Fletcher factor deficiency. A diminished rate of Hageman factor activation caused by absence of prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic activity, and kinin generation.
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Fletcher factor-deficient plasma is deficient in prekallikrein and therefore generates no bradykinin upon activation with kaolin. It also possesses a diminished rate of kaolin-activable coagulation and fibrinolysis and possesses a defect in kaolin-activable chemotactic activity. These abnormalities are also corrected by reconstitution with purified prekallikrein. Addition of intact activated Hageman factor corrected the coagulation, fibrinolytic, and chemotactic defects and addition of Hageman factor fragments corrected the fibrinolytic defect and partially corrected the chemotactic defect; neither of these corrected the kinin-generating defect. Although the Hageman factor-dependent pathways appear to be initiated by contact activation of Hageman factor, the kallikrein generated activates more Hageman factor; this feedback is necessary for the Hageman factor-dependent pathways to proceed at a normal rate. It is the absence of this feedback in Fletcher factor-deficient plasma that accounts for the diminished rate of activation of Hageman factor and therefore a diminished rate of activation of the coagulation and fibrinolytic pathways. The ability of prekallikrein to correct the coagulation, fibrinolytic, kinin-generating, and chemotactic defects of Fletcher factor-deficient plasma is consistent with the identity of the Fletcher factor and prekallikrein. (+info)
Hypocoagulable state of human preovulatory ovarian follicular fluid: role of sulfated proteoglycan and tissue factor pathway inhibitor in the fluid.
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Ovulation accompanied by tissue damage can cause an increase in the level of tissue factor (TF) in the follicular fluid, triggering the extrinsic coagulation pathway. However, follicular fluid must block fibrin formation and maintain fluidity until the release of the oocyte at ovulation. The combination of sulfated proteoglycan, antithrombin, and TF pathway inhibitor (TFPI) appears to play a critical role in the hypocoagulability of human follicular fluid. When compared with plasma, folicular fluid differs markedly in the levels of a number of important coagulation proteins. Principal among these are 15-fold, 13-fold, and 3.7-fold increases in free TFPI, thrombin-antithrombin complex, and TF, respectively. The excessively prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT) of human ovarian follicular fluid appear to be primarily due to high concentrations of sulfated proteoglycans, which accelerate the inactivation of thrombin and the anti-Xa activity of TFPI. Thus, heparitinase treatment shortened the clotting times of follicular fluid and reduced the inhibition of thrombin by the proteoglycan fraction combined with a fraction containing antithrombin. The remaining prolongation of APTT and PT may be caused by high levels of free TFPI in follicular fluid, which were confirmed by Northern blotting analysis, demonstrating TFPI mRNA expression by granulosa cells. (+info)
Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects.
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BACKGROUND: In view of the central role of the tissue factor-factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor-factor VIIa complex, in a double-blind randomized crossover study. METHODS AND RESULTS: Administration of nematode anticoagulant protein c2 (3.5 microgram/kg) caused a prolongation of the prothrombin time from 13.7+/-0.6 to 16.9+/-1.2 seconds. The subsequent injection of rVIIa (90 microgram/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75+/-0.64 to 3.29+/-6.3 nmol/L and from 2.4+/-0.6 to 10.7+/-3.9 microgram/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2. CONCLUSIONS: During treatment with an inhibitor of the tissue factor-factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor. (+info)
Prognostic significance of blood coagulation tests in lung cancer.
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Previous studies have shown that activation of coagulation has an impact on the clinical course of lung cancer. This study was carried out to assess the potential prognostic significance of platelet count (P), prothrombin time (PT), partial thromboplastin time (PTT), anti-thrombin III (AT-III), fibrinogen (F), D-dimer (DD), factor II (F-II), factor VII (F-VII), factor X (F-X), protein C clotting (PCC), plasminogen (PL), and antiplasmin (AP) in 343 consecutive new lung cancer patients. A set of 32 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was recorded prospectively for all patients. Patients were carefully followed-up, and their subsequent clinical course recorded. The most frequent abnormalities were of DD, F, and AT-III followed by F-VII, F-X, and F-II. Among the 12 clotting variables, the strongest relationships were those of F-II and F-X (Spearman rank (rs)=0.565), PT and F-VII (rs=0.562), F-VII and F-X (rs=0.514), PL and AP (rs=0.515), F and P (rs=0.490), AT-III and PCC (rs=0.476). Univariate analyses of survival showed that prolonged PT (p<0.043), and abnormally elevated DD (p<0.003), F (p<0.031), and P (p<0.047) were all associated with a poor prognosis. The multivariate model, however, did not confirm the prognostic significance of the coagulation factors. The results show subclinical activation of blood coagulation in lung cancer patients with early disease. In addition, clotting activation is confirmed as a predictor of survival, although not independently of other prognostic factors. (+info)
Lepirudin is a safe and effective anticoagulant for patients with heparin-associated antiplatelet antibodies.
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OBJECTIVE: The purpose of this study was to determine whether lepirudin, a direct thrombin inhibitor, is a safe and effective anticoagulant for patients with heparin-associated antiplatelet antibodies (HAAbs). METHODS: The charts of HAAb-positive patients who received lepirudin were reviewed. Lepirudin use was analyzed for indication, duration, and effectiveness of anticoagulation, and for adverse events. HAAb presence was determined by platelet aggregation. RESULTS: Eighteen HAAb-positive patients received lepirudin: 9 had previous documentation of HAAb, 6 had thrombocytopenia while receiving heparin; and 3 had HAAb after a thrombotic event. The indications for lepirudin anticoagulation included thromboembolism prophylaxis (5), arterial thromboses (5), pulmonary embolus (3) or deep venous thrombosis (1), and one each for atrial fibrillation, myocardial infarction, artificial heart valves, and hemodialysis access. The average duration of therapy was 4.04 days. Fifteen patients achieved adequate anticoagulation (activated partial thromboplastin time [aPTT] ratio > 2.0) with lepirudin. Seven patients had aPTTs that were sometimes supratherapeutic (aPTT > 100 seconds) but did not bleed. In all patients who had heparin-induced thrombocytopenia, platelet counts were normalized while they received lepirudin. There were two complications: one patient fell and had a calf hematoma (aPTT ratio 3.24), and one patient who received lepirudin during nine separate hospitalizations had epistaxis (aPTT ratio 2.86) during her ninth hospitalization. Another patient received lepirudin during two hospitalizations without an adverse event. CONCLUSION: Lepirudin is a safe and effective anticoagulant for patients with HAAbs. The platelet counts of all patients with heparin-induced thrombocytopenia were normalized while they received lepirudin. Careful monitoring of the aPTT and avoidance of trauma while patients are receiving lepirudin are recommended. (+info)
Normal tension glaucoma and primary open angle glaucoma associated with increased platelet aggregation.
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On purpose of the present study was to evaluate platelet aggregation and fibrinolytic systems in patients with normal tension glaucoma (NTG) or primary open angle glaucoma (POAG). For platelet aggregation, we photoelectrophotometrically investigated adenosine diphosphate (ADP) or collagen-induced platelet aggregation in consecutively selected patients with glaucoma (22 patients with NTG and 13 patients with POAG) and 42 glaucoma free control subjects with normal ocular findings. The aggregation patterns of the patients' platelets reacted abnormally to ADP 1 microM or collagen 0.5 microg/ml as evidenced by secondary aggregation were compared with those of control subjects. For blood coagulative and fibrinolytic systems, we measured prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin-antithrombin III complex (TAT), alpha2 plasmin inhibitor-plasmin complex. Seventeen of 22 patients (77%) with NTG and 5 of 13 patients (38%) with POAG showed abnormal secondary aggregation. A significant difference was observed between the two groups. No control subjects showed abnormal secondary aggregation. In the fibrinolytic test, all the parameters examined showed within normal ranges, although the log10(TAT) value was higher in NTG than in POAG. Results of the present study suggested that increased platelet aggregation as defined by ADP or collagen induced abnormal secondary aggregation in vitro is frequently associated with glaucoma patients and this tendency is more apparent in NTG than that in POAG. (+info)
Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis.
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We compared the antithrombotic efficacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt-PA-induced coronary thrombolysis. Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8), FXV673 (10, 30 or 100 microg kg(-1)+1, 3, or 10 microg kg(-1) min(-1), respectively; n=8 per dose), heparin (60 u kg(-1)+0.7 u kg(-1) min(-1), n=8), or RPR109891 (30 microg kg(-1)+0.45 microg kg(-1) min(-1), n=8), was initiated. Aspirin (5 mg kg(-1), i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt-PA was administered (100 microg kg(-1)+20 microg kg(-1) min(-1) for 60 min). The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was significantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23+/-5 min for FXV673 versus 41+/-11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P<0.05). Throughout the protocol, blood flow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose-dependent manner. Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively. In conclusion, FXV673 is more effective than heparin and at least as effective as RPR109891 when used as an adjunct during rt-PA-induced coronary thrombolysis. (+info)
A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. The PENTALYSE study.
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BACKGROUND: ORG31540/SR90107A, a synthetic pentasaccharide, is a selective inhibitor of factor-Xa. It was hypothesized that prolonged factor-Xa inhibition with pentasaccharide may be an effective and safe antithrombotic co-therapy in acute myocardial infarction. METHODS AND RESULTS: Patients (n=333) with evolving ST-segment elevation acute myocardial infarction were treated with aspirin and alteplase and randomized to unfractionated heparin, given intravenously during 48 to 72 h, or to a low, medium or high dose of pentasaccharide, administered daily for 5 to 7 days, intravenously on the first day, then subcutaneously. Coronary angiography was performed at 90 min and on days 5 to 7. Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 rates at 90 min were similar in the four treatment groups. Among patients with TIMI 3 flow at 90 min and who did not undergo a coronary intervention (n=155), a trend towards less reocclusion of the infarct-related vessel on days 5 to 7 was observed with pentasaccharide: 0.9% vs 7.0% with unfractionated heparin (P=0.065). Also, fewer revascularizations during the 30-day follow-up period were performed in patients given pentasaccharide (39% vs 51% for unfractionated heparin;P=0.054). The primary safety end-point, the combined incidence of intracranial haemorrhage and need for blood transfusion, was identical with pentasaccharide and unfractionated heparin (7.1%). One non-fatal intracranial haemorrhage occurred in the 241 patients given pentasaccharide (0.4%). CONCLUSIONS: In this study, pentasaccharide given together with alteplase was safe and as effective as unfractionated heparin in restoring coronary artery patency. Prolonged administration of pentasaccharide was associated with a trend towards less reocclusion and fewer revascularizations. Selective factor-Xa-inhibition seems to be an attractive therapeutic concept in patients presenting with ST-segment elevation acute myocardial infarction. (+info)