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 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

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

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

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

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

Background Bleeding and CPB1 Hemodilution Decreased concentration of coagulation factors Decreased platelet count Interaction of blood with extracorporeal surface Decreased platelet function Consumption of coagulation factors Increased fibrinolysis Hypothermia Drugs Heparin (inhibit coagulation / decrease platelet function) Protamine (inhibit coagulation / decrease platelet function) As a result, difficult to provide timely, targetted therapy 1) Despotis et. al, 2000

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

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

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

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

Coagulation Cascade

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

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

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 As a result, difficult to provide timely, targetted therapy 1) Ghadimi et. al, 2016

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

PCC Factor (IU) OctaplexTM BeriplexTM 2 280-760 380-800 7 180-480 200-500 9 500 400-620 10 360-600 500-1020 Antithrombin 3 - 4-30 Protein C 140-260 420-820 Protein S 140-640 240-680 Heparin 80-310 8-40 Octapharma Canada Inc., 2014 CSL Behring Canada Inc., 2015

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

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 As a result, difficult to provide timely, targetted therapy Sarode et. al, 2013

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

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

PCC Results: Safety: Sarode et. al, 2013

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

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

PCC in Cardiac Surgery More prothromotic with PCC? 1000 15mL/kg 25U/kg ETP = endogenous thrombin potential More prothromotic with PCC? Percy et. al, 2015

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) As a result, difficult to provide timely, targetted therapy Cappabianca et al, 2015

PCC in Cardiac Surgery Cappabianca et al, 2015

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

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

Rapid Preparation/Injection PCC in Cardiac Surgery What we know: Plasma PCC Storage Frozen RT, Lyophilized Volume/dose ~1000mL ~80mL Rapid Preparation/Injection No Yes Thrombin Generation Lower Higher Safety concerns TACO TRALI Infection ?Prothrombotic ?AKI Contraindications HIT

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

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

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

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

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

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

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

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

Fibrinogen in Cardiac Surgery Fibrinogen concentrate vs. placebo Multiple recent RCTs Fibrinogen concentrate vs. cryoprecipitate 1 small RCT in children No RCTs in adults As a result, difficult to provide timely, targetted therapy

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

Fibrinogen in Cardiac Surgery Endpoint Fib (n=58) Placebo OR (95%CI) p Avoidance of [n (%)]: Any 39 (67) 26 (45) 0.40 (0.19–0.84) 0.015 pRBC FFP 58 (100) 50 (86) N/A 0.006 Platelets 54 (93) 0.119 Ranucci et al, 2015

Fibrinogen in Cardiac Surgery Safety: Ranucci et al, 2015

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

Fibrinogen in Cardiac Surgery Rahe-Meyer et al, 2016

Fibrinogen in Cardiac Surgery Rahe-Meyer et al, 2016

Fibrinogen in Cardiac Surgery Endpoint Fib (n=78) Placebo (n=74) p # of transfused units: (median, IQR) Any 5 (2, 11) 3 (0, 7) 0.026 pRBC 1 (0, 3) 0 (0, 2) 0.101 FFP 4 (0, 6) 0 (0, 4) 0.017 Platelets 1 (0, 2) 1 (0, 1) 0.089 Rahe-Meyer et al, 2016

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

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

Fibrinogen in Cardiac Surgery Diffuse bleeding AND Plasma fibrinogen < 1g/L Incision End-CPB 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 Fib (60mg/kg) or Cryo (10mL/kg) Galas et al, 2014

Fibrinogen in Cardiac Surgery Patients transfused with: Endpoint Fib (n=30) Cryo (n=33) p Blood loss (mL) / 48hrs: [median, (IQR)] 320 (157, 750) 410 (215, 510) 0.672 Patients transfused with: [n (%)] pRBC 25 (83) 32 (97) 0.094 FFP 3 (10) 8 (24) 0.137 Platelets 0 (0) 3 (9) 0.240 Cryoprecipitate 13 (43) 14 (42) 0.942 Galas et al, 2014

Fibrinogen in Cardiac Surgery T0: Before treatment T3: 24hr after T1: 1hr after T4: 48hr after T2: 2hr after Galas et al, 2014

Fibrinogen in Cardiac Surgery Safety: Galas et al, 2014

Fibrinogen Supplementation Fibrinogen concentrate Cryoprecipitate Fibrinogen concentrate Storage Frozen Room temperature Shelf life 1 year >3 years Rapid Preparation/ Injection No Yes Requires thawing Requires pooling Safety concerns Allogeneic Exposure ?Hepatic ?

Fibrinogen in Cardiac Surgery Guidelines: Strong recommendation, Low quality evidence Kozek-Langenecker et al, 2013

Conclusions Bleeding after CPB requires a timely and targeted approach to management PCC and Fibrinogen concentrate have theoretical advantages over plasma and cryoprecipitate but: Currently off-label for post-CPB coagulopathy Require higher level evidence for effectiveness/safety

Conclusions

Conclusions Future research: Plasma vs PCC  No RCTs! Cryo vs. Fibrinogen concentrate  1 RCT in progress New studies should reflect contemporary CV anesthesia practice: POC-based hemostatic algorithms Moderate quality evidence Kozek-Langenecker et al, 2013

Conclusions Viscoelastic Platelet Function n=7402 Implementation of point-of-care hemostatic testing within the context of an integrated transfusion algorithm reduces RBC + platelet transfusions and major bleeding following CV surgery. Karkouti et al, 2016

Conclusions Usage of PCC and Fibrinogen concentrate at TGH in CV surgery: Patients (#)

Conclusions Future research: Plasma vs PCC  No RCTs! Cryo vs. Fibrinogen concentrate  1 RCT in progress Reflect contemporary CV anesthesia practice: POC-based hemostatic algorithms Economic evaluation Costs + effects

The End Comments/Questions?