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Biomedical subjects

D R Abendschein

Publications and source records attributed to D R Abendschein.

At least 37 records · Page 2Linked to original sources
PubMed1996

Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction. TIMI-5 Investigators. Thrombolysis in Myocardial Infarction.

Thrombin activity is increased in the setting of acute myocardial infarction (AMI) and has been shown to increase further after the administration of thrombolytic therapy for acute infarction. This increase in thrombin activity may play an important role in the 15% to 25% rate of failure to achieve initial reperfusion and in the 5% to 15% rate of early reocclusion after initially successful thrombolysis. To investigate potential mechanisms of thrombin formation in vivo, to understand better the balance of coagulation and fibrinolysis during treatment with recombinant tissue-type plasminogen activator (rt-PA), and to investigate the role of hemostatic markers as predictors of clinical events, we measured 3 markers of procoagulant activity: fibrinopeptide A (FPA), thrombin-antithrombin III complexes (TAT), and prothrombin fragment 1.2 (F1.2), and a marker of fibrinogenolytic activity (B beta 1-42) in patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI)-5 study. This trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin as adjunctive antithrombotic therapy with rt-PA administered to patients with AMI. Correlation of markers at 1 hour with clinical outcomes revealed that increased FPA and TAT levels were associated with increased mortality and TIMI grades 0, 1, or 2 flow at 90 minutes; increased F1.2 levels were associated with TIMI grade 0 or 1 flow at 90 minutes; and increased levels of all 3 procoagulant markers were associated with hemorrhagic events. Late (12 to 24 hours) increases in F1.2, TAT, and B beta 1-42 may be predictive of recurrent ischemia. These results suggest that selected markers of procoagulant and fibrinogenolytic activity may be useful in predicting clinical outcomes in patients treated with thrombolytic therapy for AMI.

Antithrombin III↗
PubMed1996

Inhibition of thrombin attenuates stenosis after arterial injury in minipigs.

OBJECTIVES: We sought to determine whether brief, profound inhibition of thrombin or prothrombin activation by factor Xa limits neointimal formation and stenosis after arterial injury. BACKGROUND: Thrombin has been implicated as a mediator of neointimal formation, but adjunctive administration of anticoagulant agents has not proven effective to decrease restenosis in patients undergoing coronary angioplasty. METHODS: We infused recombinant desulfatohirudin (r-hirudin, bolus of 2 mg/kg body weight followed by 2 mg/kg per h, n = 9), heparin (100 U/kg per h, n = 6) or recombinant tick anticoagulant peptide (rTAP, 1-mg/kg bolus followed by 3 mg/kg per h, n = 5), a specific inhibitor of factor Xa, intravenously, beginning 15 min before and for up to 3 h after repetitive balloon hyperinflations sufficient to disrupt the internal elastic lamina in a carotid artery of minipigs with hypercholesterolemia induced by feeding them an atherogenic diet. RESULTS: Partial thromboplastin time was increased six- to sevenfold over baseline levels at the end of the infusions of the anticoagulant agents. Lumen stenosis measured histologically 4 weeks after balloon-induced carotid injury was 29 +/- 16% (mean +/- SEM) in r-hirudin-treated, 52 +/- 19% in rTAP-treated and 76 +/- 18% in heparin-treated pigs (p < 0.02 for r-hirudin vs. heparin treatment). CONCLUSIONS: The marked reduction of stenosis in r-hirudin-treated animals indicates that thrombin plays a major role in neointimal formation after balloon-induced arterial injury. A relatively brief interval of profound, direct inhibition of thrombin may be particularly effective to attenuate restenosis after balloon angioplasty.

Angioplasty, Balloon↗
PubMed1996

Preincubation of Dacron grafts with recombinant tissue factor pathway inhibitor decreases their thrombogenicity in vivo.

BACKGROUND: We have previously shown that preincubation of whole blood clots with recombinants tissue factor pathway inhibitor (rTFPI) attenuates clot-associated procoagulant activity assessed ex vivo. This study was undertaken to determine whether a single local application of rTFPI induces similar attenuation of the procoagulant activity on preclotted Dacron grafts implanted in an artery in vivo. METHODS: Dacron grafts (4 mm x 4 cm long) were preclotted in porcine blood and incubated with either rTFPI (5 mg/ml) or arginine-phosphate buffer for 15 minutes. Grafts were implanted end-to-end in the femoral arteries of 10 pigs, with one rTFPI-treated and one buffer-treated graft implanted in each animal. Animals did not undergo anticoagulation either before or after graft implantation. Radiolabeled porcine fibrinogen was injected intravenously, and the grafts underwent perfusion for 1 hour. A subgroup of animals (n = 7) also had infusion of radiolabeled autologous platelets at the time of administration of radiolabeled fibrinogen. RESULTS: Fibrin(ogen) deposition was decreased in rTFPI-treated grafts by 36% +/- 7% (mean +/- SEM) compared with buffer-treated grafts (p = 0.001). Platelet deposition was also reduced in the rTFPI-treated grafts by 31% +/- 15%, although the reduction did not reach statistical significance (p = 0.10). The extent of rTFPI-mediated attenuation of fibrin(ogen) versus platelet deposition varied independently among animals. CONCLUSIONS: Clot-directed anticoagulant effects of rTFPI appear to be useful for substantially decreasing the thrombogenicity of Dacron grafts immediately after their implantation. Chronic studies to determine whether the decreases in thrombogenicity result in improved long-term graft patency appear warranted.

Animals↗
PubMed1996

Efficacy of local inhibition of procoagulant activity associated with small-diameter prosthetic vascular grafts.

PURPOSE: Graft procoagulant activity is determined by thrombin (IIa) and activated factor X (Xa) that binds to thrombus. Thrombus-associated factor Xa and thrombin are resistant to antithrombin III-dependent therapy (heparin). To avoid complications and costs associated with systemic administration, we evaluated whether locally applied antithrombotic agents inhibit prosthetic graft procoagulant activity under no-flow and low-flow conditions. METHODS: Four-millimeter-diameter collagen-coated grafts were preclotted in recalcified human plasma, washed, immersed in antithrombotic agents (either 100 nm hirudin, 20 microns D-Phe-L-Pro-L-Arg chloromethylketone, 5 microns tick anticoagulant peptide or 5 or 10 micrograms/ml tissue factor pathway inhibitor) or saline solution, and extensively rewashed. Grafts were exposed to recalcified plasma either in multiwell plates or underwent perfusion at 1 ml/min flow rate. Fibrinopeptide A, which reflects fibrin elaboration, was measured as a marker of thrombin activity. RESULTS: Inhibitors reduced fibrinopeptide generation at 8 minutes by 55% (tissue factor pathway inhibitor), 57% (hirudin), or 63% (tick anticoagulant peptide and D-Phe-L-Pro-L-Argchloromethylketone) compared with the control agents (p < 0.05). Under low-flow conditions tissue factor pathway inhibitor and hirudin reduced fibrinopeptide generation at 13 minutes by 61% and 49%, respectively, when compared with control agents (p < 0.05). CONCLUSIONS: Graft-associated inhibitors targeted at factors IIa, Xa, or tissue factor/VIIa/Xa complex effectively reduce procoagulant activity on prosthetic grafts. The success of local application of antithrombotic agents in attenuating early fibrin formation suggests that this strategy could favorably influence acute graft patency, and we speculate these agents may improve long-term graft patency as well.

Amino Acid Chloromethyl Ketones↗
PubMed1996

Sustained inhibition of whole-blood clot procoagulant activity by inhibition of thrombus-associated factor Xa.

Progression of arterial thrombosis partly depends on thrombus-associated thrombin and activated factor X (Xa) activity. However, whether Xa or thrombin is the most appropriate target for inhibition of recurrent thrombosis is unknown. This study was designed to determine whether inhibition of Xa results in more sustained attenuation of thrombus-associated precoagulant activity than does inhibition of thrombin. Clots prepared ex vivo from human whole blood and pathological arterial thrombi from patients were preincubated in citrated plasma containing no inhibitor, 0.5 to 1 U/mL heparin, 0.5 to 1 mumol/L hirudin, 5 to 10 mumol/L tick anticoagulant peptide (TAP), 0.15 to 3 mumol/L tissue factor pathway inhibitor (TFPI), or a combination of 1 mumol/L hirudin and 10 mumol/L TAP for 2 hours. After preincubation the clots were removed from first-stage plasma, extensively washed in phosphate-buffered saline, and added to nonanticoagulated whole blood. Clots preincubated in plasma without inhibitors induced marked activation of the coagulation system in whole blood, as characterized by greater increases in the concentration of fibrinopeptide A (FPA) over 7 minutes than in blood without added clots (1522 +/- 568 compared with 117 +/- 170 ng/mL, P < .01). Preincubation of clots with heparin or hirudin did not attenuate the increases in FPA in wholeblood. In contrast, compared with incubation without an inhibitor, preincubation of clots with TAP or TFPI markedly attenuated the increases in FPA when clots were added to whole blood (551 +/- 316 and 508 +/- 208 ng/mL, respectively, P < .01). Similar results were obtained with arterial thrombi from patients. Inhibition of Xa but not of thrombin results in sustained attenuation of thrombus-associated procoagulant activity. Uninhibited thrombus-associated Xa activity may account for the increases in thrombin activity that are commonly observed in clinical trials after discontinuation of thrombin inhibitors.

Anticoagulants↗
PubMed1996

Procoagulant activity on injured arteries and associated thrombi is mediated primarily by the complex of tissue factor and factor VIIa.

BACKGROUND: Rethrombosis limits the efficacy of coronary thrombolysis and may result from surface-associated thrombin, de-novo prothrombin activation, or both. This study was designed to determine the relative roles of thrombin, factor Xa, and the complex of tissue factor and factor VIIa in the procoagulant activity on injured arteries with evolving thrombi. METHODS: Extensive vascular injury and platelet-rich thrombi were induced in the abdominal aorta of 25 anesthetized rabbits by applying anodal current through a transluminal electrode for 3 h. Injured vessel segments were excised and placed in a chamber permitting perfusion over the luminal surface and associated thrombus. RESULTS: Vessel segments perfused with recalcified, citrated human plasma induced marked increases in the concentration of fibrinopeptide A, a marker of thrombin-induced fibrin formation, in the effluent plasma after 10 min (4636 +/- 1894% of fibrinopeptide A in the nonperfused plasma, n = 5). Perfusion with plasma depleted of vitamin K-dependent coagulation factors prevented the increase in fibrinopeptide A (122 +/- 30%, n = 4), indicating the lack of preformed functional thrombin. Furthermore, appearance of fibrinopeptide A was attenuated by perfusion with plasma containing 0.1 mumol/l recombinant tick anticoagulant peptide, a specific inhibitor of factor Xa (594 +/- 320%, n = 3), and by preincubation of vessel segments with a monoclonal antibody to rabbit tissue factor (438 +/- 220%, n = 3). CONCLUSIONS: Procoagulant activity on injured vessels and associated thrombi is mediated by factor Xa, a product of the functional initiation of coagulation by factor VIIa associated with tissue factor. Accordingly, inhibition of tissue factor-mediated coagulation may be effective for attenuation of active thrombogenesis on injured vessels and during thrombolysis.

Animals↗
PubMed1996

Conjunctive administration of intravenous heparin attenuates cross-linked fibrin degradation in patients treated with streptokinase.

Increases in thrombin activity occur in patients treated with streptokinase, but conjunctive therapy with intravenous heparin does not appear to improve either the rate of early infarct artery patency or survival in patients with acute myocardial infarction. In a recent study we found that concentrations of fibrinopeptide A, a marker of thrombin-mediated fibrin formation, were lower in the first 3 h in patients treated with intravenous heparin (5000 U bolus followed by a fixed-dose 1000 U/h infusion, n = 14) compared with subcutaneous (12,500 U every 12 h, started 4 h after streptokinse, n = 14) administration, but were increased in both groups of patients, consistent with persistent thrombin activity. To determine whether the differential effects of the intensity of heparinization on thrombin formation were reflected in differences in fibrin degradation, we measured cross-linked fibrin degradation products (XL-FDP) before and 1, 2, 3, 8, 12, and 24 h after streptokinase in the same cohort of patients, with a new ELISA with a D-dimer-specific capture antibody (MAb 3B6) and a fibrin-specific tag antibody (MAb 1D2, Agen, Brisbane, Australia). The incidence of early coronary recanalization assessed by creatine-kinase MM isoforms (increase in activity > or = 0.18%/min), was similar in both groups (79 vs 86%). Concentrations of XL-FDP were similar in patients with and without recanalization, but were lower in patients treated with intravenous compared with subcutaneous heparin at 8 h, but the results did not reach statistical significance (627 +/- 151 ng/ml versus 1007 +/- 157 ng/ ml, p = 0.06), and were significantly lower at 12 h (327 +/- 72 versus 781 +/- 162 ng/ml, p = 0.03 at 12 h) (mean +/- SEM). Concentrations of cross-linked fibrin degradation products were also lower in patients in whom the activated partial thromboplastin time was greater than two times the control, compared with those with inadequate anticoagulation (498 +/- 105 versus 1084 +/- 179 ng/ml; p = 0.02) (mean +/- SEM). Thus, more effective inhibition of thrombin with conjunctive intravenous heparin therapy results in less cross-linked fibrin turnover in the first 12 h after thrombolysis with streptokinase. This probably reflects decreased fibrin formation with therapeutic anticoagulation.

Cohort Studies↗
PubMed1996

Comparative sensitivity of cardiac troponin I and lactate dehydrogenase isoenzymes for diagnosing acute myocardial infarction.

Criteria for the retrospective diagnosis of acute myocardial infarction rely heavily on increases in lactate dehydrogenase (LD) isoenzymes. However, increases of LD isoenzyme activities are not specific for myocardial injury. Recently, increased concentrations of cardiac troponin I (cTnI) have been shown to be highly specific for myocardial damage and to have sensitivity comparable with that of creatine kinase MB isoenzyme for detecting cardiac injury. Furthermore, increases of cTnI persist in plasma for at least several days. The present study was designed to determine the relative sensitivities of cTnI and LD isoenzymes over time for the diagnosis of infarction. The results indicate that cTnI values are at least as sensitive as LD isoenzymes: 90% of patients with myocardial infarction had above-normal concentrations of cTnI on the 4th day after admission to the coronary care unit. Criteria based on cTnI should improve the accuracy of retrospective diagnoses of acute myocardial infarction.

Animals↗
PubMed1995

Tissue factor mediates prolonged procoagulant activity on the luminal surface of balloon-injured aortas in rabbits.

BACKGROUND: Activation of coagulation has been implicated in both acute thrombotic occlusion and restenosis after balloon angioplasty. However, concomitant administration of antithrombotic agents has thus far failed to prevent these complications. Importantly, the factors contributing to procoagulant activity of balloon-injured arteries over time have not been defined. This study was designed to determine the duration of procoagulant activity on the luminal surface of balloon-injured arteries and the relative roles of tissue factor and thrombin in this response. METHODS AND RESULTS: Abdominal aortas in rabbits were subjected to repetitive balloon hyperinflations sufficient to disrupt the internal elastic lamina. Aortas were excised at < 1, 2, 4, 8, 16, 24, 48, and 72 hours and 1, 2, and 4 weeks after injury; divided into segments; and perfused with recalcified human pooled plasma (n = 58) or plasma depleted of vitamin K-dependent coagulation factors (n = 27) or first incubated with a monoclonal antibody to rabbit tissue factor (n = 33) followed by perfusion with human plasma. Samples of the effluent and plasma perfusate were collected over 10 minutes and assayed for fibrinopeptide A (FPA) as an index of the rate of thrombin-induced fibrin formation. FPA in the effluent from segments perfused with recalcified plasma, expressed as a percentage of FPA in the perfusate, was elevated for 16 hours after balloon-induced injury and exhibited two distinct increases occurring < 1 hour (1297 +/- 473%, mean +/- SD, n = 5) and 8 hours (1052 +/- 330%, n = 6) after injury (P < or = .000001 versus uninjured vessels). Preincubation of segments at these intervals with an antibody to tissue factor markedly attenuated the increases in FPA, as did perfusion of segments with plasma depleted of vitamin K-dependent coagulation factors, indicating that the observed increases in FPA in whole plasma did not result from performed thrombin bound to the injured vessel wall. CONCLUSIONS: Tissue factor-mediated coagulation appears to be primarily responsible for prolonged procoagulant activity of balloon-injured arteries.

Angioplasty, Balloon↗
PubMed1995

Maintenance of coronary patency after fibrinolysis with tissue factor pathway inhibitor.

BACKGROUND: Pharmacological coronary fibrinolysis induces procoagulant effects that contribute to delayed recanalization and early reocclusion. This study was designed to determine whether brief inhibition of activation of the coagulation cascade with tissue factor pathway inhibitor, a physiological inhibitor of activated factor X and its activation by the tissue factor/factor VII complex, would facilitate fibrinolysis, sustain patency of recanalized arteries, or both. METHODS AND RESULTS: Platelet-rich coronary thrombi were induced with anodal current that elicited intimal injury in 21 conscious dogs. Each was randomized to human recombinant tissue-type plasminogen activator (rTPA 1.0 mg/kg IV over 1 hour) with infusion of 50 micrograms.kg-1.min-1 of human recombinant tissue factor pathway inhibitor (rTFPI, n = 7), 100 micrograms.kg-1.min-1 of rTFPI (n = 8), or 300 mmol/L arginine phosphate buffer as a control (n = 6) concomitant with and for 1 hour after infusion of the plasminogen activator. Recanalization, verified with proximal Doppler flow probes, occurred in all but 1 dog given the high dose of rTFPI. It was not accelerated by conjunctive rTFPI. Reocclusion occurred within 90 minutes after infusion of rTPA in all 6 control dogs. However, reocclusion was delayed and patency was sustained for the entire 24-hour observation interval in 2 of 6 dogs (excluding 1 that did not survive) given the low dose and in 4 of 6 dogs (excluding 1 that did not receive the desired amount) given the high dose of rTFPI (P < .05 compared with controls). Cyclic flow variations indicative of platelet aggregation and disaggregation locally were virtually eliminated by rTFPI (3 +/- 4[SD]/h in dogs given the low dose and 2 +/- 2/h in those given the high dose of rTFPI compared with 13 +/- 12/h in controls, P < .05). In addition, rTFPI increased activated partial thromboplastin time and prothrombin time only at the high dose (1.4 +/- 0.3 and 2.1 +/- 0.9 times baseline) and had no effects on platelet aggregation assayed ex vivo and only minimal effects on bleeding time assayed in vivo. CONCLUSIONS: Brief inhibition of the coagulation system by administration of rTFPI sustains patency of arteries recanalized by pharmacological fibrinolysis without markedly perturbing hemostatic mechanisms.

Animals↗
PubMed1995

Role of thrombin compared with factor Xa in the procoagulant activity of whole blood clots.

BACKGROUND: Thrombi are known to induce activation of the coagulation system, which may be a mechanism for progression of thrombosis and its recurrence after thrombolysis. This study was designed to characterize the relative role of thrombin and activated factor X (factor Xa) as mediators of procoagulant activity of whole blood clots in blood and plasma. METHODS AND RESULTS: Clots formed from human blood were incubated in recalcified (25 mmol/L CaCl2) citrated plasma or nonanticoagulated blood with increasing concentrations of recombinant desulfatohirudin (hirudin) to inhibit thrombin activity, recombinant tick anticoagulant peptide (TAP) or recombinant tissue factor pathway inhibitor (TFPI) to inhibit factor Xa, or heparin. Fibrinopeptide A (FPA) was assayed serially as an index of procoagulant (thrombin) activity. FPA generation was greatly accelerated by addition of clots to recalcified plasma (from 1251 +/- 211 ng/mL after 15 minutes without clot to 5916 +/- 1412 ng/mL with clot, n = 7, P < .01) or whole blood (4803 +/- 761 ng/mL with clot compared with 546 +/- 233 without clot, n = 5, P < .05) and was attenuated by inhibitors of thrombin (> 90% inhibition of FPA with 0.05 mumol/L hirudin and 1.0 U/mL heparin) and factor Xa (> 90% inhibition of FPA with 1.0 mumol/L TAP and 0.15 mumol/L TFPI) in a concentration-dependent manner. Preincubation of clots with tissue-type plasminogen activator sufficient to induce partial clot lysis increased the rate of thrombin-induced FPA generation by increasing the surface area of clot exposed to plasma. However, procoagulant activity induced by partially lysed clots was attenuated by lower concentrations of both thrombin and Xa inhibitors, presumably because access of the inhibitors to bound procoagulant molecules was facilitated. Comparable results were obtained with incubations in nonanticoagulated blood. CONCLUSIONS: These results indicate that factor Xa is primarily responsible for the procoagulant activity of clots in vitro and suggest a potential molecular mechanism for the observed efficacy of inhibitors of factor Xa in preventing recurrent thrombosis after coronary thrombolysis.

Arthropod Proteins↗
PubMed1995

Coronary artery mapping: a method for three-dimensional reconstruction of epicardial anatomy.

Evaluation of coronary anatomy with conventional coronary angiography requires visual integration of multiple images from different viewing orientations to generate a mental interpretation of three-dimensional (3D) structure. The epicardial surface is, in many ways, analogous to the earth's surface topography and may be effectively depicted using cartographic methods. To show coronary anatomy visualized as topographic maps, we used cartographic projection methods to analyze the coronary vessels of a canine heart after immediate postmortem injection with a radio-opaque gelatinous solution. A volumetric image data set was obtained with x-ray spiral computed tomography. The principal axis of the image volume was calculated and the image volume reformatted to a reference coordinate system defined by the principal axis as the ordinate. A cylindrical projection map of the epicardial surface was created using a maximum-intensity projection volume-rendering technique. After converting the Cartesian reference coordinate system to a polar coordinate system, additional mapping projections from user-defined orientations were generated. The results show that interpretative difficulties of coronary angiography may be diminished by generating 3D maps of coronary anatomy using volumetric datasets acquired noninvasively and displayed with cartographic methods.

Algorithms↗
PubMed1995

Potentiation of endogenous nitric oxide with superoxide dismutase inhibits platelet-mediated thrombosis in injured and stenotic arteries.

OBJECTIVES: We tested the hypothesis that dismutation of superoxide anion increases endogenous levels of nitric oxide, resulting in inhibition of cyclic variations in blood flow in arteries that are injured and stenotic. BACKGROUND: Platelet adhesion and aggregation leading to cyclic flow variations might result, in part, from generation of superoxide anion that can deplete endogenously produced nitric oxide. METHODS: Spontaneous cyclic flow variations, monitored with a proximal Doppler probe, were induced in the carotid artery of anesthetized rabbits by clamping the vessel with forceps and placing a high grade stenosis at the site of injury. Bovine copper/zinc superoxide dismutase (12 mg/kg body weight, n = 5), a synthetic low molecular weight mimetic (12 mg/kg, n = 8) or buffer vehicle (n = 8) was administered intravenously as divided boluses over 45 min, and the frequency of cyclic flow variations was monitored for 4 h. RESULTS: Cyclic flow variations remained stable for 4 h in vehicle-treated animals (15 +/- 1 [mean +/- SEM]/30 min at baseline and 16 +/- 1/30 min after 4 h, n = 8) but exhibited a marked and persistent reduction in animals given copper/zinc superoxide dismutase (from 14 +/- 1/30 min at baseline to 4 +/- 1/30 min after 4 h) or the mimetic (from 15 +/- 1/30 min at baseline to 3 +/- 1/30 min after 4 h, p < 0.005). They were restored in three of four mimetic-treated animals during infusion of NG-monomethyl- L-arginine (100 mg/kg), an inhibitor of nitric oxide production. In addition, levels of cyclic guanosine 5'-monophosphate in platelets were elevated after administration of the mimetic (from 2.4 +/- 0.5 fmol/10(6) platelets at baseline to 4.9 +/- 0.6 fmol/10(6) platelets 45 min after the mimetic, p < 0.03, n = 6), whereas mean arterial blood pressure was decreased and flow velocity in the carotid artery was increased consistent with mediation of the effect on cyclic flow variations by increased endogenous nitric oxide. CONCLUSIONS: Dismutation of superoxide anion appears to attenuate platelet thrombus formation at a site of vessel injury by potentiation of endogenously produced nitric oxide. This approach may have utility to inhibit platelet-rich thrombosis in injured and stenotic arteries where production of superoxide anion is increased.

Animals↗
PubMed1995

The biologic behavior of balloon hyperinflation-induced arterial lesions in hypercholesterolemic pigs depends on the presence of foam cells.

Lack of a large-animal model of accelerated atherosclerosis has limited study of the biologic behavior of atherosclerotic lesions. We hypothesized that mechanical vascular trauma combined with diet-induced hypercholesterolemia would result in rapid development of complex atherosclerosis-like lesions. Accordingly, we induced deep injury to a carotid artery by repetitive balloon hyperinflations in minipigs that were fed either an atherogenic diet (n = 30) or a standard diet (controls, n = 4) and examined the resultant lesions 1 month later. The neointimal lesions that evolved in 23 patent vessels from cholesterol-fed animals were complex, exhibiting infiltration of smooth muscle and foam cells and evidence of organized thrombus, recent thrombus, hemorrhage, and calcification. Lesions were separable histologically into two groups: foam-cell rich (n = 12), with 33 +/- 10 foam cells per high-power field, and foam-cell poor (n = 11), with 4 +/- 1 foam cells per high-power field. Minipigs with foam cell-rich lesions had higher serum cholesterol levels than those with foam cell-poor lesions (712 +/- 178 vs 468 +/- 240 mg/dL, P < .02). The incidence of intralesional thrombus was also significantly greater in foam cell-rich than in foam cell-poor lesions (50% vs 9%, P < .04). In addition, the degree of luminal stenosis was greater in the presence of lesions containing thrombus compared with those without thrombus (60 +/- 38% vs 30 +/- 29%, P = .05). Lesions in the control animals were fibrocellular and lacked foam cells and thrombus. Thus, hypercholesterolemia appeared to affect lesion composition and behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Failure of fixed dose intravenous heparin to suppress increases in thrombin activity after coronary thrombolysis with streptokinase.

OBJECTIVES: This study was designed to define the extent of inhibition of thrombin activity achieved with conjunctive fixed dose intravenous sodium heparin compared with fixed dose subcutaneous calcium heparin in patients receiving intravenous streptokinase for acute myocardial infarction. BACKGROUND: The role of heparin therapy during coronary thrombolysis with streptokinase is controversial, in part because the efficacy of different conjunctive heparin regimens in inhibiting early increases of thrombin activity is not known. METHODS: Twenty-eight patients treated with 1.5 million U of streptokinase and 165 mg of aspirin for acute myocardial infarction were randomly assigned to receive fixed dose subcutaneous heparin therapy (12,500 U every 12 h delayed until 4 h after the end of streptokinase therapy [n = 14]) or fixed dose intravenous heparin (5,000-U bolus followed by 1,000-U/h infusion [n = 14]). Anticoagulation was assessed with serial measurements of activated partial thromboplastin time, and thrombin activity by measuring fibrinopeptide A and thrombin-antithrombin III complex levels. Plasma concentrations of creatine kinase (CK) MM isoforms were measured for 3 h to determine recanalization (increase in activity > 0.18%/min). RESULTS: Recanalization occurred in 27%, 64% and 79% of patients given subcutaneous heparin versus 43%, 76% and 86% of those given intravenous heparin at 1, 2 and 3 h, respectively (p = 0.6). Concentrations of fibrinopeptide A (mean +/- SEM) at 1 h were higher in patients without (n = 5) than in those with (n = 23) CK-MM isoform criteria for recanalization (76.4 +/- 25.7 vs. 25.2 +/- 5.2 nmol/liter, p = 0.02), and at 1, 2 and 3 h were significantly lower with fixed dose intravenous heparin (18.4 +/- 4.8 vs. 46.7 +/- 10.2 nmol/liter at 1 h, p = 0.004) than without heparin. After fixed dose subcutaneous heparin at 4 h, fibrinopeptide A levels were similar in both groups despite lower activated partial thromboplastin times in patients who received fixed dose subcutaneous heparin. However, fibrinopeptide A was not consistently suppressed in either group (fixed dose subcutaneous heparin 8.7 +/- 1.8 nmol/liter vs. fixed dose intravenous heparin 11.8 +/- 5.2 nmol/liter) at 48 h (p = 0.4). No significant changes in the concentration of thrombin-antithrombin III complexes were found between the two groups. CONCLUSIONS: Fixed dose intravenous heparin attenuates increases in fibrinopeptide A early after streptokinase. Subsequent fixed dose intravenous and subcutaneous heparin have similar effects but are relatively ineffective in suppressing thrombin activity, suggesting a role for more potent antithrombin agents during coronary thrombolysis with streptokinase.

Aged↗
PubMed1994

Conjoint use of MM and MB creatine kinase isoforms in detection of coronary recanalization.

To determine whether differences in the kinetics of isoforms of MM and MB creatine kinase affect their ability to detect coronary patency in patients treated with thrombolytic agents, we compared MM and MB isoform profiles in 33 consecutive patients. Results were discordant in 13 of the 33 at 1 hour. When the rates of increase of both isoforms were considered, discordance was present in only 10 of the 33 patients. In five patients %MM3 rose rapidly during the second hour and infarct-related vessels were patent. Four of the five without a rapid increase had occluded infarct-related vessels. These data suggest that criteria based on rates of change in %MB2 are more sensitive than those based on %MM3. However, criteria based on %MM3 are more likely to identify patients in need of interventions to maintain coronary patency.

Aged↗
PubMed1993

Maintenance of patency after thrombolysis in stenotic coronary arteries requires combined inhibition of thrombin and platelets.

OBJECTIVES: This study was designed to determine whether maintenance of patency in coronary arteries with high grade stenosis after thrombolysis with tissue-type plasminogen activator requires inhibition of thrombin or platelets, or both. BACKGROUND: Activation of both thrombin and platelets has been implicated in delaying coronary recanalization induced with fibrinolytic drugs and in predisposing to reocclusion. METHODS: Hirudin (1.5 mg/kg body weight) or aspirin (5 mg/kg), or both, was given conjunctively with tissue-type plasminogen activator in 28 conscious dogs with coronary thrombosis induced by electrical stimulation of the vessel wall in the presence of a previously placed high grade distal stenosis (85 +/- 12% [SEM] area reduction). RESULTS: Among 22 dogs exhibiting coronary recanalization, hirudin plus aspirin, but neither agent alone, modestly shortened the interval to recanalization (31 +/- 4 min with saline solution, n = 6; 29 +/- 4 min with aspirin, n = 5; 23 +/- 9 min with hirudin, n = 6; 21 +/- 7 min with hirudin+aspirin, n = 5). Reocclusion occurred promptly and persisted in five of six dogs given only saline solution plus tissue-type plasminogen activator, in four of six dogs given hirudin and five of five dogs given aspirin; however, reocclusion was prevented in all five of the dogs given both hirudin and aspirin with tissue-type plasminogen activator (p < 0.05 compared with saline-treated dogs). In dogs given both hirudin and aspirin, the partial thromboplastin time was 2.4 +/- 0.3 times baseline, and the template bleeding time was prolonged only modestly (1.6 +/- 0.3 times baseline). CONCLUSIONS: Thus, the combination of hirudin and aspirin in doses that do not markedly perturb hemostasis prevents early reocclusion after thrombolysis despite the presence of severe stenosis. Accordingly, conjunctive administration of both anti-thrombin and antiplatelet agents appears to be necessary for optimal maintenance of patency after thrombolysis induced in the presence of high grade coronary stenosis.

Animals↗