 0.7 [95% confidence interval (CI95) 0.4–1.1] when compared with the GG genotype. For subjects homozygous for the T allele the relative risk for pre-eclampsia was 0.8 (CI950.3–2.1) when compared with the GG genotype. The risk associated with the T allele in the heterozygous and homozygous forms compared with the GG genotype was 0.7 (CI950.4–1.1). We conclude that the presence of leucine at this site is not associated with a protection against pre-eclampsia to the magnitude of that reported in other thrombotic disease.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Thrombin-induced platelet activation involves cleavage of protease-activated receptors (PARs) 1 and 4, and interaction, via glycoprotein (Gp)Ibα, with the platelet GpIb/IX/V complex. This study investigated inhibition of platelet activation by thrombin inhibitors with different modes of action: two reversible direct thrombin inhibitors, melagatran and inogatran; hirudin, a tightly binding direct thrombin inhibitor; and two indirect thrombin inhibitors, heparin and dalteparin. Up-regulation of P-selectin (CD62P) and PAR-1 cleavage was measured in human whole blood, by flow cytometry. The thrombin concentration that induced 50% of maximum (EC50) PAR-1 cleavage was 0.028 nmol/l, while that of platelet activation (CD62P) was over two-fold higher (0.64 nmol/l). The EC50of a PAR-1-independent component, defined as a further activating effect of thrombin on top of the maximum PAR-1-activating peptide (AP) effect, was 3.2 nmol/l. All anticoagulants were concentration-dependent inhibitors of thrombin-induced platelet activation and PAR-1 cleavage, but none inhibited PAR-1-AP or PAR-4-AP induced activation. Melagatran and inogatran were more potent inhibitors of CD62P up-regulation than of PAR-1 cleavage; conversely, hirudin, heparin and dalteparin were more potent inhibitors of PAR-1 cleavage.Thus, reversible direct thrombin inhibitors, such as melagatran, are potent inhibitors of thrombin-induced platelet activation, acting mainly by inhibition of a PAR-1-independent component.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The effect of recombinant factor VIIa (rFVIIa) on blood loss was evaluated in cirrhotic patients undergoing orthotopic liver transplantation. In the present study, we explored the effect of rFVIIa on coagulation and fibrinolysis during orthotopic liver transplantation. Coagulation factors, parameters of thrombin generation and parameters of fibrinolysis were measured in six patients who had received a single dose of 80 μg/kg rFVIIa and in ten controls, during and after orthotopic liver transplantation. Baseline concentrations and course of coagulation factors were similar in patients and controls. Thrombin generation did not rise after the administration of rFVIIa, but showed a sharp increase after reperfusion in patients, as compared with controls. No difference in fibrinolysis was apparent between patients and controls. No evidence of diffuse intravascular coagulation was seen. We conclude that the use of rFVIIa in orthotopic liver transplantation seems to enhance thrombin generation in a localized and time-limited matter, without causing systemic coagulation.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We used a sensitive assay to measure thrombin potential in 20 patients who underwent cardiopulmonary bypass surgery for coronary artery bypass grafts. We measured coagulation factors II, V, VII, VIII and X. Blood loss was measured as the total amount in the mediastinal drains in the first 24 h postoperatively. Thrombin potential was median 107 nmol/l.min (range 62–181) preoperatively and median 46 nmol/l.min (range 19–120) postoperatively. Coagulation factors II, V, VII,VIII and X were within normal limits preoperatively. Factor II fell from 77 IU/dl preoperatively to 37 IU/dl at 120 min postoperatively. Factor V fell from 85 IU/dl preoperatively to 61 IU/dl postoperatively. Factor VII fell from 91 IU/dl to 66 IU/dl postoperatively. Factor VIII was 128 IU/dl preoperatively and 127 IU/dl postoperatively. Factor X fell from 90 IU/dl preoperatively to 50 IU/dl postoperatively. Total blood loss in 24 h in the mediastinal drains postoperatively was mean 673 ml, median 650 ml (range 250–2000). Reduction in thrombin potential correlated inversely with postoperative blood loss,r= –0.75 (Spearman correlation). The fall in the thrombin potential correlated with the prothrombin level (r= 0.75) and factor X (r= 0.47).

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Impaired fibrinolysis is considered a sensitive marker of endothelial dysfunction. Persistent endothelial dysfunction occurs in some patients following Kawasaki disease. The aim of the present study was to assess whether impaired fibrinolysis is present in long-term survivors of Kawasaki disease. The study included 42 children with a documented history of Kawasaki disease presenting with or without coronary lesions, and 26 healthy controls. Blood samples were collected from patients and controls prior to and following venous occlusion stress testing. Significantly decreased fibrinolytic response to venous occlusion was detected in patients compared with controls due to decreased tissue plasminogen activator. In addition, patients had significantly increased plasma concentrations of plasminogen and fibrinogen, which were related to similar increases of alpha2-macroglobulin. Decreased fibrinolytic response was found in patients with coronary aneurysms but also in those without coronary lesions. In summary, a decreased fibrinolytic response to venous occlusion may reflect persistent endothelial damage following acute Kawasaki disease, potentially predisposing these patients to accelerated atherosclerosis and cardiovascular disease in early adult life.

ISSN:0957-5235    

出版商:OVID    

年代:2003

数据来源: OVID