Failure of fixed dose intravenous heparin to suppress increases in thrombin activity after coronary thrombolysis with streptokinase (original) (raw)
Related papers
Journal of the American College of Cardiology, 1998
Objectives. We sought to assess the effects of antithrombotic therapy after thrombolysis for acute myocardial infarction on markers of thrombin generation and activity and to determine the relation of these markers with clinical outcomes. Background. Thrombin activation and generation often occur with thrombolysis for acute myocardial infarction. Antithrombotic regimens have been developed to reduce the resulting thrombotic complications. Methods. We sampled plasma markers of thrombin generation and activity after thrombolysis in 292 patients. We assessed the relations of these markers with clinical outcomes at 30 days. Results. Fibrinopeptide A (FPA), a marker of thrombin activity toward fibrinogen, was elevated at baseline (12.3 ng/ml) and increased to 18.4 ng/ml by 90 min after streptokinase and subcutaneous heparin treatment. With intravenous heparin, this increase was attenuated, but intravenous heparin did not prevent thrombin generation, as measured by prothrombin fragment 1.2 (F1.2). Heparin level, measured by anti-Xa activity, correlated with activated partial thromboplastin time (aPTT, r ؍ 0.62 to 0.67). Thrombin activity, measured by FPA, was as closely related to aPTT as to the heparin level. Baseline levels of F1.2 were significantly related to the risk of death or reinfarction at 30 days (p ؍ 0.008); values 12 h after enrollment also were related to 30-day mortality (p ؍ 0.05). Conclusions. Although intravenous heparin partly suppresses the increased thrombin activity associated with thrombolysis, it does not inhibit thrombin generation. The aPTT was as good a measure of suppression of thrombin activity as the heparin level itself. Hematologic markers of thrombin generation were found to be related to the subsequent risk of thrombotic events.
Journal of Interventional Cardiology, 1994
The antithrombotic effect of three different ypes of antithrombotic agents (antithronibin:argatroban. heparin, defibrinogenating agent:batroxobirz) were evaluated in canine coronan und iliac arteries. An occlusive thrombus was produced by balloon injury. One of the three agents was infused intravenously at I hour after thrombus formation (heparin 250 U k g. argatroban 0.5 mg/kg, batroxobin 0.5 U k g) arid the eftecf of thrombus size reduction was evaluated. On the contralateral side of the iliac artep, the preventive effect of these agents on throtnbus formation was evaluated after balloon injury. In the iliac artery. angioscopic percent area obstruction by the thrombus before and 60 minutes ajier treatment reduced.from 69% to 32% in the argatroban group, and from 64% to 51% in the batroxobin group (P < 0.0001 and P < 0.05, respectively). No signijkant change was observed in the heparin group. Angiograph? demonstrated the same trend. The percent area stenosis with thrombus at 60 minutes following balloon injury was 0.75% in the argatroban group, 18.9% in the heparin group (P < 0.05 1 ' s argatroban), and 12.9% in the batroxobin group. Thrombus size at the treated site was smaller than that at the control site in all three groups (P < 0.05 I. " control). In the coronary artep. angioscopic percent area obstruction by the thrombus before arid 60 niinutes after treatment reduced from 84% to 53% in the argatroban group, and from 86% to 68% in the batroxobin group (P <0.0001 and P < 0.05, respectively). N o signifcant change was observed in the heparin group. Angiographg also demonstrated the same trend. The activated partial thromboplastiii time (APTT) ~i a s prolonged to 189% of the control \lalue with argatroban and to 1253% ofthe value with heparin (P < 0.0001). Fibrinogen was markedly reduced with batroxobin. These results showed thut both the antithrombin agent and the defbrinogenating agent hai,e a preventive effect on thrombus formation and the effect on thrombus size reduction, without marked prolongation of the A P V .
Circulation, 2002
Background-The anticoagulant effect of heparinoids is attributed to their cofactor activity for antithrombin (AT) and heparin cofactor II. In patients with thrombosis, however, thrombin is often protected from AT-dependent, heparinmediated inactivation. The purpose of this study was to compare the properties of unfractionated/standard heparin (UFH/SH) and those of a novel covalent AT-heparin complex (ATH) in a rabbit arterial thrombosis prevention and bleeding model. Methods and Results-Thrombosis in the distal aorta was triggered by vessel wall injury and critical stenosis. Blood flow in the damaged arterial segment was monitored with a flow probe placed distal to the constrictor. Rabbits were given doses of SH (62.5 to 187.5 IU · kg Ϫ1 · 90 min Ϫ1 ) or ATH (16 to 65 IU · kg Ϫ1 · 90 min Ϫ1 ). Cumulative blood loss from skin incisions was used to assess drug safety. The antithrombotic effects of ATH were greater than those of SH as measured by clot weight, blood flow, and vessel patency; eg, complete thrombus resolution was achieved with ATH (33 to 65 IU/kg), but not SH (125.0 to 187.5 IU/kg). At doses that produced equivalent vessel patency (50% to 60%), blood loss induced by ATH (60.2 L) was 2.6-fold lower (PϽ0.05) than that induced by SH (154.6 L). Conclusions-In our experimental system, ATH was able to control arterial thrombosis more effectively than its SH precursor, without pronounced bleeding. (Circulation. 2002;106:261-265.)
Circulation, 1998
Background-Thrombolytic therapy induces a procoagulant state characterized by elevated plasma levels of fibrinopeptide A (FPA), but the responsible mechanism is uncertain. Methods and Results-Washed plasma clots were incubated in citrated plasma in the presence or absence of tissue plasminogen activator (t-PA), and FPA generation was monitored as an index of unopposed thrombin activity. FPA levels are almost twofold higher in the presence of t-PA than in its absence. This primarily reflects the action of thrombin bound to soluble fibrin degradation products because (a) there is progressive FPA generation even after clots are removed from t-PA-containing plasma, and (b) clot lysates produce concentration-dependent FPA generation when incubated in citrated plasma. Using thrombin-agarose affinity chromatography, (DD)E and fragment E but not D-dimer were identified as the thrombin-binding fibrin fragments, indicating that the thrombin-binding site is located within the E domain. Heparin inhibits thrombin bound to fibrin degradation products less effectively than free thrombin. In contrast, D-Phe-Pro-ArgCH 2 Cl, hirudin and hirugen inhibit free thrombin and thrombin bound to fibrin degradation products equally well. Conclusions-Thrombin bound to soluble fibrin degradation products is primarily responsible for the increase in FPA levels that occurs when a clot undergoes t-PA-induced lysis. Like clot-bound thrombin, thrombin bound to fibrin derivatives is protected from inhibition by heparin but susceptible to inactivation by direct thrombin inhibitors. These findings help to explain the superiority of direct thrombin inhibitors over heparin as adjuncts to thrombolytic therapy. (Circulation.
Thrombosis research, 1991
The relationship between heparin and fibrinolysis is strongly suggested. We have studied the influence on fibrinolysis of standard heparin (SH), Calciparin and low molecular weight heparin (LMWH), Fraxiparin, given preventively in an elderly population. Patients were randomized into two groups (SH, LMWH). We investigated fibrinolytic parameters (ECLT, t-PA antigen, PAI-1 activity and antigen, t-PA/PAI-1 complexes) before treatment (D0) and at D30 and D60, before and after venous occlusion (VO). Values at D0, D30 and D60 were compared within each group. A significant and marked increase in t-PA and t-PA/PAI-1 complexes at D30 and D60 before and after VO was noted only in the SH group. The mechanism and clinical relevance of this increase remains to be established.
Heparin compromises streptokinase-induced arterial patency in rabbits
Thrombosis Research, 2005
Introduction: Little is known with regard to efficacy of heparin as an adjunct to fibrinolytics under conditions of severe vascular damage. In this study, we compared the effects of unfractionated heparin (UH), low-molecular weight heparin (LMWH), and recombinant desulfohirudin (HIR) in combination with streptokinase (SK) in such settings. Materials and methods: We used an established rabbit model, in which thrombosis, critical stenosis, and vascular wall damage were introduced to a segment of the abdominal aorta and the effects of the respective therapies were assessed by time to patency (TTP in minutes), cumulative patency (CP (%)), lysis of original clot (CL (%)), and net clot accretion (NCA (%)). Treatments were administered over 90 min at the following doses: SK: 33,000 U/kg, UH: 125-250 U/kg, LMWH: 1.25-2.5 mg/kg, HIR: 0.25-0.55 mg/kg. Results: Unexpectedly, UH and LMWH had a paradoxical and detrimental effect on SK-mediated recanalization as measured by both TTP and CP. Thus, administration of SK vs. SK+UH or SK+LMWH resulted in TTP values of 43F8 min vs. 70F11 min (pb0.05) and 67F12 min. (pb0.08), respectively. For CP, the corresponding values were 21F7%, 0.5F0.3% and 9F8%. This delay in vessel recanalization occurred despite excessive systemic anticoagulation (activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) ratios N6 and N34, respectively). Of interest, both heparinoids completely inhibited SK-induced fibrinogen consumption
Fibrinolysis, 1988
Thirty patients with deep venous thrombosis (DVT) (less than 7 days) were randomised into three treatment groups and received Choay's CY222 at the respective doses of 4 mg (group I), 3 mg (group II) and 2 mg/ kg/24 h (group III) administered in three subcutaneous injections. A relationship between the thrombolytic effect evaluated on phlebography and plasma fibrinolysis parameters was looked for. Phlebography was performed before (DO) and on Day 7 (D7) of treatment and scored by Marder's index (MI). The mean decrease in MI on D7 was 40%. Blood samples were taken at DO and at 8.00 am before injection on Dl, D3, D5 and D7. The following fibrinolysis parameters: euglobulin fibrinolytic activity (EFA), t-PA-Ag, PA inhibitor (PAI), showed no change during treatment in each group. Among patients with MI > 10 on DO (n = 24) two response groups, A and B, were distinguished, based upon the thrombolytic response: Group A-six patients (three in treatment group I, two in group II and one in group III) with high degree of thrombolysis (decrease in MI 3 80%); Group B-nine patients (three in each treatment group) with no thrombolytic response (decrease in MI 620%). Changes in plasma fibrinolysis parameters in Groups A and B showed no difference during treatment. On DO mean PA1 was lower in Group A than in Group B (~~0.05). The difference persisted throughout treatment. All the patients with high PA1 (> 4 U/ml) (5 of 30) before and during treatment were in Group B. These results show that CY222 is effective in the treatment of DVT. Its mechanism of action remains unclear, as no direct effect on EFA, t-PA-Ag, and PA1 level could be demonstrated. No thrombolysis occured in patients with high PA1 before treatment. Thus pre-treatment determination of PA1 could have a predictive value in the efficacy of CY222 treatment.