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Trauma-induced coagulopathy

Nature Reviews Disease Primers volume 7, Article number: 30 (2021) Cite this article

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An Author Correction to this article was published on 22 April 2022

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Abstract

Uncontrolled haemorrhage is a major preventable cause of death in patients with traumatic injury. Trauma-induced coagulopathy (TIC) describes abnormal coagulation processes that are attributable to trauma. In the early hours of TIC development, hypocoagulability is typically present, resulting in bleeding, whereas later TIC is characterized by a hypercoagulable state associated with venous thromboembolism and multiple organ failure. Several pathophysiological mechanisms underlie TIC; tissue injury and shock synergistically provoke endothelial, immune system, platelet and clotting activation, which are accentuated by the ‘lethal triad’ (coagulopathy, hypothermia and acidosis). Traumatic brain injury also has a distinct role in TIC. Haemostatic abnormalities include fibrinogen depletion, inadequate thrombin generation, impaired platelet function and dysregulated fibrinolysis. Laboratory diagnosis is based on coagulation abnormalities detected by conventional or viscoelastic haemostatic assays; however, it does not always match the clinical condition. Management priorities are stopping blood loss and reversing shock by restoring circulating blood volume, to prevent or reduce the risk of worsening TIC. Various blood products can be used in resuscitation; however, there is no international agreement on the optimal composition of transfusion components. Tranexamic acid is used in pre-hospital settings selectively in the USA and more widely in Europe and other locations. Survivors of TIC experience high rates of morbidity, which affects short-term and long-term quality of life and functional outcome.

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Fig. 1: Phenotypes of trauma-induced coagulopathy.
Fig. 2: Mechanisms of trauma-induced coagulopathy.
Fig. 3: Cell-based model of coagulation.
Fig. 4: Platelet and endothelial interactions.
Fig. 5: Multifunctional roles of thrombin.
Fig. 6: Viscoelastic haemostatic assays.
Fig. 7: Examples of goal-directed algorithms for haemostatic resuscitation.

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Acknowledgements

E.E.M. and A.S. appreciate the generous support from the National Institutes of Health for their inflammation and coagulation research over the past 35 years (NIGMS: 1-6 P50 GM49222, 1-6 T32 GM08315, 1-2 U54 GM 62119, RM1 GM 131968 and NHLBI: UM1 HL120877). H.B.M. acknowledges the generous support from the National Institutes of Health (NHBLI: K99HL1518870) L.Z.K. acknowledges the generous support from the National Institutes of Health for her platelet biology research (NIGMS: K23GM130892-01). M.D.N. acknowledges the generous support by the National Institutes of Health (NIGMS: R35 GM119526 and NHLBI R01 HL141080).

Author information

Authors and Affiliations

  1. Ernest E Moore Shock Trauma Center at Denver Health, Denver, CO, USA

    Ernest E. Moore

  2. Department of Surgery, University of Colorado Denver, Aurora, CO, USA

    Ernest E. Moore, Hunter B. Moore & Angela Sauaia

  3. Trauma and Surgical Critical Care, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA

    Lucy Z. Kornblith

  4. Pittsburgh Trauma Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Matthew D. Neal

  5. Duke University School of Medicine, Transfusion Service, Durham VA Medical Center, Durham, NC, USA

    Maureane Hoffman

  6. Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK

    Nicola J. Mutch

  7. Department of Anesthesiology and Intensive Care Medicine, AUVA Trauma Centre Salzburg, Academic Teaching Hospital of the Paracelsus Medical University, Salzburg and Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Trauma Research Centre, Vienna, Austria

    Herbert Schöchl

  8. King’s College, London, UK

    Beverley J. Hunt

  9. Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA

    Angela Sauaia

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Contributions

Introduction (all authors); Epidemiology (all authors); Mechanisms/pathophysiology (all authors); Diagnosis, screening and prevention (all authors); Management (all authors); Quality of life (all authors); Outlook (all authors); Overview of Primer (E.E.M.).

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Correspondence to Ernest E. Moore.

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Competing interests

E.E.M. currently receives research support from Haemonetics, Instrumentation Laboratory, Stago, Hemosonics, Diapharma, Prytime, Humacyte and Genentech; he is a co-founder of ThromboTherapeutics; he is listed as inventor on the following patents relating to blood coagulation or fibrinolysis (including assays): WO-2016073668-A1 (assignee: The Regents Of The University Of Colorado; status: published); US-9354243-B2 (assignee: Haemonetics Corporation, The Regents Of The University Of Colorado, A Body Corporate; status: granted); WO-2019014595-A1 (assignee: Thrombo Therapeutics, Inc.; status: published); EP-3215634-A1 (assignee: The Regents of the University of Colorado; status: published); EP-3303943-A1 (assignee: The Regents of The University of Colorado, A Body Corporate; status: published); WO-2021158799-A1 (assignee: The Regents Of The University Of Colorado, A Body Corporate; status: published); US-2020208194-A1 (assignee: Massachusetts Institute Of Technology, University Of Colorado; status: published). H.B.M. receives research support from Haemonetics and Instrumentation Laboratory; he is a co-founder of ThromboTherapeutics; he is listed as inventor on the following patents relating to blood coagulation or fibrinolysis (including assays): WO-2016073668-A1 (assignee: The Regents Of The University Of Colorado; status: published); WO-2019014595-A1 (assignee: Thrombo Therapeutics, Inc.; status: published); EP-3215634-A1 (assignee: The Regents of the University of Colorado; status: published); US-2020208194-A1 (assignee: Massachusetts Institute Of Technology, University Of Colorado; status: published). M.D.N. receives research support from Haemonetics, Janssen Pharmaceuticals, Accriva Diagnostics and Instrumentation Laboratory; he serves on the Scientific Advisory Board with equity stake in Haima Therapeutics. All other authors declare no competing interests.

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Nature Reviews Disease Primers thanks P. Cabrales, M. Levi, I. Marzi, S. Ostrowski, P. Spinella and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Potentially preventable deaths

The three criteria that must be present in a trauma-related death to qualify as potentially preventable are: the injury must have been survivable, the delivery of care was suboptimal, and the error in care must have been directly or indirectly implicated in the death of the patient.

Bleeding control bundle-of-care

A series of measures to optimize bleeding control, including: accurate identification of the bleeding patient; damage control resuscitation; haemostatic techniques with tourniquets, pelvic binders or haemostatic dressings; resuscitative endovascular balloon occlusion of the aorta; thromboelastography coagulation monitoring; tranexamic acid administration for substantial hyperfibrinolysis; decreased time to operating room and interventional radiology; and goal-directed resuscitation with blood products.

Massive transfusion

Several definitions exist. The most frequently used is >10 units of red blood cells (RBCs) per 24 hours, although this definition is liable to substantial survivor bias. Other definitions include: the critical administration threshold (CAT, ≥3 RBC units per hour in the first hour or in any of the first 4 hours from arrival); >4 RBC units or death in the first hour after injury, a definition that has the advantage of minimizing survivor bias; and >4 RBC units within the first hour, which is also known as the resuscitation intensity definition.

Crystalloid solutions

Isotonic plasma volume expanders that contain electrolytes.

Viscoelastic haemostatic assays

These assays measure change in viscoelastic properties of the whole blood during clot formation, strengthening and dissolution. The most commonly used devices are thromboelastography (TEG) and rotational thromboelastometry (ROTEM).

Goal-directed resuscitation

A procedure consisting of haemostatic resuscitation with blood components guided by viscoelastic haemostatic assays that is directed at normalizing coagulation.

Auto-dilution

A shift of interstitial fluid into the vascular compartment in response to haemorrhagic shock, which may impair haemostatic capacity.

Secondary haemostasis

Secondary haemostasis refers to the deposition of insoluble fibrin, generated by the proteolytic coagulation cascade, into the platelet plug, which forms a mesh that is incorporated into and around the platelet plug.

Primary haemostasis

Primary haemostasis refers to platelet aggregation and plug formation on an injury site.

Prothrombin time

(PT). A conventional coagulation assay that evaluates the extrinsic and the common pathways of the coagulation cascade. The PT result (measured in seconds) in a healthy individual varies between different types and batches of the tissue factor used by the manufacturer.

International normalized ratio

(INR). The INR was devised to standardize the PT results. Manufacturers assign an International Sensitivity Index (IST) for their tissue factor and the INR is calculated as (PT test/PT normal)

Activated partial thromboplastin time

(aPTT). PTT is a conventional coagulation assay that measures the clotting activity of the intrinsic pathway cascade. It tests the function of all clotting factors except factor VII and factor XIII (fibrin stabilizing factor). aPTT is often used to monitor patients’ responses to unfractionated heparin infusion, to target therapeutic anticoagulation. Activation occurs via exposure to a negatively charged substrate, which replicates contact activation and enhances the speed of the test.

Damage control resuscitation

A procedure consisting of limited (to avoid haemodilution) crystalloid fluid, permissive hypotension and administration of balanced blood components in severely injured patients to attenuate TIC.

Damage control surgery

A procedure consisting of essential operative manoeuvres: control of mechanical bleeding, shunting critical arteries, controlling gastrointestinal spillage and temporary packing of bleeding sites in patients manifesting TIC due to ongoing shock. Patients will need to return to the operating room to complete definitive reconstruction after they have stabilized.

Cryoprecipitate

A plasma-derived blood product for transfusion that contains fibrinogen (factor I), factor VIII, factor XIII, von Willebrand factor and fibronectin.

Glasgow Outcome Score–Extended

(GOSE). Global scale for functional outcome that rates patient status into eight categories (death, vegetative state, lower severe disability, upper severe disability, lower moderate disability, upper moderate disability, lower good recovery and upper good recovery).

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Moore, E.E., Moore, H.B., Kornblith, L.Z. et al. Trauma-induced coagulopathy. Nat Rev Dis Primers 7, 30 (2021). https://doi.org/10.1038/s41572-021-00264-3

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