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Traumatic injury is one of the leading causes of death, with uncontrolled hemorrhage from coagulation dysfunction as one of the main potentially preventable causes of the mortality. Hypothermia, acidosis, and resuscitative hemodilution have been considered as the significant contributors to coagulation manifestations following trauma, known as the lethal triad. Over the past decade, clinical observations showed that coagulopathy may be present as early as hospital admission in some severely injured trauma patients. The hemostatic dysfunction is associated with higher blood transfusion requirements, longer hospital stay, and higher mortality. The recognition of this early coagulopathy has initiated tremendous interest and effort in the trauma community to expand our understanding of the underlying pathophysiology and improve clinical treatments. This review discusses the current knowledge of coagulation complications following trauma.

Background: Hemorrhagic shock contributes to coagulopathy after trauma. We investigated daily changes of coagulation components and coagulation function for 5 days in hemorrhaged and resuscitated pigs., Methods: Fourteen pigs were randomized into the sham control (C) and the hemorrhage and lactated Ringer's resuscitation (H-LR) groups. On day 1, hemorrhage was induced in the H-LR group by bleeding 35% of the total blood volume, followed by LR resuscitation at three times the bled volume. Pigs in the C group were not hemorrhaged or resuscitated. Hemodynamics and coagulation were measured daily after H-LR on day 1 to day 5., Results: No changes in hemodynamics and coagulation function occurred in C. Hemorrhage decreased mean arterial pressure and increased heart rate. LR resuscitation corrected these changes within 2 hours. Compared with the baseline values (BL) on day 1, fibrinogen levels were decreased to 76% ± 6% by H-LR on day 1, increased to 217% ± 16% on day 2, and remained increased thereafter; platelet counts were decreased to 63% ± 5% by H-LR on day 1 and remained lower on days 2 and 3 but returned to BL by days 4 and 5 (all p < 0.05). Thrombin generation was decreased by H-LR on days 1 and 2 but then increased to above BL on days 4 and 5. Coagulation factor levels were decreased by H-LR on day 1 but returned to BL on day 3 except for factor XIII. Clot strength was decreased by H-LR on day 1 and returned to BL by day 2. Clot rapidity did not change on day 1 but was decreased on days 2 and 3 and returned to BL on days 4 and 5., Conclusion: Hemorrhage and resuscitation reduced coagulation components and compromised coagulation function, which showed different recovery profiles over the 5-day study period.

Background: As part of our overall interest in the mechanisms and treatment related to the development of the lethal triad of hypothermia, acidosis, and coagulopathy seen in trauma patients, the purpose of this study was to determine whether acidosis, inducible either by HCl infusion or hemorrhage/hypoventilation, leads to coagulopathy, and if correction of the acidosis will alleviate this coagulopathy., Methods: In two separate experiments, acidosis was induced in anesthetized swine by (1) HCl infusion (n = 10) or (2) hemorrhage/hypoventilation (n = 8). Arterial blood samples were taken before HCl infusion or hemorrhage (arterial pH 7.4), after HCl infusion or hemorrhage (pH 7.1), and after bicarbonate infusion to return pH to 7.4. Arterial pH and blood gases were measured every 15 minutes., Results: Acidosis (arterial pH 7.1) led to a hypocoagulation as measured by several coagulation parameters. In both experiments, acidosis was associated with a significant decrease in the maximum strength of the clot and the rate at which the clot formed. There was a significant decrease in endogenous thrombin potential and maximum thrombin concentration after acidosis in both groups (thrombin generation assay). However, the activated clotting time, prothrombin time, and activated partial thromboplastin time were significantly elevated only in the HCl-infused group. Fibrinogen concentration and platelet count were significantly reduced in both groups after acidosis. The hypocoagulation that was induced by either hemorrhage/hypoventilation or HCl infusion was not immediately corrected after returning pH to 7.4 with bicarbonate injection., Conclusions: These data suggest that acidosis induced by HCl infusion or by hemorrhage/hypoventilation leads to hypocoagulation. Simple correction of the arterial pH with bicarbonate is not sufficient to correct this coagulopathy.

Objective: To investigate the effect of tris-hydroxymethylaminomethane (THAM) pH neutralization on reversing coagulation abnormalities caused by acidosis., Design: Random and controlled study., Setting: Animal research facility and laboratory., Subjects: Yorkshire swine (n = 18)., Interventions: Acidosis was induced in 12 pigs by infusing 0.2 M hydrochloric acid (HCl). When the target pH of 7.1 was achieved, the pigs were infused with either 0.3 M THAM to achieve pH of 7.4 (intervention group) or an equal volume of lactated Ringer's solution (acid control group)., Measurements and Main Results: Blood samples were taken at baseline, 15 mins after reaching pH of 7.1, and 15 mins after THAM pH neutralization. Coagulation function was assessed by thrombin generation, prothrombin time, activated partial thromboplastin time, activated clotting time, and thromboelastography (maximum clot formation time [R+K], clotting rapidity [alpha], and clot strength [maximum amplitude]). An additional six pigs (sham group) were infused with THAM, and an equal volume of fluid as the 12 coagulopathic pigs was given to assess effects of THAM and hemodilution. Comparisons were made using a mixed model analysis of variance. No change in any indexes of coagulation was observed in sham pigs. Compared with baseline, acidosis of pH 7.1 decreased base excess from 6.6 +/- 0.5 mM to -12.4 +/- 0.5 mM; reduced fibrinogen levels to 72% +/- 2%, platelet counts to 53% +/- 3%, thrombin generation to 58% +/- 4%, alpha to 84% +/- 2%, and maximum amplitude to 75% +/- 3%; and prolonged prothrombin time to 113% +/- 2%, partial thromboplastin time to 122% +/- 4%, activated clotting time to 124% +/- 3%, and R + K to 119% +/- 3% (all p < .05). THAM infusion corrected pH to 7.40 +/- 0.02 and base excess to 2.6 +/- 0.9 mM (p < .05). However, there were no differences in thrombin generation, prothrombin time, partial thromboplastin time, activated clotting time, R+K, alpha, or maximum amplitude between the groups with or without pH correction., Conclusions: Acidosis impaired coagulation by depleting clotting factors, inhibiting thrombin generation, and affecting clot strength and stability. THAM corrected acid-base deficit but did not acutely reverse the coagulation abnormalities in the model.

Background: Coagulopathy is an important contributor to morbidity and mortality in trauma patients. Acidosis contributes to coagulopathy. Acidosis can be neutralized with intravascular bicarbonate, but it is unclear if the coagulation defect is rapidly reversed. The effects of acidosis and bicarbonate neutralization on coagulation function were investigated in vivo., Methods: Acidosis was induced in 12 pigs by infusing 0.2 mol/L HCl to pH 7.1. Pigs were then infused with either LR to maintain a pH of 7.1 (A-LR, n = 6) or 0.3 mol/L bicarbonate to a pH of 7.4 (A-Bi, n = 6). Blood samples were taken at baseline, 15 minutes after acidosis induction, and 15 minutes after bicarbonate neutralization. Coagulation function was assessed by prothrombin time (PT), partial thromboplastin time (PTT), thrombin generation, initial clot formation time (R), clotting rapidity (alpha), and clot strength (MA)., Results: Compared with baseline values, acidosis reduced fibrinogen concentration to 66% +/- 2% in A-LR and to 71% +/- 3% in A-Bi, and decreased platelet counts to 49% +/- 4% in A-LR and to 53% +/- 4% in A-Bi. Thrombin generation decreased to 60% +/- 4% in A-LR and to 53% +/- 7% in A-Bi. Acidosis prolonged PT and PTT about 20% and decreased alpha and MA. After pH neutralization, fibrinogen and platelet levels remained depleted and no reversal of acidosis-induced changes in thrombin generation, PT, PTT, alpha, and MA were observed., Conclusion: Acidosis impaired coagulation by depleting fibrinogen and platelets and by inhibiting clotting kinetics. The deficit associated with acidosis was not reversed with bicarbonate pH neutralization.

Background: Clinical coagulopathy occurs frequently in the presence of acidosis and hypothermia. The purpose of this study was to determine the relative contributions of acidosis and hypothermia to coagulopathy, as measured by current standard bedside and clinical laboratory analyses (i.e., bleeding time and prothrombin time). In addition, we investigated possible mechanisms of these effects using a modified prothrombin time test, thromboelastography, and thrombin kinetics analyses. An improved understanding of coagulopathy should facilitate hemorrhage control., Methods: Twenty-four pigs were randomly allocated into normal (pH, 7.4; 39 degrees C), acidotic (pH, 7.1; 39 degrees C), hypothermic (pH, 7.4; 32 degrees C), and acidotic and hypothermic (pH, 7.1; 32 degrees C) combined groups. Acidosis was induced by the infusion of 0.2N hydrochloric acid in lactated Ringer's solution. Hypothermia was induced by using a blanket with circulating water at 4 degrees C. Development of a clinical coagulopathy was defined as a significant increase in splenic bleeding time. Measurements were compared before (pre) and 10 minutes after (post) the target condition was achieved., Results: Acidosis, hypothermia, or both caused the development of coagulopathy, as indicated by 47%, 57%, and 72% increases in splenic bleeding time (p < 0.05, pre vs. post). Plasma fibrinogen concentration was decreased by 18% and 17% in the acidotic and combined groups, respectively, but not in the hypothermic group. Hypothermia caused a delay in the onset of thrombin generation, whereas acidosis primarily caused a decrease in thrombin generation rates. At 4 minutes' quench time, thrombin generation in the acidotic, hypothermic, and combined groups were 47.0%, 12.5%, and 5.7%, respectively, of the value in the control group. There were no changes in serum tumor necrosis factor-alpha and interleukin-6 in any group during the study., Conclusion: Acidosis and hypothermia cause a clinical coagulopathy with different thrombin generation kinetics. These results confirm the need to prevent or correct hypothermia and acidosis and indicate the need for improved techniques to monitor coagulopathy in the trauma population.