Trauma-induced coagulopathy

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.

Figures

Fig. 1 |. Phenotypes of trauma-induced coagulopathy.

Physiological clot formation and degradation represent a delicate balance of prothrombotic or antithrombotic and fibrinolytic or antifibrinolytic processes. Early and late phenotypes of trauma-induced coagulation (TIC) result from the collective insults of tissue injury, shock and traumatic brain injury (TBI), as well as individual responses to these insults. Furthermore, the mechanisms underlying the various phenotypes can occur at different times after injury. Consequently, there are a myriad of TIC phenotypes that change over time. Adapted with permission from Gonzalez, E. et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann. Surg. 263, 1051–1059 (https://journals.lww.com/annalsofsurgery/).

Fig. 2 |. Mechanisms of trauma-induced coagulopathy.

Progress in understanding the pathogenesis of trauma-induced coagulation (TIC) has been moved forward by the concept of the cell-based model of coagulation, which emphasizes the fundamental role of platelets as a platform for clotting factor assembly and their interaction with endothelium that culminates in thrombin generation and incorporation of fibrin to form a haemostatic plug. Although there are several hypotheses on the driving mechanisms, tissue injury and shock (1) synergistically activate the endothelium, platelets and the immune system (2) to generate an array of mediators that reduce fibrinogen, impair platelet function and compromise thrombin generation (3), ultimately resulting in inadequate clot formation for haemostasis (4). Increased fibrinolysis via plasmin generation further compromises haemostatic capacity. These defects are accentuated by ongoing blood loss, haemodilution, metabolic acidosis and hypothermia. A colour gradient indicates that the mechanism can result in both hypocoagulation and hypercoagulation. DAMPs, damage-associated molecular patterns; HMGB1, high mobility group protein B1; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen factor.

Fig. 3 |. Cell-based model of coagulation.

In the cell-based model of coagulation, initiation occurs on tissue factor (TF)-bearing cells, via the extrinsic pathway, and results in the activation of small amounts of thrombin. Thrombin generated on the TF-bearing cell amplifies the procoagulant response by activating additional coagulation factors and platelets. The large burst of thrombin required for formation of a fibrin clot is generated on platelet surfaces during the propagation phase. Adapted with permission from REF., Wiley.

Fig. 4 |. Platelet and endothelial interactions.

Projecting beyond the cell membrane of healthy endothelial cells is a glycocalyx of polysaccharides linked to membrane and trans-membrane proteoglycans, which is fortified with soluble glycoproteins that coordinate coagulation and immune functions. The glycocalyx provides cytoprotection, membrane integrity and anti-apoptotic antithrombotic signalling. Clot formation relies on platelet plug construction (primary haemostasis), which begins with platelet tethering and adhesion to exposed extravascular matrices including tissue factor and collagen via von-Willebrand factor (vWF). Extravascular adhesion and thrombin stimulation activate platelets, resulting in procoagulant calcium mobilization, structural changes, soluble factor degranulation, phosphatidylserine exposure and glycoprotein (GP) IIb/IIIa receptor conformational change to accept fibrin binding. Additionally, platelets control local fibrinolysis via degranulation of soluble factors from alpha granules including plasminogen activator inhibitor-1 (PAI-1) and α2 antiplasmin to maintain prothrombotic, antifibrinolytic clot architecture. Secondarily, activated platelets recruit leukocytes to local environments. Further, via reciprocal release of trophogens, platelets promote endothelial stability and angiogenesis in return for endothelial control of platelet-dependent haemostasis and release of cytokines that signal megakaryopoiesis. However, in trauma-induced coagulopathy, platelet activation pathways are maladaptive, that is, they result in primary and secondary platelet function failures. This is characterized by altered and shed glycoprotein VI and Ibα, impaired extracellular and intracellular calcium, circulating soluble platelet inhibitors, altered granule content and loss of endothelial protection and trophogenesis. Further, a procoagulant and pro-inflammatory milieu is promoted by circulating platelet–leukocyte aggregates (PLAs) and platelet ballooning, sustained exocytosis and impaired clearance of vWF by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13), and metalloproteinase (MMP) cleavage of the protective ectodomains of glycocalyx components exposing neutrophil adhesion receptors for neutrophil binding and release of chemoattractant molecules and cytokines. In this setting, the endothelium becomes denuded and leaky. These trauma-induced coagulopathy (TIC)-associated procoagulant and pro-inflammatory platelet and endothelial biologies are associated with micro-thrombosis and macro-thrombosis. EV, extravcellular vesicle; PAF, platelet activating factor; PAR, protease-activating receptor, PGI2, prostaglandin I2; RBC, red blood cell; TP, TXA2/PG endoperoxidases; TXA, tranexamic acid; TXA2, thromboxane A2.

Fig. 5 |. Multifunctional roles of thrombin.

Once it is activated by the coagulation cascade, the serin protease thrombin can function in procoagulant, anticoagulant, antifibrinolytic and pro-inflammatory or anti-inflammatory pathways. PAR1, protease-activated receptor 1; TAFI, thrombin-activatable fibrinolysis inhibitor. Adapted with permission from REF., Wiley.

Fig. 6 |. Viscoelastic haemostatic assays.

Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are currently the most widely used viscoelastic assays to assess and manage trauma-induced coagulation,. In a typical TEG device, whole blood is transferred to a cylindrical cup, a stationary pin is inserted into the blood, and an oscillating rotational movement is applied to the cup. In typical ROTEM devices, the cup is stationary and the pin oscillates. Both instruments are point-of-care devices and provide similar measurements to reflect the phases of clot formation and clot degradation. Both assays measure speed of thrombin generation, that is, time to until clot firmness of 2 mm (reaction time (R) in TEG and clotting time (CT) in ROTEM); speed of clot formation that includes the contribution of fibrinogen (α angle in both assays); maximum clot strength (maximal amplitude (MA) in TEG and maximal clot firmness (MCF) in ROTEM); and magnitude of fibrinolysis (LY30; that is, the percentage reduction in the area under the curve at 30 min after MA in TEG, and LI30, the residual clot firmness at 30 min after CT in ROTEM). Additional measurements include the contribution of fibrinogen to clot formation independent of platelets (FF, functional fibrinogen, in TEG, and FIBTEM in ROTEM), and a variety of other measurements to reflect platelet function, presence of heparin, presence of thrombin inhibitors and tranexamic acid (TXA) reversibility of fibrinolysis. For TEG, K time is the time interval between reaching a clot amplitude of 2 mm and amplitude of 20 mm, mainly dependent on fibrinogen cleavage and fibrin polymerization; and EPL is estimated percent lysis determined prior to LY30. For ROTEM, A10 is estimated clot firmness at 10 min; CFT is firmness time, the interval between reaching a clot amplitude 2 mm and an amplitude of 20 mm; and ML is maximal lysis between MCF and the lowest amplitude. Adapted from REF., Springer Nature Limited.

Fig. 7 |. Examples of goal-directed algorithms for haemostatic resuscitation.

There is substantial variation in management algorithms for early, hypocoagulable trauma-induced coagulopathy (TIC) throughout the world. These algorithms are designed for the general trauma patient. Isolated traumatic brain injury (TBI) provokes a unique TIC phenotype and, therefore, may warrant TBI-specific blood product thresholds for thromboelastography (TEG) and rotational thromboelastometry (ROTEM). a | An example of a US goal-driven approach for a patient at risk of a massive transfusion. Resuscitation is initiated with a balanced blood product strategy with a focus on reversing haemorrhagic shock. In many institutions this consists of a plasma, platelet and RBC formula at a ratio of 1:1:1 with some centres using a plasma to RBC ratio of 1:2, and more recently some have employed low-titre type O-positive whole blood. Regardless of the initial ratio, crystalloids are not administered until shock is reversed, and calcium chloride is given empirically. RBC are continued to maintain haemoglobin >10 g/dl. A rapid TEG measurement is obtained as soon as possible to guide subsequent blood product and tranexamic acid (TXA) administration, according to thresholds derived from clinical studies. If the patient requires >4 RBC during the first hour and TEG results are unavailable, cryoprecipitate and platelets are delivered. b | Examples of algorithms used in some European countries. Isotonic crystalloids and vasopressors are begun initially, and supplemented with fibrinogen and RBC or plasma and RBC at a ratio of 1:2 in the patient at risk of a massive transfusion. TXA is given to all patients, and calcium is corrected according to laboratory testing. RBC are continued to maintain haemoglobin >7 g/dl. Blood products are subsequently provided according to a goal-directed platform based on either ROTEM or conventional coagulation assays. ACT, activated clotting time; aPTT, activated partial thromboplastin time; CCA, conventional coagulation assay; LY30, percentage reduction in the area under the curve at 30 min after MA in TEG; MA, maximum amplitude; PT, prothrombin time; RBC, red blood cell; SBP, systolic blood pressure; VHA, viscoelastic haemostatic assay.