Use of Factor Concentrates in the

Perioperative Period
Lynne Uhl, MD
Vice Chair, Laboratory and Transfusion Medicine
Department of Pathology
Beth Israel Deaconess Medical Center
Associate Professor of Pathology
Harvard Medical School
Boston, MA
Goals:
Compare and contrast
plasma products and
factor concentrates
Review current approved
use of factor concentrates
as applied to the
perioperative setting
Discuss strategies to
enhance goal directed
management of
perioperative
coagulopathy
 Case presentation #1

67 y/o female with ESRD and h/o mechanical

MVR on Coumadin who presented for DDRT.
Transplant team requested preoperative
Kcentra to reverse INR prior to surgery due to
concerns for volume status.
Pertinent laboratory data:

11.9
Hematology: 6.2 122
38.3

Coags: PT/INR- 56.8s (9.4-12.5)/5.0

PTT-56.3s (25-36.5)
137 99 58
Chem7: 109
5.0 27 8.8
Albumin: 3.4 g/dL Bilirubin: 0.4 mg/dL
 Case presentation #2
78 y/o male with h/o atrial fibrillation on
apixaban who was admitted with polytrauma
sustained following a motorcycle accident.
Injuries: Subdural hematoma (2mm), multiple
facial bone fractures, multiple rib fractures, and
large thigh hematoma.
Kcentra requested given h/o FXa inhibitor and
multiple trauma.
Pertinent laboratory data are as follows:

16.0
Hematology: 15.6 197
45.4

Coags: PT/INR- 12.8s (9.4-12.5)/1.2

PTT-27.7s (25-36.5)
145 107 21
Chem7: 167
4.7 26 0.9
 Complex Biological Products

Plasma Cryoprecipitate
Albumin, Fibrinogen, Clotting Factors, Globulins Fibrinogen, VWF, FVIII,FXIII, Fibronectin
+ ???? + ????
Complex Biological Product Pure drug
 When Factor Concentrates
Might Be Considered
Congenital Factor Deficiency
Hemophilia A/B
AT-III deficiency
Urgent reversal of anticoagulants
Warfarin
NOACs [??]
Management of operative/perioperative
coagulopathy
 XII XIIa
Vitamin K
antagonists
XI XIa

Vitamin K VIIa VII

antagonists
IX IXa

VIIIa TF

X Xa X

Vitamin K Va
antagonists

Prothrombin II Thrombin IIa

Fibrinogen I Fibrin Ia Cross-linked

fibrin clot

Adapted from Sabir et al. Nat. Rev. Cardiol, 2014

 Prothrombin Complex Concentrates
3 factor concentrates: Factors II, IX, X
Relatively deficient in Factor VII

4 factor concentrates: Factors II, VII, IX, X

In addition, protein C and S
 Benefits of PCCs vs Plasma for
Warfarin Reversal
Shorter time to delivery
No need to thaw plasma
No need for blood bank testing for compatibility
Shorter infusion time
Plasma: 2-4 mL/min or faster; vol 225 mL/bag
PCC: 8 mL/min; vol ~100 mL
Concentration of factors: PCC > plasma
Reduced risk for transfusion-associated AE
The concern for plasma transfusion
TACO
TRALI
Other transfusion reactions
Allergic
FNH
Marshall et al. JTH 2015; 14:324-330
 Patients with INR > 2.0 on VKA therapy
needing urgent reversal randomized to either
PCC or plasma infusion; Vitamin K
administered to both study arms
10 endpoint: effective hemostasis and rapid
reduction of INR
 Four Factor PCC
Dosing recommendations
 Case #1 resolution
Patient given 2240 units of Kcentra + 2 units of
plasma

Post treatment laboratory values:

PT/INR- 14.2s (9.4-12.5)/1.3
PTT-34.5s (25-36.5)
Successful surgical procedure
 XII XIIa

XI XIa

IX IXa VIIa VII

VIIIa TF
Factor Xa inhibitors:
Apixaban
Betrixaban
Edoxaban X Xa X
Rivaroxaban

Va

Direct thrombin inhibitor:

Dabigatran
Prothrombin II Thrombin IIa

Fibrinogen I Fibrin Ia Cross-linked

fibrin clot

Adapted from Sabir et al. Nat. Rev. Cardiol, 2014

 Properties of NOACs
Dabigatran etexilate Rivaroxaban Apixaban

Target Thrombin Factor Xa Factor Xa

Prodrug Yes No No

Bioavailability 6.5% 80% ~ 66%

Tmax 2h 2.5-4 h 3h

Half-life 12-14 h 7-13 h 8-13 h

Routine coagulation No No No
monitoring
Dosing Fixed, BID Fixed, BID Fixed, BID

Elimination 80% renal 67% renal (half is inactive 25% renal, 75% fecal
drug), 33% fecal
Potential drug interactions Potent P-gp inhibitors and Strong dual CYP 3A4 and Strong dual CHP 3A4 and
P-gp inducers P-gp inhibitors/inducers P-gp inhibitors/inducers

Adapted from Bauer, ASH 2013

 NOAC Reversal:
Role of Factor Concentrates

Am. J. Hematol. 87:S119S126, 2012

 Recommendations
In elective surgical setting, discontinue
therapy
Dabigatran: 1-5 d prior to surgery
Xa inhibitors: at least 24 hours prior to surgery
In emergent setting, PCC, rFVIIa, or FEIBA if
bleeding situation is life-threatening and not
responsive to other therapeutic interventions
Use is off-label in the US**
 Case #2 resolution
Admitted to ICU for observation and
expectant management
Apixaban held

Non-operative management of all fractures

Cancelled Kcentra request as patient was

clinically stable
 Perioperative Coagulopathy
Etiology is multifactorial
Imbalance of pro and anticoagulant proteins
Deficiency of cellular elements [eg. Platelets]
Disruption of endothelial surfaces
Biochemical and body temperature abnormalities
Rapid changes requires anticipatory and
expedient therapeutic intervention
 Do factor concentrates have a therapeutic
role in management of
perioperative coagulopathy?
Plasma and cryoprecipitate contain multiple factors BUT
PCC/factor concentrates contain greater unit of activity/mL vs
plasma or cryopreciptate
eg. Fibrinogen content of
-Plasma = 1-3 g/L
-Cryoprecipitate = 15 g/L
-Fibrinogen concentrate = 20 g/L
NB: In the US, use of concentrates to manage coagulopathy is
off-label

No substitute for red cells and platelets

 Role of concentrates, continued
The problem
Limited number of RCTs evaluating the effectiveness
of factor concentrates vs plasma/cryoprecipitate in
management of perioperative coagulopathy.
Clinical reports are plagued by small sample size and
heterogeneous patient characteristics; thus clear
recommendations are lacking.
Consensus, however, on role of laboratory
monitoring to guide directed therapeutic
intervention
 Central Laboratory Assessment
Coagulation testing---suboptimal
PT/INR, PTT, Fibrinogen
Long turn-around time
Hematologic parameters
Platelet count and hemoglobin/hematocrit
Rapid turn-around time
BUT---not may not be informative with respect to
platelet function
 Point of Care Hemostatic Assessment
Thromboelastograpy
(TEG)/Thromboelastometry (ROTEM)
Functional assessment of coagulation/hemostatic
status
Provides information which can guide targeted
therapeutic intervention
TEG ROTEM

Bollinger et al. TMR; 26:1-13,2012

TEG: Normal and Abnormal Patterns

Da Luz et al. Scand J Trauma Resusc Emerg Med; 21:29, 2013

 Retrospective, comparative analysis of
patients who received fibrinogen concentrate
and/or PCC, but no plasma (n=80), and
patients who received plasma, but no
fibrinogen concentrate or PCC (n=160)
 Schochle et al, cont
Coagulation management
Fibrinogen-PCC group:
TEM-guided for fibrinogen, PCC, and platelet
administration
Plasma group:
Dictated by clinical practice at each trauma center
Coagulation parameters assessed by local laboratories
TEM not used
Key Results: Transfusion Avoidance in
Fibrinogen-PCC group
 Prospective, RCT, placebo-controlled trial
Treatment arm: Fibrinogen concentrate at
conclusion of surgery, dose based on
thromboelastometry profile
Control arm: saline placebo

J Am Heart Assoc; 4: 1-10, 2015

 Ranucci et al, cont
Study endpoints:
10: avoidance of allogeneic blood products up to
30 days post surgery
20: # of RC, Plasma, and Platelet units txd,
massive transfusion, post-op bleeding, surgical
revision
Safety: operative mortality and thromboembolic
complications

J Am Heart Assoc; 4: 1-10, 2015

Key Results: Transfusion Avoidance

J Am Heart Assoc; 4: 1-10, 2015

Blood Product Transfusion

J Am Heart Assoc; 4: 1-10, 2015

 Summary Points
In patients on Coumadin, 4-Factor PCCs provide
faster INR correction compared to plasma and avoid
pulmonary complications associated with plasma
transfusion
Should be used in lieu of plasma in bleeding patient or
patient in need of urgent surgical procedure
4-Factor PCCs or other PCC offer no certain
benefit in bleeding patient on NOAC
Use should be reserved for life-threatening bleeding after
all other therapeutic interventions have failed
 Summary Points
Perioperative coagulopathy is complex
Clinical studies show benefit of POC hemostatic
assessment for optimization of therapeutic
management
Need for larger RCTs to validate use of tools, and
optimal therapeutic intervention
Thank you.