Coagulopathy Research In Acute Period Post Traumatic Brain Injury

Traumatic brain injury (TBI) is one kind of trauma with high mortality and disability, which mortality reported as high as 30%-40%, and about 80% death take place within 7 days post-trauma. Moreover, head injury would have higher incidence rate and become severe public health problem because of the quickly development of the national economy and traffic. How to decrease the patients' mortality and disability and improve their living state is an important question to study and research in neuroscience. Coagulopathy is one of complication of TBI, which can make head injury more severe and worsen the patients' prognosis. Study about coagulopathy after head injury is beneficial to forecast and improve the outcome of these patients with severe head injury.How and when we can diagnosis and therapy this kind of coagulopathy post-TBI? There is not a received conclusion at present. To determine the coagulation condition immediately is necessary for giving what kind of clinical intervention to the wounded, because the patients' coagulation state can change from hypercoagulabale state to hyperfibrinolysis in a short time. Therefore, the key point of recently study always located in assessment of the diversify of clotting mechanism, finding high efficiency chemical examination, so as to know the variation of the patient's condition in time and give homologous clinical therapy to improve outcome. This is a prospective study for a series of patients with isolated severe head injury. We detect their coagulation and fibrinolysis in different time and different location, in order to comprehend the process of the coagulation and fibrinolysis, the coagulopathy is general or local in brain only, and the relationship between the coagulopathy and the patients' prognosis. In this foundation, we observe how the clinical therapy for these patients can affect on the coagulopathy and discuss how and when we can interfere in the coagulopathy.Aim of this study:1. To observe the change of coagulation and fibrinolysis in the patients with isolated severe head injury in acute period.2. The patients enrolled in the study with same inclusion and exclusion criteria, and we gave them clinical intervention in order to analysis the effect for the coagulopathy.ChapterⅠRetrospective analysis to the PT, APTT, TT, Fbg and D-dimer of the patients with head injury in acute periodObjective:112 cases with isolated head injury were analyzed retrospectively in the coagulation assays and D-dimer, and we explore the relationship of blood clotting function and the GCS, subsequent hematoma or infarction and the prognosis. Materials and methods:1. Patient's information: All the 112 patients (79 males and 33 females) admitted within 24h, and the severity of head injury was categorized according to the Glasgow Coma Score (GCS): 16 cases with GCS≤5, 37 cases with GCS 6-8 and 59 cases with GCS 9-12. The average time from head injury to getting blood sample was 10.18±5.15 h, and the venous blood samples were obtained from every patients on admission to detect TT,PT,APTT,Fbg and D-dimer respectively. The result was statistical analyzed according to their: GCS, GOS, have subsequent hematoma or not, have traumatic infarction or not.2. Statistical methods: we used SPSS11.5 software package for statistical analysis. The numerical value expressed as (x|-)±s. The methods include One-Way ANOVA, multiple comparisons (LSD and S-N-K) and K independent samples test. Significance was set at P<0.05.Results:1. PT in both the patients with subsequent hematoma or not and the patients with traumatic infarction or not had significant difference (P=0.000). APTT in the patients with traumatic infarction or not had significant difference (P=0.000). TT had significant difference in all the different GCS groups (P=0.002). Fbg had significant difference in two conditions: different GCS scores and had subsequent hematoma or not.2.TT in GOS 1 group prolonged significantly than that in the GOS2,3,4,5 group (P<0.003) and Fbg in GOS 1 group was significantly lower than that in GOS2,3,4,5 group (P<0.001).3. The GCS scores was lower, the D-dimmer positive rate was higher (P=0.000). D-dimmer positive rate was higher in the patients with better outcome or subsequent hematoma than those patients with poor outcome or without subsequent hematoma (P=0.000), and the D-dimmer positive rate had not significant difference between the patients with traumatic infarction and those without it (P=0.451).Conclusion:1. The detection about coagulation tests and D-dimmer within 24h showed blood-clotting disorder (coagulopathy) in the acute period post-head injury, which means there was coagulopathy followed traumatic brain injury.2. The abnormality of coagulation tests is more serious in those patients with severe head injury.3. These patients had obvious disorder of coagulation tests had poor outcome.4. The disorder of coagulation tests had relationship with the subsequent hematoma and traumatic infarction.ChapterⅡthe changes of coagulation in acute period of the patients with isolated severe head injury Objective:1. To comprehend the dynamic change of coagulation and fibrinolysis post-head injury and identify the coagulation function has difference or not between the brain blood circulation and the body blood circulation.2. To analyze the relationship between the coagulation function and the patients' condition or prognosis.Materials and methods:1. Patients' informationAccording to the inclusion criteria and exclusion criteria, 33 patients (24 males and 9 females) enrolled in this study, whose age range from 14 to 69 and average 38.3±17.3 years old. 11 cases had GCS≤5 and 22 cases had GCS 6-8 scores. We obtained blood samples from every patients at six time (4h, 8h, 16h, 24h, 36h and 48h post head trauma) and three sources (arterial, peripheral vein and jugular vein) respectively, and every blood sample was detected for PT,APTT,TT,Fig,FDP,D-dimmer,t-PA,PAI-1,AT-Ⅲand PIT.2. Statistical methods: we used SPSS11.5 software package for statistical analysis. The numerical value expressed as (x|-)±s. The methods include One-Way ANOVA, multiple comparisons (LSD and S-N-K) and x~2 test. Significance was set at P<0.05.Results: 1. Detection for PT, APTT, TT and FbgPT prolonged more in GCS3-5 group than it in GCS6-8 group and it had significant difference at 161k 24h,36h and 48h after head injury (P=0.027, P=0.000, P=0.000, P=0.043), and the PT had significant difference between the patients in poor outcome and better outcome group at 24h and 36h (P<0.05).Compared in same time, APTT had not significant difference among the artery, peripheral vein and jugular vein (P>0.054) and had not significant difference between GCS3-5 group and GCS6-8 group too (P>0.055). Between the patients in poor outcome and better outcome group, APTT had not significant difference (P> 0.114).TT had significant difference among the artery, peripheral vein and jugular vein at 24h, 36h and 48h (P=0.028, P=0.014, P=0.008). Multiple comparison showed it had significant difference between artery and jugular vein (P=0.017, P=0.036, P=0.046), between peripheral vein and jugular in a same time. TT had not significant difference between GCS3-5 group and GCS6-8 group too (P>0.061) . Between the patients in poor outcome and better outcome group, TT had not significant difference(P>0.113).Fbg had significant difference among the artery, peripheral vein and jugular vein at 36h and 48h after head injury (P=0.012, P=0.020). Multiple comparison showed it had significant difference between artery and jugular vein (P=0.019, P=0.029) and between peripheral vein and jugular vein (P=0.005, P=0.009) in a same time. In other hand, the change extent of Fbg level was evident in GCS3-5 group than it in GCS6-8 group at 4h, 8h, 16h, 24h and 48h (P=0.000, P=0.000, P=0.000, P=0.001, P=0.021). Fbg was lower in poor outcome patients than in better outcome patients at 16h and 24h (P<0.028).2. FDP FDP had not significant difference among artery, peripheral vein and jugular vein if compared at same time (P>0.595). FDP increased higher in the patients of GCS 3-5 group than in GCS 6-8 group and the difference was significant at all six times (P<0.003). FDP was higher in poor outcome patients than in better outcome patients at 4h, 8h, 16h, 36h and the difference was significant (P<0.035).3. D-dimerD-dimer had not significant difference among artery, peripheral vein and jugular vein (P>0.05). D-dimer in the patients of GCS 3-5 group was higher than it in GCS 6-8 group (P<0.001), and in the patients with poor outcome was higher than it in the patients with better outcome (P< 0.001).4. t-PAIf compared at same time post head injury, t-PA had not significant difference among artery, peripheral vein and jugular vein (P>0.052). But the change extent of t-PA was evident in GCS3-5 group than it in GCS6-8 group at 4h, 8h, 16h and 24h post head injury (P<0.001). It was lower in the patients with poor outcome than those with better outcome at 4h (P<0.002), and higher at 8h, 16h and 24h (P< 0.022).5. PAI-1If compared at same time post head injury, PAI-1 had not significant difference among artery, peripheral vein and jugular vein (P>0.766). The change extent of PAI-1 was evident in GCS3-5 group than it in GCS6-8 group at 4h, 8h, 16h, 24h and 36h (P=0.000) and the PAI-1 was higher in the patients with poor outcome than it in those patients with better outcome, it was significantly different (P< 0.048).6. AT-ⅢIf compared in same time post head injury, it had not significant difference among artery, peripheral vein and jugular vein (P>0.450). AT-III activity changed more obviously in the patients of GCS 3-5 group than in GCS 6-8 group and had significant difference (P=0.000), and so it is in the patients with poor outcome than in the patients with better outcome (P<0.043).7.PLTPLT count had not significant difference if compared in same time among artery, peripheral vein and jugular vein (P>0.440), and it was not significantly different between the patients with poor or better outcome too (P>0.05). However, it was lower in patients of GCS3-5 group than in those of GCS 6-8 at 4h and 8h post injury (P=0.033, P=0.000).Conclusions:1. The results showed the patients who had isolated severe head injury had hypercoagulable state at 4h post trauma, and it transformed into hyperfibrinolysis at 8h post trauma. This condition continues until 48h post trauma.2. Some laboratory examination, for example Fbg,D-dimer,t-PA,PAI-1,AT-Ⅲ, can certify this change of coagulation and fibrinolysis post traumatic brain injury. D-dimer is a better index with sensitivity and specificity, so it should be a main detection in these patients with isolated severe head injury in order to reveal the coagulopathy post head injury.3. More severe the head injury is, more severe the coagulopathy is, and the patients' outcome is poor.4. The changes of these examinations about coagulation and fibrinolysis had not significant difference among artery, peripheral vein and jugular vein. It means coagulopathy is not located in brain tissue only.ChapterⅢSub-hypothermia therapy and the change of the coagulation Objective: We observed the change of coagulation and fibrinolysis assays of the patients with severe head injury accepted sub-hypothermia therapy, and tried to analyze the relationship between this change and the patients' condition and prognosis.Materials and methods:1. Patients' information43 patients (30males and 13 females) enrolled in this study according the designed inclusion criteria and exclusion criteria. 43 cases were divided into two groups randomly by taking lot according to gender when admitted: group A was sub-hypothermia group and group B was control group. 20 cases (13 males and 7 females) enrolled into group A, whose age range from 16 to 66 years old, average 37.05±15.67 years. 23 cases enrolled into group B, whose age range from 18 to 61 years old, average 38.96±14.18 years. The patients in two groups had not significant difference in the gender and age (P=0.381, P=0.632). According to the GCS score, there was not significant difference between the 20 patients of group A (7 cases GCS range 3-5 and 13 cases range GCS 6-8) and other 23 patients of group B (8 cases range GCS 3-5 and 15 cases range GCS 6-8) (P=0.619).Patients of two groups accept same conventional therapy for severe head injury. Patients of group A admitted into sub-hypothermia treatment unit immediately with incision of trachea or tracheal intubation, assisted respiration or controlled respiration by breathing machine and reduced the body temperature to 32.0℃-35.0℃by ice blanket, ice cap and ice cubes. Hibernation and muscle relaxant composition (aminazine 100mg + promethazine 100mg + tracium 200-400mg + normal sodium 500ml) given at same time in order to reduce shakes. Patients of group B accepted generality cooling measure only to keep body temperature about 37.0℃. 1.8ml blood samples were obtained from ulnar vein of every patient in five time (6h, 12h, 24h, 48h and 72h post head trauma) respectively. The laboratory examination included: Fbg,FDP,D-dimmer,t-PA,PAI-1 and AT-Ⅲ.2. Statistical methods: we used SPSS11.5 software package for statistical analysis. The numerical value expressed as (x|-)±s. The methods include One-Way ANOVA, general linear models test and x~2 test. Significance was set at P<0.05.Results:1.FbgAccording general linear models test, Fbg level had significant difference between two groups (F=7.105, P=0.011). Fbg level was higher in sub-hypothermia group than that in control group. The detection at different times had significant difference (F=91.692, P=0.000). Treatment and time had interaction (F=14.452, P=0.000). When analyzing the solo effects, Fbg level had significant difference between two groups at 6h, 12 h, 24 h and 48 h respectively (P=0.003, P=0.000, P=0.000, P=0.024) and Fbg difference was significant among each time in a same group (P=0.000).2. FDPAccording general linear models test, FDP level was lower in sub-hypothermia group and had significant difference between two groups (F=5.033, P=0.030). The detection at different time had significant difference in same group (F=8.998, P=0.000). But the therapy and time had not interaction (F=1 .788, P=0.134). It means the tendency of FDP had not difference between two different therapy groups.3. D-dimerAccording general linear models test, although D-dimer level was lower in sub-hypothermia group than that in control group, it had significant difference between two groups (F=5.540, P=0.023). The difference was significant at different times post trauma in same group (F=51.690, P=0.000). With time prolongation, the sub-hypothermia therapy and time had interaction (F=5.419, P=0.000). It means the change tendency of D-dimer had difference between two different therapy groups. When analyzing the solo effects, D-dimer level had significant difference between two groups at 6h, 12 h and 24 h respectively (P=0.002, P=0.026, P=0.020) and didn't have difference at 48h and 72h respectively (P=0.378, P=0.247). D-dimer difference was significant among each time in a same group (P=0.000).4. t-PAAccording general linear models test, the t-PA level was lower in the patients of group A than group B, it had significant difference between two groups (F=51.690, P=0.000). The difference was significant among t-PA levels at different post-trauma time in a same group (F=85.053, P=0.000). With time prolongation, the therapy and the time had not interaction (F=0.688, P=0.601). It means the change tendency of t-PA had not difference between different therapy groups.5. PAI-1According general linear models test, PAI-1 level had not significant difference between patients of group A and group B(F=2.787, P=0.103) and had significant difference at different time in a same group (F=55.406, P=0.000). With time prolongation, the therapy and time had not interaction (F=0.605, P=0.660). It means the change tendency of PAI-1 had not difference between different therapy groups.6. AT-ⅢAccording general linear models test, AT-Ⅲactivity had not significant difference between two group (F=0.098, P=0.755) and had significant difference in different times in a same group(F=28.394, P=0.000). With time prolongation, the therapy and time had not interaction (F=2.192, P=0.072). It means the change tendency of AT-Ⅲactivity had not difference between different therapy groups.7. Patients' outcomeIn 20 patients of group A, seven cases had GOS range from 1 to 3 and 13 cases had GOS from 4 to 5. In the other 23 patients of group B, 15 cases had GOS range 1 to 3 and 8 cases had GOS from 4 to 5. The difference between group A and B was significant (P=0.047).Conclusion:1. Sub hypothermia therapy (with patients' body temperature in 32.0℃-35.0℃) could improve the hypercoagulable state of the patients with isolated severe head injury and reduce the subsequent hyperfibrinolysis.2. The outcome of the patients of sub-hypothermia group was better than that of control group and the difference was significant. It may be a study direction to correct this kind of coagulopathy after traumatic brain injury by sub-hypothermia therapy.ChapterⅣthe initial study of FFP to the coagulopathy post head injuryObjective:To observe how FFP affect on the coagulation and fibrinolysis function of the patients with isolated severe head injury in acute period.Materials and methods:1. Patients' information17 patients with isolated severe head injury enrolled in this study with same inclusion criteria, exclusion criteria in chapter III and they were set as group A. We gave FFP 10ml/kg body weight per 24h to 17 patients of group A (FFP therapy group) within 72h, besides the conventional therapy for head injury. The 23 patients of control group in chapter III acted as control group too. There were 17 patients (14 males and 3 females) in FFP therapy group, whose age ranged from 22 to 67 years old, average 39.35±12.04 years, and 23 patients (17 males and 6 females) in control group, whose age ranged from 18 to 61years old, average 38.96±14.18 years. The patients in two groups did not have significant difference in gender and age (P=0.406, P=0.926). According to the GCS score, there was not significant difference between the 17 patients of FFP therapy group (5 cases GCS range from 3-5 and 12 cases GCS from 6-8) and other 23 patients of control group (8 cases GCS range from 3-5 and 15 cases GCS from 6-8) (P=0.496). Blood samples were obtained from ulnar vein of every patient at three times (24h, 48h and 72h post head trauma) respectively. The laboratory examination included: Fbg,D-dimmer,t-PA,PAI-1 and AT-Ⅲ.2. Statistical methods: we used SPSS11.5 software package for statistical analysis. The numerical value expressed as (x|-)±s. The methods include One-Way ANOVA, general linear models test and x~2 test. Significance was set at P<0.05.Results:1.FbgAccording general linear models test, Fbg level had not significant difference between the patients of FFP therapy group and control group (F=3.903 , P=0.055) .The detection at different time had significant difference in a same group (F=8.141, P=0.001). The therapy and time had not interaction (F=1.960, P=0.148). It means the change tendency of Fbg level had not difference between two therapy groups.2. D-dimerAccording general linear models test, D-dimer level in FFP therapy group was lower than control group, the difference was significant between two groups (F=8.555, P=0.006), and the detection at different time in same group had significant difference (F=63.305, P=0.000). The therapy and the time had not interaction (F=1. 470, P=0.236). It means the change tendency of D-dimer had not difference between two therapy groups.3. t-PAAccording general linear models test, the t-PA level in the patients of FFP therapy group was lower than that of control group, and the difference was significant between two groups (F=5.565, P=0.024) and the detection at difference time in a same group had significant difference too (F=l 8.028, P=0.000). The therapy and the time had not interaction (F=0.248, P=0.781). It means the change tendency of t-PA level had not difference between two therapy groups.4. PAI-1According general linear models test, PAI-1 levle had not significant difference between two groups (F=l .344, P=0.255), but the detection at different time in a same group had significant difference (F=37.298, P=0.000). The therapy and the time had not interaction (F=2.205, P=0.117). It means the change tendency of PAI-1 had not difference between two therapy groups.5.AT-IIIAccording general linear models test, AT-Ⅲactivity had not significant difference between two groups (F=1.321, P=0.258) but the detection at different times in a same group had significant difference (F=61.114, P=0.000). The therapy and the time had interaction (F=4.992, P=0.009). It means AT-Ⅲactivity had different change tendency between two therapy groups. When analyzing the solo effects, AT-Ⅲactivity had not difference between two groups at 24h and 48h respectively (P=0.738, P=0.172) and had significant difference at 72h (P=0.029). AT-Ⅲhad significant difference among each times in a same group (P=0.000).6. Patients' outcomeAccording the GOS scores in 120 days post TBI, in group A there were 6 cases had GOS range from 1 to 3 and 11 cases had GOS from 4 to 5. In the other 23 patients of group B, 15 cases had GOS range from 1 to 3 and 8 cases had GOS from 4 to 5. The difference was not significant (P=0.616).Conclusion: 1. FFP therapy to the patients with severe head injury can increase Fbg level; reduce D-dimer, t-PA level and AT-Ⅲactivity. However, the general linear models test showed that the therapy and the time had not interaction. There was significant difference between two groups. It is beneficial to relieve hyperfibrinolysis in acute period post-head injury by transfusing FFP to supply blood coagulation factor.2. FFP transfusion had not significant effect to the patients' outcome. Dose it relate to the volume or time of FFP transfusion? A large sample study is necessary.