Cohen MJ, Brohi K, Ganter MT, Manley GT, Mackersie RC, Pittet JF. Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway

Departments of Surgery, San Francisco General Hospital, University of California, San Francisco, USA.
The Journal of trauma (Impact Factor: 2.96). 01/2008; 63(6):1254-61; discussion 1261-2. DOI: 10.1097/TA.0b013e318156ee4c
Source: PubMed


Early coagulopathy after traumatic brain injury (TBI) is thought to be the result of injury-mediated local release of tissue factor, although the precise mechanisms that cause hypoperfusion and early systemic coagulopathy in TBI patients are unknown. We have previously reported that early systemic coagulopathy after trauma is present only when tissue injury is associated with severe hypoperfusion leading to the activation of the protein C pathway. However, the role of hypoperfusion as an important mechanism for the development of coagulopathy early after TBI is unclear. The objective of the present study was to determine the importance of hypoperfusion and protein C activation in causing early coagulopathy in TBI patients.
We performed a prospective cohort study including patients with isolated brain injury admitted to a single trauma center. Blood was drawn on average 32 minutes after injury. Plasma samples were assayed for protein C and thrombomodulin by standard laboratory techniques. Routine coagulation measures (prothrombin time, partial thromboplastin time) and arterial blood gas analysis were performed concurrently. Severe hypoperfusion was evidenced by the presence of an arterial base deficit greater than 6.
Thirty-nine TBI patients were included in the study during a 15-month period. TBI patients without concurrent hypoperfusion (n = 28) did not develop an early coagulopathy after trauma, no matter the severity of injury. In contrast, patients with TBI who also had severe hypoperfusion (BD >6) (n = 11) were coagulopathic early after injury. Indeed, these patients had higher prothrombin time and partial thromboplastin time, compared with those with TBI and a BD <6 (17.6 +/- 3.6 vs. 14.3 +/- 2.3, p < 0.005; and 43.13 +/- 18.3 vs. 27.4 +/- 3.8, p < 0.0001). Unactivated protein C levels were lower in the TBI group with BD >6 (56 +/- 32 vs. 85 +/- 35, p = 0.03) and thrombomodulin levels were significantly higher (48 +/- 26 vs. 35 +/- 10, p = 0.04). Without hypoperfusion, there was no effect of increasing brain injury on protein C pathway or fibrinolysis pathway mediators.
TBI alone does not cause early coagulopathy, but must be coupled with hypoperfusion to lead to coagulation derangements, associated with the activation of the protein C pathway. This novel finding has significant implications for the treatment of coagulopathy after severe brain injury.

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    • "PAI-1 normally inhibits tissue plasminogen activator 1 (t-Pa 1) and inhibits fibrinolysis. A reduction in PAI-1 results in less clot formation, thrombin is bound and a clot more amendable to fibrinolysis [6] [7] [8]. "

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    • "More rapid reversal of coagulopathy directly translates into faster neurosurgical intervention which can make profound differences in patients’ functional and neurologic outcome. There are also a number of reports of successful use of rFVIIa as a coagulopathy reversal agent without any adverse involvement of major thrombotic complications such as deep vein thrombosis and thromboembolism.[8363738] "
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    ABSTRACT: Recombinant factor VIIa (rFVIIa) has been used as an adjunctive therapy for acute post-traumatic hemorrhage and reversal of iatrogenic coagulopathy in trauma patients in the hospital setting. However, investigations regarding its potential use in pre-hospital management of traumatic brain injury (TBI) have not been conducted extensively. In the present study, we investigated the physiology, hematology and histology effects of a single pre-hospital bolus injection of rFVIIa compared to current clinical practice of no pre-hospital intervention in a swine model of moderate fluid percussion TBI. Animals were randomized to receive either a bolus of rFVIIa (90 μg/kg) or nothing 15 minutes (T15) post-injury. Hospital arrival was simulated at T60, and animals were euthanized at experimental endpoint (T360). Survival was 100% in both groups; baseline physiology parameters were similar, vital signs were comparable. Animals that received rFVIIa demonstrated less hemorrhage in subarachnoid space (P = 0.0037) and less neuronal degeneration in left hippocampus, pons, and cerebellum (P = 0.00009, P = 0.00008, and P = 0.251, respectively). Immunohistochemical staining of brain sections showed less overall loss of microtubule-associated protein 2 (MAP2) and less Flouro-Jade B positive cells in rFVIIa-treated animals. Early pre-hospital administration of rFVIIa in this swine TBI model reduced neuronal necrosis and intracranial hemorrhage (ICH). These results merit further investigation of this approach in pre-hospital trauma care.
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    • "PAI-1 normally inhibits tissue plasminogen activator 1 (t-Pa 1) and inhibits fibrinolysis. A reduction in PAI-1 results in less clot formation, thrombin is bound and a clot more amendable to fibrinolysis [6] [7] [8]. "

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