Effects Of Intravenous Thrombolysis With Recombinant Staphylokinase On Platelet Activation Parameters In Acute Myocardial Infarction

Acute myocardial infarction (AMI) is an emergency of cardio-vascular disease.Intracoronary thrombus formation is the most important pathogenetic mechanismin AMI. The most common cause of MI is rupture of an atherosclerotic plaque andthe formation of thrombus over the plaque resulting in rapid occlusion of the vessel.Occlusion thrombosis results in loss of blood flow to vital organs producing localoxygen deprivation, cell necrsis and loss of organ function. The most importanttherapeutic goal in the management of AMI is early restoration of complete infarctartery perfusion after the occlusion, which has been initiated with induced bythrombolytic therapy results in smaller infarct size, improving left ventricularfunction and reducing mortality. Thrombolysis has become routine therapy for AMIafter GISSI Trial. AMI has been dramatically changed by the advent ofthrombolytic treatment, with a 30% mortality reduction. This treatmentnotwithstanding, failure or delay in achieving reperfusion, less the tissue ofmyocardial reperfusion, along with reocclusion and severe hemorrhagiccomplication are the main unsolved problem of coronary thrombolysis. So arecombinant staphylokinase (r-SAK) is selected which had fibrinolysis functionand explored its thrombolytic efficacy and platelet activation of therapeuticconcentration.Objection: To observe the effects in the vivo platelet activation parameters patientswith acute myocardial infarction of using r-SAK by intravenous thrombolysis,serial changes of the plasma concentration of thrombin-antithrombin complex(TAT), alpha granule membrane protein (GMP-140) and some other indexesconcentrations were measured before and at 2h after the administration of r-SAKand recombinant tissue-type plasminogen activators (rt-PA). So as to investigate theclinical thrombolytic efficacy of r-SAK therapy in AMI, comparing with rt-PAtherapy.Methods: According to the criteria of AMI within 12h after the onset of symptoms diagnosisby WHO in 1979, 33 in-patients with AMI is selected (male 21 and 12 female, ageranged from 43-75, with mean age of 62.45±11.36 years), 33 patients weredivided into two groups randomly, the r-SAK therapy group (group A, 17cases) andthe rt-PA therapy group(group B, 16 cases). There were no differences between twogroups in general clinical conditions (Table2-5). Twenty healthy blood donors wereserved as controls (group C, 20cases). In group A we used r-SAK which wasobtained from Beijing Kendle Wits Medical Consulting Company, and In group Bwe used rt-PA, which was obtained from Boehringer Ingelheim, Ingelheim amRhein, Germany. Subsequently, all patients received aspirin 300mg and anintravenous bolus of heparin (5.000IU). Thrombolytic therapy was startedimmediately after the administration of the heparin bolus. The patients wererandomized to receive r-SAK, 2mg bolus over 2min followed by an additional 8mginfused over the first 30 min; rt-PA, 8mg bolus over 6min followed by an additional42mg infused over 90 min, immediately followed by a continuous intravenousinfusion of heparin (1.000 IU/h) which was then adjusted to maintain the activatedpartial thromboplastin time at >1.5 times baseline value. Coronary arteryangiography (CAG) was performed at 90 minutes after thrombolytic therapy inpatients. A baseline blood sample was obtained from enrolled patients before anytreatment was started. Group's C blood samples came from the healthy blooddonors in blood bank of the Second Hospital, Jilin University. Additional bloodsamples were obtained at 2-h after the start of thrombolytic therapy. After the first3ml of blood was discarded, the 4ml venous samples were collected directly intocontaining an anticoagulant mixture composed of a thrombin inhibitor,ethylenediamineteraacetic acid (EDTA). The ratio of anticoagulant to blood was1:9 (vol/vol). All samples were immediately centrifuged at 4℃for 10 min at 3000r.The supernatant plasma was collected and frozen at -70℃until use. TAT andGMP-140 were measured by similar commercial enzyme-linked immunosorbentassay (ELISA). Reagent boxes of TAT and GMP-140's were supplied with biologyproject research institute in Shanghai. Numerical variables data expressed as mean±SD. The variance and the Student t test were used to evaluate the difference incontinuous variables. The chi-square test was used to evaluate the difference incategorical variables. A p value<0.05 was considered statistically significant.Results: 1. In groups A and B, the baseline plasma levels of TAT and GMP-140 5were significantly higher than group C (p<0.05). 2. In groups A and B, incomparison with baseline, at 2h after the start of thrombolytic therapy there was asignificant increase in the plasma concentration levels of GMP-140 (p<0.05). Ingroup B, the 2-h plasma levels of GMP-140 was significantly higher than baselinevalues (p<0.05). There was statistically significant in the 2-h plasma levels ofGMP-140 between groups A and B (p<0.05). 3. In groups A and B, in comparisonwith baseline, at 2-h t after the start of thrombolytic therapy here was an increase inthe plasma concentration levels of TAT. In group A, TAT plasma levels at 2-hdeterminations were no statistically significant in comparison with baseline(p>0.05). In group B, TAT plasma levels at 2-h determinations were statisticallysignificant in comparison with baseline (p<0.05). There were statisticallysignificant in the 2-h plasma levels of TAT between groups A and B (p<0.05). 4.There was no statistically significant of the reperfusion ratio at 2h after the start ofthrombolytic therapy between groups A and B (p>0.05). 5. There were statisticallysignificant in the complications incidence between the two treatment groups at 1week after the start of thrombolytic therapy (p<0.05). Bleeding complicationsincidence in the group A were less than those in the group B.Discussion: The study showed that the plasma concentration levels of TAT andGMP-140 increased in patients with AMI before the start of thrombolytic therapy.This reacted that in the vivo patients with AMI platelet activation and the activationof the hemostatic system increased, which was the same as reports of overseas andinterior[3]. The study showed that platelet activation and thrombin generation andactivity play a central role in the pathogenesis of coronary artery thrombosis andrethrombosis. There were no significant differences in the baseline plasmaconcentration levels of TAT between the two treatment groups. In groups A and B,in comparison with baseline, at 2-h after the start of thrombolytic therapy there wasan increase in the plasma concentration levels of TAT. In a pilot study, we alsoobserved a marked increase in both thrombin generation and activity in patientsreceiving thrombolytic therapy with rt-PA or streptokinase in the absence ofconcomitant anticoagulation with heparin. It is possible to speculate that at highrates of in vivo thrombin generation, as observed in patients with AMI, asignificant amount of factor Ⅹa is bound to activated platelet, thus allowing thisserine protease to resist the action of heparin. In addition, the direct activation ofplatelet and factor Ⅴa during thrombolysis, as well as the reexposure of theruptured plaque to blood flow, might lead to the generation of more factor Ⅹa and,consequently, to thrombin generation. The increase in prothrombin fragment 1+2and thrombin-antithrombin complex plasma levels in the first hours after theinitiation of thrombolysis despite heparin treatment further supports this hypothesis[63]. In group A, TAT plasma levels at 2-h determinations were no statisticallysignificant in comparison with baseline. Okada k et al. has showed that there wereless procoagulant properties during thrombolysis with r-SAK and it holds highlyfibrin-selective thrombolytic therapy [64]. The promotion of prothrombotis state wasdecreased. This experiment showed that between groups A and B in comparisonwith baseline, at 2h after the start of thrombolytic therapy there was a significantincrease in the plasma concentration levels of GMP-140. Platelets play a pivotalrole in these events through different mechanisms, and among these mechanismsare platelet interactions with physiologic fibrinolysis and pharmacologicthrombolysis. Patelet actively contribut to fibrinolysis because that they havespecific binding sites for plasminogen. Thrombolytic agents may modify plateletreactivity. Actually, platelet activation rate of platelet-bound plasminogen byplasmin is about one order of magnitude greater than that of free plasminogen. Onthe other hand, thrombolytic agents may modify platelet reactivity. Platelet may beactivated at the site of thrombolysis by plasmin or by the continued formation ofthrombin. Low plasmin concentrations may inhibit platelet activation whatever themechanism of platelet activation during coronary thrombolysis, the reduction inPGI2 biosynthesis in patients who reperfusion may further amplify plateletactivation in the setting. The loss of PGI2 formation may allow platelet activation tooccur in the reperfused the injured vascular bed and endothelial[65]. In group B, the2-h plasma levels of GMP-140 was significantly higher than baseline values.Fibrinolysis agents induced the effect of platelet activation mainly becausefibrinolysis agents appear to induce an activation of the platelet fibrinogen receptor,which is essential for platelet-platelet and platelet-subendothelium interactions,...