1. Pharmacological Methods to Reduce Blood Loss in Surgery George Despotis, MD Associate Professor of Anesthesiology, Pathology and Immunology Department of Anesthesiology and Blood Bank Washington University School of Medicine St. Louis, Missouri

2. Reexploration for Bleeding: Risk Factors and Outcomes Moulton et al (n=6015) Dacey et al (n=8586) Unsworth et al (n=2221) Dacey LJ et al, Arch Surg 1998; 133: 442-7 Moulton MJ et al, J Thorac Cardiovasc Surg 1996; 111: 1037-46 Unsworth-White et al, Ann Thorac Surg 1995; 59: 664-7 Reexploration for bleeding4.2%3.6%3.8% Adverse Outcomes Mortality  x4  x3  x4 Renal Failure  x18   Mech vent support / ALI  x5   Sepsis / arrhythmias / IABP  x2   Hospitalization interval  x2  x6 Risk Factors  time CPB time Non-coronary OP  # grafts Valve/Repeat Procedure  Age,  Cr  Age,  BSA Other factors

3. Pathophysiology of CPB-Related Hemostatic Abnormalities Despotis GJ et al, Anesthesiology 1999; 91: 1122-51 HEMODILUTION  CPB prime (crystalloid/colloid)  Cardioplegia volume  Extensive use of cell salvage systems (loss of platelets/ coagulation factors)  Contact activation XIIa, Kallikrein  Tissue Factor activation Tissue Injury Monocyte-related Pericardial blood  Activation of fibrinolysis Increased tPA via: -endothelial cells -pericardial cavity Intrinsic activation Heparin or Protamine ACTIVATION  Thrombin-mediated  Plasmin-mediated  Inflammation-mediated: Elastase Complement Leukocyte-platelet complexes  Mechanical (ECC): oxygenator, cardiotomy suction, roller/centrifugal pump, filter CONSUMPTION

4. Non-Bleeders (n=31)Bleeders (n=42) Despotis GJ et al, J Thorac Cardiovasc Surg 1994;107:271-79 121 minCPB Time200 min * 1051±509 mLCTD 24 hrs1594±1440 mL * 1.9±4.2 UPostop TDE8.2±11.1 U * % Decrease 0 -20 -40 -60 -80 p < 0.05 * FIB 170 FVIII 90 FVII 48 FIX 98 FXII 40 FX 36 PLT 83 FV 26 * * * * * * FIB 196 FIX 122 FVII 58 FVIII 137 FXII 53 FX 53 FV 42 PLT 118 pre-CPBpost-CPB

5. OPERATIVE PREDICTORS OF MICROVASCULAR BLEEDING Operative History Single vs Combined Procedures 0 0.5 1.0 0 0.5 1.0 Incidence of MVB Despotis GJ et al, J Thorac Cardiovasc Surg 1994;107:271-79 25/61 (0.41) [0.44] Combined Primary Operation 37/248 (0.15) [0.14] Single 12/42 (0.29) [0.33] Reoperation 9/10 (0.9) [0.71]

6. Platelet inhibition: - Dipyridamole - Prostacyclin (PGI2), PGE1 - IIb/IIIa receptor inhibition: Abxcimab, integrelin PHARMACOLOGIC PRESERVATION OF THE HEMOSTATIC SYSTEM Broad-spectrum inhibition: Aprotinin Plasmin inhibition: Tranexamic Acid, EACA Thrombin and Factor Xa inhibition: - Heparin: LMWH (Xa) vs UFH (Xa/IIa) - Heparin Adjuncts: AT III, HCF II (Dermatan Sulfate) - Warfarin - Direct Thrombin Inhibitors

7. Reduction in Blood Loss and Transfusion by Aprotinin 15 12 9 6 3 0 Mean Total Donor Exposures (U) 1200 800 400 1600 2000 0 Blood Loss: CTD (mL) AAAA Repeat Levy 1995 n=126 (278) Primary Lemmer 1996 n=317 (704) Primary Alderman 1998 n=870 Lemmer 1994 n=216 Both PPPP 1.6% 4% 0 3% 0 5% 1% 3%

8. Efficacy of Aprotinin Based on Dose and Operative Risk 1200 800 400 1600 0 Blood Loss: CTD (mL) Levy 1995 n=278 repeat Lemmer 1996 n=704 primary 9 6 3 0 12 Mean Total Donor Exposures (U) P PO LD HD No ASA ASA

9. Reduction in Blood Loss & Transfusion: Aprotinin vs EACA 1200 800 400 1600 2000 0 Blood Loss: CTD (mL) 15 12 9 6 3 0 Mean Total Donor Exposures (U) 15 12 9 6 3 0 EACA: 9 studies (n = 932) Aprotinin: 4 studies (n = 1529) 27% in PRBC Tx P P 4.0% 1.6% p=0.006 A E

10. Mechanisms of Action: Aprotinin vs Antifibrinolytic Agents AprotininEACA / TA Antifibrinolytic Actions: Effect on Hemostatic System Activation: Inhibition of Contact Activation Yes*No Yes Preservation of Fibrinogen, Factors V, VIII Preservation of Platelet GP 1b receptors Yes Reduced Platelet Inhibition via FDPs Yes Inhibition of Tissue Factor Activation Probable*No Inhibition of Platelet Activation / Consumption Yes*No Antiinflammatory Properties Yes*No Inhibition of Protein C Activity Yes**No *200 KIU/mL** > 250-300 KIU/mL

11. CHALLENGES TO HEMOSTATIC SYSTEM BALANCE DURING CPB GOAL: EFFECTIVE HEMOSTASIS HEMORRHAGE ADEQUATE AND REVERSIBLE ANTICOAGULATION THROMBOSIS  DECREASED PROCOAGULANTS CPB hemodilution, consumption  INHIBITION OF HEMOSTASIS - Antibodies to platelets, coag proteins - Xa/IIa inhibitors (e.g. LMWH, r-hirudin) - Platelet inhibitors (e.g Plavix, ? Reopro) - Heparin rebound, FFP Tx (i.e., ATIII)  Pre-existing HYPERCOAGULABILITY:  ATIII/Protein C/S, FV Leiden, LA/ACLAbs,  homocysteine, HIT, h/o thromboembolism, h/o CHF, hypoperfusion  INHIBITION OF FIBRINOLYSIS (e.g. EACA) or PROTEIN C (e.g. >300 KIU/mL Aprotinin)  INCREASED PROCOAGULANTS DDAVP (e.g. vWF), Tx (e.g. platelets, FEIBA)  INADEQUATE SUPPRESSION OF HEMOSTATIC ACTIVATION DURING CPB

12. Summary for Bleeding Complications Perioperative Bleeding Complications:  Can lead to adverse outcomes related to complications associated with reexploration, transfusion and CNS injury  Patients at high-risk include those: with congenital defects, on long-acting anti-thrombotic agents, with trauma, or patients who require complex cardiac procedures (  CPB) Prevention  When compared to EACA/TA, aprotinin (full-dose regimen): - is probably more effective in reducing bleeding, transfusion and reexploration in high-risk patients - and has an extensive safety record  Optimal Anticoagulation results in preservation of the hemostatic system especially with prolonged CPB which leads to reduced blood loss / transfusion and possibly thrombotic complications

13. Summary for Bleeding Complications Optimal Management of excessive bleeding:  Although laboratory-based tests may be helpful, the history and physical exam should preoperatively identify patients at risk who require further laboratory evaluation  Use of POC diagnostic tests along with a standardized transfusion approach (e.g. algorithm) can optimize perioperative transfusion/pharmacologic (e.g. DDAVP) management  Although factor concentrates used as a rescue therapy can be life-saving, thrombotic risk and cost preclude routine use