Coagulopathy: Measuring and Management Nina A. Guzzetta, M.D. Children s Healthcare of Atlanta Emory University School of Medicine
No Financial Disclosures
Objectives Define coagulopathy of trauma Define massive transfusion Measuring: Conventional coagulation tests Viscoelastic tests New concepts in coagulation monitoring
Objectives Management: Treatment of acidosis and hypothermia Component approach Predetermined ratios or massive transfusion protocols (MTPS) ROTEM- or TEG-guided algorithms Recombinant clotting factors
Trauma and Coagulopathy Coagulopathy is one of the major causes of mortality in trauma patients Up to 20% of all trauma related deaths are linked to coagulopathy Lethal Triad: hypothermia, metabolic acidosis and hemodilution
Trauma and Coagulopathy Acute Traumatic Coagulopathy (ATC) or Trauma Induced Coagulopathy (TIC) Present in up to 25% of trauma patients on presentation to the ED TIC is an independent predictor of massive transfusion, protracted ICU stay, multi-organ failure and death
Trauma and Coagulopathy
Trauma and Coagulopathy
Trauma and Coagulopathy Etiology of TIC: Tissue hypoperfusion induces a physiologic increase in thrombomodulin and tpa Increased thrombomodulin inactivates FVa and FVIIIa decreases thrombin production Increased tpa hyperfibrinolytic state
Defining Massive Transfusion In adults: Transfusion of 10 units or more of PRBCs in 24 hours Holcomb JB et al. Ann Surg 2008; 248:447 Loss of 50% blood volume in 3 hours or loss of 100% blood volume in 24 hours Erber WN. Transfus Apher Sci 2002; 27:83 Ongoing blood loss at > 150 mls/min Peterson A. Int Anesthesiol Clin 1987; 25:61
Defining Massive Transfusion In adults: Physiologic definition: when blood loss is so rapid and severe that blood product support with red cells and volume replacement with fluids exceeds the compensatory mechanisms of the body Hocker et al. Acta Anaesthesiol Scand 1997; 111:205
Defining Massive Transfusion In pediatrics: Administration of 1 blood volumes in a 24 hour period or 0.5 blood volume in a 12 hour period Handbook of Pediatric Transfusion Medicine 2004 Acute administration of 1.5 the estimated blood volume Hendrickson JE et al. J Pediatr 2012; 160:204
Laboratory Tests Conventional Coagulation Tests: PT and aptt Performed in platelet poor plasma Change in the optical dense of plasma is used to detect and time clot formation International normalized ratio INR = PT test / PT normal
Laboratory Tests Conventional Coagulation Tests: Platelet count Does not assess function Fibrinogen level Does not assess function D-dimers?
Laboratory Tests Spahn DR. Br. J. Anaesth. 2005;95:130-139
Laboratory Tests Lack of consensus on the definition of traumatic coagulopathy and cut-off values Time to obtain results 45-75 minutes Performed in plasma only CCTs represent only a small portion of the coagulation system
Laboratory Tests Point of care devices PT, aptt and ACT ABG and Hgb Prehospital or hospital use Correspond poorly to lab analyses in the setting of lower hematocrits
Laboratory Tests New thoughts on what to measure In a pediatric civilian Level I trauma center: Significant positive correlation between apc and PT and aptt Significant negative correlation between apc and FVa and FVIIIa Significant positive correlation between apc and tpa and D-dimers Cohen et al. Ann Surg 2012; 255:379
Laboratory Tests In a pediatric civilian Level I trauma center: Strong positive correlation between apc and transfusion requirements With PC activation: 1.6-fold increase odds of MODS 1.9-fold increase odds of ALI 2.1-fold increase odds of mortality Cohen et al. Ann Surg 2012; 255:379
Viscoelastic Methods Thrombelastography or TEG Thrombelastometry or ROTEM Whole blood Timely Allow for the differentiation between deficiency of coagulation factors, fibrinogen, platelets or FXIII and the presence of fibrinolysis
Viscoelastic Methods
Viscoelastic Methods
Viscoelastic Methods
Viscoelastic Methods In an adult Level I trauma center Impact of ROTEM in 334 trauma victims Significant association with mortality: EXTEM MCF < 45mm FIBTEM MCF < 7mm LI60 > 6.9% Tauber et al. BJA 2011; 107:378
Viscoelastic Methods In an adult Level I trauma center Prospective observational study to identify an accurate diagnostic tool for TIC 325 adult trauma patients Correlated various ROTEM measures with TIC TIC is characterized by a reduction in clot strength CA5 35 mm could predict the need for transfusion and identify TIC Davenport et al. Crit Care Med 2011;39:2652
Viscoelastic Methods In a pediatric Level I trauma center Impact of rteg in 86 pediatric trauma victims K time and α = strong correlation to PTT MA = strong correlation to platelet count All rteg values were predictive of mortality The rteg MA was predictive of life saving events Vogel et al. J Pediatr Surg 2013; 48:1371
Viscoelastic Methods Using the Trauma Registry of the American College of Surgeons Hyperfibrinolysis on admission occurred more frequently in pediatrics (24%) than adults (9%) Mortality increased from 6 to 14% with a LY30 3% LY30 3% had an ORs 6.2 for mortality LY30 > 30% was associated with 100% mortality Liras; Surgery 2015, in press
Thrombin Generation Testing Measures thrombin generation with a chromogenic or fluorogenic substrate
Thrombin Generation Testing May be obtained from the thrombelastogram
Trauma and Coagulopathy Concept of Damage Control Resuscitation Step 1: stop the bleeding - may require a surgical intervention Step 2: gain control of the coagulopathy - which involves treating hypoperfusion, correcting acidosis, reversing hypothermia
Management: Hypothermia Profound effect on platelet adhesion/aggregation when temperature drops from 37-33 o C Altered enzymatic activity at temperatures below 33 o C Wolberg et al. J Trauma 2004;56:1221
Management: Acidosis Profound effect on enzymatic activity ph = 7.0 decreases: FVIIa activity by > 90% TF/FVIIa activity by 60% FXa/FVa activity by 70% Meng et al. J Trauma 2003;55:886
Management Massive transfusion models: Component approach Predetermined blood product ratios TEG-guided algorithms
Management Component Approach Intent: Utilizes traditional laboratory tests to correct coagulopathy Majority of research is based on PT, INR or aptt
Management Role for conventional coagulation tests in pediatric trauma Scores that take into account coagulopathy are more predictive of mortality BIG score = base deficit + [2.5 x INR] + [15-GCS] Borgman et al. Pediatrics 2011;127:e892
Management In an adult combat hospital Admission INR > 1.5x normal Increased mortality of 24% vs 4% Greater incidence of MODS Longer ICU length of stay Longer hospital length of stay Niles et al. J Trauma 2008; 64:1459
Management In a pediatric combat hospital Admission INR > 1.5x normal Increased mortality of 22% vs 3.9% Patregnani et al. Ped Crit Care Med 2012; 13:273
Management In a pediatric civilian Level I trauma center: Abnormal PT, aptt and low platelet count were independently associated with mortality 77% of children had a prolonged PT 20% had a fibrinogen < 100 mg/dl Direct relationship between initial INR and mortality If admission INR > 1.8, mortality = 70% Hendrickson JE et al. J Pediatr 2012; 160:204
Management Massive Transfusion Protocols Intent: lessen hemodilution of coagulation proteins caused by the infusion of crystalloid and/or colloid solutions and RBCs Co-infusion of RBC:FFP:Platelets Limited research What is the optimal ratio?
Massive Transfusion Protocol CHOA: Infant 6-10 kgs Package Cryo RBC Plasma Platelet 1 1 1 2 2 1 1 ½ apheresis 3 1 1 4 2 1 1 ½ apheresis 5 1 1
Massive Transfusion Protocol CHOA: Young Child (11-25 kgs) Package Cryo RBC Plasma Platelet 1 2 2 2 4 2 2 1 apheresis 3 2 2 4 4 2 2 1 apheresis 5 2 2
Management Prospective study Primary aim: to evaluate the use of MTP on mortality 55 pediatric patients: 22 MTP group 33 conventional group Similar demographics between groups Chidester et al. J Trauma Acute Care Surg 2012;73:1273
Management Intent: FFP/RBC = 1:1 Actual: FFP/RBC = 1:3 Crystalloid resuscitation prior to blood transfusion was the same MTP group transfused a greater amount of overall blood products (p<0.0003) No difference in mortality (45% in each group) More thromboembolic complications in the non-mtp group (12% vs 0%) Chidester et al. J Trauma Acute Care Surg 2012;73:1273
Management ROTEM- or TEG-guided algorithms Intent: Obtain a fast, accurate coagulation profile Provide goal-directed resuscitation Best at determining slow clot formation and reduced clot strength Do MTPs result in unnecessary transfusion of FFP? Address the hypercoagulable state after trauma
Management TEG-guided resuscitation versus standardized MTP Adult patients receiving 6U RBCs in the first 24 hours MTP (n = 124) 1:1:1 ratio RBC:FFP:Platelets TEG-guided (n = 165) Tapia et al. J Trauma Acute Care Surg 2013;74:378
TEG-guided algorithm
Management For all patients: TEG-guided patients receive more crystalloid initially Equivalent transfusion volumes and ratios Patients with penetrating injury and 10U RBCs: early mortality + 30-day mortality was improved with TEG-guided algorithm 30 day mortality: 33% TEG vs 54% MTP
Management Role of fibrinogen in massive bleeding In pediatric cardiac surgery patients: post-cpb fibrinogen level was independently associated with postoperative bleeding Faraoni et al. Eur J Anaesthesiol 2014:31:317 In craniosynostosis patients: administration of fibrinogen concentrate maintained clot strength with platelets or FFP. Haas et al. Anesth Analg 2008;106:725
Management Critical reductions in clotting factors are difficult to correct with FFP: Low concentration of clotting factors in FFP Volume expanding effects counterbalance the intended increase Cooling to sub-physiological temperatures Complications associated with FFP: TRALI MODS Infection Delays in thawing
Management Ability of recombinant clotting factor concentrates to reverse dilutional coagulopathy in a pig model 60% of blood volume was withdrawn and replaced with hydroxyethyl starch Randomized to receive: Fibrinogen Fibrinogen + PCC Fibrinogen + rfii Fibrinogen + 3F (rfii, rfviia, rfx) Saline Mitterlechner et al. J Thromb Haemost 2011; 9:729-37
Blood loss following liver injury
Management Survival following injury (%) Fibrinogen group 80 PCC group 90 rfii group 90 3F group 70 Saline group 40
Summary TIC is present on arrival to the hospital, independent of hemodilution and associated with mortality Highly prevalent in pediatric trauma victims Etiology: Activation of the thrombomodulin system decrease in thrombin Increase in tpa hyperfibrinolysis
Summary Measuring and Management: Conventional approach MTPs ROTEM- or TEG-guided algorithms Combination of the above Opportunity to explore new technologies and further research