The Immediate Coagulation Mornioring In The Disseminated Intravascular Coagulation

PART I The effect of the immediate coagulation mornioring in the predicting the occurrence of DICObjective To evaluate the diagnostic effect of the effect of the immediate coagulation mornioring in the predicting the occurrence of Disseminated intravascular coagulation(DIC).Methods Consecutive patients admitted to intensive care unit (ICU) were initially assessed.498cases of patients with suspected DIC according to the potential risk factors, clinical symptoms and experimental data were prospectively included and divided into2groups:overt DIC group with ISTH DIC score≥5and non DIC group with the International Society of Thrombosis and Haemostasis (ISTH) DIC score<5. The prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen level(FIB), international normalized ratio (INR), blood platelet count(PLT), D-dime were examined, as long as Sonoclot indexes such as the actived clotting time (ACT), the clot rate (CR) and platelet function (PF) and the common characteristics like ages, sex, Acute Physiology and Chronic Health Evaluation (APACHE Ⅱ) score and length of stay in ICU and hospital. The above parameters were then compared in the overt DIC group and non-DIC group to search possible diagnostic indexes. furtherly, the overt DIC group were divided into early DIC group with definite diagnosis made less than6hours, and medium-term DIC group in6-12hours and late DIC group more than12hours. The variation trend of all parameters were analyzed to provide evidence for diagnosis and determining severity of disease at different stages of DIC. Based on the above data, related diagnostic tests were used to analyze the Sonoclot parameters with other conventional coagulation indexes, and receiver-operating characteristic curve (ROC) was applied to explore the best threshold of above indexes and calculate the sensitivity and specificity of their prediction in diagnosis of DIC.Results498patients met the inclusion criteria were enrolled, with average age of52.5+19.8years old and362(72.7%) cases of male,136(27.3%) cases of female.1. There were no differences in the age and sex between overt DIC group and non-DIC group (P=0.400and0.453, respectively). The APACHE II scores and ISTH scores were much higher (APACHE II score:24.8+6.0vs18.5+5.5, P<0.001, ISTH score:5.0vs3.0, P<0.001, respectively), and the coagulation parameters such as APTT, PT, ACT and INR were much longer in the overt DIC group than those in the non-DIC group (APTT:76.6±46.2s vs55.7±40.1s, P<0.001; PT:21.4±9.5s vs16.1±3.3s, P<0.001; ACT:231.1±165.4s vs134.8±71.3s, P<0.001; INR:2.2±1.1vs1.5±0.7, P<0.001). The D-dime level was more significantly increased in the overt DIC group than those in the non-DIC group (5880.2±2733.5ng/L vs3695.0±2510.3ng/L, P<0.001). The fibrinogen level, blood platelet count, and platelet function were much lower in the overt DIC group than those in the non-DIC group(FIB:2.5±2.1g/L vs4.2±2.1g/L, P<0.001; PLT:54.5±38.1×109/Lvs154.1±90.4×109/L, P<0.001; PF:1.1vs2.4, P<0.001).2. The association between conventional coagulatory parameters such as APTT, PT, PLT, Fib, D-dimer and INR, sonoclot indexes like ACT, CR and PF and DIC occurrence were discussed with univariate analysis by logistic regression analysis. Both the conventional and sonoclot coagulatory parameters were closely related with DIC occurrence (p<0.001). Furthermore, after randomization of0～1by SPSS,70%of total sample were chosen as training pattern, and the rest were chosen as verification sample. Multi-variate analysis were processed to evaluate the conventional coagulatory parameters with DIC occurrence, and the model equation was Log(P/1-P)=-2.586-0.226PT+0.675INR-0.233FIB+0.000D-dimer-0.037PLT, with matching R Square of0.551and the AUC of0.841. After ACT was sequentially introduced, the model equation shifted into Log(P/1-P)=-3.066+0.171PT+0.521INR-0.226FIB+0.000D-Dimer-0.031PLT+0.006ACT, with matching R Square of0.540and the AUC of0.845. After CR was sequentially introduced, the model equation shifted into Log(P/1-P)=-3.843+0.200PT+0.487INR-0.216FIB+0.000D-Dimer+0.010ACT-0.022CR, with matching R Square of0.559and the AUC of0.845. After PF was sequentially introduced, the model equation shifted into Log(P/1-P)=-2.827+0.000D-dimer+0.009ACT+0.069PT+0.498INR-0.401FIB-0.449PF-0.002PLT, with matching R Square of0.454and the AUC of0.876.3. The CR was negatively correlated with the blood platelet count (r=-0.154,p=0.0018), PF was negatively correlated with the APTT (r=-0.134, p=0.039) and positively with FIB (r=0.189, p=0.003). We also found that the PF was more positively correlated with the blood platelet count in the late subgroup(r=0.513,p=0.000) than other two subgroup. In the early subgroup, the AUC of the conventional coagulation parameters like APTT, PT, D-dime and INR were0.699,0.759,0.635and0.762, respectively(P<0.001). Compared with conventional coagulation indexes, the AUC of ACT along was0.765. We also founde tha the AUC of PLT,FIB, CR and PF were less than0.5, with poor predicting importance. When transformed, AUC of them were0.741,0.896,0.682and0.603, respectively (P<0.001). To predict early overt DIC, the specificity was95.9%and the sensitivity was50.6%in single ACT index. We used "0" and "1" as non-DIC and overt-DIC respectively, and applied Logistic regression with enter method to established model of prediction probability of Sonoclot index. The equation of model of ACT combined with CR was P=exp(-2.265+0.021ACT-0.046CR)/1+exp(-2.265+0.021ACT-0.046CR)(x2=7.310, P=0.504), and when combined with CR and PF, The equation of model was P=exp(-1.517+0.022ACT-0.041CR-0.398PF)/l+exp(-1.517+0.022ACT-0.041CR-0.398PF)(χ2=6.001, P=0.647). The AUC of ACT combined with CR and with PF were0.814and0.828, respectively (P<0.001). The sensitivity was increased to when ACT combined with CR and PF, it increased significantly to84.9%, and the specificity was87.8%, respectively. Both more significantly useful than those of conventional parameters. In the ROC analysis of medium-term subgroup, the AUC of the conventional coagulation parameters like APTT, PT, INR and D-dime were0.624,0.768,0.713and0.736, respectively (P<0.001). The AUC of ACT was0.787. We also founde tha the AUC of FIB, PLT and PF were less than0.5, with poor predicting importance. When transformed, AUC of them were0.780,0.870and0.712, respectively (P<0.001). Logistic regression analysis of ACT combined with CR showed CR was of no significant. The equation of model of ACT combined with CR was P=exp(-3.197+0.022ACT)/1+exp(-3.197+0.022ACT)(x2=12.538,P=0.129), and when combined with CR and PF, The equation of model was P=exp(-2.810+0.023ACT-0.041CR-0.804PF)/1+exp(-2.810+0.023ACT-0.041CR-0.804PF)(x2=5.903, P=0.658). The AUC of ACT combined with CR and PF were0.846, respectively (P<0.001). To predict overt DIC, sensitivity of63.3%and specificity of88.9%in single ACT index. When combined with CR and PF, the specificity of87.8%and sensitivity of84.9%. In the ROC analysis of12hour subgroup, the AUC of the conventional coagulation parameters like APTT, PT, INR and D-dime were more than0.8(P<0.001). The AUC of ACT was0.733. We also founde tha the AUC of FIB, PLT, CR and PF were less than0.5, with poor predicting importance. When transformed, AUC of them were0.794,0.907,0.688and0.826, respectively (P<0.001). Logistic regression analysis of ACT combined with CR and with CR, PF showed CR was of no significant. The equation of model of ACT combined with CR was P=exp(-0.856+0.006ACT)/1+exp(-0.856+0.006ACT)(x2=5.208,P=0.735), and when combined with CR and PF, The equation of model was P=exp(1.145+0.003ACT-0.979PF)/1+exp(1.145+0.003ACT-0.979PF)(x2=1.964, P=0.0.982). The AUC of ACT combined with CR and PF were0.839(P<0.001). When ACT combined with CR and PF, the specificity of72.5%, but sensitivity of84.9%was higher than conventionnal parametres.Conclusions Sonoclot analysis can predict the coagulation dysfunction in the patents with DIC, and is more effective and accurate to diagnose and monitor the consumed hypocoagulable stage of overt DIC than conventional coagulation parameters. It can be widespread used as a routine diagnostic method to predict DIC occurrence due to its rapid, comprehensive, and low-consumable advantages. PART II The immediate coagulation mornioring as a potential prognostic predictor in overt DIC patientsObjective Disseminated intravascular coagulation (DIC) contributed to high mortality. The study was performed to investigate the effect of immediate coagulation mornioring as a potential prognostic predictor in overt DIC patients.Methods We performed prospective investigation test design.237cases of patients with overt DIC according to ISTH score were prospectively included in the study, and was divided into2groups:non-survival group and survival group Clinical and demographic data at admission included the age, sex, conventional coagulation parameters, Sonoclot indexes and outcome were collected and compared. For multivariate analysis of prognosis, COX regression model was used to analyze the correlation in conventional parameters(PT, APTT, INR, D-dime, FIB and blood platelet count), Sonoclot indexes, ISTH and APACHE Ⅱ scores and clinical manifestations of DIC. Kaplan-Meier analysis or the log-rank test were applied to evaluate the prognostic importance of sonoclot indexes. Based on the above data, related diagnostic tests were used to analyze the Sonoclot parameters with ISTH and APACHE Ⅱ scores, and receiver-operating characteristic curve (ROC) was applied to explore the best threshold of above indexes and calculate the sensitivity and specificity of their prediction in prognosis of DIC.Results A total of237patients met the inclusion criteria were enrolled.1. The average age was51.7+17.6years old, with176(74.2%) males,61(25.8%)femal and91(38.4%) death cases. There were103(43.5%) cases with multiple organ dysfunction (MODS) and13(5.4%) cases with clinical symptoms of DIC.2. The age and sex was no difference between two groups (P=0.971and0.088, respectively). In the non-survival group, the DIC manifestation rate (13.6%vs0.1%, P<0.001), MODS rate (59%vs34.2%,P=0.001) and ISTH score (6vs5, P=0.004), ISTH score (25.9±6.3vs24.1±5.7, P=0.022) were much higher. The significantly increased D-dime levetl (6471.5±2565.9ng/L vs5511.6±2778.3ng/L, P=0.008), delayed ACT (289.5±200.5s vs194.6±126.8s, P<0.001) and much shorter PF (1.2±0.9vs1.6±1.2, P=0.010) were also found in the non-survival group.3. COX regression analysis showed that clinical manifestations of DIC(OR=2.509, P=0.013), increased APACHE Ⅱ score (RR=1.043, P=0.04) and ISTH score (RR=1.424, P=0.026), delayed ACT (RR=1.002, P=0.001) and reduced PF (RR=0.763, P=0.017) were risk factor of mortality in DIC. Kaplan-Meier survival curve analysis of abnormal sonoclot indexes indicated that100%of7cases with normal sonoclot indexes survived (n=7),85.9%of78cases with one abnormal index survived (n=67),57.8%of102cases with two abnormal index survived (n=59),40%of50cases with all abnormal3indexes survived (n=20). The above data suggested that patients with one pathological Sonoclot findings have better outcome (P<0.05), and there was no difference between with one pathological and all abnormal3Sonoclot index. The patients were furtherly divided into ACT delaying group(ACT>195s) and ACT reducing group(ACT<119s), CR delaying group(CR>23Sig/min) and CR reducing group(CR<7Sig/min) and PF reducing group(PF<1.5), and30-day survival curve analysis were repeated. Compared with normal ACT and normal PF group, the mortality rate of abnormal ACT and abnormal PF group were significantly increased(P<0.05), with no difference in the abnormal CR group and normal CR group(P>0.05). Compared with ISTH scores and APACHE Ⅱ scores, the AUC of ACT was0.682, with statistically difference (P<0.01). To predict the prognosis of DIC, the specificity was68.5%and the sensitivity was69.2%of single ACT index. The specificity of ISTH scores and APACHE Ⅱ scores were87.7%and80.1%, respectively, however, the sensitivity were only28.6%and40.7%, respectively. We also founde tha the AUC of PF was0.420(P=0.039), with poor predicting importance. When transformed, AUC of PF were0.580(P=0.039). We used "0" and "1" as Survival and non-Survival respectively, and applied Logistic regression with enter method to established model of prediction probability of Sonoclot index. The model of ACT combined with PF was poor fitting. When ACT combined with PF and ISTH score, we found that PF was of no significent(P=0.110). The equation of model was P=exp(-3.918+0.004ACT+0.502ISTH)(x2=14.590, P=0.068). When ACT combined with PF and ISTH, the AUC of0.717was much larger than those combined with ACT and PF(P<0.01), with specificity of78.1%and sensitivity of64.8%. In conclusion, ACT with PF and ISTH scores have better prognostic importance to predict30-day survival rate in DIC.Conclusions Sonoclot analysis can effectively assess the severity and prognosis of DIC. Delayed ACT and reduced PF suggest the increased mortality risk. Combined Sonoclot parameters with ISTH scores, it can effectively make up for the inadequacy of ISTH scores and is superior to predict the30-day prognostics than APACHE Ⅱ and ISTH scores alone. Since Sonoclot analysis provide easy-obtained quantitative indexes and can fully reflect the whole process of blood coagulation course, it can be used as an effective tool to forecast the severity and prognosis of DIC. PART Ⅲ Protocol based on immediate coagulation mornioring to guide blood replacement and anticoagulant therapy during DICObjective To explore the guidance of immediate coagulation mornioring in the individualized treatment of DICMethods237cases of DIC patients with ISTH scores≥5were randomly divided into either Sonoclot group (n=121) and control groups (n=116) according to the principle of random numbers. The control group was received the conventional treatment according to2009ISTH DIC guidelines and2012China expert consensus. The sonoclot group was received conventional treatment under sonoclot guidance. The types, doseage, and duration of replacement treatment and the outcome like complication rate, ICU stay and30-day survival rate were recorded and compared.Results A total of237patients met the inclusion criteria were enrolled.1. There were no differences in the demographic data including age, sex, body weight, APACHE Ⅱ score, ISTH score and the ratio of patients with renal replacement treatment, APTT, PT, INR, platelet count, FIB,D-dime, ACT, CR and PF between two groups(P>0.05). The ratio of clinical symptoms of DIC like bleeding, purpura or limb bleeding was not statistically significant (P>0.05).2. In Sonoclot group, the ratio of heparin using were much higher (32.76%vs19.01%, P=0.018), with shorter duration (11.0±7.2d vs5.2±3.4d, P=0.001) and reduced dosage (65739.1±43322.5U vs31263.2±20222.7U, P=0.001) than those in control group. Since protamine were not given in both of two groups, the regional bleeding rate were significantly lower in Sonoclot treatment group(13.1%vs43.4%, P=0.003).116cases of patients were received RRT, with50cases of heparin usage(20cases in control group and30cases in sonoclot group, P=0.164). Compared with control group, the heparin duration (11.5±7.5d vs4.9±3.6d, P=0.001) and dosage (69000.0±45257.2U vs294000.0± 21393.8U, P=0.001) were decreased significantly in sonoclot group, with reduced regional bleeding rate(35%vs10%,P=0.039). Besides, the fresh frozen plasma (1760±1757.1ml vs1104.6±762.7ml, P<0.05), PLT (44.2±50.9u vs25.7±15. lu, P<0.05) and Cryoprecipitate replacement dosage42.4±36.6u vs29.9±24.3u, P<0.05) was much lower in the sonoclot treatment group. There was no difference in the duration of replacement therapy and DIC improvement rate in two groups (P=0.054). There was no difference in improvement of DIC between two groups(P=0.676).The shorter ICU stay (9(1,92)d vs10(1,120)d, P=0.009) were found in the sonoclot treatment group. The Sonoclot group significantly improve the prognosis by Kaplan-Meier analysis curve (P<0.05).Conclusions The Sonoclot analysis can be more accurate and rigorous to select and control the quantity and composition in the blood replacement therapy. It can also reduce the duration and doseage of blood product. It is useful and effective to guide the clinical anticoagulant therapy, to significantly reduce the bleeding risk and mortality in patients with DIC.