Overwhelming TPA Release, Not PAI-1 Degradation, is Responsible for Hyperfibrinolysis in Severely Injured Trauma Patients

Overview

Journal J Trauma Acute Care Surg

Specialty Critical Care

Date 2015 Oct 23

PMID 26491796

Citations 79

Authors

Michael P Chapman

Ernest E Moore

Hunter B Moore

Eduardo Gonzalez

Fabia Gamboni

James G Chandler

Sanchayita Mitra

Arsen Ghasabyan

Theresa L Chin

Angela Sauaia

Anirban Banerjee

Christopher C Silliman

Affiliations

Soon will be listed here.

Abstract

Background: Trauma-induced coagulopathy (TIC) is associated with a fourfold increased risk of mortality. Hyperfibrinolysis is a component of TIC, but its mechanism is poorly understood. Plasminogen activation inhibitor (PAI-1) degradation by activated protein C has been proposed as a mechanism for deregulation of the plasmin system in hemorrhagic shock, but in other settings of ischemia, tissue plasminogen activator (tPA) has been shown to be elevated. We hypothesized that the hyperfibrinolysis in TIC is not the result of PAI-1 degradation but is driven by an increase in tPA, with resultant loss of PAI-1 activity through complexation with tPA.

Methods: Eighty-six consecutive trauma activation patients had blood collected at the earliest time after injury and were screened for hyperfibrinolysis using thrombelastography (TEG). Twenty-five hyperfibrinolytic patients were compared with 14 healthy controls using enzyme-linked immunosorbent assays for active tPA, active PAI-1, and PAI-1/tPA complex. Blood was also subjected to TEG with exogenous tPA challenge as a functional assay for PAI-1 reserve.

Results: Total levels of PAI-1 (the sum of the active PAI-1 species and its covalent complex with tPA) are not significantly different between hyperfibrinolytic trauma patients and healthy controls: median, 104 pM (interquartile range [IQR], 48-201 pM) versus 115 pM (IQR, 54-202 pM). The ratio of active to complexed PAI-1, however, was two orders of magnitude lower in hyperfibrinolytic patients than in controls. Conversely, total tPA levels (active + complex) were significantly higher in hyperfibrinolytic patients than in controls: 139 pM (IQR, 68-237 pM) versus 32 pM (IQR, 16-37 pM). Hyperfibrinolytic trauma patients displayed increased sensitivity to exogenous challenge with tPA (median LY30 of 66.8% compared with 9.6% for controls).

Conclusion: Depletion of PAI-1 in TIC is driven by an increase in tPA, not PAI-1 degradation. The tPA-challenged TEG, based on this principle, is a functional test for PAI-1 reserves. Exploration of the mechanism of up-regulation of tPA is critical to an understanding of hyperfibrinolysis in trauma.

Level Of Evidence: Prognostic and epidemiologic study, level II.

Citing Articles

D-dimer cutoff values for predicting functional prognosis in patients with severe head trauma: a multi-centre prospective observational study.

Onuki T, Nakahara S, Miyake Y, Sakamoto T, Morimura N Eur J Trauma Emerg Surg. 2025; 51(1):47.

PMID: 39853364 DOI: 10.1007/s00068-024-02739-w.

Navigating Hemorrhagic Shock: Biomarkers, Therapies, and Challenges in Clinical Care.

Meza Monge K, Rosa C, Sublette C, Pratap A, Kovacs E, Idrovo J Biomedicines. 2025; 12(12.

PMID: 39767770 PMC: 11673713. DOI: 10.3390/biomedicines12122864.

Hyperfibrinolysis: a crucial phenotypic abnormality of posttraumatic fibrinolytic dysfunction.

Takahashi K, Yamakawa K, Siletz A, Katsura M, Holcomb J, Wade C Res Pract Thromb Haemost. 2024; 8(7):102568.

PMID: 39430866 PMC: 11488401. DOI: 10.1016/j.rpth.2024.102568.

Understanding the systemic effects of intrapleural tPA and DNase by evaluating effects on coagulation.

Marston T, Rajdev K, Samson K, Hershberger D J Thorac Dis. 2024; 16(1):91-98.

PMID: 38410602 PMC: 10894429. DOI: 10.21037/jtd-23-847.

Blood failure: traumatic hemorrhage and the interconnections between oxygen debt, endotheliopathy, and coagulopathy.

Lee J, Ward K Clin Exp Emerg Med. 2023; 11(1):9-21.

PMID: 38018069 PMC: 11009713. DOI: 10.15441/ceem.23.127.

References

Kutcher M, Ferguson A, Cohen M . A principal component analysis of coagulation after trauma. J Trauma Acute Care Surg. 2013; 74(5):1223-9. PMC: 3638007. DOI: 10.1097/TA.0b013e31828b7fa1. View

Chapman M, Moore E, Ramos C, Ghasabyan A, Harr J, Chin T . Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013; 75(6):961-7. PMC: 4072127. DOI: 10.1097/TA.0b013e3182aa9c9f. View

MacLeod J, Winkler A, McCoy C, Hillyer C, Shaz B . Early trauma induced coagulopathy (ETIC): prevalence across the injury spectrum. Injury. 2014; 45(5):910-5. DOI: 10.1016/j.injury.2013.11.004. View

Cardenas J, Matijevic N, Baer L, Holcomb J, Cotton B, Wade C . Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients. Shock. 2014; 41(6):514-21. DOI: 10.1097/SHK.0000000000000161. View

Valle E, Allen C, Van Haren R, Jouria J, Li H, Livingstone A . Do all trauma patients benefit from tranexamic acid?. J Trauma Acute Care Surg. 2014; 76(6):1373-8. DOI: 10.1097/TA.0000000000000242. View

Bontekoe I, van der Meer P, de Korte D . Determination of thromboelastographic responsiveness in stored single-donor platelet concentrates. Transfusion. 2013; 54(6):1610-8. DOI: 10.1111/trf.12515. View

Moore H, Moore E, Gonzalez E, Chapman M, Chin T, Silliman C . Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014; 77(6):811-7. PMC: 4370273. DOI: 10.1097/TA.0000000000000341. View

Chin T, Moore E, Moore H, Gonzalez E, Chapman M, Stringham J . A principal component analysis of postinjury viscoelastic assays: clotting factor depletion versus fibrinolysis. Surgery. 2014; 156(3):570-7. PMC: 4150833. DOI: 10.1016/j.surg.2014.04.030. View

Cao Y, Dua A, Matijevic N, Wang Y, Pati S, Wade C . Never-frozen liquid plasma blocks endothelial permeability as effectively as thawed fresh frozen plasma. J Trauma Acute Care Surg. 2014; 77(1):28-33. DOI: 10.1097/TA.0000000000000276. View

10.

Moore H, Moore E, Gonzalez E, Hansen K, Dzieciatkowska M, Chapman M . Hemolysis exacerbates hyperfibrinolysis, whereas platelolysis shuts down fibrinolysis: evolving concepts of the spectrum of fibrinolysis in response to severe injury. Shock. 2014; 43(1):39-46. PMC: 4373619. DOI: 10.1097/SHK.0000000000000245. View

11.

Cole E, Davenport R, Willett K, Brohi K . Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg. 2014; 261(2):390-4. DOI: 10.1097/SLA.0000000000000717. View

12.

Harvin J, Peirce C, Mims M, Hudson J, Podbielski J, Wade C . The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015; 78(5):905-9. DOI: 10.1097/TA.0000000000000612. View

13.

Bounameaux H, Kruithof E . On the association of elevated tPA/PAI-1 complex and von Willebrand factor with recurrent myocardial infarction. Arterioscler Thromb Vasc Biol. 2000; 20(8):1857-9. DOI: 10.1161/01.atv.20.8.1857. View

14.

Hosomi N, Lucero J, Heo J, Koziol J, Copeland B, Del Zoppo G . Rapid differential endogenous plasminogen activator expression after acute middle cerebral artery occlusion. Stroke. 2001; 32(6):1341-8. DOI: 10.1161/01.str.32.6.1341. View

15.

Armand R, Hess J . Treating coagulopathy in trauma patients. Transfus Med Rev. 2003; 17(3):223-31. DOI: 10.1016/s0887-7963(03)00022-1. View

16.

Hrafnkelsdottir T, Ottosson P, Gudnason T, Samuelsson O, Jern S . Impaired endothelial release of tissue-type plasminogen activator in patients with chronic kidney disease and hypertension. Hypertension. 2004; 44(3):300-4. DOI: 10.1161/01.HYP.0000137380.91476.fb. View

17.

de Fouw N, van Hinsbergh V, de Jong Y, Haverkate F, Bertina R . The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells. Thromb Haemost. 1987; 57(2):176-82. View

18.

de Fouw N, de Jong Y, Haverkate F, Bertina R . Activated protein C increases fibrin clot lysis by neutralization of plasminogen activator inhibitor--no evidence for a cofactor role of protein S. Thromb Haemost. 1988; 60(2):328-33. View

19.

Gando S, Tedo I, Kubota M . Posttrauma coagulation and fibrinolysis. Crit Care Med. 1992; 20(5):594-600. DOI: 10.1097/00003246-199205000-00009. View

20.

de Fouw N, VAN Tilburg N, Haverkate F, Bertina R . Activated protein C accelerates clot lysis by virtue of its anticoagulant activity. Blood Coagul Fibrinolysis. 1993; 4(2):201-10. DOI: 10.1097/00001721-199304000-00001. View