Keyvan Karkouti, MD FRCPC, MSc
Department of Anesthesia and Pain Management
University Health Network, Sinai Health System, and Women’s College Hospital
University of Toronto
Bleeding and Transfusion Targets in Cardiac Surgery
Disclosures
• Research support and honoraria from Octapharma and Instrumentation Laboratory
Summary
• Hemoglobin targets for red cells– Restrictive unless clinically indicated
• POC assays– More informative (higher cost) than standard assays
• Fibrinogen replacement– Fibrinogen level <1.5-2 g/L in BLEEDING patients– Fibrinogen concentrate non-inferior to cryoprecipitate
• Factor replacement– No good assay– No comparative data on plasma vs. PCC
Hemoglobin Target for RBC Transfusion
Hemoglobin Target for RBC Transfusion
Mueller et al. JAMA 2019;321:983-997
Hemoglobin Target for RBC Transfusion
Mueller et al. JAMA 2019;321:983-997
Hemoglobin Target for RBC Transfusion
Mazer et al. NEJM 2017;377:2133-44
Hemoglobin Target for RBC Transfusion
• Higher-risk cardiac surgery
• Randomized before surgery
• Restrictive group: – Transfuse if Hb < 75 g/L
• Liberal group: – Transfuse if Hb < 95 g/L during surgery/ICU stay
– Transfuse if Hb < 85 g/L on ward
• Protocol suspended if rapid bleeding or hemodynamic instability due to bleeding
Mazer et al. NEJM 2017;377:2133-44
Hemoglobin Target for RBC Transfusion
Mazer et al. NEJM 2017;377:2133-44
Hemoglobin Target for RBC Transfusion
0%
10%
20%
30%
40%
50%
TransfusionAvoidance
Mortality CompositeOutcome
Infection
Liberal
Restrictive
Mazer et al. NEJM 2017;377:2133-44
Hemoglobin Target for RBC Transfusion
• “If sole consideration for transfusion is the hemoglobin level, then a restrictive threshold should be used.”
• Our targets:
– 70 g/L during CPB
– 80 g/L post-CPB
– 90 g/L in bleeding or unstable patients
Role of POC Assays
Role of POC Assays
• Viscoelastic assays
– TEG; ROTEM
• Platelet function assays
– Aggregometry; VerifyNow; PFA-100; PlateletWorks
• Compared with standard coagulation assays
– Faster results
– Use whole-blood vs. plasma
• More physiological measure of coagulation defects
Critical Components of Coagulation
Ghadimi et al. Anesth Analg 2016;122:1287-1300
Critical Components of Coagulation
1.Thrombin
Ghadimi et al. Anesth Analg 2016;122:1287-1300
Critical Components of Coagulation
Ghadimi et al. Anesth Analg 2016;122:1287-1300
1.Thrombin
2.Fibrinogen
Critical Components of Coagulation
3.Platelets
Ghadimi et al. Anesth Analg 2016;122:1287-1300
1.Thrombin
2.Fibrinogen
2 of 3 are not measured by standard coagulation assays!
3.Platelets
Ghadimi et al. Anesth Analg 2016;122:1287-1300
1.Thrombin
2.Fibrinogen
X
X
Karkouti et al. Circulation 2016;134:1152-1162
Karkouti et al. Circulation 2016;134:1152-1162
Fibrinogen Replacement
Fibrinogen Replacement
• 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
Karkouti et al. Anesth Analg 2013;117:14-22
Fibrinogen Replacement
Fibrinogen Replacement
Fibrinogen Replacement
CRYO: 10-15 U
FC: 4-6 g
Fibrinogen Replacement
Attributes Cryoprecipitate Fibrinogen Concentrate
Storage Frozen RT, Lyophilized
Long shelf life 1 year 3 years
Volume 300 mL 200 mL
Near-Patient Storage No Yes
Rapid preparation/injection No Yes
Pathogen reduction No Yes
Impact on platelet
production
Loss of 1 U of platelet per 1
U of cryoprecipitate
None
Contents High variability Lower variability
Effectiveness Unpredictable Predictable
Cryoprecipitate vs. Fibrinogen Concentrate
Available at jama.com
Published October 21, 2019
Jeannie Callum, MD, Michael E. Farkouh, MD, Damon C. Scales, MD, et al; FIBRES ResearchGroup
Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery
The FIBRES Randomized Clinical Trial
FIBRES
• Design
– Pragmatic randomized trial at 11 Canadian centers
• Study question
– In bleeding cardiac surgery patients with confirmed or suspected acquired hypofibrinogenemia, is fibrinogen concentrate non-inferiorto cryoprecipitate?
Callum et al. JAMA 2019
Callum et al. JAMA 2019
Primary Outcome and Analysis
• Total number of allogeneic blood components administered during first 24 hours after termination of bypass– Red cells + Plasma + Platelets
• Primary analysis:– Ratio of mean total units transfused
• Fibrinogen concentrate group/cryoprecipitate group
– Non-inferiority threshold <1.2
– 90% power to illustrate non-inferiority with 1200 patients (trial stopped at pre-planned interim analysis)
Callum et al. JAMA 2019
Baseline CharacteristicsCharacteristic Fibrinogen Concentrate
(N=372)
Cryoprecipitate
(N=363)
Non-elective surgery – no. (%) 141 (37.9) 128 (35.3)
Complex surgeryb – no. (%) 267 (71.8) 260 (71.6)
Procedurec – no. (% of procedures)
Total number of procedures
Aortic valve procedure
Surgery on aorta
Aortocoronary bypass
Mitral valve procedure
Tricuspid valve procedure
ASD/VSD repair
Heart transplant
Complex congenital
Other
653 (100.0)
165 (25.3)
161 (24.7)
153 (23.4)
68 (10.4)
31 (4.7)
20 (3.1)
18 (2.8)
11 (1.7)
26 (4.0)
612 (100.0)
146 (23.9)
177 (28.9)
146 (23.9)
70 (11.4)
35 (5.7)
8 (1.3)
10 (1.6)
11 (1.8)
9 (1.5)
Median CPB duration (IQR) – min 143 (102–209) 134 (99–200)
Callum et al. JAMA 2019
Characteristic Fibrinogen Concentrate
(N=372)
Cryoprecipitate
(N=363)
Median age (IQR) – years 65 (54–72) 64 (53–72)
Male sex – no. (%) 259 (69.6) 258 (71.1)
Diabetes mellitus – no. (%) 80 (21.5) 74 (20.4)
Atrial fibrillation – no. (%) 81 (21.8) 80 (22.0)
CCS Class IV angina – no. (%) 15 (4.0) 13 (3.6)
Peripheral vascular disease – no. (%) 37 (10.0) 34 (9.4)
Hypertension – no. (%) 234 (62.9) 240 (66.1)
Active endocarditis – no. (%) 19 (5.1) 18 (5.0)
Stroke/TIA – no. (%) 46 (12.4) 49 (13.5)
Congestive heart failure – no. (%) 113 (30.4) 91 (25.1)
Intra-aortic balloon pump – no. (%) 10 (2.7) 3 (0.8)
VAD/ECMO – no. (%) 9 (2.4) 9 (2.5)
Critical state before surgerya – no. (%) 63 (16.9) 38 (10.5)
Callum et al. JAMA 2019
Baseline Characteristics
Callum et al. JAMA 2019
Primary Outcome
Adverse eventsCharacteristic Fibrinogen Concentrate
(N=372)
Cryoprecipitate
(N=363)
Any adverse event – no. (%) [no.
events]
248 (66.7) [623] 264 (72.7) [673]
Any serious adverse event – no. (%)
[no. events]
117 (31.5) [224] 126 (34.7) [264]
Thromboembolic adverse events – no.
(%) [no. events]
26 (7.0) [27] 35 (9.6) [39]
Stroke/TIA 17 (4.6) 18 (5.0)
Amaurosis fugax 0 (0) 1 (0.3)
Myocardial infarction 3 (0.8) 4 (1.1)
DVT/PE 5 (1.3) 9 (2.5)
Other vessel thrombosis 0 (0) 7 (1.9)
Disseminated intravascular
coagulation
1 (0.3) 0 (0)
Thrombophlebitis 1 (0.3) 0 (0.0)
Callum et al. JAMA 2019
Conclusions
• In bleeding cardiac surgery patients with confirmed or suspected acquired hypofibrinogenemia, fibrinogen concentrate is non-inferior to cryoprecipitate
• Given its safety and logistical advantages, fibrinogen concentrate may be considered in bleeding patients with acquired hypofibrinogenemia
Factor Replacement
Factor Replacement
• The goal is to enhance thrombin generation
• There are no good assays for measuring thrombin generation
– INR: measures thrombin initiation
– CT: measures thrombin initiation
– CFT: measures dynamics of clot formation, a component of which is thrombin generation
Impaired Thrombin Generation
Percy et al. Blood Coag Fibrinol 2015;26:357-367
0
50
100
150
200
250
300
350
Factor II (IU/dL) TFPI (ng/mL) ETP (nmol/L/min)
Pre-CPB
Post-CPB
Enhancing Thrombin Generation
Enhancing Thrombin Generation
Enhancing Thrombin Generation
PCC
PCC Versus Plasma
Attributes Plasma PCC
Storage Frozen Lyophilized
Long shelf life 1 year 2 years
Volume 1000 mL 80 mL
Near-Patient Storage No Yes
Rapid preparation/injection No Yes
Pathogen reduction No Yes
Safety concerns TRALI, TACO Pro- vs anti-coagulant
imbalance
Contents High variability Lower variability
Effectiveness ++ +++
1000
1000
Percy et al. Blood Coag Fibrinol 2015;26:357-367
PCC Versus Plasma
Prothrombin Complex Concentrate versus Frozen Plasma in Bleeding Adult Cardiac Surgical Patients
A multicentre, randomized, active-control, pragmatic pilot study
FARES - I(Factor Replacement in Surgery)
Summary
• Hemoglobin targets for red cells– Restrictive unless clinically indicated
• POC assays– More informative (higher cost) than standard assays
• Fibrinogen replacement– Fibrinogen level <1.5-2 g/L in BLEEDING patients– Fibrinogen concentrate non-inferior to cryoprecipitate
• Factor replacement– No good assay– No comparative data on plasma vs. PCC
Summary
• Hemoglobin targets for red cells– Restrictive unless clinically indicated
• POC assays– More informative (higher cost) than standard assays
• Fibrinogen replacement– Fibrinogen level <1.5-2 g/L in BLEEDING patients– Fibrinogen concentrate non-inferior to cryoprecipitate
• Factor replacement– No good assay– No comparative data on plasma vs. PCC
Summary
• Hemoglobin targets for red cells– Restrictive unless clinically indicated
• POC assays– More informative (higher cost) than standard assays
• Fibrinogen replacement– Fibrinogen level <1.5-2 g/L in BLEEDING patients– Fibrinogen concentrate non-inferior to cryoprecipitate
• Factor replacement– No good assay– No comparative data on plasma vs. PCC
Summary
• Hemoglobin targets for red cells– Restrictive unless clinically indicated
• POC assays– More informative (higher cost) than standard assays
• Fibrinogen replacement– Fibrinogen level <1.5-2 g/L in BLEEDING patients– Fibrinogen concentrate non-inferior to cryoprecipitate
• Factor replacement– No good assay– No comparative data on plasma vs. PCC
Summary
• Hemoglobin targets for red cells– Restrictive unless clinically indicated
• POC assays– More informative (higher cost) than standard assays
• Fibrinogen replacement– Fibrinogen level <1.5-2 g/L in BLEEDING patients– Fibrinogen concentrate non-inferior to cryoprecipitate
• Factor replacement– No good assay– No comparative data on plasma vs. PCC
Thank you