The Coagulation And Fibrinolytic Function Changes After Transcatheter Closure Of Atrial Septal Defect: A Randomized, Controlled Clinical Study

Background and objectiveThe2004"congenital heart disease interventional therapy guideine"and "2009common congenital heart disease interventional therapy Chinese expert consensus"areclearly suggest that during peri-operation period of transcatheter closure of atrial septaldefect, it should be the prevention of thrombosis, especially anticoagulation and antiplateletat postoperation. There are mang differences between the guideline with consensus onwhether oral aspirin preoperative and anticoagulant protocols postoperative.There is notentirely consistent about the changes of coagulation and fibrinolytic function aftertranscatheter closure of atrial septal defect in such research, and the anticoagulantprotocols to prevent thrombosis is also a lack of large, randomized, controlled clinicalstudy.The first part of this study, through the observation and comparison of prothrombinfragment1+2(F1+2), thrombin antithrombin complex (TAT), beta thromboglobulin(β-TG), platelet factor fourth (PF4), tissue plasminogen activator (tPA), D-dimer (D-D)after transcatheter closure of atrial septal defect on the heparin group、low molecular weightheparin group and prolonged low molecular weight heparin group, elucidating thecoagulation and fibrinolytic function changes after transcatheter closure of atrial septaldefect to provide science, reasonable anticoagulant protocols. The second part of this study,through the observation of tumor necrosis factor alpha (TNFα), interleukin6(IL-6), vonWillebrand factor (vWF) and relationship between TNFα, IL-6, vWF with F1+2, TAT, β-TG, PF4, tPA, D-D after transcatheter closure of atrial septal defect on the low molecularweight heparin group and prolonged low molecular weight heparin group to investigate themechanism of changes of coagulation and fibrinolytic function. Part1: Dynamic changes and clinical significance of coagulation andfibrinolytic system following three different antithrombotic protocols aftertranscatheter closure of ASDPatients and MethodsAccording to the predetermined inclusion and exclusion criterion,156patients withisolated ASD who underwent successful interventional therapy from2010January to2011December in our institute and finished the whole follow-up were chosen as the researchobject of our study. All patients were randomized into3groups receiving differentanticoagulant therapies within1hour after procedure according to the principle of"minimization schemes" by comparing the patients’ gender, age and device size betweengroups: the UFH group received UFH (10IU kg-1h-1) intravenous drip for24hours, theLMWH group received subcutaneous injection of LMWH (1mg/kg, every12hours)2timeswithin24hours, the prolonged LMWH (pLMWH) group received LMWH for up to3days(usage and dose as the LMWH group). All patients were instructed to take aspirin3-5mg/kg daily for6months and receive antibiotic therapy for2-3days after transcatheterclosure. During the follow-up, bleeding and thrombo-embolisem complications wereobserved and evaluated. On day1-2,30&90after interventional therapy, transthoracicechocardiography and electrocardiogram were performed. Measurements of F1+2,TAT,β-TG, PF4, tPA, D-D serum levels were taken at baseline before intervention, andimmediately, day1,2,3,7,30&90after procedure via ELISA methods.Continuous variables are expressed as mean±SD. Statistical analysis was performedwith Statistical Package for Social Sciences13.0(SPSS13.0) statistical software.Comparisons of marker serum levels at different time points in same group were analyzedwith one way multivariate analysis of variance (MANOVA) for repeated measurements.Comparisons of marker serum levels at different time points between different groups weremade with two ways MANOVA for repeated measurements. All assumptions were verifiedwith two-sided test (Dunnett test). Differences were regarded as significant if P <0.05.Results were considered remarkably significant if P <0.01. ResultsThere was no statistics significant deferences in F1+2, TAT,β-TG, PF4, tPA, D-Dserum levels at baseline between3groups.1. F1+2and TAT in3groups all rose to the maximal values immediately afterintervention procedure (P<0.05). On day1,2,3,7,30&90, F1+2gradually declined, andfell to baseline on day90. On day1,2,3,7&30, TAT gradually declined, and fell tobaseline on day30. There was no significant differences in F1+2and TAT levels between3groups on immediately, day1,2,7,30&90after procedure. On day3, F1+2and TAT inpLMWH group was significantly lower than UFH and LMWH group (P<0.05), but therewas no significant differences between UFH group and LMWH group.2. From baseline, β-TG and PF4in3groups all increased significantly immediatelyafter transcatheter ASD closure (P<0.05), declined slightly on day1&2, then rose to amaximal levels on day3(P<0.05) and fell to baseline on day7,30&90after intervention.There was no statistics significant differences in β-TG, PF4levels between3groups atbaseline and immediately, day1,2,3,7,30&90after ASD closure.3. tPA, D-D in3groups all rose to the maximal values immediately after interventionprocedure (P<0.05) and declined slightly on day1&2which were still little higher thanbaseline. On day3,7,30&90, tPA and D-D in3groups all fell to baseline. There was nostatistics significant differences in tPA, D-D levels between3groups at baseline andimmediately, day1,2,3,7,30&90after procedure.Part2: Mechanism of the dynamic changes of coagulation and fibrinolyticsystem after transcatheter closure of ASDPatients and MethodsPatients in LMWH group and pLMWH group in Part1were chosen as the researchobject. The follow-up was similar to Part1. Measurements of TNFα, IL-6, vWF serumlevels were taken at baseline before intervention, and immediately, day1,2,3,7,30&90after procedure via ELISA methods. Then correlations between TNFα, IL-6, vWF and F1+2,TAT, β-TG, PF4, tPA, D-D would be analyzed. Continuous variables are expressed as mean±SD. Statistical analysis was performedwith Statistical Package for Social Sciences13.0(SPSS13.0) statistical software.Comparisons of marker serum levels at different time points in same group were analyzedwith one way multivariate analysis of variance (MANOVA) for repeated measurements.Comparisons of marker serum levels at different time points between different groups weremade with two ways MANOVA for repeated measurements. Correlations between twofactors were assessed by Pearson test. All assumptions were verified with two-sided test(Dennett test). Differences were regarded as significant if P <0.05. Results were consideredremarkably significant if P value was <0.01.ResultsThere were no statistics significant differences in TNFα, IL-6and vWF serum levels atbaseline between LMWH group and pLMWH group.1. TNFα and IL-6in LMWH, pLMWH group all increased significantly immediatelyafter transcatheter ASD closure (P<0.05), declined slightly on day1&2, then rose to amaximal levels on day3(P<0.05) and fell to baseline on day7,30&90after intervention.There was no statistics significant differences in TNFα, IL-6levels between this2groups atbaseline and immediately, day1,2,3,7,30&90after ASD closure. On immediately, day1&2after procedure, correlations between TNFα, IL-6and F1+2, TAT,β-TG, PF4, tPA, D-Dall existed. On day3&7, TNFα and IL-6were only associated with β-TG, PF4, there wasno correlations between F1+2, TAT, tap, D-D levels. On day30&90, no correlationsexisted.2. vWF in LMWH, pLMWH group rose to the maximal values immediately afterintervention procedure (P<0.05). On day1,2, vWF gradually declined, and fell to baselineon day3. On immediately, day1&2after procedure, correlations between vWF and F1+2,TAT,β-TG, PF4, tPA, D-D all existed. On day3, vWF was only associated with tPA and D-D,there was no correlations between F1+2, TAT, β-TG, PF4levels. On day7,30&90, nocorrelations existed.Conclusions1. Percutaneous transcatheter closure of ASD induces significant coagulationactivation, platelet activation and fibrinolytic activation. Platelet activation sustained for7 days, coagulation sustained for90days and fibrinolytic activation sustained for3days.2. Subcutaneous injection of LMWH for3days, based on taking aspirin, can inhibitcoagulation activation more sufficiently after transcatheter ASD closure to preventthrombosis.3. The immediately activation of platelet, coagulation and fibrinolytic system weretriggered by the foreign body circulating blood contact during procedure, the endothelialinjury and inflammation.