Safety and efficacy of tissue-type plasminogen activator produced by recombinant DNA technology

Because of its enhanced activation of plasminogen in association with fibrin compared with free plasminogen, tissue-type plasminogen activator (t-PA) evoked excitement as a potentially useful pharmacologic activator of the fibrinolytic system. Initial studies in experimental animals and patients demonstrated that it induced coronary thrombolysis rapidly and without concomitant, marked fibrinogenolysis in contrast to streptokinase. Large scale clinical trials soon followed. Their results indicate that intravenous administration of t-PA produced by recombinant DNA technology (rt-PA) elicits coronary thrombolysis in two-thirds or more of treated patients with angiographically documented thrombotic occlusions generally without perturbing hemostatic mechanisms or inducing marked fibrinogenolysis. Bleeding is usually confined to vascular access sites and episodes of major bleeding are rare. Overall 6 week survival for treated patients with documented acute myocardial infarction may be as high as 95%

Ingenuous interpretation of elevated blood levels of macromolecular markers of myocardial injury: a recipe for confusion

AbstractSeveral assumptions about elevations of macromolecular markers of myocardial injury in blood require critical consideration. The dichotomy of modest, persistent elevations of troponins I and T as prognostic factors in patients with unstable angina and absent elevations of isoenzymes of creatine kinase is presently unexplained. Factors influencing the appearance of macromolecular markers of myocardial injury in blood are considered, including the need to estimate baseline values, to consider elevations as deviations from baseline rather than simply points within a distribution of baseline values in normal subjects, to recognize operative biochemical and physiologic determinants of marker release from injured myocytes and washout and to take into account the influence of apoptosis. Elucidation and consideration of mechanisms underlying the appearance of specific macromolecular markers in blood appear likely to improve diagnosis and explain the prognostic power of the troponins in patients with unstable angina. Detection of proteolytic breakdown products of troponins in blood is likely to explain the modest, persistent elevations seen in some patients with unstable angina and their prognostic implications

Activation of prothrombin accompanying thrombolysis with recombinant tissue-type plasminogen activator

AbstractIncreases in thrombin activity in patients given fibrinolytic agents for acute myocardial infarction have been shown to be important in limiting the ultimate success of coronary thrombolysis. The present study was designed to determine whether increases in thrombin activity reflect, in part, activation of prothrombin accompanying thrombolysis. Plasma concentrations of prothrombin fragment 1.2, a polypeptide released when prothrombin is activated by factor Xa, were measured in 22 patients with acute myocardial infarction before and after treatment with 100 mg of recombinant tissue-type plasminogen activator (rt-PA). Concentrations of prothrombin fragment 1.2 increased from 0.83 ± 1.1 nM(mean ± SD) before rt-PA infusion to 1.5 ± 1.5 nM2 h after initiation of the infusion (p < 0.05). After a 5,000-U intravenous dose of heparin given at the end of the infusion of rt-PA, concentrations of prothrombin fragment 1.2 decreased from 1.8 ± 1.5 to 1.1 ± 0.9 nM(n = 20, p < 0.05), although values were still increased compared with concentrations before rt-PA.These results indicate that thrombin activity increases in patients given rt-PA at least in part because of activation of the coagulation system leading to activation of prothrombin. Thus, inhibition of the reactions involving coagulant proteins that lead to activation of prothrombin may be of value as conjunctive treatment to potentiate the efficacy of pharmacologic thrombolysis

“Plasminogen steal” and clot lysis

AbstractAlthough initially developed to reduce the risk of bleeding, second-generation (clot-selective) thrombolytic agents have been found to induce more prompt and frequent recanalizatton than do nonselective, first-generation agents. To determine whether they do so in part by preserving clot-associated plasminogen, human whole blood clots formed in Chandler tubes were studied. Addition of suprapharmacologic concentrations of recombinant tissue-type plasminogen activator (rt-PA) to the media bathing mature clots led to a paradoxic impairment of clot lysis and a concomitant concentration-dependent depletion of clot-associated plasminogen (Western blot analysis). In contrast, supplementation of the plasma with plasminogen (0.27 mg/ml) led to significant conservation of both plasma and clot-associated plasminogen (p ≤ 0.05, n = 4), and prevented the diminution of clot lysis (p ≤ 0.05; n = 4).Fibrinogen degradation products did not account for the attenuation of lysis with the highest concentrations of rt-PA. In concentrations equivalent to those that were induced by the highest concentrations of rt-PA evaluated, fibrinogen degradation products potentiated rather than inhibited lysis (p ≤ 0.05, n = 4), probably by stimulating rt-PA activity directly. When preformed clots were incubated with plasminogen-depleted plasma plus 1,000 ng/ml rt-PA, the plasminogen content in residual clot declined (9.36 ± 0.46 versus 12.39 ± 0.69 ng/mg clot found in nondepleted plasma; p ≤ 0.05; n = 6). Furthermore, clot lysis was attenuated completely.Thus, clot lysis induced by activation of plasminogen is dependent on clot-associated plasminogen, which in turn depends on the concentration of plasminogen in plasma. Depletion of both is likely to contribute to the lower frequency and rapidity of coronary recanalization induced with nonclot-selective compared with selective fibrinolytic agents because of the depletion of plasma plasminogen and the plasminogen steal they characteristically induce

Reduction of Experimental Myocardial Infarct Size by Corticosteroid Administration

The influence of the administration of pharmacologic doses of hydrocortisone on the extent and severity of acute myocardial ischemic injury and on subsequent necrosis after acute coronary occlusion was investigated in 28 dogs. In order to study acute myocardial injury, repeated epicardial electrocardiograms were recorded from 10 to 15 sites on the anterior surface of the left ventricle. Average ST segment elevation (ST) and the number of sites in which ST segment elevation exceeded 2 mV (NST), indices of the magnitude and extent of myocardial injury, respectively, were analyzed at 30 and 60 min after coronary occlusion. In the control group ST and NST did not change significantly in this time interval while in the treated group, which received 50 mg/kg hydrocortisone just after the 30 min recording, ST fell from 3.5+/-0.8 to 1.1+/-0.4 mV (P 2 mV) in the control group showed histologic changes compatible with early myocardial infarction in 96% of specimens, while this occurred only in 61% and 63% of specimens, respectively, in the treated groups, showing that over one third of the sites were protected from undergoing necrosis due to the intervening hydrocortisone treatment. Thus pharmacological doses of hydrocortisone prevent myocardial cells from progressing to ischemic necrosis even when administration is initiated 6 h after coronary occlusion

Increased platelet expression of FcGammaRIIa and its potential impact on platelet reactivity in patients with end stage renal disease

<p>Abstract</p> <p>Background</p> <p>Increased platelet reactivity has been implicated in cardiovascular disease – the major cause of death in patients with end stage renal disease (ESRD). FcGammaRIIA is a component of glycoprotein VI and Ib-IX-V that mediate activation of platelets by collagen and von Willebrand factor. To determine whether expression of FcGammaRIIA impacts platelet reactivity we quantified its expression and platelet reactivity in 33 patients with ESRD who were undergoing hemodialysis.</p> <p>Methods</p> <p>Blood samples were obtained from patients immediately before hemodialysis and before administration of heparin. Platelet expression of FcGammaRIIA and the activation of platelets in response to low concentrations of convulxin (1 ng/ml, selected to mimic effects of collagen), thrombin (1 nM), adenosine diphosphate (ADP, 0.2 uM), or platelet activating factor (PAF, 1 nM) were determined with the use of flow cytometry in samples of whole blood anticoagulated with corn trypsin inhibitor (a specific inhibitor of Factor XIIa).</p> <p>Results</p> <p>Patients were stratified with respect to the median expression of FcGammaRIIA. Patients with high platelet expression of FcGammaRIIA exhibited 3-fold greater platelet reactivity compared with that in those with low expression in response to convulxin (p < 0.01) and 2-fold greater activation in response to thrombin, ADP, and PAF (p < 0.05 for each). For each agonist, expression of FcGammaRIIA correlated modestly but positively with platelet reactivity. The strongest correlation was with thrombin-induced activation (r = 0.6, p < 0.001).</p> <p>Conclusion</p> <p>Increased platelet reactivity in response to low concentrations of diverse agonists is associated with high expression of FcGammaRIIA and may contribute to an increased risk of thrombosis in patients with ESRD.</p

Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis

Factors responsible for initial success or failure of coronary thrombolysis and persistent recanalization or early reocclusion have not been thoroughly elucidated. Both adequate initial clot lysis and preclusion of rethrombosis are required. Failure may reflect clot lysis followed immediately or somewhat later by rethrombosis. To determine whether differences in the intensity and persistence of the activation of thrombin are determinants of success or failure of recanalization, plasma fibrinopeptide A, a fibrinogen product liberated by thrombin, was serially assayed in 19 patients treated with intravenous streptokinase. In patients exhibiting recanalization (n = 9), plasma fibrinopeptide A decreased after administration of streptokinase but before administration of heparin. In patients without initially apparent recanalization, fibrinopeptide A increased, suggesting ongoing thrombosis, and subsequently decreased promptly after heparin. In patients with initial recanalization followed by overt reocclusion the pattern was different. Despite recanalization, fibrinopeptide A continued to rise markedly. Elevations persisted despite administration of heparin. Thus, inhibition of activation of thrombin is associated with successful recanalization. Conversely, persistent activation of thrombin may be a predisposing factor to both apparent initial failure of recanalization and nvprt early reocclusion

Effect of combination glipizide GITS/metformin on fibrinolytic and metabolic parameters in poorly controlled type 2 diabetic subjects

WSTĘP. Wyniki badań epidemiologicznych wskazują, że podwyższone stężenie inhibitora aktywatora plazminogenu 1 (PAI-1) w surowicy krwi może być wskaźnikiem lub predyktorem przyspieszonego rozwoju choroby wieńcowej u chorych na cukrzycę typu 2. Celem pracy było określenie, czy poprawa wyrównania metabolicznego, niezależnie od rodzaju stosowanych leków doustnych, wpływa na stężenie PAI-1 u chorych ze znaczną hiperglikemią. MATERIAŁ I METODY. Do badania zakwalifikowano 91 chorych. Po okresie 4 tygodni, w którym pacjenci nie przyjmowali żadnych leków, chorych losowo przydzielono do grupy leczonej glipizydem GITS (w dawce maksymalnej 20 mg, n = 46) lub grupy otrzymującej metforminę (maksymalnie 2550 mg, n = 45) w monoterapii. Po okresie monoterapii wprowadzono leczenie skojarzone, dodając drugi lek do preparatu już stosowanego. U wszystkich pacjentów przed i po randomizacji oraz podczas badania oznaczono glikemię (na czczo i po posiłku), stężenie HbA1c, fruktozaminy oraz PAI-1. U części chorych zmierzono również wątrobową produkcję glukozy (HGO, hepatic glucose output) oraz oznaczono rozkład brzusznej tkanki tłuszczowej. WYNIKI. Wyrównanie glikemii na początku badania było niezadowalające (średnie stężenie HbA1c 10,4 &plusmn; 0,2% w grupie glipizydu GITS; 10,0 &plusmn; 0,2% w grupie metforminy), ale poprawiło się istotnie w obu grupach, stosujących monoterapię oraz w wyniku leczenia skojarzonego (p < 0,0001 vs. wyniki wyjściowe), co oceniono na podstawie badania tolerancji posiłku, stężenia fruktozaminy oraz HGO. Masa ciała oraz rozkład brzusznej tkanki tłuszczowej nie zmieniły się istotnie w żadnej z grup. Stężenie PAI-1 było wyjątkowo wysokie (5-10-krotnie wyższe od wartości prawidłowych) na początku badania (202 &plusmn; 12 ng/ml w grupie glipizydu GITS; 201 &plusmn; 13 ng/ml w grupie metforminy), ale istotnie obniżyło się podczas badania, w sposób porównywalny w monoterapii w obu grupach. Podczas leczenia skojarzonego stężenie to uległo dalszemu obniżeniu. WNIOSKI. W przypadkach nasilonej hiperglikemii stężenie PAI-1 jest również znacznie podwyższone. Obniżenie hiperglikemii za pomocą leku nasilającego wydzielanie insuliny, glipizydu GITS lub metforminy, stosowanych w monoterapii, w porównywalny sposób powoduje obniżenie stężenia PAI-1.INTRODUCTION. Epidemiological studies have implicated increased plasminogen-activated inhibitor 1 (PAI-1) as a marker or predictor of accelerated coronary atherosclerotic disease in type 2 diabetes. We sought to determine whether metabolic control, independent of its oral mode of implementation, affects PAI-1 in patients with marked hyperglycemia. MATERIAL AND METHODS. A total of 91 subjects were screened, subjected to a 4-week drug washout, and randomized to daily treatment with glipizide GITS (maximum 20 mg, n = 46) or metformin (maximum 2,550 mg, n = 45) as monotherapy. After monotherapy, combination therapy was initiated by adding the second agent to the regimen. Plasma glucose (fasting and postprandial), HbA1c, fructosamine, and PAI-1 were assayed before and after randomization and sequentially thereafter in all subjects; hepatic glucose output (HGO) and abdominal fat distribution were each measured in a subset of subjects. RESULTS. Glycemic control was markedly impaired at baseline (mean HbA1c 10.4 &#177; 0.2% glipizide GITS; 10.0 &#177; 0.2% metformin) but improved comparably with each agent as monotherapy and in combination (P < 0.0001 vs. baseline), as assessed with meal tolerance studies, fructosamine values, and HGO. Body weight and abdominal fat distribution did not change significantly in either group. PAI-1 concentrations were extraordinarily high (5- to 10-fold more than normal) at baseline (202 &#177; 12 ng/ml glipizide GITS; 201 &#177; 13 ng/ml metformin) but declined comparably, and significantly, after treatment with either agent as monotherapy and decreased further with combination therapy. CONCLUSIONS. When hyperglycemia is profound, increases in PAI-1 are also profound. Control of hyperglycemia with either glipizide GITS, an insulin secretagogue, or metformin as monotherapy comparably ameliorates elevated PAI-1