Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway?

Abstract

Objectives: Coagulopathy following major trauma is conventionally attributed to activation and consumption of coagulation factors. Recent studies have identified an acute coagulopathy present on admission that is independent of injury severity. We hypothesized that early coagulopathy is due to tissue hypoperfusion, and investigated derangements in coagulation associated with this.

Methods: This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1+2, fibrinogen, thrombomodulin, protein C, plasminogen activator inhibitor-1, and D-dimers. Base deficit (BD) was used as a measure of tissue hypoperfusion.

Results: A total of 208 patients were enrolled. Patients without tissue hypoperfusion were not coagulopathic, irrespective of the amount of thrombin generated. Prolongation of the partial thromboplastin and prothrombin times was only observed with an increased BD. An increasing BD was associated with high soluble thrombomodulin and low protein C levels. Low protein C levels were associated with prolongation of the partial thromboplastin and prothrombin times and hyperfibrinolysis with low levels of plasminogen activator inhibitor-1 and high D-dimer levels. High thrombomodulin and low protein C levels were significantly associated with increased mortality, blood transfusion requirements, acute renal injury, and reduced ventilator-free days.

Conclusions: Early traumatic coagulopathy occurs only in the presence of tissue hypoperfusion and appears to occur without significant consumption of coagulation factors. Alterations in the thrombomodulin-protein C pathway are consistent with activated protein C activation and systemic anticoagulation. Admission plasma thrombomodulin and protein C levels are predictive of clinical outcomes following major trauma.

FIGURE 1. Effects of tissue hypoperfusion on coagulation. A: Increasing partial thromboplastin time with increasing BD. BD in quartiles. *P = 0.003 comparing BD ≤2.1 mEq/L with BD ≥7.7 mEq/L. B: Increasing prothrombin time with increasing BD. BD in quartiles. *P = 0.01 comparing BD ≤2.1 mEq/L with BD ≥7.7 mEq/L. C: Partial thromboplastin time is prolonged only in the presence of a raised BD. While the BD remains low (white bars), increasing thrombin generation has no effect on the prothrombin time. With a raised BD (black bars), prolongation of the prothrombin time is seen with increasing thrombin generation. PF1+2 in tertiles. *P = 0.01 comparing PF1+2 >4.0 nM with PF1+2 <2.0 nM for BD >6 mEq/L. ⁺P = 0.03 comparing BD ≤6 and >6 mEq/L for PF1+2 >4.0 nM. D: Prothrombin time is prolonged only in the presence of a raised BD (as C). PF1+2 in tertiles. *P = 0.002 comparing PF1+2 >4.0 nM with PF1+2 <2.0 nM for BD >6 mEq/L. ⁺P = 0.008 comparing BD ≤6 and >6 mEq/L for PF1+2 >4.0 nM.

FIGURE 2. Changes in thrombomodulin and protein C. A: Increased plasma thrombomodulin levels with increasing BD. BD in quartiles. *P = 0.01 compared with BD ≤2.1 mEq/L. B: Reduced plasma protein C levels with increasing BD. BD in quartiles. *P < 0.001 compared with BD ≤2.1 mEq/L. C: Reduced plasma protein C levels with increasing prothrombin fragment levels occur only in the presence of an increased BD (>6 mEq/L). Prothrombin fragments in tertiles. *P = 0.002 comparing PF1+2 <2 nM to PF1+2 2–4 nM, P < 0.001 to PF1+2 >4 nM for BD >6 mEq/L. +P = 0.014 comparing BD ≤6 mEq/L and BD >6 mEq/L for PF1+2 >4 nM. D: Reduced plasma protein C levels with increasing prothrombin fragment levels occurs only in the presence of increased thrombomodulin levels (>53 ng/mL). Prothrombin fragments in tertiles. *P = 0.03 comparing thrombomodulin ≤53 ng/mL and thrombomodulin >53 ng/mL for PF1+2 >4 nM.

FIGURE 3. Indirect evidence for activation of protein C. A: Partial thromboplastin time is prolonged as protein C falls. Protein C in quartiles. *P < 0.001 compared with protein C ≥102%. B: Prothrombin time is prolonged as protein C falls. Protein C in quartiles. *P < 0.001 compared with protein C ≥102%. C: Plasma plasminogen activator inhibitorI-1 (PAI-1) levels fall as protein C falls. Protein C in quartiles. *P = 0.004 compared with protein C ≥102%. D: Plasma d-dimer levels rise as protein C levels decrease. Protein C in quartiles. *P = 0.01 for protein C 58–78%, P < 0.001 for protein C ≤57% compared with protein C ≥102%.

FIGURE 4. Mortality associated with early activation of the thrombomodulin-protein C pathway. A: Low plasma protein C levels on admission are associated with increased mortality. Protein C in quartiles. *P < 0.001 compared with protein C ≥102%. B: High plasma thrombomodulin levels on admission are associated with increased mortality. Thrombomodulin in quartiles. *P < 0.001 compared with thrombomodulin >42.2 ng/mL.