Effects Of Different Routes Of Low Molecular Weight Heparin On Platelet Activation And Aspirin Intervention

Objective: Low molecular weight heparin (LMWH) is the smaller molecular weight fragment derived from unfractionated heparin (UFH) by laminar analysis,chemical modification or degradation of the enzyme system. The use of LMWH is preferred to UFH as it provides many advantages, including a longer plasma half-life and higher bioavailability, as well as a lower incidence of bleeding complications. LMWH is widely employed in therapeutic antithrombotic regimens for acute myocardial infarction, unstable angina, cerebral infarction and other diseases. Plaque rupture may lead to vessel thrombosis, which causes many acute clinical events of thromboembolic diseases. Activation of coagulation system also penetrates into the whole process of acute events. Accordingly, antiplatelet and anticoagulant therapy plays a pivotal role in the management of thromboembolic diseases, such as coronary heart disease and so on. Anticoagulation therapy mainly includes application of UFH and LMWH. Previous studies suggest that both intravenous administration of UFH and LMWH can increase platelet activation. Compared with UFH, intravenous injection of LMWH has less effect on platelet activation. In the present clinical treatment, subcutaneous injection of LMWH, but not intravenous injection, is the more frequently used administration route. But the effect of subcutaneous application of LMWH on platelet activation and whether the two administration routes have any difference in treating the activation had been seldom reported in literature before, which would be investigated in this study.Aspirin is the most commonly used therapeutic agent in prevention of platelet activation. Aspirin reduces platelet activation through the irreversible acetylation of COX-1 and, thus, reduces the production of TXA2 by inhibiting arachidonic acid. The frequently used dosage form is enteric-coated aspirin and the recommended dose is 100 mg/d for patients with coronary heart disease. Platelet activation induced by LMWH has an adverse impact on the organism obviously. The article also focused on the roles of conventional dose of aspirin (100 mg/d) treating the activation caused by LMWH.Dalteparin Sodium injection (Fragmin) is a common clinical LMWH product, and it is approved for use in coronary heart disease, cerebral infarction and peripheral vascular disease. Plateletα-granule membrane glycoprotein-140 (GMP-140, p-section,CD62P),von willebrand factor antigen (vWF:Ag) and platelet membrane glycoproteinⅡb/Ⅲa (GPⅡb/Ⅲa) receptor complexes are valid indicators for platelet activation. The purpose of the present study was to investigate the effects of different routes of LMWH on platelet activation by testing GMP-140,vWF:Ag and GPⅡb/Ⅲa after intravenous or subcutaneous injection of LMWH and the roles of conventional dose of enteric-coated aspirin treating the activation.Methods: 107 patients were enrolled between December 2006 and October 2007, including 80 patients with coronary heart disease (9 patients with stable angina and 71 patients with unstable angina), 18 patients with paroxysmal supraventricular tachycardia (PSVT) and 9 patients with primary hypertension. There were 67 males and 40 females. The ages ranged from 22 to 80 years, with a mean age of 53.31±13.18 years. All patients were divided into intravenous Dalteparin Sodium group (group A), subcutaneous Dalteparin Sodium group (group B) intravenous Dalteparin Sodium with aspirin group (group C) and subcutaneous Dalteparin Sodium with aspirin group (group D). Patients with coronary heart disease were randomly divided into group A, group C and group D. Patients with PSVT and primary hypertension were assigned to group B. Patients in the four groups were all the new admitted patients, and all of them had never received any antiplatelet and anticoagulant treatment one month before hospitalization. The first blood samples were collected before administration in all groups. The second blood samples were collected half an hour after intravenous administration of Dalteparin Sodium 5000 IU in group A. Blood samples were collected after subcutaneous injection when reaching first dose peak amplitude and steady state concentration (three hours after the first and fifth subcutaneous administration of Dalteparin Sodium 5000 IU) in group B. Patients in group C were given intravenous injection of Dalteparin Sodium 2.5 hours after 100 mg aspirin intake, and blood samples were collected half an hour later. Patients in group D took enteric-coated aspirin orally (100 mg/d) while given subcutaneous injection of Dalteparin Sodium ( Dalteparin Sodium was administered subcutaneously twice daily ), and blood samples were collected three hours after the first and fifth injection, so as to measure the plasma GMP-140,vWF:Ag and the expression of GPⅡb /Ⅲa respectively.Statistical analysis: Continuous variables were expressed as the mean value±standard deviation (SD). Student's t-test was performed to determine the differences between the two groups. The comparison of determination values before and after administration was evaluated by repeated measure variance analysis. Categorical variables were summarized as percentages and compared using chi-square test. All the statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS13.0). Statistical significance was defined as P<0.05.Results: The baseline characteristics such as gender composition, height, weight, smoking and drinking history were comparable (P>0.05).1 Effects on platelet activation by administration of LMWH through different routes The plasma level of GMP-140 and the expression of GPⅡb/Ⅲa after intravenous injection when reaching peak time were both significantly higher than the levels before treatment in group A (P<0.05). These data showed that intravenous administration of LMWH could increase platelet activation.The plasma levels of GMP-140 and vWF:Ag, the expression of GPⅡb /Ⅲa after subcutaneous administration of Dalteparin Sodium when reaching first dose peak amplitude and steady-state concentration were higher than the levels before injection in group B. There were statistical differences in the expression of GPⅡb/Ⅲa especially when Dalteparin Sodium injection reaching steady-state concentration (P<0.05). Therefore, subcutaneous administration of LMWH could also increase platelet activation after the first injection, which was much higher when reaching steady-state concentration.Both intravenous and subcutaneous injection of Dalteparin Sodium made the expression of GPⅡb/Ⅲa significantly higher than the levels before injection. There were no statistical differences in the expression of GPⅡb/Ⅲa between group B when reaching steady-state concentration and group A after intravenous injection (P>0.05).2 Effects on platelet activation by enteric-coated aspirin (100 mg/d) intake in the two groupsThe plasma levels of GMP-140 and vWF:Ag after Dalteparin Sodium injection and aspirin intake were lower than the levels before LMWH injection in group C. Moreover, there were statistical differences in the levels of vWF:Ag before and after treatment (P < 0.05). The expression of GPⅡb/Ⅲa restored to the level before LMWH injection in general (P>0.05). The results indicated that conventional dose of enteric-coated aspirin could effectually inhibit the increased activity of platelet caused by intravenous administration of LMWH.After taking aspirin orally (100 mg/d), the plasma levels of GMP-140 and vWF:Ag, the expression of GPⅡb/Ⅲa after subcutaneous administration of Dalteparin Sodium when reaching first dose peak value and steady-state concentration mainly restored to the level before LMWH injection in group D. The figures showed that conventional dose of enteric-coated aspirin could effectually inhibit the increased activity of platelet caused by subcutaneous administration of LMWH and made the data restore to the level before LMWH injection in general.Conclusions: The present study demonstrates that both intravenous and subcutaneous administration of LMWH can activate the platelet. At the same time, we find that there is no statistical significance between two injection routes of LMWH on platelet activation, but the activation caused by subcutaneous administration of LMWH is relatively moderate. Accordingly, subcutaneous administration of LMWH is more widely recommended in clinical therapy. However, the platelet activation caused by LMWH should bring to people's attention. In addition, the results show that conventional dose (100 mg/d) of enteric-coated aspirin can effectually inhibit the increased activity of platelet caused by LMWH and make the data restore to the level before LMWH injection on the whole. Therefore, no matter which injection route we use LMWH, it is essential for us to take aspirin orally in the same time as far as possible, so as to efficaciously inhibit platelet activation caused by LMWH.