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David Orlov, MD, FRCPC Toronto General Hospital Cardiovascular Anesthesia November 18, 2016

Fractionated Blood Products in Cardiac Surgery: A review of the literature and directions for the future. David Orlov, MD, FRCPC Toronto General Hospital Cardiovascular Anesthesia November 18, 2016. Disclosures. No conflicts of interest to disclose. Outline.

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David Orlov, MD, FRCPC Toronto General Hospital Cardiovascular Anesthesia November 18, 2016

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  1. Fractionated Blood Products in Cardiac Surgery: A review of the literature and directions for the future David Orlov, MD, FRCPC Toronto General Hospital Cardiovascular Anesthesia November 18, 2016

  2. Disclosures • No conflicts of interest to disclose

  3. Outline • Cardiopulmonary bypass (CPB) and perioperative bleeding • Brief review of coagulation • Fractionated blood products in cardiac surgery: • a) Prothrombin complex concentrates (PCC) • b) Cryoprecipitate / Fibrinogen concentrate

  4. Outline • Cardiopulmonary bypass (CPB) and perioperative bleeding • Brief review of coagulation • Fractionated blood products in cardiac surgery: • a) Prothrombin complex concentrates (PCC) • b) Cryoprecipitate / Fibrinogen concentrate

  5. Background • Excessive bleeding carries a heavy burden of illness in cardiac surgery with CPB • Affects 10-20% of patients who consume 80% of the blood supplies in this setting1 • Cardiac surgery continues to be one of the greatest consumers of blood products among fields in medicine2-3 • Blood products:4-7 • Scarce • Expensive • Infectious and non-infectious risks • Ferraris et. al, 2007 • Horvath et al, 2013 • Mehta et al, 2009 • Williamson et al, 2013 • Goodnough, 2013 • Drackley, et al., 2012 • Shander et al., 2010

  6. Background • Bleeding and CPB1 • Hemodilution • Decreased concentration of coagulation factors • Decreased platelet count • Interaction of blood with extracorporeal surface • Decreased platelet count • Decreased platelet function • Consumption of coagulation factors • Increased fibrinolysis • Hypothermia • Decreased platelet function • Drugs • Heparin (inhibit coagulation /decrease platelet function) • Protamine (inhibit coagulation /decrease platelet function) 1) Despotis et. al, 2000

  7. Background • Bleeding and CPB1 • Hemodilution • Decreased concentration of coagulation factors • Decreased platelet count • Interaction of blood with extracorporeal surface • Decreased platelet count • Decreased platelet function • Consumption of coagulation factors • Increased fibrinolysis • Hypothermia • Decreased platelet function • Drugs • Heparin (inhibit coagulation / decrease platelet function) • Protamine (inhibit coagulation / decrease platelet function) 1) Despotis et. al, 2000

  8. Background • Bleeding and CPB1 • Hemodilution • Decreased concentration of coagulation factors • Decreased platelet count • Interaction of blood with extracorporeal surface • Decreased platelet count • Decreased platelet function • Consumption of coagulation factors • Increased fibrinolysis • Hypothermia • Decreased platelet function • Drugs • Heparin (inhibit coagulation / decrease platelet function) • Protamine (inhibit coagulation / decrease platelet function) 1) Despotis et. al, 2000

  9. Background • Bleeding and CPB1 • Hemodilution • Decreased concentration of coagulation factors • Decreased platelet count • Interaction of blood with extracorporeal surface • Decreased platelet count • Decreased platelet function • Consumption of coagulation factors • Increased fibrinolysis • Hypothermia • Decreased platelet function • Drugs • Heparin (inhibit coagulation / decrease platelet function) • Protamine (inhibit coagulation / decrease platelet function) 1) Despotis et. al, 2000

  10. Background • CPB-induced coagulation defects: • Platelet consumption / dysfunction • Coagulation factor deficiency • Fibrinolysis X X 

  11. Background • CPB-induced coagulation defects: • Platelet consumption / dysfunction • Coagulation factor deficiency • Fibrinolysis Plasma Prothrombin Complex Concentrates Cryoprecipitate Fibrinogen Concentrate rFVIIa Platelets ?DDAVP X X Antifibrinolytics  October 2016

  12. Outline • Cardiopulmonary bypass (CPB) and perioperative bleeding • Brief review of coagulation • Fractionated blood products in cardiac surgery: • a) Prothrombin complex concentrates (PCC) • b) Cryoprecipitate / Fibrinogen concentrate

  13. Coagulation Cascade

  14. Coagulation Cascade Injury 9 9a 10 10 TF 8a 8 7a 100X 7 Extrinsic Tenase Intrinsic Tenase 10a 2 5a 2a - Thrombin No timely intraoperative assay at present 1 - Fibrinogen 1a - Fibrin

  15. Outline • Cardiopulmonary bypass (CPB) and perioperative bleeding • Brief review of coagulation • Fractionated blood products in cardiac surgery: • a) Prothrombin complex concentrates (PCC) • b) Cryoprecipitate / Fibrinogen concentrate

  16. PCC • Isolated from cryosupernatant in plasma • 3-factor (2, 9, 10) or 4-factor (2, 7, 9, 10) • In Canada OctaplexTM and BeriplexTM (both 4-factor) • Initially emerged from search for purified F9 (Hemophilia B) • Each factor concentration communicated in IUs per 100IU of F9 1) Ghadimi et. al, 2016

  17. PCC Injury 9 9a 10 10 TF 8a 8 7a 100X 7 Extrinsic Tenase Intrinsic Tenase 10a 2 5a 2a - Thrombin 1 - Fibrinogen 1a - Fibrin

  18. PCC • Octapharma Canada Inc., 2014 • CSL Behring Canada Inc., 2015

  19. PCC • Approved indications • Vitamin K Antagonist (VKA) reversal for: • Bleeding manifestations or • Surgical intervention required within 6 hrs of bleeding • Dzik et. al, 2011

  20. PCC • International, non-inferiority RCT – 36 centres, n=202 • BeriplexTM (4F-PCC) vs. Plasma • Urgent reversal of vitamin K antagonist therapy • Outcomes: • 24-hour clinical hemostatic efficacy • INR correction (<1.3) 30mins after infusion • Time profiles of individual coagulation factors • Sarode et. al, 2013

  21. PCC • Results: • Hemostatic efficacy: • PCC (72.4%) vs. Plasma (65.4%)  PCC Non-inferior • Rapid INR correction: • Sarode et. al, 2013

  22. PCC • Results: • Factor levels: 2 7 9 10 • Sarode et. al, 2013

  23. PCC • Results: • Safety: • Sarode et. al, 2013

  24. PCC in Cardiac Surgery • CV Surgery in patients not on VKA: • Few small studies: • Humans, prospective, ex-vivo (n=102) • FFP and PCC (Beriplex, 4F PCC) added to samples from same patient, taken at two time points: • Before CPB • After heparin reversal • Primary outcome = potential for thrombin (2a) generation • Endogenous thrombin potential (ETP) • Percy et. al, 2015

  25. Coagulation Cascade Injury 9 9a 10 10 TF 8a 8 7a 7 Extrinsic Tenase Intrinsic Tenase 10a 2 5a 2a - Thrombin No timely intraoperative assay at present 1 - Fibrinogen 1a - Fibrin

  26. PCC in Cardiac Surgery 1000 1000 15mL/kg 25U/kg More prothromotic with PCC? • Percy et. al, 2015

  27. PCC in Cardiac Surgery • CV Surgery in patients not on VKA: • Few small studies: • Humans • Retrospective, single-centre • Propensity-matching • n=225 matched pairs from 3454 CV surgery patients • 3F PCC (median=1500IU) vs. FFP (median=2U) • Cappabianca et al, 2015

  28. PCC in Cardiac Surgery • Cappabianca et al, 2015

  29. PCC in Cardiac Surgery No difference No difference Favours FFP Favours PCC • Cappabianca et al, 2015

  30. PCC in Cardiac Surgery • Volume excess given with FFP  protective effect on kidney function? • Limitations: • Retrospective • Propensity-matching • Cappabianca et al, 2015

  31. PCC in Cardiac Surgery • What we know:

  32. PCC in Cardiac Surgery • Guidelines: Weak recommendation, Low quality evidence • Kozek-Langenecker et al, 2013

  33. Outline • Cardiopulmonary bypass (CPB) and perioperative bleeding • Brief review of coagulation • Fractionated blood products in cardiac surgery: • a) Prothrombin complex concentrates (PCC) • b) Cryoprecipitate / Fibrinogen concentrate

  34. Coagulation Cascade Injury 9 9a 10 10 TF 8a 8 7a 7 Extrinsic Tenase Intrinsic Tenase 10a 2 5a 2a - Thrombin 1 - Fibrinogen 1a - Fibrin

  35. Cryoprecipitate • Derived from plasma • Fibrinogen (1), F8, F13, vWF • 432±264 mg fibrinogen per unit • ~10units/dose  ~4g fibrinogen  increase plasma concentration by ~1.0g/L

  36. Fibrinogen Concentrate • Derived from plasma (RiaSTAPTM) • Lyophilized fibrinogen (1) • 1g per vial – reconstituted with 50mL sterile water • 4g/dose  increase plasma concentration by ~1.0g/L

  37. Fibrinogen Supplementation • Wide normal range: 2.0 – 4.0 g/L • Treatment thresholds: <0.8 – 1.0 g/L • Based on old, small studies not relevant to perioperative bleeding • No longer applicable • Current recommendations: 1.5 – 2.0 g/L • Based on large, relevant observational data

  38. Fibrinogen Supplementation • Approved indications • Cryoprecipitate • Congenital hypofibrinogenemia • Acquired hypofibrinogenemia (i.e. CPB) • Fibrinogen concentrate • Congenital hypofibrinogenemia • Europe + North America • Acquired hypofibrinogenemia (i.e. CPB) • Europe ONLY

  39. Fibrinogen in Cardiac Surgery • Fibrinogen concentrate vs. placebo • Multiple recent RCTs • Fibrinogen concentrate vs. cryoprecipitate • 1 small RCT in children • No RCTs in adults

  40. Fibrinogen in Cardiac Surgery • Fibrinogen concentrate vs. placebo • Multiple recent RCTs • Fibrinogen concentrate vs. cryoprecipitate • 1 small RCT in children • No RCTs in adults

  41. Fibrinogen in Cardiac Surgery Incision FIBTEM End-CPB Protamine pRBC Plt FFP / PCC *Fibrinogen Fibrinogen (FIBTEM-based) or Placebo (NS) CPB • Single-centre, double-blind RCT • n = 116 (58/group) • 1º outcome = Avoidance of ABP • Ranucci et al, 2015

  42. Fibrinogen in Cardiac Surgery • Ranucci et al, 2015

  43. Fibrinogen in Cardiac Surgery • Safety: • Ranucci et al, 2015

  44. Fibrinogen in Cardiac Surgery Incision 5min BM > 60g End-CPB 5min BM > 60g Protamine Algorithm: • pRBC • Plt • FFP Fibrinogen (FIBTEM-based) or Placebo CPB • Multicentre, international, RCT • n = 519 rand., only 142 treated • 1º outcome = #ABP • 2º outcome = Specifics of ABP • Rahe-Meyer et al, 2016

  45. Fibrinogen in Cardiac Surgery • Rahe-Meyer et al, 2016

  46. Fibrinogen in Cardiac Surgery • Rahe-Meyer et al, 2016

  47. Fibrinogen in Cardiac Surgery • Rahe-Meyer et al, 2016

  48. Fibrinogen in Cardiac Surgery • Adverse events: • Comparable between groups • Limitations: • ?5-minute bleeding mass (x 5) • Normal mean fibrinogen prior to FC administration in treatment group • Rahe-Meyer et al, 2016

  49. Fibrinogen in Cardiac Surgery • Fibrinogen concentrate vs. placebo • Multiple recent RCTs • Fibrinogen concentrate vs. cryoprecipitate • 1 small RCT in children • No RCTs in adults

  50. Fibrinogen in Cardiac Surgery Diffuse bleeding AND Plasma fibrinogen < 1g/L Incision End-CPB Protamine pRBC Plt FFP *Cryo • Single-centre RCT - Brazil • n = 63 (30 Fib, 33 Cryo) • Median age – 3.5months • 1º outcome = Blood loss/48hrs • 2º outcome = Specifics of ABP CPB Fib (60mg/kg) or Cryo (10mL/kg) • Galas et al, 2014

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