Trauma-Induced Coagulopathy: From Endotheliopathy and Fibrinolysis Phenotypes to Viscoelastic-Guided Resuscitation

Abstract

Trauma-induced coagulopathy is a maladaptive, multifactorial response to severe injury that affects approximately one quarter of severely injured patients and substantially increases mortality. It arises from combined tissue injury and shock and is characterized by endothelial dysfunction, platelet abnormalities, fibrinogen depletion, and dysregulated fibrinolysis, with thrombin generation typically preserved early and reduced only later, evolving through early hypocoagulable, balanced, and later hypercoagulable phases. Recognition of trauma endotheliopathy, including glycocalyx shedding and the von Willebrand factor-ADAMTS-13 axis, has broadened understanding beyond simple consumption and dilution. Viscoelastic hemostatic assays, thromboelastography and rotational thromboelastometry, characterize clot initiation, propagation, strength, and lysis in near-real time and can detect fibrinolysis, fibrinogen deficiency, and platelet dysfunction that conventional tests miss; early clot amplitude parameters enable rapid, goal-directed decisions, although the largest randomized trial to date did not demonstrate a mortality benefit over conventional testing, and most thresholds remain expert-derived and platform-specific. Contemporary therapy focuses on damage-control resuscitation with permissive hypotension, balanced ratio-based transfusion, early tranexamic acid, calcium replacement, and targeted rather than empiric fibrinogen replacement, with recombinant activated factor VII reserved for rescue. Preinjury antithrombotic therapy and liver disease call for agent-specific adjustments, summarized in an accompanying reference table. This review synthesizes the mechanisms, viscoelastic diagnosis, and goal-directed treatment of trauma-induced coagulopathy and highlights persistent knowledge gaps, including the significance of fibrinolysis shutdown, endotheliopathy-directed therapy, and the optimal timing of venous thromboembolism prophylaxis and resumption of antithrombotic therapy.

1 |. Introduction

Trauma-induced coagulopathy (TIC) is a response to severe injury and shock that substantially increases the risk of hemorrhage, organ dysfunction, and death. TIC affects nearly one quarter of severely injured patients and carries an approximate 50% mortality, even when bleeding is considered controlled. TIC is characterized by five interacting mechanisms: endothelial dysfunction, platelet abnormalities, fibrinogen depletion, dysregulated fibrinolysis, and time-dependent changes in thrombin generation (Figure 1). Thrombin generation is dynamic, generally preserved or increased early and impaired only in later, evolved coagulopathy as detailed below. These mechanisms drive a three-phase model of coagulation: an early hypocoagulable bleeding phase, a balanced physiologic stage marked by hemorrhage control and clot formation, and a subsequent hypercoagulable stage associated with organ failure [1].

FIGURE 1 |.

Mechanisms of trauma-induced endotheliopathy and glycocalyx shedding. Cross-section of a small vessel. The mechanisms of TIC are illustrated as follows: shedding of syndecan-1 ectodomains (1), heparanase-mediated release of heparan sulfate side chains (2), TRPV4 activation with calcium influx that disrupts VE-cadherin junctions and produces vascular hyperpermeability (3), release of procoagulant extracellular vesicles bearing tissue factor and phosphatidylserine (4), and release of ultralarge vWF multimers (5), whose proteolysis is impaired by relative ADAMTS-13 deficiency, promoting platelet tethering. Loss of antithrombotic signaling results in sequenced downstream consequences: Vascular leak, inflammation, microvascular thrombosis, coagulopathy, and eventually organ dysfunction. Therapeutic targets in TIC include TXA and FFP (solid filled boxes). Experimental therapies with physiologic basis include recombinant ADAMTS-13 and vWF A1-domain blockade of the caplacizumab type (dashed boxes), which have not yet been studied in trauma, and glycocalyx-protective strategies (dotted box), which remain preclinical. *Lyophilized plasma is an ABO-alternative to FFP, but no trial has yet demonstrated a mortality benefit, and its strongest advantages are logistical rather than clinical; it can be stored at room temperature, reconstituted in minutes, and given without thawing or blood-type matching. ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; FFP, fresh frozen plasma; PS, phosphatidylserine; TF, tissue factor; TIC, trauma-induced coagulopathy; TRPV4, transient receptor potential vanilloid 4; TXA, tranexamic acid; VE-cadherin, vascular endothelial cadherin; vWF, von Willebrand factor.

2 |. Methods

This nonsystematic narrative review searched PubMed/MEDLINE and the Cochrane Library for English-language publications in adult trauma populations. Landmark randomized controlled trials, meta-analyses, and current society guidelines were prioritized. Additional sources were identified through reference list hand-searching. Final inclusion reflected author consensus; the review does not follow PRISMA methodology.

2.1 |. TIC: Three-Phase Model and Fibrinolysis Phenotypes

In the early hypocoagulable phase, endothelial activation, hyperfibrinolysis, and fibrinogen depletion combine to produce diffuse bleeding. As hemorrhage is controlled and resuscitation proceeds, many patients pass through a balanced physiologic phase. Survivors frequently enter a later hypercoagulable phase characterized by fibrinolysis shutdown and a prothrombotic state that predisposes to venous thromboembolism (VTE) and organ dysfunction [1]. Three fibrinolysis phenotypes have been described using viscoelastic testing (VET): hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown. Both early hyperfibrinolysis and later fibrinolysis shutdown are independently associated with higher mortality [1]. Reported prevalence and mortality for each phenotype depend heavily on the chosen LY30 (or comparable lysis) threshold and device used. Admission hyperfibrinolysis identified by VET is uncommon, occurring in roughly 2% of patients with major trauma in one large cohort, yet it carries high early mortality and can be treated with antifibrinolytics [2]. Physiologic fibrinolysis, defined by low but detectable lysis on VET, has been associated with the lowest mortality. Whether routine VET actually captures plasmin-mediated fibrinolysis within this range is a point of contention, which is explored more in Section 2.10. Fibrinolysis shutdown is characterized by suppressed fibrinolytic activity, is associated with intermediate mortality, and is frequently the most prevalent phenotype among severely injured patients [1]. The clinical significance of fibrinolysis shutdown remains debated. Some have proposed it represents a hypercoagulable state predisposing to thromboembolic complications, while others have characterized it as a moderate form of coagulopathy with ongoing fibrinogen consumption and a marker of injury severity. A retrospective analysis of 473 trauma patients found that prehospital tranexamic acid (TXA) administration increased the rate of the shutdown phenotype and that shutdown was independently associated with increased mortality (OR 2.4). These findings suggest that shutdown should not lead to withholding antifibrinolytic therapy [3].

2.2 |. Fibrinogen Depletion

Fibrinogen is typically the first clotting factor to reach critically low levels in major trauma owing to hemorrhage, consumption, dilution, acidosis, and plasmin-mediated degradation. It, therefore, represents a pillar of TIC. At admission, low fibrinogen is a strong predictor of need for massive transfusion and early mortality [4].

2.3 |. Dysregulated Fibrinolysis

Dysregulated fibrinolysis can manifest either as excessive clot breakdown or suppression of fibrinolysis. Early massive endothelial release of tissue plasminogen activator (tPA), combined with depletion of natural fibrinolysis inhibitors such as plasminogen activator inhibitor-1 (PAI-1) and alpha2-antiplasmin, drives fibrinolysis and uncontrolled bleeding. Hypoperfusion has also been proposed to amplify fibrinolysis through the protein C–thrombomodulin pathway, where the thrombin–thrombomodulin complex generates activated protein C (APC) that can inactivate factors Va and VIIIa and derepress fibrinolysis by inhibiting PAI-1 [5]. The importance of this pathway in acute TIC is contested, however. In vitro, the APC concentrations reported after trauma (approximately 175 pM, versus roughly 40 pM normally) are well below those required to produce an anticoagulant effect. Physiologic platelet counts largely abolish APC’s anticoagulant activity because platelet-derived factor Va is relatively resistant to APC cleavage. Finally, thrombin generation is preserved or increased despite APC [6, 7]. It is, therefore, suggested that APC is unlikely to be the dominant driver of early coagulopathy, and the early hyperfibrinolysis of TIC is instead attributed principally to massive endothelial tPA release rather than to APC-mediated PAI-1 inhibition [8].

As noted, early bleeding in TIC is driven predominantly by fibrinolysis and fibrinogen loss rather than by a thrombin deficit which helps explain why bleeding can persist despite preserved thrombin generation [5]. In late-course resuscitation, a swing toward elevated PAI-1 levels likely leads to decreased fibrinolysis, micro- and macro-thrombosis, VTE, and organ failure [1].

2.4 |. Thrombin Generation

Thrombin generation in TIC is time-dependent rather than uniformly impaired. Contrary to what prolonged conventional clotting times (CTs) might suggest, global thrombin-generating capacity is typically preserved or even increased in the early phase after severe injury. Using thrombin generation assays, trauma patients with acute coagulopathy show shorter lag times and markedly higher peak thrombin than healthy controls, driven in part by concurrent depletion of natural anticoagulants such as antithrombin [9]. Preserved early thrombin generation has since been confirmed in severely injured patients at emergency-department admission, including those requiring massive transfusion [10, 11]. Prolonged prothrombin time/INR and viscoelastic CTs therefore reflect the kinetics of clot initiation and the contributions of fibrinogen and factor consumption, not a global thrombin deficit [12]. An INR above 1.2 marks coagulopathy for diagnostic purposes but should not be equated with impaired thrombin generation.

Reduced thrombin generation instead emerges later, often with ongoing hemorrhage, marked hemodilution, prolonged operative management, or sustained shock when consumption of procoagulant factors outpaces resynthesis. Acidosis-related suppression of thrombin generation, and perhaps to a lesser degree APC-mediated factor inactivation, contribute to this late decline while impairing platelet function and weakening fibrin polymerization [5, 13]. This temporal distinction carries therapeutic weight. Since early thrombin generation is generally intact, empiric strategies to augment it such as prothrombin complex concentrate do not improve outcomes and may push an already-adequate thrombin response higher, increasing thrombotic risk [11].

2.5 |. Platelet Dysfunction

Beyond changes in platelet count, trauma induces a qualitative platelet dysfunction characterized by impaired aggregation in response to ADP, arachidonic acid, and collagen. This defect appears early and can be demonstrated independently of the platelet count. In a five-day trajectory study in which aggregometry was normalized to a platelet count of 250 G/L, platelet function was maximally deranged within the first 24 h after injury without subsequent recovery in that tested period [14]. Interpretation of the wider literature is nonetheless complicated by methodology: impedance aggregometry (multiplate) and platelet function analyzers (PFA-100/200) are themselves strongly influenced by platelet count; and, for PFA, by hematocrit and von Willebrand factor. So studies that did not normalize for thrombocytopenia may have overestimated both the magnitude and the duration of intrinsic platelet dysfunction by conflating low counts with impaired function [14, 15].

2.6 |. Endotheliopathy and Glycocalyx Shedding

Trauma endotheliopathy has emerged as a central mechanism, promoting vascular leak, inflammation, microvascular thrombosis, and loss of normal antithrombotic signaling, all of which contribute to coagulopathy. Hypoperfusion, catecholamine release, and metabolic acidosis activate the endothelium, causing a shedding of its luminal glycocalyx, releasing Syndecan-1, heparan sulfate (HS), procoagulant extracellular vesicles (EVs) bearing tissue factor and phosphatidylserine, and ultra-large von Willebrand factor (UL-VWF) multimers, among other mediators, opening potential therapeutic targets [1].

Syndecan-1, the most widely studied biomarker of endotheliopathy, is independently associated with coagulopathy and inflammation. In adults, elevated syndecan-1 has been associated with roughly threefold higher unadjusted mortality, though the per-unit effect is markedly attenuated after adjustment [16]. HS, released during glycocalyx shedding and elevated in trauma, is hypothesized to exert heparin-like anticoagulant effects via auto-heparinization; however, thromboelastometry studies have failed to show a measurable coagulation effect at clinically relevant concentrations, and its impact remains debated [17]. EVs peak within the first 3 h of injury and exhibit procoagulant activity sufficient to induce endothelial dysfunction and coagulopathy in animal models [18].

Trauma also triggers early release of hyper-adhesive UL-VWF multimers from Weibel–Palade bodies alongside a reduction in ADAMTS-13 activity (median 66% versus 100% in healthy controls) detectable within hours of injury, an imbalance that independently associates with coagulopathy, transfusion requirements, and organ failure [19]. Its contribution to hemorrhage is uncertain, however. An excess of UL-VWF relative to ADAMTS-13 is classically prothrombotic, favoring platelet–VWF microthrombi and microvascular obstruction, so the association with the bleeding phenotype of early TIC may be indirect, for example, through platelet consumption, or may mark the severity of endothelial injury rather than a direct hemorrhagic mechanism.

A truncated, hyperactive form of ADAMTS-13, identified in approximately 23% of patients in shock, is associated with hyperfibrinolysis and higher mortality (44% vs. 3%). TXA prevented this degradation in vitro, suggesting an antifibrinolytic mechanism beyond plasmin inhibition [20]. VWF A1 domain blockade, recombinant ADAMTS-13, and TXA have each shown protective effects on this axis in preclinical models, but the net effect on bleeding versus thrombosis in patients remains unresolved [19].

2.7 |. Coagulation Testing

TIC is often suspected with diffuse or disproportionate bleeding, particularly during hemorrhagic shock or massive transfusion. Diagnosed by laboratory tests, therapy should precede testing in emergencies. The basic tests of coagulation are platelet count, prothrombin time (PT-INR), activated partial thromboplastin time (aPTT), and fibrinogen level. VET, including thromboelastography (TEG) and rotational thromboelastometry (ROTEM), is a well-established point-of-care tool for measuring clotting dynamics.

2.8 |. Conventional Laboratory Tests

Platelets are essential in initial hemostasis by forming the platelet plug. Platelet count is a major determinant of microvascular bleeding in massively transfused patients [21]. Count-based transfusion thresholds for the bleeding trauma patient are addressed under Goal-Directed Component Therapy (Table 2). Beyond the count, platelet function can be assessed with point-of-care assays such as the platelet function analyzer (PFA-100/200), multiple electrode aggregometry, and other tests (VerifyNow, Plateletworks, TEG platelet mapping). Their role in unselected trauma is limited. In major trauma patients not taking platelet inhibitors, admission Multiplate testing was not associated with transfusion requirements or mortality and did not predict massive transfusion, so routine platelet function testing is not recommended in this group [30]. Its principal current use is to detect and guide reversal of pharmacologic platelet inhibition.

TABLE 2 |.

Viscoelastic and conventional triggers for goal-directed transfusion in the bleeding trauma patient.

Target	Conventional trigger	TEG thresholda (citrated kaolin)	rTEG thresholda	ROTEM thresholda	ACS TQIP (2014)b	Recommended intervention
Plasma/coagulation factorsc	INR > 1.5; PT > 18 s or aPTT > 35s	R > 4.45min [22]	ACT ≥ 128 s [23]	EXTEM CT > 80s persisting after fibrinogen correction (> 150 mg/dL or FIBTEM CA5 corrected) [24]	R > 9 min; EXTEM CT > 100 s	Fresh frozen plasma, or 4-factor PCC, only once clot firmness is corrected
Fibrinogen	< 150–200 mg/day; goal > 200 mg/dL	α < 67° [22]	α <65° [23]	FIBTEM CA5 ≤ 10 mm (70% sensitivity [25]); α < 70° [26] (VISOR)	α < 60°; FIBTEM MCF < 8 mm	Fibrinogen concentrate 3–4 g (approximately 50 mg/kg), or cryoprecipitate 2 pools
Platelets/clot strength	< 50000/μL (general); < 100000/μL for TBI	MA < 60 mm [22]	MA ≤ 55 mm [23]	EXTEM-FIBTEM CA5 < 30 mm [25]	MA < 55 mm; EXTEM MCF < 45 mm	1 apheresis platelet unit
Fibrinolysisd	Not reliably detected	LY30 > 4.55% [22]	LY30 ≥ 5% [23]	EXTEM LI30/ML elevated [25]	LY30 > 7.5% (TEG)/> 3% (rTEG); EXTEM ML > 15%	TXA 1 g IV over 10 min then 1 g over 8 h, or EACA
Massive transfusion prediction	Clinical scores (ABC, TASH)	Not established	Not established	EXTEM CA5 ≤ 40 mm (72.7% sensitivity); FIBTEM CA5 ≤ 9 mm (77.5% sensitivity) [27]. EXTEM CA5 < 41 mm identifies TIC, INR > 1.2 [25]e	Not specified	Activate massive transfusion protocol

Note: Reference ranges for orientation: Citrated kaolin TEG: R: 3–8 min, K: 1–3 min, α: 55°–78°, MA: 51–69 mm, LY30: 0%–3%. ROTEM EXTEM: CT: 42–74 s, α: 63°–81°, MCF: 49–71 mm; FIBTEM MCF: 9–25 mm.

Abbreviations: ABC, Assessment of Blood Consumption score; ACS TQIP, American College of Surgeons Trauma Quality Improvement Program; ACT, activated clotting time; aPTT, activated partial thromboplastin time; AUC, area under the receiver operating characteristic curve; CA5, clot amplitude at 5 min; CT, clotting time; EACA, epsilon-aminocaproic acid; EXTEM, tissue-factor-activated ROTEM assay; FIBTEM, fibrin-based ROTEM assay; INR, international normalized ratio; IV, intravenous; LI30, lysis index at 30 min; LY30, percent lysis 30 min after maximum amplitude; MA, maximum amplitude; MCF, maximum clot firmness; ML, maximum lysis; PCC, prothrombin complex concentrate; PT, prothrombin time; R, reaction time; ROTEM, rotational thromboelastometry; rTEG, rapid thromboelastography; TASH, Trauma Associated Severe Hemorrhage score; TBI, traumatic brain injury; TEG, thromboelastography; TIC, trauma-induced coagulopathy; tPA, tissue plasminogen activator; TXA, tranexamic acid; VET, viscoelastic testing; α, alpha-angle.

^aAll thresholds are platform-specific and assay-specific; values from the TEG 5000 and ROTEM delta are not interchangeable with the TEG 6 s or ROTEM sigma cartridge-based systems. Validate locally before adopting any cutoff.

^bData-driven thresholds (Stettler, Einersen, Baksaas-Aasen, Chow/VISOR) generally propose lower cutoffs than the 2014 ACS TQIP expert-derived values, which may undertreat established coagulopathy [22, 23, 25, 28].

^cClot initiation times (ROTEM CT, TEG R, rTEG ACT) depend on fibrin polymerization as well as thrombin generation, and hypofibrinogenemia alone prolongs them. They are not surrogate markers of thrombin generation. Correct fibrinogen first, then repeat the test. Rossaint (Rec. 28) recommends PCC for delayed clot initiation only above a fibrinogen of 1.5 g/L [24]. Listed triggers are thresholds for treating, not targets.

^dStandard VET lysis parameters have low sensitivity for clinically significant fibrinolysis; EXTEM maximum lysis detected hyperfibrinolysis in only approximately 5% of trauma patients. When suspicion is high despite normal lysis indices, consider tPA-augmented VET (combined rTEG plus tPA-TEG mortality-prediction AUC 0.80 vs. 0.63 for rTEG alone) [29]. A tPA-challenge assay is sold only on ClotPro (TPA-test) and MultiClot (Apiro TPA reagent). The tPA-augmented TEG and ROTEM protocols in the literature spike tPA manually and are research-use only.

^eA reduced EXTEM CA5 reflects reduced clot firmness from hypofibrinogenemia, thrombocytopenia, or both, and is not specific to trauma-induced coagulopathy.

Post-traumatic coagulopathy is often defined by a prolonged conventional clotting test, but the exact threshold varies across the literature, generally falling between an INR of 1.2 and 1.5. An admission INR greater than 1.2 has been used to define TIC in data-driven diagnostic work, whereas an INR greater than 1.5 has been applied as a prognostic threshold for worse outcomes [25, 31]. Recognizing which cutoff is in use is important when comparing studies and protocols.

2.9 |. VET (TEG and ROTEM)

VET measures real-time clotting dynamics of the entire coagulation process in whole blood [32]. In TEG, blood is placed in a rotating cup with a stationary pin; in ROTEM, the pin rotates instead. Both generate a tracing representing clot initiation, propagation, strength, and lysis, providing hemostatic information not captured by conventional testing [33].

There are several key TEG parameters. The R-time (reaction time) reflects plasma coagulation factor activity, the K-time (kinetics) reflects the rate of clot strengthening predominantly driven by fibrinogen, the alpha-angle is the slope between R and K, representing the speed of fibrin buildup and cross-linking, and the maximum amplitude (MA) reflects clot strength via fibrin-platelet interactions wherein an estimated 80% of MA comes from platelet contribution [33]. Finally, the LY30 measures the percentage of clot lysis occurring 30 min after MA, reflecting fibrinolytic activity [32]. A rapid TEG variant (rTEG) uses tissue factor to accelerate results to approximately 15 min, and it has a separate channel using abciximab that isolates the fibrinogen contribution to clot strength [34].

ROTEM uses analogous nomenclature. CT corresponds to TEG’s R-time, clot formation time (CFT) corresponds to K-time, and maximum clot firmness (MCF) corresponds to MA. ROTEM also reports clot amplitude at fixed time points, which appear earlier than MCF and have proven useful for rapid decision-making [25]. Reference ranges for TEG and ROTEM parameters vary by platform, and institution-specific validation is recommended [33].

A key ROTEM advantage is its use of multiple assay channels that isolate different components of hemostasis (Table 1). EXTEM evaluates the extrinsic coagulation pathway, reflecting the contributions of coagulation factors, fibrinogen, and platelets. INTEM evaluates the intrinsic pathway. FIBTEM identifies hypofibrinogenemia by inhibiting the platelet contribution to clot strength, APTEM confirms hyperfibrinolysis when lysis seen on EXTEM is corrected by aprotinin, and HEPTEM identifies a heparin effect by comparing heparinase-neutralized with standard INTEM results.

TABLE 1 |.

ROTEM reagent-specific assay channels in the bleeding trauma patient.

Channel	Activator or reagent	Pathway or component isolated	Conventional analog	Representative reference range (ROTEM delta)a	Primary clinical use
EXTEM	Tissue factor	Extrinsic pathway: combined effect of coagulation factors, fibrinogen, and platelets	PT	CT: 42–74 s; CFT: 46–148 s; α: 63–81; MCF: 49–71 mm	Global screen of clot initiation, propagation, and strength
INTEM	Ellagic acid plus phospholipid (contact activation)	Intrinsic (contact) pathway	aPTT	CT: 137–246s; CFT: 40–100s; α: 71–82; MCF: 52–72 mm	Screen of the intrinsic/contact system; baseline for HEPTEM comparison
FIBTEM	Cytochalasin Db	Fibrinogen/fibrin contribution to clot strength	Correlates with Clauss fibrinogenc	MCF: 9–25 mm	Low FIBTEM MCF or CA5 identifies hypofibrinogenemia
APTEM	Aprotinind	Fibrinolysis confirmation	None	Similar to EXTEM if no hyperfibrinolysis	Lysis on EXTEM corrected on APTEM confirms hyperfibrinolysis
HEPTEM	Heparinasee	Heparin effect	None	Similar to INTEM if no heparin present	HEPTEM vs. INTEM identifies heparin as the cause of a prolonged CT

Note: Nomenclature crosswalk (ROTEM to TEG): ROTEM CT corresponds to TEG R-time; CFT to K-time; MCF to MA; and ML or LI30 approximates LY30. ROTEM additionally reports clot amplitude at 5 min (CA5).

Abbreviations: aPTT, activated partial thromboplastin time; APTEM, aprotinin-modified EXTEM assay; CA5, clot amplitude at 5 min; CFT, clot formation time; CT, clotting time; deg, degrees; EXTEM, tissue-factor-activated ROTEM assay; FIBTEM, fibrin-based ROTEM assay; HEPTEM, heparinase-modified INTEM assay; INTEM, contact-activated ROTEM assay; K-time, kinetic time (TEG); LI30, lysis index at 30 min; LY30, percent lysis 30 min after maximum amplitude; MA, maximum amplitude (TEG); MCF, maximum clot firmness; ML, maximum lysis; PT, prothrombin time; R-time, reaction time (TEG); ROTEM, rotational thromboelastometry; s, seconds; TEG, thromboelastography; α, alpha-angle.

^aReference ranges are device and reagent specific (values shown are for ROTEM delta) and population dependent; they are not interchangeable with ROTEM sigma or with TEG, and require local validation before clinical use [35].

^bCytochalasin D inhibits the platelet contribution to clot strength, isolating the fibrin component.

^cFIBTEM MCF or CA5 reflects the fibrin contribution to clot strength and correlates with, but is not numerically equivalent to, the Clauss fibrinogen concentration; the correlation is population dependent.

^dAprotinin inhibits fibrinolysis.

^eHeparinase neutralizes unfractionated heparin.

Multiple studies demonstrate that VET parameters better predict transfusion requirements than conventional tests. The alpha-angle predicts plasma transfusion better than fibrinogen levels, MA predicts platelet transfusion better than platelet counts, and VET can identify fibrinolysis that conventional tests miss entirely [25]. A multicenter prospective study of 2287 trauma patients developed data-driven thresholds. FIBTEM CA5 less than 10 mm detected hypofibrinogenemia with 70% sensitivity, EXTEM CA5 less than 41 mm helped identify TIC (defined as INR > 1.2), and EXTEM-FIBTEM CA5 < 30 mm detected thrombocytopenia [25]. Of note, CA5 cutoffs remain debated, as several clinically used cutoffs (≤ 35–40 mm) display only moderate specificity [36]. A prospective validation study of 808 trauma patients confirmed that EXTEM CA5 of 40 mm or less predicted massive transfusion with 72.7% sensitivity, and FIBTEM CA5 of 9 mm or less with 77.5% sensitivity [27]. Another study of 722 TEG-fibrinogen pairs found that ACS-recommended K-time and alpha-angle cutoffs had low sensitivity (3% to 29%) for diagnosing hypofibrinogenemia; optimized cutoffs (K-time > 1.5 min, alpha-angle < 70°, MA < 60.9 mm) improved sensitivity to 74%, suggesting current thresholds may undertreat coagulopathy [28]. Parameter interpretation and component therapy linkage are summarized in Figure 2 and Table 2.

FIGURE 2 |.

Viscoelastic assay tracings and parameter crosswalk. Representative idealized normal tracings with the key parameters annotated, each followed by a crosswalk of parameter, clinical meaning, and a representative reference range. (A) Thromboelastography (TEG), citrated kaolin activation. (B) Rotational thromboelastometry (ROTEM), EXTEM (tissue factor) activation. TEG and ROTEM measure analogous phases of coagulation (R-time and CT, K-time and CFT, MA and MCF, LY30 and ML or LI30) but use different activators and platforms, so values are not numerically interchangeable. The ROTEM clot amplitude at 5 min (CA5) is available within minutes and correlates with the final MCF; it is shown as a clinical threshold (EXTEM CA5 of 40 mm or less predicts massive transfusion) because no population reference interval is established. Tracings are idealized, not patient data; the ROTEM tracing rises earlier because its clotting time is reported in seconds. Reference ranges are device-, reagent-, and platform-specific (TEG, Hunt et al.; ROTEM EXTEM, Lang et al.) and should be validated locally. CA5, clot amplitude at 5 min; CFT, clot formation time; CT, clotting time; LY30, lysis 30 min after maximum amplitude; MA, maximum amplitude; MCF, maximum clot firmness; ML, maximum lysis; ROTEM, rotational thromboelastometry; TEG, thromboelastography.

2.10 |. Limitations and Evidence Gaps of VET

An important limitation of conventional VET is its low sensitivity for detecting clinically significant fibrinolysis. The EXTEM maximum lysis parameter detected hyperfibrinolysis in only 5% of trauma patients, and only in those with plasmin-antiplasmin complexes elevated to 30 times normal [26]. Significant fibrinolysis can be present even when the lysis index at 30 min appears normal if EXTEM and FIBTEM clot amplitudes are decreased, suggesting that early clot dissolution may be masked [36].

A line of recent research culminating in a 2026 paper by Smudla et al. suggests that TF-triggered VET may not measure plasmin-mediated fibrinolysis across the physiologic range at all. In 120 healthy adults, and still to be confirmed in injured patients, the small degree of maximum lysis recorded was essentially unchanged by complete fibrinolysis inhibition with TXA, indicating that this physiologic lysis is largely plasmin-independent and likely reflects platelet-mediated clot retraction rather than true fibrinolysis [37]. These findings carry two implications. First, the “physiologic fibrinolysis” category defined by routine VET should be interpreted cautiously, as it may not represent balanced plasmin activity. Second, low ML/LY30 values labeled “fibrinolysis shutdown” may partly reflect impaired platelet contractility rather than suppressed fibrinolysis, which could explain their association with mortality. Equating low VET lysis with true shutdown risks misclassification and misdirected antifibrinolytic decisions. Assays that directly probe fibrinolytic capacity, notably the tPA-challenge, more reliably characterize fibrinolytic phenotypes [37]. Tissue plasminogen activator-augmented VET (tPA-VET) challenges the fibrinolytic system and more effectively distinguishes fibrinolysis phenotypes. The combination of rTEG and tPA-TEG had significantly better prediction of mortality than either test alone (AUC 0.80 vs. 0.63 and 0.75, respectively) [29]. Availability of tPA-VET is another caveat. Although research groups have applied tPA-challenge protocols to TEG by adding tPA in the laboratory, standardized commercially available tPA-augmented assays currently exist only on the ClotPro platform (TPA-test) and the newly developed MultiClot system using Apiro reagents, with no equivalent standardized assay for the widely deployed cartridge-based TEG 6 s or ROTEM sigma analyzers. This restricts the real-world applicability of tPA-VET to centers equipped with these platforms. These limitations do not negate the prognostic associations reported for VET lysis phenotypes, but they reframe what those phenotypes measure and caution against relying on routine VET lysis parameters to diagnose the underlying state of fibrinolysis.

VET transfusion protocols therefore have not necessarily translated to better outcomes. The ITACTIC trial, the largest multicenter trauma trial, found no difference in mortality or transfusion needs between VET-guided and conventional coagulation test-guided major hemorrhage protocols [38]. Importantly, a secondary analysis found that only half of the patients received indicated treatments, and only 20% had their coagulopathy corrected with treatment [39]. In contrast, smaller studies have shown improved 28-day survival, reduction in massive transfusion rates, and lower cost. A 2026 Cochrane review of two trauma RCTs found no mortality difference in trauma subgroups, though TEG/ROTEM-guided algorithms may reduce the proportion of patients requiring fresh frozen plasma (FFP) and platelet transfusion (RR 0.46 and 0.52, respectively; very low-certainty evidence) [40]. Variable protocol implementation and incomplete practice standardization may explain these discrepancies. Additional studies comparing transfusion protocols are needed.

2.11 |. Therapeutic Management

Therapy is generally directed at hemorrhage control, correction of TIC, and prevention of complications such as hypothermia and acidosis (Table 3). The sections below proceed from the overarching resuscitation strategy to specific component and pharmacologic targets, the complications of large-volume transfusion, and thromboprophylaxis after hemorrhage control. Figure 3 presents the overall goal-directed, viscoelastic-guided transfusion algorithm that the following sections describe.

TABLE 3 |.

Pharmacologic and component therapy in the bleeding trauma patient.

Therapy/agent	Indication or trigger	Dose/regimen	Key evidence	Evidence quality	Safety/notes
Balanced-ratio resuscitation	Hemorrhagic shock; MTP activation	Plasma:platelets:RBC 1:1:1	PROPPR [41]	RCT	1:1:1 achieved hemostasis more often and reduced exsanguination death at 24h vs. 1:1:2; each 1-min delay to first product cooler: ~5% higher mortality (adjusted)
Crystalloid restriction	During active MTP	< 3 L within first 6 h	[13]	Narrative review	Excess crystalloid linked to dilutional coagulopathy, respiratory failure, and abdominal compartment syndrome
Permissive hypotension	Until hemorrhage control	Target SBP ~80–90 mmHg; higher if TBI	European guideline [24]	Guideline	Restrictive target raised to preserve cerebral perfusion in TBI
Tranexamic acid (TXA)	As early as possible, within 3 h of injury	1 g IV over 10 min, then 1 g over 8 h	CRASH-2 [42]; PATCH-Trauma [43]; EAST PMG [44]	RCT/meta-analysis	All-cause mortality RR 0.91; delayed dosing (> 3 h) may increase deatha; dose-dependent thromboembolism at higher doses
Epsilon-aminocaproic acid (EACA)	Hyperfibrinolysis when TXA is unsuitable	5 g IV over the first hour, then 1 g/h for up to 8 h (or until bleeding controlled)	FDA aminocaproic acid label	Label	Reserve for TXA intolerance or unavailability; no trauma outcome data; continuous infusion exceeding 24 g/day is associated with prolonged bleeding time
Calcium	During or after the first unit, then after every 4 units (target ionized calcium above 1.0 mmol/L, ideally ≥ 1.2)	1 g CaCl2 IV	AAST/ACS-COT [45]	Guideline/retrospective	Hypocalcemia independently associated with mortalityb
Fibrinogen replacement	Fibrinogen < 150–200 mg/dL (1.5–2.0 g/L) or FIBTEM CA5 reduced	Concentrate 3–4 g (~50 mg/kg) or cryoprecipitate 2 pools (~4g fibrinogen equivalent)	RETIC [46]; CRYOSTAT-2 [47]c	RCT/meta-analysis	Targeted to a measured deficit, not empiric; goal > 200 mg/dL (2.0 g/L)
Platelets	< 50000/μL (general); < 100000/μL (TBI or active CNS bleed)	Apheresis unit(s)	European guideline [24]	Guideline	No rise after 2 units suggests consumption or HLA alloimmunization
Plasma (FFP)	Coagulopathy (INR > 1.5; PT > 18 s or aPTT > 35 s) when component-based resuscitation used	FFP; higher FFP:RBC ratio (1.0–1.5) may benefit blunt or truncal trauma	PROPPR, RCT [41]; observational ratio data [48]	RCT/observational	PROPPR found no significant mortality difference between ratios; observational ratio data are subject to survivorship bias
Recombinant activated factor VII (rFVIIa)	Rescue only, or a clinical trial. Not first-line [24] (Rec. 32)	200 μg/kg, then 100 μg/kg at 1 and 3h (off-label, ~2× the 90 μg/kg hemophilia dose)	Cochrane [49]	RCT/meta-analysis	No mortality benefit in either pivotal trauma RCT; CONTROL stopped early for futility. Cochrane pooled analysis found a consistent trend toward increased thromboembolism (RR 1.45; nonhemophilia pooled)
Desmopressin (DDAVP)	Investigational. Neurosurgical candidates on antiplatelet therapy only	0.4 μg/kg IV	Meta-analysis [50]; NCS/SCCM [51]; ACS TBI Best Practices	Meta-analysis/guideline	Meta-analysis of 5 studies (n = 598): no significant reduction in hematoma expansion (RR 0.80, 95% CI 0.51–1.24) and significantly worse neurological outcomes (RR 1.31, 95% CI 1.07–1.61) [50], Guidance conflicts: NCS/SCCM recommend a single dose, ACS TBI Best Practices do not. Risk of hyponatremia and tachyphylaxis
Vitamin K	Warfarin reversal adjunct	10 mg IV (life-threatening bleed); 1–5 mg oral (supratherapeutic INR without bleeding)	ACC [52]; European guideline [24]	Guideline	Full effect at 12–24 h; give with PCC for immediate reversald
Protamine	Reversal of unfractionated heparin; partial reversal of LMWH	1 mg per 100 U heparin given in the preceding 2–3 h (max 50 mg, slow IV)	Enoxaparin label	Guideline	Only available agent for UFH; partially reverses LMWH (up to ~60% of anti-Xa activity, incomplete); anaphylaxis risk; excess protamine can cause paradoxical bleeding
Four-factor PCC, empiric (nonreversal) use	Not recommended for routine empiric use in trauma	Studied as 25 IU/kg in PROCOAG	PROCOAG [53]	RCT	No reduction in blood-product use; more thromboembolic events (35% vs. 24%); reserve PCC for documented anticoagulant reversal
Cell salvage (autotransfusion)	Active hemorrhage; reduce allogeneic exposure	Anticoagulate, centrifuge, wash; Hct ~50%–80%	[54]	Observational	Dilutional coagulopathy if > 15 units returned
Active warming	Maintain normothermia; rewarm if temperature < 36°C	Warm products and patient (rapid infusers ~500–1000 mL/min)	European guideline [24]	Guideline	Hypothermia independently increases mortality; warming is a graded resuscitation measure

Abbreviations: AAST, American Association for the Surgery of Trauma; ACC, American College of Cardiology; ACS-COT, American College of Surgeons Committee on Trauma; aPTT, activated partial thromboplastin time; CaCl2, calcium chloride; CA5, clot amplitude at 5 min; CI, confidence interval; CNS, central nervous system; DDAVP, desmopressin; EACA, epsilon-aminocaproic acid; EAST, Eastern Association for the Surgery of Trauma; FFP, fresh frozen plasma; FIBTEM, fibrin-based thromboelastometry assay; Hct, hematocrit; HLA, human leukocyte antigen; INR, international normalized ratio; IU, international units; IV, intravenous; LMWH, low-molecular-weight heparin; MTP, massive transfusion protocol; NCS, Neurocritical Care Society; OR, odds ratio; PCC, prothrombin complex concentrate; PMG, practice management guideline; PT, prothrombin time; RBC, red blood cell; RCT, randomized controlled trial; rFVIIa, recombinant activated factor VII; RR, risk ratio; SBP, systolic blood pressure; SCCM, Society of Critical Care Medicine; TBI, traumatic brain injury; TXA, tranexamic acid; U, units; UFH, unfractionated heparin.

^aTXA should be given as early as possible; administration beyond 3 h from injury may increase the risk of death from bleeding.

^bNo prospective trial has yet shown an outcome benefit from correcting hypocalcemia.

^cEmpiric (unguided) fibrinogen supplementation was negative overall in CRYOSTAT-2, which tested 3 pools (~6 g) on top of standard care and showed a prespecified-subgroup signal of harm in penetrating trauma (28-day mortality 16.2% vs. 10.0%; OR 1.74; p = 0.006); the 2-pool (~4 g) dose listed here is the standard targeted-replacement dose, not the empiric high-dose strategy. The trauma fibrinogen-concentrate dose is ~50 mg/kg, whereas the 70 mg/kg figure is the label dose for congenital fibrinogen deficiency.

^dSee Table 4 for the full INR-stratified four-factor PCC reversal regimen.

FIGURE 3 |.

Goal-directed transfusion algorithm using viscoelastic testing in trauma. An actively bleeding trauma patient enters at the top. Gray badges on the left mark the phase of care, and numbers 1–6 mark the decision steps. The two series are independent. Damage-control resuscitation (dashed box, right) runs continuously alongside the algorithm rather than as a step within it, and specifies balanced 1:1:1 product ratios, tranexamic acid within 3 h, restricted crystalloid, permissive hypotension, and correction of calcium, temperature, and acidosis. The emergency override (dashed box, left) takes the exsanguinating patient and the patient going immediately to surgery off the pathway, since they receive empiric products without waiting for a result. Every other patient goes to a viscoelastic test, ROTEM or TEG. The result directs the patient to one of three substrate defects, corrected in the fixed order set by the descending arrows and each shown in its own color across the criteria, the defect, and the product. Excess clot lysis (EXTEM maximum lysis > 15%, CK-TEG LY30 > 4.55%) identifies hyperfibrinolysis, treated with tranexamic acid and confirmed on APTEM. A low fibrin contribution (FIBTEM CA5 ≤ 10 mm, CK-TEG alpha angle < 67°) identifies hypofibrinogenemia, treated with fibrinogen concentrate 3–4 g (about 50 mg/kg) or cryoprecipitate to a target above 200 mg/dL. A low platelet contribution (EXTEM CA5 minus FIBTEM CA5 < 30 mm, CK-TEG maximum amplitude < 60 mm with an adequate alpha angle) is treated with platelets to a target above 50 000/μL, or above 100 000/μL in traumatic brain injury. That branch triggers on the difference between the two amplitudes rather than on EXTEM amplitude alone, because EXTEM amplitude carries the fibrin and the platelet contribution together. A heparin effect is identified by an INTEM clotting time that corrects on HEPTEM and is reversed with protamine, 1 mg per 100 U of heparin. A prolonged clotting time is not interpreted until fibrinogen exceeds 150 mg/dL and clot firmness has corrected, because a viscoelastic clotting time is the interval until the clot reaches 2 mm of amplitude and so depends on fibrin polymerization as much as on thrombin generation. A patient who passes it and whose EXTEM clotting time remains above 80 s (CK-TEG R above 4.45 min) has a residual initiation defect, treated with plasma or four-factor prothrombin complex concentrate. After each product the patient is reassessed for bleeding and retested. The algorithm exits once bleeding and the repeat test have corrected, to de-escalation of the massive transfusion protocol and venous thromboembolism prophylaxis at 24–48 h. ^aA normal native lysis index does not exclude clinically significant fibrinolysis, which EXTEM maximum lysis detects in about 5% of trauma patients. Tissue plasminogen activator-augmented testing is available only on the ClotPro platform and on the Multiclot platform using Apiro reagents. APTEM, aprotinin-modified EXTEM assay; CA5, clot amplitude at 5 min; CK-TEG, citrated kaolin thromboelastography; CT, clotting time; EXTEM, tissue-factor-activated ROTEM assay; FIBTEM, fibrin-based ROTEM assay; HEPTEM, heparinase-modified INTEM assay; INTEM, contact-activated ROTEM assay; LY30, percent lysis 30 min after maximum amplitude; MA, maximum amplitude; ML, maximum lysis; MTP, massive transfusion protocol; PCC, prothrombin complex concentrate; R, reaction time (TEG clot initiation time); RBC, red blood cells; ROTEM, rotational thromboelastometry; SBP, systolic blood pressure; TBI, traumatic brain injury; TEG, thromboelastography; TXA, tranexamic acid; VET, viscoelastic test; VTE, venous thromboembolism; α, alpha angle.

2.12 |. Damage-Control Resuscitation (DCR) and Permissive Hypotension

Historically, damage-control surgery emphasized mechanical control of bleeding followed by blood-product resuscitation. The focus has shifted toward DCR, which combines balanced blood-product transfusion with permissive hypotension, often alongside or before definitive surgical intervention. Permissive hypotension targets a systolic blood pressure of 80–90 mmHg until hemorrhage is controlled, with a higher target for traumatic brain injury to preserve cerebral perfusion [24].

Whole-blood resuscitation has gained renewed interest for delivering balanced therapy, supported by observational data. However, two recent randomized trials, SWiFT and TOWAR, were both negative for their primary outcomes despite the positive observational signal [59, 60]. TOWAR favored component therapy (30-day mortality 25.9% vs. 20.5%; adjusted OR 1.24). Resuscitative endovascular balloon occlusion of the aorta has likewise been proposed as a temporizing hemorrhage-control adjunct, but the UK-REBOA randomized trial found a posterior probability of harm of approximately 87% (90-day mortality 54% vs. 42% with standard care), leaving its role unproven [61]. Cell salvage reduces allogeneic transfusion requirements without increasing rates of infection or mortality, though dilutional coagulopathy may occur in patients receiving large transfusion volumes [54].

2.13 |. Massive Transfusion Protocols

Massive transfusion is currently defined as the transfusion of 10 or more units of red blood cells within 24 h or 3 or more units within 1 h [45]. Current guidance for MTPs favors a 1:1:1 ratio of plasma, platelets, and red blood cells. The 2015 PROPPR trial (n = 680), the largest randomized comparison, found no significant difference in 24-h mortality (12.7% vs. 17.0%; p = 0.12) or 30-day mortality (22.4% vs. 26.1%; p = 0.26) between 1:1:1 and 1:1:2 ratios, but the 1:1:1 group achieved hemostasis more often and had fewer deaths from exsanguination at 24 h (9.2% vs. 14.6%; p = 0.03) [41]. Thresholds for MTP activation and the structure of DCR protocols follow the 2024 AAST/ACS-COT clinical protocol [45].

The timeliness matters as much as the ratio. A PROPPR subanalysis found that each 1-min delay from MTP activation to delivery of the first blood product was associated with a 5% increase in mortality (adjusted OR 1.05 per minute) [62]. Crystalloid should be limited to 3 L within the first 6 h of activation to avoid unnecessary risk of respiratory failure, compartment syndromes, and worsened coagulopathy [13]. MTP laboratory testing should include hemoglobin and hematocrit, PT/INR, aPTT, fibrinogen, ionized calcium, blood-gas analysis, lactate, and VET when available. VET is suitable where expertise is available for rapid interpretation and intervention [34].

2.14 |. TXA and Antifibrinolytics

Hyperfibrinolytic bleeding in TIC occurs primarily in the early minutes to hours after severe injury, driven principally by massive tPA release from hypoperfused endothelium, with any contribution from APC-mediated PAI-1 inhibition now regarded as secondary and uncertain. It is described as continuous venous oozing from mucosa or puncture sites, or a propensity to bleed with minor trauma. It differs from classic disseminated intravascular coagulation (DIC) in that the phenotype is hemorrhagic with excessive fibrinolysis rather than thrombotic with suppressed fibrinolysis. Because the 2025 International Society on Thrombosis and Haemostasis (ISTH) recognized both thrombotic and hemorrhagic DIC phenotypes, screening for DIC remains warranted to distinguish whether antifibrinolytic therapy is appropriate [63].

TXA, which blocks plasminogen from binding to fibrin, is the principal antifibrinolytic in trauma. The CRASH-2 trial, a randomized controlled trial of 20 211 adult trauma patients, showed that 1 g IV over 10 min, followed by 1 g over 8 h, given as early as possible and within 3 h of injury, was associated with reduced all-cause mortality (14.5% vs. 16.0%; RR 0.91, 95% CI: 0.85–0.97) and reduced death due to bleeding (RR 0.85, 95% CI: 0.76–0.96) [42]. The often-cited 21% relative reduction (RR 0.79, 95% CI: 0.64–0.97) derives from an exploratory analysis of bleeding deaths in patients treated 1–3 h after injury, not to all-cause mortality, with a significant treatment-by-time stratification (p < 0.0001) [64]. Delayed administration may increase the risk of death, and a dose-dependent increase in thromboembolic events has been reported [65].

The PATCH-Trauma trial added nuance: prehospital TXA did not improve the primary functional outcome, although 28-day mortality was lower (17.3% vs. 21.8%). A secondary analysis found this mortality benefit only with administration within 90 min of injury (adjusted RR 0.64), with no benefit thereafter [43]. The prehospital STAAMP trial did not reduce 30-day mortality overall (8.1% vs. 9.9%; p = 0.17) but suggested benefit in patients treated within 1 h or in severe shock, and a 2026 Bayesian reanalysis estimated an 84%–99% posterior probability of a mortality benefit [66, 67]. In traumatic brain injury, the CRASH-3 trial (n = 12 737) found no overall reduction in head-injury-related death (RR 0.94, 95% CI: 0.86–1.02) but a benefit in mild-to-moderate head injury (RR 0.78, 95% CI: 0.64–0.95) [68]. Reflecting this evidence, the 2025 Eastern Association for the Surgery of Trauma practice management guideline conditionally recommends routine prehospital and in-hospital TXA for patients at risk of hemorrhage, and a joint position statement of the National Association of EMS Physicians, the American College of Emergency Physicians, and the American College of Surgeons Committee on Trauma supports prehospital administration within 3 h of injury [44, 69].

The 2025 update of the German S3 polytrauma guideline takes a more selective stance, reserving TXA for patients with life-threatening hemorrhage, shock, or confirmed hyperfibrinolysis on the rationale that only about 20% of injured patients are hyperfibrinolytic and that TXA may be detrimental in their absence [70]. When TXA is unsuitable, epsilon-aminocaproic acid (EACA) is an alternative, dosed as an initial 5 g IV over the first hour followed by 1 g per hour for up to 8 h (Table 3).

2.15 |. Calcium Replacement

Citrate in stored blood products chelates free calcium, and the resulting hypocalcemia has been independently associated with mortality (OR 1.29, 95% CI: 1.13–1.47) [13, 71]. Following the 2024 AAST/ACS-COT protocol, 1 g of calcium chloride is given intravenously during or immediately after transfusion of the first unit of blood product and again after every 4 units, or more often as needed. The target is an ionized calcium above 1.0 mmol/L and ideally 1.2 mmol/L or higher [45]. This effect is more pronounced in patients with acidosis, hypothermia, or hepatic dysfunction, all of which decrease citrate metabolism. Regular ionized-calcium monitoring is widely advised, although this guidance derives in part from a narrative review rather than a formal trauma guideline, and it should be regarded as a relatively weak recommendation [45]. No prospective trial has yet demonstrated improved outcomes from correcting hypocalcemia.

2.16 |. Goal-Directed Component Therapy

Once bleeding is controlled and ratio-based resuscitation has stabilized the patient, therapy transitions to goal-directed transfusion guided by conventional and viscoelastic parameters (Table 2). Fibrinogen replacement in TIC should be targeted. When fibrinogen falls below 150 mg/dL (1.5 g/L), the European treatment guidelines trigger, or when FIBTEM CA5 is reduced on VET, administer either fibrinogen concentrate (approximately 50 mg/kg or a fixed 3–4 g) or a standard cryoprecipitate dose (2 pools [10 units], approximately 4 g of fibrinogen), aiming to raise levels above 200 mg/dL (2.0 g/L) [24, 46]. A secondary analysis of the RETIC trial found that post-treatment fibrinogen below 200 mg/dL was associated with an increased need for massive transfusion, although the discriminatory accuracy was modest (area under the curve approximately 0.65) and the sample small [46].

The CRYOSTAT-2 trial (n = 1604) showed no mortality benefit from early empiric high-dose cryoprecipitate (3 pools, about 6 g of fibrinogen, given in addition to standard care), and a prespecified subgroup analysis raised a signal of harm in penetrating trauma (28-day mortality 16.2% vs. 10.0%; odds ratio 1.74, 95% CI: 1.20–2.51; p = 0.006). Given the open-label design and the number of subgroups examined, this finding is hypothesis-generating [47]. A 2025 meta-analysis of five RCTs (n = 1758) found no association between early empiric fibrinogen replacement and improved mortality [72]. Clinicians should therefore obtain fibrinogen levels (conventional or viscoelastic) as early as possible and replace to a measured target.

Platelet and plasma transfusion are directed by different triggers and should not be conflated. Platelet transfusion is guided by platelet count, whereas in patients on antiplatelet agents, it is guided by platelet dysfunction rather than INR. For platelets, the transfusion threshold is below 50 000/μL for a bleeding patient, with a higher threshold of 100 000/μL for traumatic brain injury [73]. If the platelet count fails to rise after transfusion of 2 units, a consumptive process or HLA alloimmunization should be investigated [21].

Plasma is directed at prolonged clotting times with guidelines recommending FFP for a PT greater than 18 s, aPTT greater than 35 s, or INR greater than 1.5 [74]. The PROPPR trial remains the definitive randomized comparison and found no significant mortality difference for higher plasma ratios during initial resuscitation. Observational data nonetheless associate higher FFP:RBC ratios (approximately 1.0–1.5) with lower mortality, for example an adjusted odds ratio of 0.73 in severe blunt trauma; though such analyses are subject to survivorship bias as early death precludes further transfusions [48].

2.17 |. Coagulation Factor Concentrates

Empiric four-factor prothrombin complex concentrate (4F-PCC) is not recommended in bleeding trauma patients without a specific reversal indication. The PROCOAG trial showed no reduction in 24-h blood-product consumption and found increased thromboembolic events, a prespecified secondary safety outcome (35% vs. 24%; absolute difference 11 percentage points, 95% CI: 1–21; relative risk 1.48, 95% CI: 1.04–2.10; p = 0.03) [53].

2.18 |. Recombinant Activated Factor VIIa

Recombinant activated factor VIIa (rFVIIa, NovoSeven) is likewise not recommended for routine use. In the CONTROL randomized trial, it reduced blood-product use but did not improve mortality and was stopped for futility, consistent with the earlier Boffard trials, while pooled analyses indicate increased arterial thromboembolism (approximately 45%; RR 1.45, 95% CI: 1.02–2.05) [49]. No trauma dose is established, and any use is confined to last-resort rescue after standard measures and correction of physiology have failed [73].

2.19 |. Complications of Massive Transfusion

The major complications of massive transfusion overlap with the lethal triad of trauma: acidosis, hypothermia, and coagulopathy. Maintaining normothermia is a resuscitation priority. The 2024 AAST/ACS-COT protocol targets 37°C, with active rewarming initiated below 36°C, as hypothermia independently increases mortality and transfusion requirements [45]. Blood product warming is accomplished with rapid-infusion devices, though efficiency decreases at the highest flow rates [24].

Electrolyte derangements are the second major complication. Citrate chelation of free calcium produces hypocalcemia in up to 97% of massively transfused patients; management is addressed in the Calcium Replacement section above [75]. Hyperkalemia is a concern primarily in pediatric patients and those with renal impairment, as stored red cells leak potassium at approximately 1 mmol/L per day, with additional risk from irradiation, rapid infusion, acidosis, hyperglycemia, and hypothermia [76].

Although stored blood has a pH of 6.5–6.9, metabolic alkalosis from hepatic conversion of citrate to bicarbonate is the more common acid–base sequela. Empiric bicarbonate is not recommended given the risk of overcorrection. Acidosis severity nonetheless correlates with mortality, and management should focus on temperature control, calcium replacement, and appropriate blood-product resuscitation [13].

2.20 |. VTE Prophylaxis

Trauma patients are at high risk for VTE, and the timing of pharmacologic prophylaxis requires balancing the competing risks of bleeding and thrombosis. Mechanical prophylaxis with intermittent pneumatic compression should be applied early while the patient remains at risk of bleeding, and the European guideline recommends initiating combined pharmacologic and mechanical thromboprophylaxis within 24 h once bleeding has been controlled [24]. In traumatic brain injury, low-molecular-weight heparin is generally preferred once repeat imaging confirms that the intracranial hemorrhage (ICH) is stable [77].

2.21 |. Special Populations: Preinjury Antithrombotics and Liver Disease

A minority of trauma patients take antithrombotic drugs or have liver disease, and although the core resuscitation sequence is unchanged, a few agent-specific points intersect with TIC management and VET. Preinjury anticoagulation (roughly 1%–2% of the population, now predominantly direct oral anticoagulants) and antiplatelet therapy (~12% of trauma patients) chiefly raise the risk of traumatic intracranial hemorrhage [78, 79]. The decision to reverse should be driven by bleeding severity and procedural urgency. For factor Xa inhibitors requiring reversal, 4F-PCC is now the practical default following the 2025 US withdrawal of andexanet alfa, whose confirmatory trial showed excess thromboembolism [52, 58]. Idarucizumab remains first-line for dabigatran based on the RE-VERSE AD trial and protamine for heparin [51, 55]. No agent rapidly reverses antiplatelet drugs, and platelet transfusion did not improve outcomes in the PATCH trial, so it is generally avoided outside neurosurgical candidates [57]. In advanced liver disease where there is often abnormal fibrinogen and fibrinolysis, conventional INR and PT poorly reflect bleeding risk and should not guide transfusion. VET is preferred, with cryoprecipitate or 4F-PCC favored over high-volume plasma due to risk of worsening portal hypertension [80]. Reversal strategies and doses are summarized in Table 4; readers are referred to dedicated guidelines for comprehensive management.

TABLE 4 |.

Reversal of anticoagulant and antiplatelet agents in the bleeding trauma patient.

Agent or class	Half-life	Scenario	Reversal strategy	Dose	Onset of reversal	Evidence or notes
Direct factor Xa inhibitor (apixaban 8–15 h; rivaroxaban 5–13 h)	5–15h	Life-threatening or critical-site bleeding	4F-PCC (practical default); andexanet alfa only where still stocked	4F-PCC fixed 2000 U IV	~10 min (4F-PCC)	Andexanet was withdrawn from the US market in 2025a
Direct factor Xa inhibitor	As above	Nonlife-threatening bleeding	Discontinue; supportive care	Not applicable	Not applicable	Weigh time since last dose and renal function; relatively short half-lives often allow watchful waiting
Edoxaban (direct factor Xa inhibitor)	10–14 h	Life-threatening or critical-site bleeding	4F-PCC (practical default)	4F-PCC fixed 2000 U IV	~10 min	Andexanet was off-label for edoxaban even before its market withdrawal; 4F-PCC is the practical option
Dabigatran (direct thrombin inhibitor)	12–17 h	Life-threatening or critical-site bleeding	Idarucizumab; activated PCC if unavailable	5 g IV (two 2.5 g vials)	< 5 min (idarucizumab)	Near-complete reversal in RE-VERSE AD [55]
Warfarin (vitamin K antagonist)	36–42 h	Life-threatening or major bleeding	4F-PCC, INR-stratified, plus IV vitamin K	4F-PCC 25 U/kg (INR 2–<4), 35 U/kg (INR 4–6), 50 U/kg (INR >6), max 5000 U with dosing weight capped at 100 kg; vitamin K 10 mg IV [52]	~10 min (4F-PCC); 4–6 h (IV vitamin K)	A 2024 meta-analysis found fixed dosing (at least 2000 U suggested optimal) achieved clinical hemostasis more often than weight-based dosing (74.1% vs. 61.6%), but reached INR < 1.5 less often (64.6% vs. 74.3%) [56].
Warfarin	As above	Urgent surgery, no active bleeding	4F-PCC plus low-dose IV vitamin K	Same INR-stratified 4F-PCC dosing; vitamin K 2.5–5 mg IV	~10 min (4F-PCC)	Reserve full INR-stratified protocol for immediate, complete reversal
Warfarin	As above	Supratherapeutic INR, no bleeding	Hold warfarin; oral vitamin K	Vitamin K 1–2.5 mg PO (INR 4.5–10), 2.5–5 mg PO (INR > 10)	18–24 h (oral vitamin K)	PCC not indicated in the absence of bleeding
Unfractionated heparin	~1 h (IV)	Active bleeding	Protamine sulfate	1 mg per 100 U heparin given in the preceding 2–3 h; max 50 mg; slow IV over 10 min	Immediate	Anaphylaxis risk; excess protamine can paradoxically prolong bleeding
Low-molecular-weight heparin (enoxaparin)	4.5–7 h	Active bleeding	Protamine sulfate (partial reversal)	1 mg per 1 mg enoxaparin if within 8 h, 0.5 mg per 1 mg if 8–12 h; max 50 mg	Immediate	Reverses up to ~60% of anti-Xa activity (enoxaparin prescribing information)
Antiplatelet agents (aspirin, P2Y12 inhibitors)	Variableb	Acute injury	Stop all antiplatelet therapy; no approved reversal agent	Not applicable	Not applicable	2024 ACS TBI guidance: no specific reversal agent
Antiplatelet agents, nonsurgical ICH	Variableb	ICH, not a surgical candidate	Avoid platelet transfusion; standard care	Not applicable	Not applicable	Platelet transfusion worsened outcomes in PATCHc [57]
Antiplatelet agents, neurosurgical candidate	Variableb	ICH requiring surgery	Single apheresis platelet unit; DDAVP investigational	1 apheresis platelet unit; DDAVP 0.4 μg/kg IV	~30 min (DDAVP)	No proven benefit. Worse neurological outcomes [50]. See Table 3
Antiplatelet agents	Variableb	Restart timing	Resume antiplatelet therapy	As early as ~4 days postinjury	Not applicable	Expert opinion; most rebleeds occur within the first 3 days

Abbreviations: 4F-PCC, four-factor prothrombin complex concentrate; ACS, American College of Surgeons; CI, confidence interval; DDAVP, desmopressin; h, hours; ICH, intracranial hemorrhage; INR, international normalized ratio; IV, intravenous; min, minutes; PCC, prothrombin complex concentrate; PO, by mouth; TBI, traumatic brain injury; U, units.

^aThe confirmatory ANNEXA-I trial reported more thromboembolic events with andexanet than with usual care (10.3% vs. 5.6%) [58]. The agent was withdrawn from the US market in 2025.

^bAntiplatelet effect is governed by platelet turnover (roughly 7–10 days for irreversible agents such as aspirin and clopidogrel) rather than by plasma drug half-life, so reversal decisions depend on the clinical scenario rather than on a pharmacokinetic half-life.

^cIn PATCH (spontaneous, nontraumatic ICH, surgical candidates excluded), platelet transfusion increased the odds of death or dependence (adjusted common odds ratio 2.05, 95% CI 1.18–3.56); direct applicability to traumatic ICH is uncertain.

2.22 |. Future Directions and Knowledge Gaps

Several knowledge gaps warrant further investigation. Prospective trials are needed to establish VET thresholds and to determine whether improved protocol adherence can translate VET-guided resuscitation into measurable outcome benefits. The clinical significance of fibrinolysis shutdown and whether antifibrinolytic therapy should be withheld or continued remains unresolved. Prospective trials are needed to address the lack of antiplatelet reversal agents and the unsettled roles of desmopressin and platelet-function-guided transfusion. Translational studies are required to evaluate glycocalyx-protective strategies and ADAMTS-13 supplementation as endotheliopathy-targeted therapies. Optimal timing for restarting antithrombotics and initiating VTE prophylaxis posthemorrhage, particularly in patients with high thrombotic risk, ICH, or ongoing coagulopathy, remains under investigation.

3 |. Conclusions

TIC is a dynamic, multifactorial process that evolves through distinct hypocoagulable, physiologic, and hypercoagulable phases. Recognition of trauma endotheliopathy has expanded understanding beyond a simple consumption-dilution model, and viscoelastic assays now characterize coagulopathy in real time, although a mortality benefit over conventional testing has not been demonstrated. The central trajectory of the field is a shift from empiric, ratio-based resuscitation toward individualized, mechanism-informed, and test-guided care. Realizing that shift will depend on institution-specific viscoelastic thresholds, clearer roles for endotheliopathy-directed and antifibrinolytic therapy, and rigorously evaluated treatment algorithms, because the outcome evidence for many current practices remains incomplete.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.