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 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

7. 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

8. 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

9. 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

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

11. 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

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. 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

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

17. 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

18. PCC Factor (IU) OctaplexTM BeriplexTM 2 280-760 380-800 7 180-480 9
500 10
Antithrombin 3 -
4-30
Protein C
Protein S
Heparin
80-310
8-40
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
As a result, difficult to provide timely, targetted therapy
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. 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

26. 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

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

28. PCC in Cardiac Surgery
Cappabianca et al, 2015

29. PCC in Cardiac Surgery 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. 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

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 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

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
Europe + North America
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
As a result, difficult to provide timely, targetted therapy

41. 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

42. 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

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

44. 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

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
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

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
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

51. 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

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

53. Fibrinogen in Cardiac Surgery
Safety:
Galas et al, 2014

54. 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 ?

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

56. 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

57. Conclusions

58. 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

59. 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

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

61. 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

62. The End
Comments/Questions?