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  • Transfusion and Transfusion and Coagulopathy Coagulopathy

    Anthony Holley Intensivist Royal Brisbane & Women’s Hospital

  • ExsanguinationExsanguination

     Haemorrhage remains a major and potentially reversible cause of all trauma deaths.

     More pronounced in the setting of penetrating trauma.

     Mortality in this group is 20-50%

  • Rev Gonsky @coolholdenv8R

  • The MissionThe Mission

  • On arrival in EDOn arrival in ED  Groom HR 123, BP 118/60, Extensive

    pelvic #. INR 1.3  Bride HR 100, BP 110/80, bilateral femur

    fractures. INR1.2  Driver HR 140, BP 80/35, pelvic #,

    moderate severity head injury, bilateral tib/fib compound #. INR1.7

     Front passenger HR 100 BP 80/46, +FAST. INR 1.1

  • Coagulopathy is present at Coagulopathy is present at admission in 25% of trauma admission in 25% of trauma patients.patients. Associated with a 5-fold increase Associated with a 5-fold increase in mortality.in mortality.

  • Early coagulopathy in trauma patients: an Early coagulopathy in trauma patients: an on-scene and hospital admission study.on-scene and hospital admission study.

     Prospective, observational study investigating the on-scene coagulation profile and its time course.

     N = 45 patients  At the scene of the accident, before fluid

    administration.  to hypoperfusion.

  • MeasuredMeasured  Prothrombin time  Activated partial thromboplastin time

    Fibrinogen concentration  Factors II, V and VII activity,  Fibrin degradation products  Antithrombin and protein C activities  Platelet counts and base deficit.

  •  On-scene coagulation status was abnormal in 56% of patients.

     Protein C activities were decreased  Factor V levels decreased significantly

    with the severity of the trauma.

  • Why?Why?

  • Acute Coagulopathy of TraumaAcute Coagulopathy of Trauma  Syndrome of non-surgical bleeding from mucosal

    lesions, serosal surfaces, wound and vascular access sites associated with serious injury

     INR > 1.5 reliably predicts those who will require massive transfusion

     Seen in most severely injured upon admission to ED ◦ Coagulopathy correlates with ISS

     Also associated with: ◦ Hypothermia (temp < 35oC) ◦ Acidosis (pH < 7.2 or BD > 6) ◦ Haemodilution

  • A Time to ConsiderA Time to Consider

     Mechanism of coagulopathy  Strategies to best manage patients  Best modality to assess coagulopathy

  • Coagulopathy

    Acidosis Hypothermia


    Kashuk JL, Moore EE, Millikan JS, Moore JB. Major abdominal vascular trauma—a unified approach. J Trauma 1982; 22:672-679.

    Classically Trauma-induced Coagulopathy

  • Time to Challenge the Time to Challenge the Dogma?Dogma?

    “None of these appears to be responsible for acute coagulopathy, and it appears that shock is the prime initiator of the process!"

    “Trauma-induced coagulopathy can develop in 24.4% of patients independent of acidosis and hypothermia but secondary to trauma by itself”

    – J Trauma, Aug 08, p272

  • Coagulopathy

    Acidosis Hypothermia


    I nj


    Hy p er f i b r i nol y si s

    Classically Trauma-induced Coagulopathy

    AP C

  • Dilution?Dilution?

     Little or no dilutional effect of crystalloid therapy on the standard tests of coagulation either in vitro or in healthy volunteers

     London study ~ median fluid 500 ml  German study ~ median fluid 2.2 L  Colloid vs Crystalloid  Coagulopathy was present in 10% of patients who

    received less than 500 ml of fluid  ? Alternative mechanism

  •  Moderate/severe hypothermia present < 9% of trauma patients

     Relationship between hypothermia, shock and injury severity a weak independent predictor of mortality (OR 1.19)

     Very little effect of moderate hypothermia on coagulation proteases.

     Significant effects on function and clinical bleeding only at temperatures < 33°C.


  •  Effects of IV HCL acid on human volunteers.  Definite dose–response of acidaemia on clotting function

    by thromboelastometry.  Little clinically significant effect on protease function down

    to a pH of 7.2 in in-vitro studies  Animal studies: pH of 7.1 produces only a 20%

    prolongation of the PT & APTT.


  •  Consumption regarded as a primary cause of traumatic coagulopathy

     Little evidence for consumption of clotting factors as a relevant mechanism

     In patients without shock coagulation times are never prolonged, regardless of the amount of thrombin generated


  •  Shock and systemic hypoperfusion?  Dose-dependent prolongation of clotting

    times with increasing systemic hypoperfusion.

     Base deficit (BD) as a surrogate for perfusion

     2% of patients with a BD < 6 mEq/l had prolonged clotting times

     20% of patients with a BD > 6 mEq/l.

    Drivers of Traumatic Coagulopathy?

  •  Acute coagulopathy in massive transfusion appears to be due to activation of anticoagulant and fibrinolytic pathways.

     Thrombomodulin–protein C pathway is implicated.

    Mechanism of Acute Traumatic Coagulopathy

  • Normal




    Antifibrinolytic activity

    Anticoagulant Activity

    fibrinolytic activity



  •  With tissue hypoperfusion the endothelium expresses thrombomodulin which complexes with thrombin.

     Less thrombin is available to cleave fibrinogen  Thrombin complexed to thrombomodulin

    activates protein C, which inhibits cofactors V and VIII

    Protein C Activation

  • Protein C Anticoagulant PathwayProtein C Anticoagulant Pathway

  • . Brohi et al. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 2007 May. 2007 May;245(5):812-8 ,


  • Biological Response Pathological Biological Response Pathological in Shockin Shock

     Tissues subjected to low-flow states generate an anticoagulant milieu

     Avoids thrombosis of vascular beds.

  •  Trauma is associated with increased fibrinolytic activity.

     Tissue plasminogen activator (tPA) is released from the endothelium following injury and ischaemia.

     Local control mechanism to reduce propagation of clot to normal vasculature


  • HyperfibrinolysisHyperfibrinolysis

    Reduction in plasminogen activator inhibitor-1 (PAI-1) levels in tissue hypoperfusion


  • CRASH-2 trial collaborators. The Lancet. 2010;376:23-32

    Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with

    significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial

    Tranexamic acid

  • ACEM ASM 2010

    Plasminoge n activator

    Plasmin Plasminoge


    Blockade Blockade

    Tranexamic AcidTranexamic Acid Tranexamic AcidTranexamic Acid Fibrino lysis

  • The StudyThe Study

     Prospective double blind  274 hospitals  40 countries  n=20211  Tranexamic (n=10 060) acid vs placebo

    (10115)  1 g over 10 minutes then 1 g over 8 hours  Primary outcome: in hospital four week


  • Tranexamic AcidTranexamic Acid

  • Tranexamic AcidTranexamic Acid

  • But............But............

     Entrance criteria soft (HR>110 bpm, SBP 90 mmHg  Only 16% of patients SBP

  • Arch Surg. 2012;147(2):113-119. 2011

    Study profi le illustrating the overall cohort and study groups.


  • Arch Surg. 2012;147(2):113-119.2011


  • From: Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study Arch Surg. 2012;147(2):113-119.

    Percentage of patients with hypocoagulopathy on admission to the emergency department (ED) and then the intensive care unit (ICU) following the initial operation. Coagulation data were available for 462 patients in the overall cohort and 155 patients in the groups that received massive transfusion. TXA indicates tranexamic acid. * P < .05.


  • Arch Surg. 2012;147(2):113-119.

    Kaplan-Meier survival curve of the overall cohort, including patients receiving tranexamic acid (TXA) vs no TXA. P = .006, Mantel- Cox log-rank test.


  • From: Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study Arch Surg. 2012;147(2):113-119.

    Kaplan-Meier survival curve of the massive transfusion group receiving tranexamic acid (TXA) or no TXA. P =