trauma induced coagulopathy and acute traumatic coagulopathy

1. TRAUMAINDUCED
COAGULOPATHY
& HEMORRHAGIC SHOCK
DR YOGESH RATHOD
CHRISTIAN MEDICAL COLLEGE, VELLORE
MODERATOR – DR PRITISH KORULA

2. INTRODUCTION
• Trauma is leading cause of death and disability in spite of advances in
resuscitation, surgical management, and critical care.
• 25-35% of trauma patients develop a coagulopathy
• Coagulopathy may be result of
• acidosis,
• hypothermia, or
• hemodilution related to fluid or blood administration
• Acute coagulopathy can also occur independent of, or in addition to,
these factors.

3. IMPACT
• Coagulopathy in trauma patients necessitates
• higher transfusion requirements,
• longer intensive care unit and hospital stays,
• more days requiring mechanical ventilation, and
• a greater incidence of multiorgan dysfunction.
• threefold to fourfold greater mortality, and upto eight times more likely to
die within the first 24 hrs following injury.
• Coagulopathy is one of the most preventable causes of death in trauma
and has been implicated as the cause of almost half of hemorrhagic deaths
in trauma patients

4. ETIOLOGY
• There is a balance between hemostatic and fibrinolytic processes
• The etiology of coagulopathy is multifactorial with overlapping
contributions depending upon the injury and nature of
resuscitation.
• Etiologies include classic elements of the “vicious triad”:
• acidosis related to tissue injury and shock,
• hypothermia from exposure and fluid administration, and
• hemodilution due to fluid or component blood product administration.

5. • ATC is a biochemical response to injury and shock leading to
hyperfibrinolysis and hypocoagulability that appears to be mediated
by dysregulation of the Protein C system.
• In addition to the above,release of endothelial-, platelet-, and
leukocyte-derived circulating microparticles and injury-associated
primary platelet dysfunction have both been identified as
contributors to injury-associated coagulopathy

7. ACIDOSIS
• Inadequate tissue perfusion metabolic (lactic) acidosis
(ecerbated by excessive chloride and component blood administration.)
• Acidosis  clotting dysfunction at pH<7.2 by interfering with the assembly of
coagulation factor complexes involving calcium and negatively-charged
phospholipids.
• Activity of the factor Xa/ Va/ phospholipid/ prothrombin (“prothrombinase”)
complex is reduced by 50, 70, and 90 percent at a pH of 7.2, 7.0, and 6.8,
respectively.
• Correction of acidosis alone does not always correct the associated coagulopathy,
indicating that tissue injury causes coagulopathy via additional mechanisms

8. HYPOTHERMIA
• Hypothermia following injury is due to
• cold exposure at the time of injury,
• during transport
• during the trauma examination and
• administration of cold intravenous fluids.
• Patients who require surgery are at a greater risk for hypothermia due to
further physical exposure in the operating room, additional fluid
administration, and the effects of general anaesthesia.
• It causes platelet dysfunction and impaired enzymatic function.
• Thrombin generation is generally preserved at a temperature of 33°C,
but impairment of tissue factor activity, platelet aggregation, and
platelet adhesion are evident at temperatures between 33 to 37°C.

9. • It is important to note that no effects on coagulation tests (either
standard or viscoelastic) are seen in hypothermia-induced
coagulopathy without special sample handling due to the standard
practice of pre-warming blood samples to 37°C prior to analysis,
which corrects the defect.
• Specific measures to correct hypothermia include
• controlling physical exposure,
• the administration of warmed fluids, and
• passive rewarming with blankets and forced-air devices.
• Rapid identification and control of bleeding is vital to preserve normal
temperature.

10. Resuscitation-associated (dilutional)
coagulopathy
• RENAMED AS IATROGENIC COAGULOPATHY
• Refers to alterations of the coagulation system induced by large volumes of IV fluids or
unbalanced component blood administration during the management of shock
• Large volume resuscitation with crystalloid, colloid, and packed red blood cells leads to
dilution of plasma clotting proteins
• The ‘storage lesion’ (stored blood transfusion) includes decreased pH, chelation of
calcium, low 2,3 diphosphoglycerate levels, and decreased clotting factor conc.
• Transfusion of older blood can further impair microvascular perfusion, and has
inflammatory and immunomodulatory effects

11. CLASSIFICATION
• Cap & Hunt Classification of Trauma Induced Coagulopathy
• 1st phase is immediate activation of multiple hemostatic pathways, with increased
fibrinolysis, in association with tissue injury and/or tissue hypoperfusion.
• 2nd phase involves therapy-related factors during resuscitation.
• 3rd phase (post-resuscitation) is an acute-phase response leading to a
prothrombotic state predisposing to venous thromboembolism

12. Acute traumatic coagulopathy
• It is an impairment of hemostasis and activation of fibrinolysis that occurs early
after injury and is biochemically evident prior to, and independent of, the
development of significant acidosis, hypothermia, or hemodilution.
• The risk of ATC increases with hypotension, higher injury severity scores,
worsening base deficit, and head injury. Once established, ATC is often
compounded by other etiologies
• The concept of DIC as a final common pathway for several different phenomena is
insufficient to explain the hematologic abnormalities post-injury.
• Coagulopathy in the absence of thrombocytopenia and hypofibrinogenemia, as
seen in ATC, argues against consumption as a necessary underlying mechanism

13. Acute traumatic coagulopathy may not be a DIC
• DIC is a systemic process producing consumptive coagulopathy in
concert with diffuse microvascular thrombosis.
• In trauma patients, tissue-injury-induced exposure of tissue factor
and activation of the extrinsic coagulation cascade leads to thrombin
generation proportional to injury severity.
• In addition, systemic embolism of tissue-specific thromboplastins
from sites of injury (including bone marrow lipid material, amniotic
fluid, and brain phospholipids) may predispose patients to DIC

14. • D-dimer levels are frequently elevated and fibrinogen levels depleted in
acutely injured patients, indicating intravascular fibrin deposition and
active fibrinolysis, functional thrombin generation (assayed by the
presence of prothrombin fragments and thrombin-antithrombin
complexes) remains intact.
• ATC occurs only when tissue injury is combined with systemic
hypoperfusion.
• Thus, it is most likely that ATC is mechanistically distinct from DIC but that
these frequently overlap. Exploring this distinction is an area of ongoing
research.

15. Mechanism
• There is a correlation between ATC and elevated levels of activated protein C (aPC),
reduced levels of non-activated protein C, and elevated soluble thrombomodulin.
• Activation of the thrombomodulin-protein C system is a principle pathway mediating
ATC, a mechanism that is distinct from clotting factor consumption or dysfunction
• Under normal circumstances, tissue injury leads to thrombin generation, fibrin
deposition, and clot formation via the extrinsic pathway
• Initiation of the clotting process is localized to the site of tissue injury.
• Systemic coagulation due to the escape of thrombin from the injury site is inhibited by
circulating antithrombin III, or by the binding of thrombin to constitutively-expressed
thrombomodulin on nearby undamaged endothelial cells

19. • Activated protein C is a serine protease that proteolytically
inactivates factors Va and VIIIa and depletes plasminogen inhibitors
• Sustained hypoperfusion  increased circulating soluble
thrombomodulin levels  increase the availability of
thrombomodulin-bound thrombin  diverted from a
predominantly procoagulant role to a pathologic, anticoagulant role
via excess activation of protein C.
• Inhibition of protein C by an antibody-mediated mechanism in an
animal model has been shown to prevent the development of ATC
in response to trauma and hemorrhagic shock.

21. • Widespread protein C activation  thrombin generation is inhibited, impairing
clot formation, and fibrinolysis is enhanced causing degradation of existing
clot.
• Consumption of endogenous plasminogen activator inhibitor-1 (PAI-1) by ATC-
mediated aPC destabilizes the fibrinolytic balance, leading to uninhibited
tissue plasminogen activator (tPA)-mediated conversion of plasminogen to
plasmin.
• Diversion of thrombin to protein C activation may also reduce activation of
thrombin-activatable fibrinolysis inhibitor (TAFI), further enhancing fibrinolytic
activity.
• These mechanisms lead to the hyperfibrinolytic state seen in trauma patients
with ATC, which is reflected in increased levels of tissue plasminogen activator
(tPA), decreased plasminogen activator inhibitor (PAI-1), and increased D-
dimer.

22. • Activated protein C also has antiinflammatory and cytoprotective
effects. Profound activation and consumption of protein C can
deplete protein C stores, potentially leading to infectious and later
thrombotic sequelae.
• These effects are mediated via binding of aPC to a protease-
activated receptor-1 (PAR-1) and endothelial protein C receptor
(EPCR) that are likely independent of the role of aPC as an
anticoagulant.

23. • Early coagulopathy is linked to high levels of aPC, and later, protein C
depletion as early as six hours after injury.
• Patients who demonstrated protein C depletion had a significantly
increased risk of ALI, VAP, MOF and death.
• Deficits in fibrinogen, thrombin, Factor V, Factor VIII, Factor IX, Factor X,
and aPC levels are principal drivers of coagulopathy.
• Protein C depletion in trauma patients found elevated markers of
endothelial injury and coagulopathy, and noted a threefold higher risk of
mortality.

24. • ATC-associated depletion of protein C stores after traumatic injury
suggests a potential mechanism for later hypercoagulability and
risk of thromboembolic complications after trauma.
• However, the potential link between protein C depletion and late
hypercoagulability after trauma requires further investigation.
• Despite initial trials demonstrating the efficacy of recombinant aPC
supplementation in sepsis, the recent PROWESS-SHOCK trial failed
to show a survival benefit in severe sepsis.

25. • Emerging effectors of coagulopathy areas of emerging research suggest
additional factors influencing coagulopathy-associated with injury.
• Release of microparticles – Prompt release of thrombin-rich
microparticles into systemic circulation; the local effects of these may
contribute to hemostasis, while wider systemic release may lead to a
DIC-like phenotype that may tip the balance towards coagulopathy.
• Platelet dysfunction – Platelets play a pivotal role in hemostasis after
injury. Platelet count at the time of admission has been noted to be
inversely correlated with transfusion and early mortality in injured
patients, even for platelet counts well in the normal range.

26. DIAGNOSIS
• Standard coagulation tests
• Confirmation of ACT with prothrombin time (PT)>18 seconds, international normalized ratio
(INR)>1.5, activated partial thromboplastin time (aPTT)>60 seconds, or any of these values
at a threshold of 1.5 times the laboratory reference value.
• The prevalence of prolonged PT is higher, but prolongation of the aPTT is more specific.
• Thromboelastography
• To diagnose immediate hypocoagulability and later hypercoagulability following moderate
injury despite normal-range standard coagulation tests.
• Studies involving trauma patients have correlated thromboelastography parameters with
increased mortality. (EARLY TEG HELPFUL!!!!)

34. Factor levels
• Although coagulation factors are not commonly assessed in injured patients, coagulation factor
depletion due to hemodilution and unbalanced component blood transfusion exacerbates
coagulopathy associated with trauma.
• Fibrinogen (factor I) is the first factor to become depleted. Of the commonly numbered
coagulation factors, V and VIII are the most labile and may become selectively depleted during
trauma resuscitation, particularly in the setting of low plasma to red blood cell unit transfusion
ratios.
• Deficits in fibrinogen, thrombin, Factor V, Factor VIII, Factor IX, Factor X, and aPC levels as age-,
injury-, and shock-adjusted can act as predictors of coagulopathy.

35. Clinical scoring systems
• Rapid clinical assessment of the trauma patient provides information that helps predict the
potential for coagulopathy and empiric need for massive transfusion
• Several clinical scoring systems have been evaluated for this purpose, but are not widely used.
• Trauma-Associated Severe Hemorrhage (TASH) score
• McLaughlin score
• Assessment of Blood Consumption (ABC) score
• None of these scoring systems include coagulation parameter measurements, highlighting the
fact that massive hemorrhage is generally due to active bleeding requiring surgical or
interventional control, not as a result of coagulopathy.
• While a sensitive scoring system designed to identify patients at risk of requiring massive
transfusion likely also identifies patients at higher risk of coagulopathy, these scoring systems
have not been designed or validated as diagnostic tests for coagulopathy.

36. TREATMENT
• ATC predicts significantly higher transfusion requirements in the first 24
hours of hospitalization.
• The need for blood transfusion and number of units transfused is a
predictor of systemic inflammation, ARDS and mortality following traumatic
injury
• Although RBC transfusion improves perfusion and oxygen carrying capacity,
there is an increasing awareness that traditional transfusion protocols
produce or exacerbate resuscitation-associated coagulopathy.
• Resuscitation protocols continue to vary widely between trauma centers
and ratios of plasma:PRBC range from 1:1 to 1:10.

37. • With low plasma ratios, treatment of coagulopathy becomes
delayed, and ultimately a greater volume of blood is required.
• The recognition of this problem has led to a widespread re-
evaluation of transfusion protocols, particularly in patients who
demonstrate acute traumatic coagulopathy.
• Patients with ATC are at risk for massive transfusion, and they may
benefit from a resuscitation protocol using FFP or similar products
(eg, PF24), packed red blood cells, and platelets in equal (1:1:1)
ratios given early and aggressively, while limiting crystalloid.

38. STUDIES
• The PROMMTT (PRospective, Observational, Multicenter, Major Trauma
Transfusion) study
• The authors found that “early” transfusion of plasma was associated with reduced
24-hour and 30-day mortality compared with patients who received lower
plasma:RBC ratios, or who did not received early plasma but “caught up” to ratios
approaching 1:1 by 24 hours.
• Inadequate numbers precluded similar analysis of early platelet transfusion.
• Overall, the study suggested that the benefit of hemostatic resuscitation is
principally clinically relevant in preventing death by hemorrhage within the first six
hours, and that competing risks from nonhemorrhagic causes of death overshadow
mortality differences at later time points

39. • The PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma
Ratios) trial
• randomly assigned severely injured patients identified as at risk of requiring
massive transfusions of plasma, platelets, and red blood cells in ratios of either
1:1:1 or 1:1:2.
• There were no significant differences in primary outcomes of 24-hour or 30-day
mortality between the groups. Similar to the PROMMTT study, death from
hemorrhage was significantly less common in the 1:1:1 cohort at three hours after
injury; however, no significant difference was seen at any later time point.
• Overall, whether 1:1:1 “hemostatic” resuscitation is appropriate for all,
or for an as of yet undefined subset of, trauma patients requiring
transfusion continues to be an unanswered question and a focus of
ongoing research

40. Thromboelastography-based transfusion
• Thromboelastography-guided “thrombostatic” resuscitation protocols have
emerged as the standard.
• Where TEG is available, TEG-based goal-directed resuscitation should be
considered for trauma patients requiring massive transfusion.
• Standard coagulation assays may be performed in parallel to facilitate
communication with practitioners unfamiliar with TEG parameters.
• At centers where TEG is unavailable, empiric plasma-forward transfusion
strategies guided by standard coagulation assays remains standard of care.

41. Pharmaceutical hemostatic agents
• In addition to repletion of coagulation factors by transfusion,
• Recombinant factor VIIa – An adjunctive treatment for coagulopathy associated with trauma
but should be reserved for salvage therapy. When used, it is important to correct acidosis,
hypothermia, thrombocytopenia, and hypofibrinogenemia prior to its use.
• Prothrombin complex concentrate – Preliminary studies in animal models of hemorrhagic
shock are promising, but PCC has not been thoroughly evaluated in trauma patients.
• Antifibrinolytic therapy – Antifibrinolytic therapy may be appropriate for patients with
ongoing hemorrhagic shock who have an elevated D-dimer and depleted fibrinogen.
• The best studied agent in the trauma population is tranexamic acid.
• Other antifibrinolytic agents, such as aminocaproic acid and aprotinin, have not been evaluated in
patients with traumatic coagulopathy.
• Desmopressin – There is insufficient clinical evidence to support the use of desmopressin in
the trauma population (except in those patients with preexisting bleeding diatheses).

42. Monitoring
• Reliance upon standard serial laboratory measurements is not compatible with the
timely correction of coagulopathy.
• Serial TEG, when available, should be used to monitor the patient’s coagulation status,
and to guide transfusion and the correction of coagulopathy.
• Where TEG is not available, serial PT/INR, aPTT, Hb/Hct, platelet count, and fibrinogen
levels should be obtained on arrival and following transfusion to verify an appropriate
response to blood products and/or pharmaceutical hemostatic agents, before and after
operative interventions, and as dictated by the patient’s clinical course.
• Serial measurements of ABG for pH and base deficit are indicated for monitoring the
resolution of acidosis and tissue hypoperfusion in response to resuscitation.
• Central temperature monitoring should be performed until normothermia is
reestablished.
• Early institution of intermittent IAP transducer to monitor for the development of
abdominal compartment syndrome and the need for abdominal decompression.

43. SUMMARY AND RECOMMENDATIONS
• Coagulopathy is associated with greater transfusion requirements, longer
intensive care unit and hospital stays, more days of mechanical ventilation, and a
greater incidence of multiorgan failure and mortality.
• The identification and early correction of coagulopathy is important
• The etiology of coagulopathy in the injured patient is multifactorial
• ATC is an impairment of hemostasis and activation of fibrinolysis that is mediated
primarily by activation of the thrombomodulin-protein C system.
• Standard coagulation tests including (PT/INR), (aPTT), fibrinogen level, and
platelet count are part of the initial laboratory evaluation of trauma patients.
• Clinically relevant ATC can occur in patients who have normal platelet and
fibrinogen levels.

44. • TEG is emerging as an important tool for ATC identification and real-time
monitoring of ongoing resuscitation efforts.
• TEG-based goal-directed resuscitation rather than transfusion based on standard
coagulation assays
• For patients diagnosed with ATC, plasma-based resuscitation, targeting ratios of
packed red blood cells, Fresh Frozen Plasma (FFP) or similar products (eg, PF24),
and platelets approaching 1:1:1 over protocols with lower ratio.
• Pharmaceutical hemostatic agents available as adjuncts for the treatment of
severe coagulopathy in the injured patient include recombinant factor VIIa,
prothrombin complex concentrate, antifibrinolytic agents (tranexamic
acid, aminocaproic acid, aprotinin) and desmopressin.

45. ANY
QUESTIONS?