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PRIMER
Trauma-induced coagulopathy
Ernest E. Moore 1,2 ✉, Hunter B. Moore2, Lucy Z. Kornblith 3, Matthew D. Neal4,
Maureane Hoffman5, Nicola J. Mutch6, Herbert Schöchl7, Beverley J. Hunt 8 and
Angela Sauaia 2,9
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.
Injury is the fourth leading cause of mortality world- after mechanical control of bleeding sites — in other
wide, accounting for 9% of deaths globally (4.9 million words, they were due to coagulopathy12. The remain-
people) in 2016 (ref.1). Moreover, the burden is highest ing ongoing quagmire is the inability to distinguish
in individualsPrimer
Author addresses investigators from diverse disciplines to pursue answers
to the substantial gaps in knowledge.
1
Ernest E Moore Shock Trauma Center at Denver Health, Denver, CO, USA.
2
Department of Surgery, University of Colorado Denver, Aurora, CO, USA. Epidemiology
3
Trauma and Surgical Critical Care, Zuckerberg San Francisco General Hospital, Uncontrolled bleeding has been reported to cause
University of California San Francisco, San Francisco, CA, USA.
25% of all injury-related deaths19–27, and 40–80% of
4
Pittsburgh Trauma Research Center, University of Pittsburgh Medical Center, Pittsburgh,
potentially preventable deaths 28, both in military and
PA, USA.
5
Duke University School of Medicine, Transfusion Service, Durham VA Medical Center, in civilian settings (Supplementary Table 1). At least
Durham, NC, USA. a quarter of the haemorrhagic deaths probably have a
6
Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences and TIC component29. Uncontrolled bleeding as a cause of
Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK. death following injury is observed globally; for exam-
7
Department of Anesthesiology and Intensive Care Medicine, AUVA Trauma Centre ple, Australian25 and Canadian30 studies implicated
Salzburg, Academic Teaching Hospital of the Paracelsus Medical University, Salzburg and haemorrhage in 15–33% of injury-related deaths. In
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Trauma Stavanger, Norway, 25% of trauma-related deaths
Research Centre, Vienna, Austria. between 1996 and 2004 were due to exsanguination26.
8
King’s College, London, UK.
In a Turkish hospital, from 2010 to 2013, circulatory
9
Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
collapse accounted for 33% of injury-related deaths31.
In Brazil, haemorrhage caused 18% of trauma-related
Potentially preventable
Coagulopathy, metabolic acidosis and hypothermia were deaths in an urban hospital32. Two European studies33,34
deaths
The three criteria that must be initially emphasized as the three pillars of life-threatening found lower proportions of haemorrhagic deaths; how-
present in a trauma-related post-injury bleeding (known as the ‘lethal triad’). ever, these studies underestimated death attributable
death to qualify as potentially For discussion purposes, we suggest the terms ‘early to bleeding because they classified polytrauma, chest
preventable are: the injury TIC’ and ‘late TIC’ but acknowledge that the pheno- injury and cardiac arrest as separate, non-haemorrhagic
must have been survivable,
the delivery of care was
types can vary substantially within these time periods. causes of death. Differences in populations, injury
suboptimal, and the error in Early TIC (generally within 6 hours of injury) is char- mechanisms and health-c are resources explain the
care must have been directly acterized by the inability to achieve haemostasis, which disparities in statistics. Since the 1990s, when bleed-
or indirectly implicated in the may lead to uncontrolled haemorrhage and protracted ing caused over one third of trauma fatalities20,, we
death of the patient.
shock; whereas late TIC (usually >24 hours after injury) have made little progress, as currently haemorrhage
Bleeding control is represented by a hypercoagulable state, which may accounts for 20–34% of trauma-related mortality24,35.
bundle-of-care result in excessive macro-clotting and micro-clotting Although a reduction in bleeding-related deaths was
A series of measures to leading to thromboembolic events (for example, deep observed in a US urban trauma centre after implement-
optimize bleeding control, venous thrombosis (DVT) and pulmonary embolism) ing a bleeding control bundle-of-care (from 36% to 25%)27,
including: accurate
identification of the bleeding
or to acute respiratory distress syndrome (ARDS) and haemorrhage remained frequent among potentially pre-
patient; damage control multiple organ failure. Of note, early and late TIC are ventable deaths despite the bundle (decreasing from 48%
resuscitation; haemostatic not mutually exclusive, that is, patients may develop to 43%)36.
techniques with tourniquets, early TIC due to massive blood loss but die of exten- Understanding the timing of haemorrhagic deaths
pelvic binders or haemostatic
sive microvascular occlusion recognized as irreversible is crucial to determine when haemostatic therapies
dressings; resuscitative
endovascular balloon occlusion shock. Furthermore, the transition from hypocoagula- are most effective, and which outcomes (such as the
of the aorta; thromboelastog- bility to hypercoagulability may occur within minutes or need for massive transfusion, all-cause or haemorrhagic
raphy coagulation monitoring; hours or be delayed for days. deaths, and early or late mortality) they may affect4,37.
tranexamic acid administration Notably, disseminated intravascular coagulation Trauma-related deaths immediately after injury are often
for substantial hyperfibrinolysis;
decreased time to operating
(DIC) is a syndrome related to but distinct from TIC. due to irreparable injuries; thus, haemostatic interven-
room and interventional DIC is defined as “an acquired syndrome character- tions are more likely to affect haemorrhagic deaths
radiology; and goal-directed ized by the intravascular activation of coagulation with over the ensuing hours. Randomized controlled trials
resuscitation with blood a loss of localization arising from different causes”16. (RCTs)2,5,6,38–41 and observational studies30,31,42 unequiv-
products.
A consensus statement from the International Society ocally show that haemorrhagic deaths occur within
Massive transfusion on Thrombosis and Haemostasis (ISTH) clarified the 24 hours of injury, mostly within 3–6 hours. Traumatic
Several definitions exist. common as well as distinct mechanisms of DIC ver- brain injury (TBI) is also a prevalent cause of death in the
The most frequently used is sus TIC17. Early TIC is dominated by acute blood loss 6–24-hour period, and multiple organ failure becomes
>10 units of red blood cells with associated shock (and ischaemia–reperfusion prevalent after the first week2. In the CRASH-2 trial, rep-
(RBCs) per 24 hours, although
this definition is liable to
damage), impaired clot formation and, in severe cases, resenting mainly developing countries, 34% of all deaths
substantial survivor bias. Other hyperfibrinolysis (Fig. 1). In TIC, tissue factor (TF; a were attributed to bleeding, 50% of which were due to
definitions include: the critical procoagulant factor) facilitates clot formation at sites haemorrhage occurring within 10 hours40. Analyses of
administration threshold (CAT, of endothelial injury, whereas in DIC there is unbridled three recent US RCTs focusing on post-injury haemor-
≥3 RBC units per hour in the
systemic clotting often promoted by TF expression on rhage control, with comparable populations, methods
first hour or in any of the first
4 hours from arrival); >4 RBC several cell surfaces. Ultimately, the late systemic pro- and health-care resources, showed that most haemor-
units or death in the first hour thrombotic–antifibrinolytic TIC phenotype mirrors rhagic deaths occurred in the first 6 hours7,43. Half of all
after injury, a definition that certain DIC phenotypes18. deaths in the first 3–6 hours in these three RCTs were
has the advantage of minimizing In this Primer, we describe what is known of TIC, due to haemorrhage.
survivor bias; and >4 RBC units
within the first hour, which is
but perhaps more importantly we acknowledge what The incidence of TIC diagnosed via laboratory
also known as the resuscitation remains to be defined. Our primary objective is to tests varies (Supplementary Table 2), but most studies
intensity definition. provide a broad picture of the entity TIC to inspire converge around a TIC incidence of 25% of severely
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Trauma-induced coagulopathy
Hypocoagulability Hypercoagulability
Platelet Fibrinogen Decreased thrombin Increased thrombin Platelet Fibrinolysis
Hyperfibrinolysis dysfunction depletion generation generation Hyperfibrinogenaemia activation shutdown
Bleeding phenotypes Mixed phenotypes Thrombotic phenotypes
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/)39.
injured patients, with an associated 35–50% mortality. coagulation and thereby prevent clot formation at inap-
Children in general develop TIC later and less frequently propriate times and places. Physiological haemostasis is
than adults44, and TIC in children is typically associ- terminated when the area of injury is surrounded by a
ated with TBI. Older individuals are more vulnerable platelet–fibrin clot that stops bleeding, forms a physical
to TIC than younger adults45,46. Severe tissue injury and barrier to the diffusion of activated factors and provides
shock or hypoperfusion are the major risk factors for a provisional scaffold for healing processes. Coagulopathy
TIC (Supplementary Table 2). Studies in civilian47 and occurs not only when procoagulants are consumed or
military48 populations have indicated that TIC is more diluted, but also when one or more of the control mech-
severe when both severe tissue injury and shock are anisms are disrupted. Thus, not only can the amount
present. Metabolic acidosis and penetrating injury of thrombin generation be abnormal, but thrombin
are commonly reported risk factors for TIC (Table S2). localization can also be abnormal. Because trauma is
Long pre-hospital times49 and pre-hospital treatment such a heterogeneous event, it is difficult to define a
with crystalloid solutions49,50 worsen TIC. The severity dominant mechanism of TIC. Furthermore, haemostatic
of TIC correlates with the severity of TBI (Table S2), function changes over time as bleeding continues, com-
but studies51,52 have suggested that hypoperfusion is an pensatory mechanisms are engaged and inflammation
important cofactor. An often-neglected factor is hypo progresses.
calcaemia, caused by both shock and blood products
containing citrate (especially plasma and platelets), Cell-based model of haemostasis
which has an anticoagulant effect by chelating calcium The cell-based model of haemostasis proposes that cells
ions, and it has been suggested that the ‘lethal triad’ have active roles in regulating and localizing the coagu-
should include hypocalcaemia and become the ‘lethal lation reactions56. Receptors, lipids and other structures
diamond’53,54. Of note, it is important to recognize that of cell surfaces are crucial to defining the roles of spe-
although TIC is common in severely injured individuals, cific cell types in haemostasis. Platelets and endothelial
many patients with laboratory-based TIC do not have cells are the two key players. Platelets adhere at a site of
substantial bleeding14. injury and provide the surface on which procoagulant
reactions occur, and they control the rate and locali-
Mechanisms/pathophysiology zation of thrombin production57. Endothelial cells are
The biochemical reactions of physiological haemostasis physiologically actively antithrombotic and prevent
are subject to control at several levels. Some control mech- propagation of clotting from a site of injury throughout
anisms act on the various factors and steps of the coag- the vasculature55.
ulation cascade; additional regulation levels involve the Impaired cell-mediated regulation of haemostasis
Crystalloid solutions
Isotonic plasma volume
anticoagulants and protease inhibitors, as well as the cellu- can lead to haemostasis failure, even when the levels
expanders that contain lar and tissue localization of coagulation55. These control of the protein components are within normal ranges.
electrolytes. mechanisms are barriers to the activation and spread of This concept is particularly relevant to understanding
NATURE REVIEwS | DISEASE PrIMErS | Article citation ID: (2021) 7:30 3
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the mechanisms of bleeding and thrombosis induced transient haemorrhagic shock may be tolerated, when
by trauma. In the cell-based model of haemostasis, it is compounded by tissue injury, haemodilution and
the overlapping events of initiation (via the extrinsic coagulation factor abnormalities, it is a major driver
pathway on TF-bearing cells), amplification (positive of TIC. It is important to distinguish early, hypocoag-
feedback of thrombin on platelets) and propagation of ulable TIC (Fig. 2) from iatrogenic coagulopathy due to
large-scale thrombin generation (via the intrinsic path- resuscitation with large volumes of cold fluids and blood
way on activated platelets) are regulated by cell surfaces products, which leads to dilution of enzymes required
rather than by the protein components alone (Fig. 3). for clot formation, and hypothermia, which impairs
clotting factor activity and platelet function12,58. The
Haemorrhagic shock hypocoagulable TIC phenotype can be attributed par-
The pathophysiology of haemorrhagic shock is fun- tially to metabolic acidosis as a result of reduced oxygen
damentally blood volume depletion with diminished delivery to tissue beds and organs49,59–63. In animal stud-
oxygen delivery to the microcirculation, ultimately ies and in vitro experiments, acidosis has been shown
resulting in metabolic acidosis. Although isolated to retard fibrin polymerization and clot strengthening
Hypocoagulability Hypoperfusion Tissue injury
Hypercoagulability
1 Hypoxia DAMPS Modifying factors
• Histones or DNA • Genetics
• Epinephrine • Polyphosphates • Comorbidities
• Tissue factor exposure • HMGB1 • Medications
Endothelial activation
2 Clotting Platelet activation • Complement
activation
• NETosis
• Extravascular
Immune system activation vesicles
Thrombin Factors Platelet Fibrinogen tPA PAI-1
consumption dysfunction depletion
Activated Heparan Metabolites
3 sulphate
protein C • Succinate
• Taurocholic acid
• Acidosis Haemolysis
• Hypothermia • α enolase
Factor Va • Dilution α2 antiplasmin • α globin
Annexin A2
Fibrinogen Fibrin Plasmin Plasminogen
4
Reduced clot formation Platelet
Increased clot formation dysfunction
Fig. 2 | Mechanisms of trauma-induced coagulopathy. Progress in mediators that reduce fibrinogen, impair platelet function and compromise
understanding the pathogenesis of trauma-induced coagulation (TIC) has thrombin generation (3), ultimately resulting in inadequate clot formation
been moved forward by the concept of the cell-based model of coagulation, for haemostasis (4). Increased fibrinolysis via plasmin generation further
which emphasizes the fundamental role of platelets as a platform for compromises haemostatic capacity. These defects are accentuated by
clotting factor assembly and their interaction with endothelium that ongoing blood loss, haemodilution, metabolic acidosis and hypothermia.
culminates in thrombin generation and incorporation of fibrin to form a A colour gradient indicates that the mechanism can result in both
haemostatic plug. Although there are several hypotheses on the driving hypocoagulation and hypercoagulation. DAMPs, damage-associated
mechanisms, tissue injury and shock (1) synergistically activate the molecular patterns; HMGB1, high mobility group protein B1;
endothelium, platelets and the immune system (2) to generate an array of PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen factor.
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to adrenaline, vasopressin and thrombin signalling as
Initiation Amplification
well as hypoperfusion, which drives the fibrinolytic
Tissue FX Prothrombin FVIII FVIIIa phenotype of TIC74.
factor
Priming amount In addition, metabolic by-products, such as succi-
of thrombin FXI nate, have been associated with early TIC75, and oxi-
FXa
FVIIa FVIIa Thrombin dative stress has been shown to modify fibrinogen
FVa
polymerization resulting in weakened clots76. Finally,
FV FVa FXIa hypocalcaemia is another mechanism by which haem-
Endothelial
cell orrhagic shock can impair coagulation. Calcium has
Platelet an important role in the formation and stabilization of
FV fibrin polymerization sites and, consequently, it affects
FVIIa FIX all platelet-dependent functions77. Of note, laboratory
coagulation tests may not detect the negative effect of
hypocalcaemia on coagulation, as blood samples are
Propagation FX Prothrombin re-calcified prior to being assayed. Hypocalcaemia is
prevalent after haemorrhage, owing to resuscitation
FXa with citrated blood products, low hepatic clearance of
FIXa
Thrombin citrate due to defective hepatic perfusion78, and other still
FVa
FVIIIa Large amount poorly understood shock-related mechanisms53,67.
of thrombin As haemorrhagic shock progresses, hypercoagulabil-
FIX FXIa Activated ity ensues, owing to prothrombotic changes and fibrinol-
platelet ysis shutdown (see below) that promote organ damage
by generating thrombi and occluding the microvascu-
lar circulation, leading ultimately to organ failure9,79.
Hypocoagulability and increased fibrinolysis during
shock may well represent intrinsic mechanisms to pre-
Fig. 3 | Cell-based model of coagulation. In the cell-based model of coagulation, vent these events from occurring; it remains debatable
initiation occurs on tissue factor (TF)-bearing cells, via the extrinsic pathway, and results whether these are adaptive or pathological responses80.
in the activation of small amounts of thrombin. Thrombin generated on the TF-bearing
cell amplifies the procoagulant response by activating additional coagulation factors Tissue injury
and platelets. The large burst of thrombin required for formation of a fibrin clot is Tissue injury promotes both early hypocoagulability and
generated on platelet surfaces during the propagation phase. Adapted with permission contributes to later hypercoagulability. Tissue damage
from ref.318, Wiley.
with endothelial disruption activates the coagulation
system at the injury site via TF, a transmembrane pro-
in viscoelastic haemostatic assays (VHAs)60; to decrease tein expressed within the sub-endothelium that becomes
factors V and IX activity and platelet aggregation64; to exposed. TF complexes to factor VIIa and activates the
increase fibrinogen consumption61; to reduce platelet coagulation system, resulting in thrombin generation
count, thrombin generation and maximum clot strength; and fibrin formation81. Moreover, tissue trauma pro-
and to induce abnormal conventional coagulation test vokes the release of damage-associated molecular pat-
results59. A pH drop from 7.4 to 7.2 reduces the activity of terns (DAMPs), which stimulate inflammatory pathways
each of the coagulation proteases by more than half 63,65. by the release of several mediators. Inflammation and
Viscoelastic haemostatic
assays
Hypothermia is now less frequent with modern haemo- coagulation are interrelated processes that robustly
These assays measure change static, goal-directed resuscitation with warm fluids66,67, but influence one another.
in viscoelastic properties of it should not be overlooked. An in vitro study of blood The development of TIC is typically associated with
the whole blood during clot from healthy volunteers68 found a substantial reduc- the severity and extent of tissue injury48,82. Tissue dam-
formation, strengthening
tion in both platelet function and coagulation enzyme age and shock-related hypoperfusion frequently occur
and dissolution. The most
commonly used devices activity at temperaturesPrimer
inhibitors84,85. Damage to organs with high contents of injuries is unknown. It is similarly unclear whether any
tissue plasminogen factor (tPA; which is profibrino- pre-existing chronic conditions in these tPA-rich organs
lytic), such as the pancreas, lung and urogenital system, may modulate TIC dynamics. In addition, tissue injury
may also compromise haemostasis via fibrinolytic acti- has also been directly correlated with fibrinolysis shut-
vation. However, the exact contribution of these organ down through release of cellular by-products of injury,
Adaptive Maladaptive
1 Vascular 2 Response to 3 Clot Fibrin 4 Haemorrhagic shock, 5 Microvascular and
breach endothelial signals formation mesh hypofusion macrovascular thrombosis
RBC and inflammation
Endothelial cell Activated
NETosis
Collagen Quiescent platelet platelet Vascular leak
Glycocalyx and exposed
Weibel-Palade body endothelium
vWF Fibrinogen
Tissue ADAMTS13 Glycocalyx
factor Thrombus Ultra shed
Platelet growth large
tethering ↓ ADAMTS13
vWF
Neutrophil
Leukocyte
migration Monocyte
Thrombin Increased
Epinephrine, Development activated platelets
Development of circulating
PAF, calcium and of PLAs platelet balloons
other platelet
surface stimulants Platelet primary and
secondary function failures
Dysfunctional
Platelet adhesion thrombus
and thrombus formation
Platelet
activation
Thrombin
generation
Fluid leak
Quiescent platelets Endothelial glycocalyx Platelet activation Loss of barrier function
ADP and vascular leak
Thrombin
MMP
↑ Ca2+
Ca2+
Intercellular
junction
PAF
↑ NO Exposed basement membrane
↑ PGI2
Hyaluronan P-selectin Epinephrine TXA2 PAR4 GPIbV-IX complex
Heparan sulfate Adhesion receptor Platelet soluble factors TP PAR1 GPIIb/IIIa
Glycosaminoglycan Phosphatidylserine exposure α granule P2Y1 PAFR GPIa/IIa
Syndecan 1 EVs Dense granule P2Y12 α2A GPVI
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as well as mechanical trauma to red blood cells (RBCs) EOT is mediated by hypoperfusion and is charac
and platelets, leading to the release of their contents86. terized by circulating markers of shed endothelial glyco
A recent study suggested that myosin can bind factors calyx associated with coagulopathy, inflammatory
Xa and Va, thereby increasing their ability to create pro- complications, vascular thrombosis, organ failure and
thrombinase and generate thrombin87. In both preclini- death92–94 (Fig. 4). The glycosaminoglycan syndecan-1
cal models and patient studies, tissue injury results in the is the most well-characterized circulating biomarker
production of extracellular vesicles from multiple cellu- induced by sheddases90 (membrane-bound enzymes
lar sources, which are strongly prothrombotic and may that cleave and release ectodomains) in TIC, as its hep-
result in coagulation factor depletion after injury88,89. aran sulfate ectodomain is shed with hypoperfusion,
catecholamine surges and oxidative stress. It remains
Endothelial dysfunction controversial whether auto-heparinization due to the
The endothelial cell surface network governs coagu- heparan sulfate domain contributes to impaired clot
lation, inflammation, microcirculation, and barrier formation, as endogenous anticoagulation due to hep-
function crucial to vascular homeostasis and oxygen aran is variably identifiable by viscoelastic assays95.
delivery (Fig. 4). Trauma-associated damage to this net- Pathological cleavage of the syndecan-1 ectodo-
work, termed the endotheliopathy of trauma (EOT), is main may be mediated by matrix metalloproteinases
characterized by loss of barrier function, leukocyte adhe- (MMPs) of the ADAM (a disintegrin and metallo
sion, endothelial activation, clinical expression of coagu- proteinase) family. However, it is unclear whether poor
lopathy, micro-thrombosis and macro-thrombosis, and outcomes associated with shed proteoglycans are due
organ dysfunction. Mechanistically, it is probable that to direct or downstream effects of altered protective
TIC contributes to EOT as well as vice versa90. The role glycoproteins. Experimental work suggests that the
of the intrinsic (also known as contact) pathway activa- tissue injury-driven and shock-driven activation of
tion of the coagulation system as a result of exposure to the thrombin–thrombomodulin system, and ultimate
disrupted endothelium remains unclear91. In the intrin- depletion of protein C, diminish endogenous cyto
sic pathway, a negatively charged surface activates fac- protective effects on the endothelium51,73,96. Additionally,
tor XII, and factor XIIa cleavage of prekallikrein results altered platelet–endothelium regulation in TIC may
in the serine protease kallikrein, which can cleave high disrupt an important symbiosis, as soluble CD40, a
molecular weight kininogen to generate bradykinin. platelet ligand for endothelial inflammatory cascades,
Bradykinin can both induce the expression of TF and is associated with TIC97. Further, both sustained exo-
generate tPA. cytosis of structurally ultra-large von Willebrand factor
(vWF; an adhesive protein) and impaired clearance of
vWF by ADAMTS13 (a disintegrin and metalloprotein-
◀ Fig. 4 | Platelet and endothelial interactions. Projecting beyond the cell membrane ase with thrombospondin motifs 13) have been identi-
of healthy endothelial cells is a glycocalyx of polysaccharides linked to membrane fied in injured patients with TIC98, and are associated
and trans-membrane proteoglycans, which is fortified with soluble glycoproteins that with prothrombotic and pro-inflammatory biology98,99,
coordinate coagulation and immune functions. The glycocalyx provides cytoprotection, highlighting the importance of endothelial biology in
membrane integrity and anti-apoptotic antithrombotic signalling. Clot formation relies
mediating micro-thrombosis and macro-thrombosis
on platelet plug construction (primary haemostasis), which begins with platelet tethering
(Fig. 4). Cerebral endothelial release of vWF has been
and adhesion to exposed extravascular matrices including tissue factor and collagen via
von-Willebrand factor (vWF). Extravascular adhesion and thrombin stimulation activate suggested to be important in TIC provoked by TBI100.
platelets, resulting in procoagulant calcium mobilization, structural changes, soluble Animal studies have shown that endothelial barrier
factor degranulation, phosphatidylserine exposure and glycoprotein (GP) IIb/IIIa receptor function is restored with plasma90,101–104, and early plasma
conformational change to accept fibrin binding. Additionally, platelets control local transfusion of injured patients is associated with reduced
fibrinolysis via degranulation of soluble factors from alpha granules including plasminogen levels of circulating shed syndecan-1 ectodomain105, pro-
activator inhibitor-1 (PAI-1) and α2 antiplasmin to maintain prothrombotic, antifibrinolytic viding mechanistic insights for improved outcomes5,6.
clot architecture. Secondarily, activated platelets recruit leukocytes to local environments. Plasma transfusion might reduce syndecan-1 shedding
Further, via reciprocal release of trophogens, platelets promote endothelial stability and via tissue inhibitor of metalloproteinase (TIMP) or
angiogenesis in return for endothelial control of platelet-dependent haemostasis
decreased activation of ADAM MMPs106. Additionally,
and release of cytokines that signal megakaryopoiesis. However, in trauma-induced
coagulopathy, platelet activation pathways are maladaptive, that is, they result in primary new hypotheses on the mechanisms of tranexamic acid
and secondary platelet function failures. This is characterized by altered and shed (TXA) in injured patients centre on abrogation of the
glycoprotein VI and Ibα, impaired extracellular and intracellular calcium, circulating EOT through serine protease inhibition, suppression of
soluble platelet inhibitors, altered granule content and loss of endothelial protection the release of DAMP mitochondrial DNA, stimulation
and trophogenesis. Further, a procoagulant and pro-inflammatory milieu is promoted of mitochondrial respiration and increase in oxidative
by circulating platelet–leukocyte aggregates (PLAs) and platelet ballooning, sustained phosphorylation107,108. It remains unknown whether the
exocytosis and impaired clearance of vWF by ADAMTS13 (a disintegrin and EOT is cause or effect in TIC, but investigations to iden-
metalloproteinase with thrombospondin motifs 13), and metalloproteinase (MMP) tify therapeutic targets for recovery of endothelial cell
cleavage of the protective ectodomains of glycocalyx components exposing neutrophil surface networks, including characterization of soluble
adhesion receptors for neutrophil binding and release of chemoattractant molecules
reparative molecules in plasma, are continuing.
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- Platelet dysfunction
thrombosis. EV, extravcellular vesicle; PAF, platelet activating factor; PAR, protease- Despite being subcellular in size and anucleate in
activating receptor, PGI2, prostaglandin I2; RBC, red blood cell; TP, TXA2/PG structure, platelets are biologically dynamic in coor-
endoperoxidases; TXA, tranexamic acid; TXA2, thromboxane A2. dinating haemostasis, endothelial health and immune
NATURE REVIEwS | DISEASE PrIMErS | Article citation ID: (2021) 7:30 7
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function 109–111 (Fig. 4) . Interest in the role of plate- hypercoagulability. Whether the diverse qualitative
lets in TIC intensified following the description of changes in platelet behaviour characteristic of TIC are
the cell-based model of haemostasis in 2001 (ref.56). favourable remains unclear80, and investigations beyond
Subsequent accumulating evidence has supported the platelet biomarkers including microfluidics, cell cul-
presence of quantitative and qualitative112 deficits in all ture, mitochondrial respiration, ultrastructure micros-
platelet functions113,114 in human and animal TIC mod- copy and genomic methods, are necessary to uncover
els, and it has implicated platelets in the pathogenesis platelet targets for alternative TIC therapies beyond
of post-injury venous thromboembolism (VTE) and human-donated blood products89,99,127,134,135.
multiple organ failure.
Failures of both primary (haemostatic) and second- Inappropriate thrombin generation
ary (immunoregulatory) platelet functions are char- In initial phases of bleeding, thrombin generation may
acteristic of TIC and can be identified in up to 50% of be insufficient, whereas later excessive thrombin gen-
injured patients, regardless of injury severity or presence eration may contribute to adverse thrombotic events.
of shock112 (Fig. 4). Secondary platelet function should Insufficient thrombin concentration results in clots
not be confused with the term secondary haemostasis. composed of thick fibrin fibres with diminished stabil-
Quantitative consumptive and dilutional thrombocyto- ity, which are prone to fibrinolysis. Thus, the balance
Secondary haemostasis penia are independently associated with bleeding115,116. between thrombin generation and inhibition is cru-
Secondary haemostasis refers However, most patients with TIC have preserved platelet cial to haemostatic capacity. Depletion of endogenous
to the deposition of insoluble
counts and evidence of circulating populations of acti- inhibitors after injury can offset a decrease in pro-
fibrin, generated by the
proteolytic coagulation vated platelets, yet paradoxically impaired ex vivo aggre- coagulants and increase the risk of thromboembolic
cascade, into the platelet plug, gation responses117,118. This phenomenon is described complications136,137.
which forms a mesh that is as ‘platelet exhaustion’, due to injury and shock119 and Thrombin generation can be altered by dilution of
incorporated into and around is driven by endothelial release of TF, platelet activat- coagulation factors following fluid therapy, rapid coag-
the platelet plug.
ing factor and vWF99,120 that activates platelets beyond ulation factor consumption immediately after injury,
Primary haemostasis what is needed for primary haemostasis at the local sites shock-related systemic acidosis and hypothermia65,138,139.
Primary haemostasis refers to of injury, thereby creating a pool of activated circulat- Severely injured patients are prone to having reduced
platelet aggregation and plug ing platelets that are ‘spent’ or exhausted following the levels of factor V5,140,141, factor VII141, factor X141 and
formation on an injury site.
release of their procoagulant and anticoagulant factors. fibrinogen early after injury139,141. However, the reports
Prothrombin time These circulating exhausted platelets cannot contribute of decreases in the activity of coagulation factors fol-
(PT). A conventional to primary haemostasis or ex vivo aggregation assays that lowing severe injury are inconsistent. Concentrations of
coagulation assay that require platelets to respond to stimulation112,119. Injured coagulation factors >30% of physiological levels are gen-
evaluates the extrinsic and patients with impaired platelet aggregation responses erally accepted as sufficient for effective haemostasis142,
the common pathways of the
coagulation cascade. The PT
also exhibit increased sensitivity to tPA-mediated although this threshold is based on studies on single fac-
result (measured in seconds) fibrinolysis, perhaps due to impaired platelet PAI-1 tor deficiencies. Data from the pre-hospital COMBAT
in a healthy individual varies release121. Importantly, these acquired platelet dysfunc- study revealed that coagulation factor activities in
between different types and tions of TIC may not be reversed by transfusion of plate- severely wounded patients were all >64% of physiologi-
batches of the tissue factor
lets stored at room temperature122,123, perhaps owing to cal values upon hospital arrival, suggesting adequate fac-
used by the manufacturer.
injury-induced and shock-induced circulating platelet tor activity for clot formation. Consequently, we do not
International normalized inhibitors124. Recent work suggests cold-stored platelets know the optimal threshold for clotting factor activity
ratio may be more effective in restoring platelet contribution levels after injury, when there are multiple deficiencies
(INR). The INR was devised to haemostasis125,126. coexisting5.
to standardize the PT results.
Manufacturers assign an
Efforts for deeper molecular phenotyping89,127–130 have Importantly, a reduction in procoagulants is not
International Sensitivity Index uncovered multiple molecular phenotypes of platelet necessarily accompanied by impaired thrombin
(IST) for their tissue factor and dysfunction characteristic of TIC, both adaptive and generation141,143. Even though the levels of multiple
the INR is calculated as maladaptive in nature (Fig. 4). Whereas the primary procoagulants were reduced in patients with trau-
(PT test/PT normal)
effects of platelets contribute to early TIC and haem- matic injury, circulating markers of thrombin gen-
Activated partial orrhage, TIC-associated immunoregulation of platelets eration (including prothrombin fragment 1.2 and
thromboplastin time probably contributes to later TIC hypercoagulability114,131. thrombin–antithrombin complexes) were higher than
(aPTT). PTT is a conventional Specifically, injury induced platelet activation stimu- in uninjured individuals or patients without evidence of
coagulation assay that lates platelet and leukocyte binding, creating circulat- TIC141. Elevation of these markers reflects formation
measures the clotting activity
of the intrinsic pathway
ing platelet–leukocyte aggregates, which are associated of thrombi in sites where they are needed and may con-
cascade. It tests the function with promoting a procoagulant milieu through the stitute a physiological response to injury, with increased
of all clotting factors except release of platelet factor 4 and increased expression of thrombin generation in vivo leading to depletion of both
factor VII and factor XIII (fibrin TF, fibrinogen and factor Xa in animal models118. procoagulant and anticoagulant factors. Importantly,
stabilizing factor). aPTT is often
Further, platelet-mediated Toll-like receptor 4 (TLR4) standard coagulation assays do not reflect the activity
used to monitor patients’
responses to unfractionated signalling, attachment of histone H4 to platelets, plate- of the anticoagulant systems. Thus, a slightly prolonged
heparin infusion, to target let ballooning (a shape change that has procoagulant prothrombin time (PT), international normalized ratio (INR)
therapeutic anticoagulation. effects), recruitment of monocytes by platelet-derived or activated partial thromboplastin time (aPTT) could
Activation occurs via exposure high mobility group protein B1 (HMGB1), and neu- reflect a modest depletion of procoagulants, which is
to a negatively charged
substrate, which replicates
trophil extracellular trap formation 89,132,133 are all not necessarily accompanied by diminished thrombin
contact activation and pro-inflammatory mechanisms identified in associa- generation and a bleeding tendency in vivo, as it is off-
enhances the speed of the test. tion with early failures in platelet haemostasis and later set by depletion of anticoagulants143,144. Blood samples
8 | Article citation ID: (2021) 7:30 www.nature.com/nrdp
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from patients with traumatic injury displayed a higher force to contract the fibrin matrix and stabilize the
peak ‘native’ (no activator added) plasma thrombin forming clot149.
concentration than samples from healthy individu- Fibrinogen is synthesized by hepatocytes, with
als despite prolonged standard coagulation tests143. ~98% of circulating human fibrinogen being derived
Recent data indicated that upon hospital admission, from the liver150. Circulating fibrinogen levels increase
patients with traumatic injury exhibited 2.5-fold higher up to 20-fold in the acute phase response, mediated
average plasma thrombin generation capacity than by IL-6 release following tissue injury, infection and
uninjured individuals145. However, low thrombin gen- inflammation151. Despite its high circulating concentra
eration capacity was evident in 17% of severely injured tions, fibrinogen is the first coagulation factor to reach
patients, and a low peak concentration was linked to a critically low levels in severe bleeding events 152,153.
fourfold increased odds of requiring a massive transfu- In major trauma, key contributors to hypofibrinogenae-
sion and a threefold greater odds of 30-day mortality145. mia include haemodilution (due to fluid resuscitation),
Furthermore, there may be substantial differences blood loss, consumption in clot formation at the wound
between plasma and whole-blood thrombin assays146. sites, hypothermia (which impairs fibrinogen synthe-
Recent data from whole-blood assays indicate that sis), fibrinogenolysis and increased degradation due
patients who required a massive transfusion had throm- to acidosis138,153. Trauma and haemorrhagic shock are
bin generation levels below that in healthy controls18. associated with a hyperfibrinolytic state, that occurs in
With respect to late TIC, thrombin is at the cross-road the first few minutes and sometimes persists for hours
of coagulation and inflammation (Fig. 5), and excessive after injury154. These observations are linked to excessive
thrombin generation may have an important role in release of tPA from the endothelium, which overwhelms
delayed hypercoagulability in injured patients137. the availability of its natural inhibitor PAI-1 (ref.155),
thereby driving activation of circulating plasminogen to
Fibrinogen depletion plasmin. Increased plasmin generation shifts the balance
Fibrinogen is the most abundant coagulation factor in of the fibrinolytic system, promoting premature break-
blood, with circulating levels in the range of 2–4 g/l in a down of fibrin in clots and also fibrinogen degradation.
healthy adult and a circulating half-life of ~4 days147. Low fibrinogen levels upon admission are inde-
Conversion of fibrinogen to fibrin occurs via thrombin- pendently associated with an increase in injury severity and
mediated cleavage at two sites, exposing binding sites shock156. Moreover, the fibrinogen level upon admission
for other fibrin molecules, thereby giving rise to spon- is an independent predictor of the need for transfusion,
taneous polymerization. Each fibrin fibre comprises and 24-hour and 28-day mortality156–158. Fibrinogen level
several hundred to several thousand protofibrils aligned has been identified as the most important independent
side by side, which provide extraordinary strength and predictor of mortality, but whether this value represents
resilience to the scaffold protein77. Fibrin fibres are a biomarker (as opposed to a mediator) in patients with
crosslinked by the transglutaminase enzyme, activated traumatic injury remains to be determined.
factor XIII, that provides additional mechanical strength
and resistance to fibrinolytic degradation148. In addition, Dysregulated fibrinolysis
fibrinogen binds with high affinity to integrin αIIbβ3 Fibrinolysis activation following severe injury has been
(also termed glycoprotein IIb/IIIa) on platelets, thereby documented for over half a century11. Although the exact
facilitating further platelet aggregation and generating pathophysiology remains unclear, haemorrhagic shock
Proinflammatory Coagulation Endothelial C5a inactivation
cascade PAR1 activation
Procoagulant
Anticoagulant
Antifibrinolytic Protein C activation TAFI activation
Anti-inflammatory
Fibrin
clipping
Downregulation
Feedback activation Thrombin of coagulation
Reduced
plasminogen
activation
Antithrombin
Platelet Clot stabilization
activation
PAR activation Blood clotting Thrombin inhibition Crosslinking
Cell α2AP Fibrin
signalling Crosslinked fibrin FXIII
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.319, Wiley.
NATURE REVIEwS | DISEASE PrIMErS | Article citation ID: (2021) 7:30 9
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is common in patients who present to the hospital with low fibrinolytic activity, measured by viscoelastic activ-
elevated fibrinolytic activity9,159–162. Hyperfibrinolysis is ity tests and elevated D-dimer or plasmin–antiplasmin
associated with elevated levels of tPA155,163. The source levels, have increased mortality compared with patients
of tPA release during haemorrhagic shock is presumed with balanced fibrinolytic activity, with significantly
to be Weibel–Palade vesicles in the endothelium, which less blood product utilization than patients with
are released in response to multiple stimuli164. Weibel– hyperfibrinolysis162,178,179. Patients in fibrinolysis shut-
Palade vesicles also store vWF165, and circulating levels of down tend to have delayed mortality from brain injury
these factors are increased following trauma166. and organ failure, whereas patients with hyperfibrinol-
Hyperfibrinolysis is exacerbated by loss of fibrino- ysis die early from haemorrhage9. To add complexity, a
lytic inhibitors155,163,166, including α2 antiplasmin167, and subset of patients with traumatic injury do not generate
platelet dysfunction168 (Fig. 2). Elevated tPA activity with a robust fibrinolytic response and present to the hospital
PAI-1 depletion is the hallmark of patients with trau- in a low fibrinolytic state, which is also associated with
matic injury with hyperfibrinolysis52,155,163,169. In addition, increased mortality166. Hypofibrinolysis, defined as lack
depletion of secondary tPA inhibitors (plasma protease of fibrinolysis activation with low fibrinolytic activity,
C1 inhibitor and α1 antitrypsin) or factors that modu- remains poorly described in trauma but may contribute
late inhibitor function (such as vitronectin, the cofactor to thrombotic complications.
for PAI-1) also occurs162. Platelet alpha granules are the Ongoing work on fibrinolysis in trauma has focused
primary circulating source of PAI-1, which is secreted on the temporal changes of fibrinolysis following injury.
following stimulation and retained on the surface of acti- Most patients with traumatic injury transition to a
vated platelets170. PAI-1 can also be generated in several depressed fibrinolytic state following severe injury180.
cells, including endothelial cells. Additional factors that Patients with traumatic injury who retain low fibrino-
govern clot dissolution, including thrombin-activatable lytic activity beyond 24 hours (both adults174,180,181 and
fibrinolysis inhibitor (TAFI; alternatively named car- children182) exhibit increased mortality. This phenom-
boxypeptidase U, encoded by CPB2) and factor XIII168, enon could be attributed to elevated PAI-1, which is
are depleted in hyperfibrinolytic patients with traumatic associated with poor outcomes in sepsis, but requires
injury171. The antifibrinolytic function of factor XIII is further investigation in trauma. Alternative mechanisms
conferred by crosslinking of the plasmin inhibitor α2 to inhibit fibrinolysis include activation of a persistent
antiplasmin into the forming fibrin matrix172. Depletion inflammatory state, in which neutrophil elastase has
of factor XIII levels to ~50% has a negative effect on been demonstrated to reduce fibrinolytic activity183.
clot stability173. This observation is important, as factor
XIII circulates in complex with fibrinogen, which is also Sex dimorphism
depleted in trauma156,158. Sex dimorphisms in coagulation have been described
Hyperfibrinolysis is suppressed in most patients with in humans, with women manifesting a more hyperco-
traumatic injury by a surge of PAI-1 that initiates at agulable profile than men184. As women often have less
2 hours from injury and results in shutdown of fibrino- severe and less penetrating trauma (both important TIC
lytic activity in the majority of patients by 12 hours174. risk factors) than men, isolating the independent role of
This concept, termed fibrinolysis shutdown175, is evident sex in TIC is difficult (Supplementary Tables 1, 2). The
in a broad range of diseases, including viral infections effect of sex on post-injury morbidity and mortality has
such as COVID-19 (ref.176). Although PAI-1 upregulation been somewhat controversial185–188. In one study, men
occurring hours after injury seems to be a physiological up to 50 years of age with blunt injuries had a higher
event, fibrinolysis shutdown that occurs within an hour risk of death than women189; among those of ≥50 years
of severe injury is associated with twofold to sixfold of age, no difference in survival was noted following
increased mortality177. These patients exhibit hallmarks of blunt trauma, but women with penetrating injuries had
prior fibrinolysis activation, including elevated levels a higher mortality than men. Other studies across the
of D-dimer (a degradation product of crosslinked fibrin) world have shown that following trauma, premenopau-
and depletion of fibrinolytic inhibitors, and have low sys- sal women have a survival advantage over men185,190,191.
temic fibrinolytic activity on presentation to the emer- The presence of TIC may change this picture, as a multi-
gency department162. The precise mechanism of acute centre trauma study187 found increased mortality among
fibrinolysis shutdown remains unclear. There is some evi- women presenting with TIC, independent of age.
dence that the plasminogen-binding protein, S100-A10, With regard to TIC-associated hypercoagulability,
is shed into the circulation and may associate with tPA, we also observe disparities between women and men.
thereby impeding fibrinolysis178. Resuscitation promotes Although men have higher VTE rates than women in
PAI-1 elevation in most injured patients, and the increase their lifetime192,193, women are at increased risk of VTE
is pathological if sustained beyond 24 hours174. during pregnancy, when using sex hormones and after
Prior fibrinolytic activation with subsequent ovarian stimulation. In trauma, there is controversy,
shutdown is associated with ongoing coagulation with some studies showing no sex differences194,195 in
abnormalities, including platelet dysfunction and VTE rates, and others showing an increased risk in
prolonged PT178,179. It remains controversial whether men193. Interestingly, the study showing an increased
these patients may have fibrinolysis shutdown at the risk in men included post-d ischarge VTEs, which
systemic level while having ongoing bleeding at represented 62% of the events. In studies using native
the local tissue level, a phenomenon termed ‘occult’ thromboelastography (TEG), healthy women showed
hyperfibrinolysis178. Regardless of terms, patients with faster clot initiation and stronger clots than men184,196.
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These differences were more pronounced in pregnant patients may die of haemorrhage early, before having the
women than in their non-pregnant counterparts184, fur- opportunity to receive more blood). Second, although
ther suggesting that female sex hormones are involved several scores have been proposed, the positive predic-
in coagulation. Oestrogen increases the levels of many tive value remains low. Consequently, the lack of scoring
clotting factors via gene transcription197. Lower oestra- systems with good predictive performance represents a
diol levels were associated with higher levels of PAI-1 major challenge in identifying patients who will develop
in a large prospective study of women in the age range TIC, and consequently in designing clinical studies.
42–52 years198. There were no significant differences in For example, in the large CRASH-2 international trial
haemostatic factors from before to after menopause, but of TXA for traumatic haemorrhage214, which included
hormone therapy was associated with lower PAI-1 con- >20,000 patients, only half of those who were clinically
centrations. Most studies have found no cyclic variation assessed as being at risk of major bleeding received a
in coagulation and fibrinolytic factors199. In one study200 blood transfusion.
using rapid TEG (with TF activation), injured women
had faster clot formation, increased clot strength and less Diagnosis
fibrinolysis than men, after adjustment for risk factors. Early TIC. While the rates of patients receiving a massive
Moreover, women were less likely than men to die when transfusion requiring trauma team intervention are low
presenting with abnormal clot strength or hyperfibrinol- (3–17%), massively bleeding patients are at great risk of
ysis, despite being older, having longer time from injury TIC215–217. Identification of TIC within a cohort of mas-
to admission, and presenting with lower systolic blood sively bleeding patients can be augmented by laboratory
pressure. This sex-specific relative hypercoagulability did testing. The conventional tests include a platelet count,
not seem to increase the risk of thrombotic morbidity, Clauss assay to measure fibrinogen level, PT and aPTT.
and it was not dependent on age. It is conceivable that Major limiting factors with these assays are the time to
epigenetic or post-translational processes due to lifetime obtaining results from multiple tests and the inability
exposure to female sex hormones could alter platelet pro- to identify hyperfibrinolysis. The alternative currently is
genitor function or cellular clotting biology, leading to VHAs, which provide several measurements in a single
a persistent hypercoagulable state during menopause201. readout (Fig. 6). These individual VHA measurements
The same group202 described that healthy women of correspond to the requirement for a specific blood com-
18–55 years of age had shorter time to clot formation, ponent better than conventional tests202. Conventional
higher rate of clot propagation, and increased clot coagulation assays can take up to 40 minutes before
strength than their men counterpart. The study showed actionable data are available, whereas VHAs provide
higher levels of total and functional fibrinogen in women real-time data with results in half the time215, with some
than men, but no difference in fibrinolysis. Collectively, newer VHAs providing actionable results in 5 minutes,
these findings suggest that more circulating functional enabling the identification of patients at risk of massive
fibrinogen and faster coagulation activation may be bleeding167,218. Additionally, a clinical scoring system for
involved in women’s resilience to TIC. Other studies assessing TIC, which includes subclassifications for the
have found that men have lower fibrinogen levels as well anatomic location of injury and interventions required
as platelet count and function then women203. Platelets for bleeding control, has been proposed219. This scoring
express receptors for oestrogens, which might affect their system correlates well with laboratory-detected coagu-
function and haemostatic ability204, and testosterone lopathy and blood transfusions but requires assessment
reduces agonist-induced platelet aggregation205; however, in the operating room166. The rapid availability of the
there are conflicting results regarding platelet aggregation comprehensive information provided by VHAs has
over the menstrual cycle206,207. Platelets from healthy men led to the recommendation that VHAs should replace
who were pretreated with oestradiol approximated the conventional coagulation testing in TIC assessment215,
activation response to platelet-activating factor of plate- although their additional costs limit their accessibility
lets from women208, suggesting that donor sex should in under-resourced settings. VHAs use to guide resus-
be considered in platelet transfusions and encouraging citation in trauma has been associated with reduced
investigation of the therapeutic potential of oestradiol in mortality in a US-based RCT39. The recent ITACTIC
TIC. Timing is also a potential factor, as serial viscoelastic study220, however, found no difference in clinical out-
tests suggest that women convert to a hypercoagulable comes between resuscitations guided by VHAs and those
profile after injury earlier than their male counterparts209. guided by conventional coagulation tests. However, the
VHA transfusion thresholds were based on the same
Diagnosis, screening and prevention thresholds as for conventional testing used in the control
Clinical trials have demonstrated challenges in identi- group, thereby creating a circular logic that resulted in
fying patients at risk of major bleeding, and, therefore the two groups being treated similarly. The conclusion
clinically relevant TIC. First, there is controversy over from the ITACTIC study is that resuscitation based on
the definition of massive transfusion. Early definitions such VHA thresholds did not offer benefit over conven-
included the military description of 10 units of RBCs in tional test guidance, but the study did not provide evi-
a 24-hour period210. These definitions have matured to dence for different, outcome-based VHA resuscitation
focus on shorter intervals207,208, for example, >4 units of thresholds. Although the evidence in trauma is limited at
RBCs in the first hour211–213, on the basis that the median this time, substantial evidence from elective cardiac and
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