Abstract
A severe burn injury is characterized by the activation of inflammation and coagulation mediators. The hemostatic imbalance includes the activation of procoagulant pathways, the decreased fibrinolysis, and the impairment of natural anticoagulants activity. Early postburn coagulation and fibrinolysis abnormalities are clinically evident as disseminated intravascular coagulation (DIC) syndrome that may become an important factor in the pathogenesis of organ failure after thermal injury. Several studies published recently suggested that treatment with Antithrombin (AT) might be beneficial in patients with burn related DIC, ameliorating organ dysfunction and possibly reducing mortality. AT is a broad-spectrum plasma serine protease inhibitor with marked anticoagulant and anti-inflammatory action. AT levels are rapidly depleted as a result of complex formation with thrombin, increased loss in intersticium due to impaired vascular permeability and reduced synthesis due to liver dysfunction. ...
A severe burn injury is characterized by the activation of inflammation and coagulation mediators. The hemostatic imbalance includes the activation of procoagulant pathways, the decreased fibrinolysis, and the impairment of natural anticoagulants activity. Early postburn coagulation and fibrinolysis abnormalities are clinically evident as disseminated intravascular coagulation (DIC) syndrome that may become an important factor in the pathogenesis of organ failure after thermal injury. Several studies published recently suggested that treatment with Antithrombin (AT) might be beneficial in patients with burn related DIC, ameliorating organ dysfunction and possibly reducing mortality. AT is a broad-spectrum plasma serine protease inhibitor with marked anticoagulant and anti-inflammatory action. AT levels are rapidly depleted as a result of complex formation with thrombin, increased loss in intersticium due to impaired vascular permeability and reduced synthesis due to liver dysfunction. Furthermore, AT is a negative acute phase protein and is susceptible toenzymatic destruction by neutrophil proteases, such as elastase, released during postburn systemic inflammatory states. The magnitude of coagulation abnormalities in early postburn period, the relationship with organ failure, the outcome and the efficacy of the AT administration continues to be discussed in the literature. The aim of this prospective study was to evaluate the early activation of coagulation and fibrinolysis after severe thermal injury, to correlate the coagulation status alterations with prognosis, as well as to estimate the treatment effect of AT administration on coagulation parameters and organ failure. Thirty one patients with severe burn injury admitted to the four bed Burn Unit in “Papanikolaou” General Hospital from April 2004 to December 2005 were prospectively investigated in a randomized trial. The study protocol was approved by the local ethics committee and written consent was obtained by the patients or their closest relatives. The patients were enrolled in the study during the first 24 hours after the burn injury. Patients with known hematological disease, with hepatic and renal failure, malignancies and associated trauma were excluded from our study (n=5). AT were administered for four consecutive days after admission in the burn unit at a dose 64.9±11.4 u/kg/day to achieve the level of 150%. Patients’ clinical management was guided by the written treatment protocol of our ICU. Anthropometric characteristics (age, sex) were recorded. Severity of the burn injury was estimated by the percentage of total burn surface area (TBSA) and the Abbreviated Burn Severity Index (ABSI). The severity of the illness was determined by the APACHE II score (Acute Physiology and Chronic Health Evaluation II) and SAPS II score (Simplified Acute Physiological Score II). For the diagnosis of multiple organ dysfunction or failure, the Sequential Organ Failure Assessment score (SOFA) was used. According to the International Society on Thrombosis and Haemostasis (ISTH) definition [18] DIC score have been validated and the value of the diagnosis of overt DIC in predicting the 28th day mortality was examined. The following coagulation parameters were evaluated on admission in the ICU and daily thereafter for four consecutive days: Antithrombin (AT) activity was measured in the plasma by chromogenic assay (Dade- Bering; normal values 80-120%), as was the protein C (PC) activity (Dade- Bering; normal values 70-130%). The free protein S levels (PS) were also measured by electroimmunodiffusion method (Dade- Bering; normal values 70-130%). The plasminοgen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) antigens were measured by the micro-enzyme-linked immunosorbent assay (ELISA) technique (Diagnostica Stago), (normal values 4-43 ng/ml ng/ml for PAI-1, 1-12 ng/ml for t-PA). To assess the activation of the fibrinolytic system, the thrombin generation and neutralization and the use of the coagulation inhibitors, the following markers were measured: thrombin/antithrombin complexes (TAT), plasmin/α₂ antiplasmin complexes (PAP), prothrombin fragment F1.2 (F1.2) and fibrin degradation product D-dimer (D-d). TAT and PAP were measured by micro-ELISA assay (normal values 1-4.1 μg/l for TAT, 120-700 μg/L for PAP). D-d was measured by a latex semi-quantitative method (Diagnostica Stago; negative: less than 0.5μg/ml). The F1.2 antigen levels were measured by the enzyme-linked immunoassay (normal values 0.4-1.1nmol/L). The patients’ mortality was recorded on the 28th day of ICU admission. ANOVA methodology was conducted for the study of continuous variable measurements over time. Multivariative logistic regression was used to evaluate the prognostic influence of DIC on mortality rate. The corresponding Odds Ratios were also calculated. Kaplan-Meier survival trend was used and statistically significant difference was evaluated according to Log Rank (Mantel-Cox) test between AT-treated and control groups. Results were considered statistically significant for p-values less than 0.05. Statistical analysis was conducted with SPSS 14.0. The levels of coagulation system markers did not differ significantly between 2 groups of patients on admission. Nine patients (29%) fulfilled the criteria of overt DIC, and 19 (61.3%) had non-overt DIC. Only the small number of the survivors (three) had no criteria of DIC diagnosis. The forward stepwise multivariative logistic regression analysis revealed that the presence of overt DIC is significantly related to the outcome (p=0.002, OR=0.021, 95% CI = 0.002-0.251). On admission all patients had severe acquired deficiency of AT, PC and PS. With the supplementation of AT its levels were increased, but never achieved the desirable levels (>150%). The t-PA levels were within the physiological range in both groups of patients on admission and were decreased significantly at day four compared to day one values only in the AT-treated group. PAI-1 was increased above the physiological levels at day 1 after burn injury both in the control and in the AT-treated group. There was statistically significant decrease in PAI-I levels in both groups of patients from the first day to the fourth day. The levels of TAT were above the physiologic range during the investigation period in both groups of patients. The TAT levels decreased significantly in the AT treated groups from day one to day four. PAP levels were within physiological range in the AT-treated and the control groups during the first postburn day and there were no statistically significant difference between two groups of patients during the investigation period. The levels of F1.2 were elevated during the first day and were decreased significantly in both groups of patients from day one to day four. D-d levels were also elevated permanently during the first postburn days in all patients, and changed in the opposite direction for the two groups from day one to day four (elevated in control group and decreased in AT-treated group). AT-treated patients showed a decrease in SOFA score in day three and four compared to the admission SOFA. On the contrary, the control group patients didn’t change their SOFA score in the same period. AT-treated patients had an absolute reduction in 28-day mortality of 25% compared to control group (p=0.004). No treatment related side effects were observed. None of the patients who received AT showed hemorrhagic complication. Activation of coagulation mediators was detected in ICU patients with severe burn injury. Most of these patients fulfilled the criteria of DIC syndrome. The diagnosis of DIC was related to mortality. Treatment with AT seems to decrease hypercoagulation (decreased TAT and D-d). Improvement of organ function and mortality was observed in patients after AT administration.
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