Brohi K, Cohen MJ, Ganter MT, Manley GT, Mackersie RC, Pittet JF. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis
Department of Surgery, The Royal London Hospital, London, United Kingdom. The Journal of trauma
(Impact Factor: 2.96).
06/2008; 64(5):1211-7; discussion 1217. DOI: 10.1097/TA.0b013e318169cd3c
Coagulopathy is present at admission in 25% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock.
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 (PF1 + 2), fibrinogen, factor VII, thrombomodulin, protein C, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), and D-dimers. Base deficit was used as a measure of tissue hypoperfusion.
Two hundred eight patients were studied. Systemic hypoperfusion was associated with anticoagulation and hyperfibrinolysis. Coagulation was activated and thrombin generation was related to injury severity, but acidosis did not affect Factor VII or PF1 + 2 levels. Hypoperfusion-induced increase in soluble thrombomodulin levels was associated with reduced fibrinogen utilization, reduction in protein C and an increase in TAFI. Hypoperfusion also resulted in hyperfibrinolysis, with raised tPA and D-Dimers, associated with the observed reduction in PAI-1 and not alterations in TAFI.
Acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. There was no evidence of coagulation factor loss or dysfunction at this time point. Soluble thrombomodulin levels correlate with thrombomodulin activity. Thrombin binding to thrombomodulin contributes to hyperfibrinolysis via activated protein C consumption of PAI-1.
Available from: Mark L Ryan
- "Significant elevations were found in prothrombin fragment 1 + 2 as well as plasminogen activator inhibitor-1. Elevations in F1 + 2 occur secondary to increased thrombin generation and have previously been described in association with evidence of hypoperfusion and deinhibition of fibrinolysis in critically injured patients, while PAI-1 is normally decreased in the setting of acute coagulopathy of trauma, resulting in hyperfibrinolysis . Decreased activity of coagulation inhibitor proteins C and S was also noted. "
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Coagulation changes in pediatric trauma patients are not well defined. To fill this gap, we tested the hypothesis that trauma evokes a hypercoagulable response.
A prospective observational study was conducted in hospitalized patients (age 8 months to 14 years) admitted for trauma or elective surgery. Informed consent was obtained from the parents and informed assent was obtained in patients 7 years of age or older. Coagulation changes were evaluated on fresh whole blood using thromboelastography (TEG) and on stored plasma using assays for special clotting factors.
Forty three patients (22 trauma, median injury severity score = 9; and 21 uninjured controls) were evaluated. With trauma vs control, prothrombin time (PT) was higher by about 10% (p < 0.001), but activated partial thromboplastin time was not altered. TEG clotting time (R; p = 0.005)) and fibrin cross-linking were markedly accelerated (K time, alpha angle; p < 0.001) relative to the control patients. D-Dimer, Prothrombin Fragment 1 + 2, and Plasminogen Activator Inhibitor-1 were all elevated, whereas Protein S activity was reduced (all p < 0.01). Importantly, a large fraction of TEG values and clotting factor assays in the pediatric control group were outside the published reference ranges for adults.
A hypercoagulable state is associated with minor trauma in children. More work is needed to determine the functional significance of these changes and to establish normal pediatric reference ranges.
Available from: Charles Wade
- "However, about one quarter of all severe trauma patients experience acute, excessive, and uncontrolled hemorrhage, requiring administration of transfusion products. Trauma induced coagulopathy (TIC) develops early after injury and results from the combination of severe injury and hemorrhagic shock, including tissue damage, hypoperfusion, hemodilution, hypothermia, acidosis, inflammation, and with alterations of blood hemostasis system  . Despite recent advances in trauma research, the pathophysiology and mechanisms of hemostatic and cellular alterations in early response to trauma are not well characterized. "
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Trauma-induced coagulopathy following severe injury is associated with increased bleeding and mortality. Injury may result in alteration of cellular phenotypes and release of cell-derived microparticles (MP). Circulating MPs are procoagulant and support thrombin generation (TG) and clotting. We evaluated MP and TG phenotypes in severely injured patients at admission, in relation to coagulopathy and bleeding.
As part of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, research blood samples were obtained from 180 trauma patients requiring transfusions at 5 participating centers. Twenty five healthy controls and 40 minimally injured patients were analyzed for comparisons. Laboratory criteria for coagulopathy was activated partial thromboplastin time (APTT) ≥ 35 sec. Samples were analyzed by Calibrated Automated Thrombogram to assess TG, and by flow cytometry for MP phenotypes [platelet (PMP), erythrocyte (RMP), leukocyte (LMP), endothelial (EMP), tissue factor (TFMP), and Annexin V positive (AVMP)].
21.7% of patients were coagulopathic with the median (IQR) APTT of 44 sec (37, 53), and an Injury Severity Score of 26 (17, 35). Compared to controls, patients had elevated EMP, RMP, LMP, and TFMP (all p<0.001), and enhanced TG (p<0.0001). However, coagulopathic PROMMTT patients had significantly lower PMP, TFMP, and TG, higher substantial bleeding, and higher mortality compared to non-coagulopathic patients (all p<0.001).
Cellular activation and enhanced TG are predominant after trauma and independent of injury severity. Coagulopathy was associated with lower thrombin peak and rate compared to non-coagulopathic patients, while lower levels of TF-bearing PMPs were associated with substantial bleeding.
Available from: Michael Meledeo
- "High concentrations of aPC are thought to facilitate fibrinolysis, possibly through binding plasminogen activator inhibitor-1 (PAI-1) , . This is further corroborated by a correlation between decreasing protein C and PAI-1 with increasing tissue plasminogen activator (tPA) and d-dimer , . However, the profibrinolytic properties of aPC are dependent on its downstream effects on thrombin-activatable fibrinolysis inhibitor (TAFI); inactivation of fVa reduces fIIa production which reduces TAFI activation . "
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Acute traumatic coagulopathy (ATC) has been linked to an increase in activated protein C (aPC) from 40 pM in healthy individuals to 175 pM. aPC exerts its activity primarily through cleavage of active coagulation factor Va (fVa). Platelets reportedly possess fVa which is more resistant to aPC cleavage than plasma fVa; this work examines the hypothesis that normal platelets are sufficient to maintain coagulation in the presence of elevated aPC.
Coagulation responses of normal plasma, fV deficient plasma (fVdp), and isolated normal platelets in fVdp were conducted: prothrombin (PT) tests, turbidimetry, and thromboelastography (TEG), including the dose response of aPC on the samples.
PT and turbidimetric assays demonstrate that normal plasma is resistant to aPC at doses much higher than those found in ATC. Additionally, an average physiological number of washed normal platelets (200,000 platelets/mm3) was sufficient to eliminate the anti-coagulant effects of aPC up to 10 nM, nearly two orders of magnitude above the ATC concentration and even the steady-state pharmacological concentration of human recombinant aPC, as measured by TEG. aPC also demonstrated no significant effect on clot lysis in normal plasma samples with or without platelets.
Although platelet fVa shows slightly superior resistance to aPC's effects compared to plasma fVa in static models, neither fVa is sufficiently cleaved in simulations of ATC or pharmacologically-delivered aPC to diminish coagulation parameters. aPC is likely a correlative indicator of ATC or may play a cooperative role with other activity altering products generated in ATC.
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