- Letter to the Editor
- Open Access
Activated protein C does not increase in the early phase of trauma with disseminated intravascular coagulation: comparison with acute coagulopathy of trauma-shock
Journal of Intensive Care volume 4, Article number: 1 (2016)
We hypothesized that activated protein C does not increase in disseminated intravascular coagulation (DIC) after trauma and that the same is true for acute coagulopathy of trauma-shock (ACOTS). Activated protein C levels were prospectively measured in 57 trauma patients: 30 with DIC and 27 without DIC. Normal to more decreased activated protein C levels were observed in DIC patients than in the controls and non-DIC patients. The activated protein C levels in ACOTS patients were similar to those in DIC patients. In conclusion, activated protein C does not increase in either DIC or ACOTS in the early phase of trauma.
The present study demonstrated lower to normal activated protein C levels in DIC patients in the early phase of trauma. The same was true in ACOTS patients.
An impairment of the anticoagulation pathways, including protein C and thrombomodulin system, has been confirmed in disseminated intravascular coagulation (DIC), which suggests lower levels or dysfunction of activated protein C (APC), leading to systemic thrombin generation . On the contrary, higher levels of APC and newly synthesized thrombomodulin with full function play pivotal roles in the development of thrombin shutoff in acute coagulopathy of trauma-shock (ACOTS) [2, 3]. The purpose of this study was to test the hypothesis that APC does not increase in DIC at the early phase of trauma and compare the obtained results with those in ACOTS.
Methods and results
With the approval of the Institutional Review Board (No. 013–0215), 57 severe trauma patients defined as having an Injury Severity Score (ISS) ≥9 (at least one abbreviated injury scale ≥3) were enrolled. The patient population was same as our previous studies [4, 5]. Twelve healthy volunteers not matched by age served as control subjects. The diagnosis of DIC was made based on the Japanese Association for Acute Medicine (JAAM) DIC diagnosis criteria on the day of the admission. The overt DIC scores based on the International Society on Thrombosis and Haemostasis (ISTH) were also calculated. ACOTS was defined as a prothrombin time ratio >1.2. The APC levels were measured by an ELISA kit (USCN Life Science Inc. Wuhan; Cloud-Clone Corp., Houston, TX) within 12 h after arrival to the emergency department. The Mann-Whitney U test was performed to compare the APC levels and p values <0.05 were considered statistically significant. The IBM SPSS 22.0 for MAC OSX software program (IBM Japan, Tokyo) was used for the statistical analyses and calculations.
The 57 patients were classified into 30 patients with DIC and 27 patients without DIC. Baseline characteristics (age, sex, and ISS) were identical between the two groups. Nine of 30 DIC patients simultaneously met the ISTH overt DIC criteria. Eighteen patients met the definition of ACOTS. There was no difference in the APC levels between the control and DIC patients. In patients who simultaneously met the ISTH over DIC criteria, however, significantly lower APC levels than those in the controls and non-DIC patients were observed. ACOTS patients showed significantly lower levels of APC than those in the controls and non-ACOTS patients (Fig. 1).
The present study demonstrated lower to normal APC levels in DIC patients in comparison with those observed in the control subjects and non-DIC patients. Taken together with the findings of the previous study , which show higher levels of thrombin generation markers, the results indicate that APC levels are insufficient to prevent systemic thrombin generation in DIC patients.
A study, using the same assay kit used in the present study, failed to demonstrate APC-mediated suppression of thrombin generation in ACOTS patients . The other two studies on ACOTS showed the levels of APC to be about 5 to 10 ng/mL (90 to 175 pM) [3, 6]. The estimated circulating APC levels were 40 pM in healthy subjects . Although higher than normal, the levels in these two studies did not reach to a concentration (70–80 ng/mL) sufficient to inhibit thrombin generation . Furthermore, in vitro study confirmed no alterations in coagulation parameters by thromboelastography at APC concentration of 10 ng/mL (175 pM) . These results indicate that normal to mild increases in APC levels are unlikely to suppress thrombin generation in ACOTS.
Liberal transfusion of fresh frozen plasma containing protein C, a source of APC, would theoretically inhibit thrombin formation and aggravate bleeding in ACOTS. However, the results of the present study may suggest that the control of anticoagulant mechanisms, including protein C, APC, and thrombomodulin system, is crucial to prevent a progression of both DIC and ACOTS to inhibit critical bleeding in trauma patients.
We demonstrated the normal to decreased levels of APC in DIC patients at the early stage of trauma. Contrary to its definition, increased levels of APC were not observed in patients with ACOTS.
acute coagulopathy of trauma-shock
activated protein C
disseminated intravascular coagulation
International Society on Thrombosis and Haemostasis
Japanese Association for Acute Medicine
Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341:2301–11.
Johansson PI, Sørensen AM, Perner A, Welling KL, Wanscher M, Larsen CF, et al. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An Observational Study Crit Care. 2011;15:R272.
Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012;255:379–85.
Hayakawa M, Sawamura A, Gando S, Kubota M, Uegaki S, Shimojima H, et al. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase. Surgery. 2011;149:221–30.
Yanagida Y, Gando S, Hayakawa M, Sawamura A, Uegaki S, Kubota N, et al. Normal prothrombinase activity, increased systemic thrombin generation, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock. Surgery. 2013;154:48–57.
Kutcher ME, Xu J, Vilardi RF, Ho C, Esmon CT, Cohen MJ. Extracellular histone release in response to traumatic injury: implications for compensatory role of activated protein C. J Trauma Acute Care Surg. 2012;73:1389–94.
Griffin JH, Fernandez JA, Gale AJ, Mosnier LO. Activated protein C. J Thromb Haemost. 2007;5 Suppl 1:73–80.
Campbell JE, Meledo MA, Cap AP. Comparative response of platelet fV and plasma fV to activated protein C and relevance to a model of acute traumatic coagulopathy. PLoS One. 2014;9:e99181.
The authors declare that they have no competing interests.
JS measured the APC. All authors contributed to study design, data analysis, and manuscript preparation. All authors read and approved the final manuscript.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Jesmin, S., Gando, S., Wada, T. et al. Activated protein C does not increase in the early phase of trauma with disseminated intravascular coagulation: comparison with acute coagulopathy of trauma-shock. j intensive care 4, 1 (2016). https://doi.org/10.1186/s40560-015-0123-2
- Disseminated intravascular coagulation (DIC)
- Activated protein C