G.K.Kumar

 What is Thromboelastography?  Where does it “fit into” our usual coagulation monitoring and what (if any) new information does it give us  Why is it useful in Cardiac Surgery?

 TEG was developed by Hartert in 1948  Thromboelastogradphy originally monitors the thrombodynamic properties of blood as it is induced to clot under a low shear environment resembling sluggish venous flow.  This enable the determination of the kinetics of clot formation and growth as well as the strength and stability of the formed clot.  The strength and stability of the clot provide information about the ability of the clot to perform the work of haemostasis, while the kinetics determine the adequacy of quantitative factors available to clot formation

 Clot formation  Clot kinetics  Clot strength & stability  Clot resolution

Heated (37C) oscillating cup Pin suspended from torsion wire into blood Development of fibrin strands “couple” motion of cup to pin “Coupling” directly proportional to clot strength  tension in wire detected by EM transducer

 Electrical signal amplified to create TEG trace  Result displayed graphically on pen & ink printer or computer screen  Deflection of trace increases as clot strength increases & decreases as clot strength decreases

TEG accelerants / activators / modifiers  Celite / Kaolin / TFaccelerates initial coagulation  Reopro (abciximab) blocks platelet component of coagulation  Platelet mapping reagentsmodify TEG to allow analysis of Aspirin / Clopidigrol effects Heparinase cups  Reverse residual heparin in sample  Use of paired plain / heparinase cups allows identification of inadequate heparin reversal or sample contamination

Where does the TEG fit into coagulation monitoring and what new information does it give us?

Tests of coagulation  Platelets number function  Clotting studies PT APTT TCT  Fibrinogen levels Tests of fibrinolysis  Degradation products

The TEG gives us dynamic information on all aspects of conventional coagulation monitoring

r time  represents period of time of latency from start of test to initial fibrin formation  in effect is main part of TEG’s representation of standard”clotting studies”  normal range mins (native blood) mins (kaolin-activated)

r time  by Factor deficiency Anti-coagulation Severe hypofibrinogenaemia Severe thrombocytopenia r time  by Hypercoagulability syndromes

k time  represents time taken to achieve a certain level of clot strength (where r time = time zero ) - equates to amplitude 20 mm  normal range mins (native blood) mins (kaolin-activated)

k time  by Factor deficiency Thrombocytopenia Thrombocytopathy Hypofibrinogenaemia k time  by Hypercoagulability state

 angle  Measures the rapidity of fibrin build-up and cross-linking (clot strengthening)  assesses rate of clot formation  normal range (native blood) (kaolin-activated)

 Angle  by Hypercoagulable state  Angle  by Hypofibrinogenemia Thrombocytopenia

Maximum amplitude  MA is a direct function of the maximum dynamic properties of fibrin and platelet bonding via GPIIb/IIIa and represents the ultimate strength of the fibrin clot  Correlates to platelet function 80% platelets 20% fibrinogen  normal range 47 – 58 mm (native blood) mm (kaolin-activated) > 12.5 mm (ReoPro-blood)

MA  by Hypercoagulable state MA  by Thrombocytopenia Thrombocytopathy Hypofibrinogenemia

LY30  measures % decrease in amplitude 30 minutes post-MA  gives measure of degree of fibrinolysis  normal range < 7.5% (native blood) < 7.5% (celite-activated)  LY60 60 minute post-MA data

A30 (A60)  amplitude at 30 (60) mins post-MA EPL  earliest indicator of abnormal lysis  represents “computer prediction” of 30 min lysis based on interrogation of actual rate of diminution of trace amplitude commencing 30 secs post- MA  early EPL>LY30 (30 min EPL=LY30)  normal EPL < 15%

Fibrinolysis leads to:  LY30 /  LY60  EPL  A30 /  A60

 Clot formation  Clotting factors - r, k times  Clot kinetics  Clotting factors - r, k times  Platelets - MA  Clot strength / stability  Platelets - MA  Fibrinogen - Reopro-mod MA  Clot resolution  Fibrinolysis - LY30/60; EPL A30/60

Conventional tests test various parts of coag cascade, but in isolation out of touch with current thoughts on coagulation plasma tests may not be accurate reflection of what actually happens in patient difficult to assess platelet function static tests take time to complete  best guess or delay treatment TEG global functional assessment of coagulation / fibrinolysis more in touch with current coagulation concepts use actual cellular surfaces to monitor coagulation gives assessment of platelet function dynamic tests rapid results  rapid monitoring of intervention

 It is dynamic, giving information on entire coagulation process, rather than on isolated part  It gives information on areas which it is normally difficult to study easily – fibrinolysis and platelet function in particular  Near-patient testing means results are rapid facilitating appropriate intervention  It is cost effective compared to conventional tests

Because patients bleed postoperatively It is often difficult to identify exactly why they are bleeding

 Why do patients bleed postoperatively?  Can we do anything to prevent/minimize this blood loss  How is the bleeding patient managed conventionally?  what factors may force us to readdress this  How can the TEG change the way we manage the bleeding patient?  (Does use of the TEG improve patient care?)

 Aspirin &/or Clopidigrol - anti-platelet effects  Reopro - abciximab; anti GpIIb/IIIa agent  Warfarin / Heparin anticoagulation  Pre-existing clotting factor &/or platelet abnormalities Preoperative / factors

 Decreased platelet count  Heparin effect  Alien contact Intraop factors

 Reversal of heparin  Non-functional platelet  Fibrinolysis Postop factors

 Type of Surgery complicated surgery redo surgery  Cardiac surgery can be bloody! Big pipes, big holes, big vessels

 Blood and Surgery  Lung of pig, Pancreas of cow, Sperm of salmon  Foreign surfaces & cellular trauma  Drug effects  Thrombin activation  Non-functional Platelets  Altered blood flow  Abnormal Coagulation & Fibrinolysis  Inflammatory response to CPB

Stop Aspirin / Clopidigrol Use of anti-fibrinolytics “Cell-salvage” techniques Surgical technique Blood Component therapy

 More Stitches / Surgicell / topical haemostatic agents  More Protamine  Tranexamic acid  Aprotinin /Aprotinin infusion  Platelets  FFP  “Coagulation factor crash packs”  Blood  More Protamine  More Platelets & FFP +/- Cryoprecipitate  Reopening

 Drain on donor pool supply v demand  Financial consequences direct and indirect  Patient consequences “Hazards of Transfusion” Infective / Immunogenic / Thrombogenic problems “Other” problems Patients don’t want it

We need to move away from the traditional “carpet bombing” of the coagulation system in the bleeding postoperative cardiac surgical patient with all its associated risks towards a more “targeted” clinical therapeutic approach? Can we use the TEG to facilitate and support this change in the management of the bleeding patient?

We know the problems Bloody surgery Anticoagulants Abnormal platelet function Damaged / ineffective platelets Abnormal fibrinolysis Can the TEG help us? Clot formation  Clotting factors Clot kinetics  Clotting factors  Platelets Clot strength & stability  Platelets Clot resolution  Fibrinolysis

 Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Shore-Lesserson, Manspeizer HE, DePerio M et al Anesth Analg 1999; 88 :  Reduced Hemostatic Factor Transfusion using Heparinase Modified TEG during Cardiopulmonary Bypass. von Kier S, Royston D Br J Anaesthesia 2001 ; 86 : 575-8

 Prospective blinded RCT  Patients randomized to either routine transfusion practice or TEG- guided transfusion therapy for post-cardiac surgery bleeding  Inclusion surgery types single / multiple valve replacement combined CABG + valve surgery cardiac reoperation thoracic aortic surgery  Standard anaesthetic / CPB management routine use of EACA

 Surgeon / Anaesthetist “blinded” to group - TEG / coag results reviewed by independent investigator who then instructed clinicians what to give  Data collection Coagulation studies and TEG data appropriate to each group Multiple time point assessment of Transfusion requirements FFP requirements platelet transfusion requirements Mediastinal tube drainage (MTD)

Routine transfusion group Coagulation tests taken after Protamine administration used to direct transfusion therapy in presence of bleeding Transfused when Hct <25% (<21% on CPB)

TEG-guided group Platelet count + Celite & TF-activated TEG’s with heparinase modification taken at rewarm on CPB (36C) - result used to order blood products from lab TEG samples run after Protamine administration (celite & TF activated plus paired plain / heparinase cups) used to direct actual transfusion therapy (in the presence of bleeding) Transfused when Hct <25% (<21% on CPB)

Routine transfusion group 52 patients 31/52 (60%) received blood 16/52 (31%) received FFP 15/52 (29%) received Platelets TEG-guided group 53 patients 22/53 (42%) received blood (p=0.06) 4/53 (8%) received FFP (p=0.002) (p<0.04 for FFP volume) 7/53 (13%) received Platelets (p<0.05) MTD no statistical difference

 Study design  2 groups of 60 patients Group 1 - conventional v retrospective TEG-predicted therapy Group 2 - prospective RCT - clinician-guided v TEG-guided  Complex surgery  transplants  multiple valve / valve + revascularisation  multiple revascularisation with CPB > 100 mins  Outcomes  FFP usage  Platelet usage  Mediastinal tube drainage (MTD)

Group 1 Microvascular bleeding managed conventionally using standard coag tests  Microvascular bleeding  Blood loss > 400ml in first hour  Blood loss > 100ml/hr for 4 consecutive hours  Triggers to treat  PT & / or APTT ratio >1.5 x normal  Platelet count < 50,000 /dl  Fibrinogen concentration < 0.8 mg/dl  Patients who returned to theatre (3) “replaced” by additional pts

Group 1 Predicted transfusion requirements using TEG algorithm  Retrospective analysis of TEG data at PW (post-warm) sample point

Group 1 - conventional therapy 60 patients 22/60 given blood component therapy Actual usage 38 units FFP 17 units Platelets Group 1 - TEG predicted therapy 60 patients 7/60 predicted to need component therapy(p<0.05) Predicted usage 6 units FFP 2 units Platelets (p<0.05)

Group 2  Prospective RCT arm of study  60 patients randomly allocated to one of two groups  Clinician-directed therapy products given for bleeding as judged clinically by clinical team responsible for case  TEG algorithm-directed therapy products given for bleeding as directed by TEG- driven protocol  Patients who returned to theatre for bleeding (1 in each group) were “replaced” with additional patients

Sampling protocol  all celite-activated heparinase modified samples Baseline (BL) Post-warm (PW) Post-protamine (PP) + celite-activated plain sample TEG treatment algorithm r>7 min but <10.5 minmild  clotting factors 1 FFP r>10.5 min but <14 minmod  clotting factors 2 FFP r>14minsevere  clotting factors 4 FFP MA<48mmmod  in platelet no / function1 platelet pool MA<40mmsevere  in platelet no / function 2 platelets pools LY30 >7.5%  fibrinolysis Aprotinin

Group 2 - Clinician-directed 30 patients 10/30 received blood component therapy 16 units FFP 9 units Platelets 12 hour MTD losses [median (lower & upper quartile)] 390 (240, 820) Group 2 - TEG directed 30 patients 5/30 given blood component therapy (p<0.05) 5 units FFP 1 unit Platelets (p<0.05) 12 hour MTD losses [median (lower & upper quartile)] 470 (295, 820) (NS)

There appears to be good clinical evidence that TEG can guide therapy and decrease our blood product usage

 studies looked at wide range of procedures & patient management - difficult to extrapolate study findings to all units  considerable variability in pre-study management across units  concomitant introduction of postoperative transfusion protocols at same time as TEG may cloud TEG outcomes  variability in TEG-guided protocols and sources of derived data- what exactly is normal in post-cardiac surgery population?  by its very nature use of TEG facilitates early intervention, whereas use of conventional tests delays intervention. Is this enough in itself to explain apparent differences?

How do I use it?

Sampling protocol  all kaolin-activated heparinase modified samples  Baseline (BL)  Post-warm (PW)  Post-protamine (PP) + kaolin-activated plain sample  further paired CITU samples for bleeding if required

Is the patient bleeding? Check samples running / already run = PW, PP, CITU “Eyeballing” of trends PP r-Plain > r-Heparinase Inadequate heparin reversal Protamine r>9-10 min  clotting factors FFP MA<48mm  platelet no / function Platelets LY30 >7.5% (or EPL > 15%) Hyperfibrinolysis Antifibrinolytic Still bleeding? repeat TEG  still abnormal  further factors as indicated  normal  consider surgical bleeding

 Thromboelastography (TEG) provides near-patient, real-time, dynamic measurements of coagulation and fibrinolysis  It is ideally designed to provide useful information amidst the cauldron of factors which contribute to post-cardiac surgical bleeding  Use of TEG to drive post-cardiac surgery protocols for management of bleeding has been shown to be cost-effective and will decrease the patient’s exposure to blood and blood component therapy with its concomitant well-documented risks  Appropriate use of TEG can result in genuine cost savings in Cardiac Surgery patients