Heparin after percutaneous intervention (HAPI): a prospective multicenter randomized trial of three heparin regimens after successful coronary intervention.
(1/98)
OBJECTIVES: The purpose of this study was to determine the incidence of bleeding, vascular, and ischemic complications using three different heparin regimens after successful intervention. BACKGROUND: The ideal dose and duration of heparin infusion after successful coronary intervention is unknown. METHODS: Patients were randomized to one of three heparin strategies after coronary intervention: Group 1 (n = 157 patients) received prolonged (12 to 24 h) heparin infusion followed by sheath removal; Group 2 (n = 120 patients) underwent early removal of sheaths, followed by reinstitution of heparin infusion for 12 to 18 h; Group 3 (n = 137 patients) did not receive any further heparin after intervention with early sheath removal. The primary end point of the study was the combined incidence of in-hospital bleeding and vascular events. Secondary end points included in-hospital ischemic events, length of stay, cost and one-month outcome. RESULTS: After successful coronary intervention, 414 patients were randomized. Unstable angina or postinfarction angina was present in 83% of patients before intervention. The combined incidence of bleeding and vascular events was 21% in Group 1, 14% in Group 2 and 8% in Group 3 (p = 0.01). The overall incidence of in-hospital ischemic complications was 2.2%; there were no differences between groups. Length of hospital stay was shorter (p = 0.033) and adjusted hospital cost was lower (p < 0.001) for Group 3. At 30 days, the incidence of delayed cardiac and vascular events was similar for all three groups. CONCLUSIONS: Heparin infusion after successful coronary intervention is associated with more minor bleeding and vascular injury, prolonged length of stay and increased cost. In-hospital and one-month ischemic events rarely occur after successful intervention, irrespective of heparin use. Routine postprocedure heparin is not recommended, even in patients who present with unstable ischemic syndromes. (+info)
Platelet-activated clotting time does not measure platelet reactivity during cardiac surgery.
(2/98)
BACKGROUND: Platelet dysfunction is a major contributor to bleeding after cardiopulmonary bypass (CPB), yet it remains difficult to diagnose. A point-of-care monitor, the platelet-activated clotting time (PACT), measures accelerated shortening of the kaolin-activated clotting time by addition of platelet activating factor. The authors sought to evaluate the clinical utility of the PACT by conducting serial measurements of PACT during cardiac surgery and correlating postoperative measurements with blood loss. METHODS: In 50 cardiac surgical patients, blood was sampled at 10 time points to measure PACT. Simultaneously, platelet reactivity was measured by the thrombin receptor agonist peptide-induced expression of P-selectin, using flow cytometry. These tests were temporally analyzed. PACT values, P-selectin expression, and other coagulation tests were analyzed for correlation with postoperative chest tube drainage. RESULTS: PACT and P-selectin expression were maximally reduced after protamine administration. Changes in PACT did not correlate with changes in P-selectin expression at any time interval. Total 8-h chest tube drainage did not correlate with any coagulation test at any time point except with P-selectin expression after protamine administration (r = -0.4; P = 0.03). CONCLUSIONS: The platelet dysfunction associated with CPB may be a result of depressed platelet reactivity, as shown by thrombin receptor activating peptide-induced P-selectin expression. Changes in PACT did not correlate with blood loss or with changes in P-selectin expression suggesting that PACT is not a specific measure of platelet reactivity. (+info)
Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver.
(3/98)
We demonstrate that a single intraportal vein injection of a recombinant adeno-associated virus (rAAV) vector encoding canine factor IX (cFIX) cDNA under the control of a liver-specific enhancer/promoter leads to a long-term correction of the bleeding disorder in hemophilia B dogs. Stable expression of the therapeutic level of cFIX (5% of normal level) was detected in the plasma of a dog injected with an AAV vector at a dose of 4.6 x 10(12) particles/kg for over 7 months. Both whole-blood clotting time (WBCT) and activated partial thromboplastin time (aPTT) of the treated dogs have been greatly decreased since the treatment. No anti-canine factor IX antibodies have been detected in the treated animals. Importantly, no bleeding has been observed in the dog that expresses a therapeutic level of cFIX for 7 months following vector administration. Moreover, no persistent significant hepatic enzyme abnormalities were detected in the treated dogs. Thus, a single intraportal injection of a rAAV vector expressing cFIX successfully corrected the bleeding disorder of hemophilia B dogs, supporting the feasibility of using AAV-based vectors for liver-targeted gene therapy of genetic diseases. (+info)
Novel, bedside, tissue factor-dependent clotting assay permits improved assessment of combination antithrombotic and antiplatelet therapy.
(4/98)
BACKGROUND: Because optimal use of combinations of antiplatelet and antithrombotic drugs requires improved methods for assessment of therapeutic efficacy, we developed an assay designed to increase sensitivity that is based on initiation of clotting by tissue factor in minimally altered whole blood. METHODS AND RESULTS: Blood samples were obtained from healthy subjects, and the contact pathway of coagulation was inhibited with corn trypsin inhibitor (a specific factor XIIa inhibitor without effect on other coagulation factors). Clotting was initiated with relipidated tissue factor and detected with a Hemochron ACT instrument. Results were reproducible with samples from 25 healthy volunteers (mean time to clot, 125+/-17 seconds). Blood was also exposed to pharmacological concentrations of antithrombotic and antiplatelet agents in vitro. Heparin (0.25 anti-IIa/Xa U/mL) prolonged the time to clot by 2.4-fold (172 seconds, P:<0.05); hirudin (1.0 anti-IIa U/mL), by 3-fold (250 seconds P:<0.05); and enoxaparin (0.6 anti-Xa U/mL), by 2 -fold (123 seconds, P:<0.05). Additive effects of antiplatelet agents were readily detectable with both heparin and hirudin. Thus, addition of 3 microg/mL abciximab to 1.0 anti-IIa/Xa U/mL heparin and to 1.0 anti-IIa U/mL hirudin further prolonged the times to clot by 140 and 67 seconds, respectively (P:<0.05 for each). Addition of abciximab to enoxaparin did not further prolong the time to clot (increment, 13 seconds; P:=NS). CONCLUSIONS: The assay developed should facilitate improved dose selection, titration, and monitoring of combination antithrombotic and antiplatelet treatment regimens. (+info)
Zinc-dependent conformational changes in domain D5 of high molecular mass kininogen modulate contact activation.
(5/98)
Human high molecular mass kininogen (HK) participates as nonenzymatic cofactor in the contact system. Here, we show that recombinant domain D5 of HK (rD5) prolongs the clotting time of the intrinsic pathway of coagulation and attenuates the generation of bradykinin. Further studies indicate that a correct fold of domain D5 within HK is required for the activation of the contact system. The folding of rD5 seems to be modulated by the metal ions Zn2+, Ni2+, and Cu2+ as a specific antibody directed against the zinc-binding site in HK binds to HK and rD5 in a metal ion concentration dependent manner. The finding that these three metal ions specifically affect contact activation suggests that they regulate the accessibility of rD5 for negatively charged surfaces. Support for the assumption that the observed phenomena are due to conformational changes was obtained by fluorescence spectroscopy of rD5, demonstrating that its fluorescence spectrum was changed in the presence of ZnCl2. Moreover, negative staining electron microscopy experiments suggest that the zinc-induced changes in D5 also affect the conformation of the entire HK protein. The present data emphasize the role of zinc and other metal ions in the regulation of contact activation. (+info)
Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials.
(6/98)
BACKGROUND: Unfractionated heparin has been the primary anticoagulant therapy for percutaneous coronary intervention for >20 years. Despite the availability of rapid "point of care" testing, little clinical data defining the optimal level of anticoagulation are available. Furthermore, recent reports have advocated the use of low-dose heparin regimens in the absence of large-scale, well-conducted studies to support this practice. METHODS AND RESULTS: We pooled the data from 6 randomized, controlled trials of novel adjunctive antithrombotic regimens for percutaneous coronary interventions in which unfractionated heparin constituted the control arm. Patients were divided into 25-s intervals of activated clotting times (ACTs), from <275 s to >476 s. In a total of 5216 patients, the incidence of death, myocardial infarction, or any revascularization and major or minor bleeding at 7 days were calculated for each group and compared. An ACT in the range of 350 to 375 s provided the lowest composite ischemic event rate of 6.6%, or a 34% relative risk reduction in 7-day ischemic events compared with rates observed between 171 and 295 s by quartile analysis (P=0.001). CONCLUSIONS: Contrary to recent reports, the optimal suppression of ischemic events with unfractionated heparin therapy in patients undergoing percutaneous coronary intervention demands treatment to ACT levels that are substantially higher than currently appreciated. These data define a goal for heparin dosing within coronary interventions and establish a benchmark of optimal unfractionated heparin therapy against which future trials of novel antithrombotic regimens in percutaneous interventions can be compared. (+info)
Amelioration of collagen-induced arthritis by thrombin inhibition.
(7/98)
The deleterious role of fibrin deposition in arthritic joints prompted us to explore the effect of the thrombin inhibition on the course of collagen-induced arthritis (CIA) in the mouse. CIA was induced in male DBA/1J mice using native chicken type II collagen. The thrombin inhibitor polyethyleneglycol-hirudin (PEG-hirudin) was given for 16 days, starting 20 days after the first immunization (preventive treatment) or at the onset of clinical signs of arthritis (curative treatment). All the mice treated with PEG-hirudin had a significantly prolonged clotting time compared with control mice. PEG-hirudin, administered in a preventive way, led to significantly reduced incidence and severity of CIA during most of the treatment period, as assessed by clinical scoring. Accordingly, histological features showed a significant diminution of synovial hyperplasia in PEG-hirudin-treated mice compared with untreated mice. There was also a significant downmodulation of the synovial proinflammatory IL-1beta and IL-12p35 cytokine mRNAs in treated mice. Intra-articular fibrin, evaluated by immunohistochemistry, was significantly reduced in treated mice compared with control mice and correlated with both clinical and histological scorings. Most importantly, once arthritis was established, PEG-hirudin also showed a curative effect. In conclusion, PEG-hirudin can both prevent the onset of CIA in a dose-dependent manner and ameliorate established arthritis, suggesting that thrombin inhibition may offer a new therapeutic approach in arthritis. (+info)
Oral anticoagulation thresholds.
(8/98)
BACKGROUND: Monitoring patients on oral anticoagulation is essential to prevent hemorrhage and recurrent thrombosis. We studied tissue factor-induced whole-blood coagulation in patients on warfarin therapy with similar international normalized ratios (INRs). METHODS AND RESULTS: Contact pathway-suppressed whole-blood coagulation initiated with tissue factor was studied in 8 male subjects (group W) and in 1 individual multiple times (subject A). Coagulation profiles for group W showed that subjects with similar INRs had widely varying clot times (6.2 to 23 minutes) and thrombin-antithrombin III (TAT) profiles with rates of 25 to 40 nmol. L(-1). min(-1) and maximum levels varying from 192 to 349 nmol/L. The normal control group exhibited clot times of 5.7+/-0.3 minutes and TAT rates of 57+/-13 nmol. L(-1). min(-1), reaching maximum levels of 742+/-91 nmol/L. Subject A, who was stably anticoagulated at an INR of 2.1+/-0.4 for 6 months, had widely ranging profiles with clot times of 9.0 to 22.7 minutes, TAT maximums varying from 141 to 345 nmol/L, and TAT formation rates of 10 to 57 nmol. L(-1). min(-1). INR did not correlate with TAT formation. Platelet activation was decreased by anticoagulants but also displayed variability. Fibrinopeptide A generation showed threshold variability independent of the INR. Factor VIII levels were increased (P=0.03) in group W (204+/-34.4%) compared with normal control subjects (149.4+/-37.4%). A significant correlation was identified between increasing factor VIII levels and years on warfarin therapy (r=0.78, P=0.01), suggesting a possible factor VIII compensatory mechanism. CONCLUSIONS: These results suggest that control of anticoagulation in patients to a set INR therapeutic range may be less secure than anticipated. Patients with similar INRs show significant individual variability in their tissue factor coagulation response, suggesting different risks to anticoagulation when confronted with underlying vascular anomalies. (+info)