Coagulation, Fluid, and
Blood Management for
Cardiac Surgery
Maureane Hoffman, MD, PhD
Professor of Pathology, Duke University
and
Director, Transfusion Service and Hematology Laboratory
Durham Veterans Affairs Medical Center
Durham, NC
Blood Coagulation
and Lack Thereof……
A topic which may be of
concern during cardiac surgery
Objectives
 Appreciate differences between
the “coagulation cascade” and
how hemostasis works in vivo
 Understand that the PT and aPTT
provide information about
coagulation factor levels, but don’t
necessarily reflect bleeding risk
 Consider approaches to restoring
hemostasis in bleeding patients
There are
reasons why
many people
don’t want to
hear a talk
about blood
coagulation
Our group has been trying to
develop better models to
help us understand
coagulation
In the 1960’s the coagulation
factors were organized into a
“cascade” or “waterfall” model.
This evolved into the current
cascade model …
Macfarlane RG. An enzyme cascade in the blood clotting mechanism, and
its function as a biological amplifier. Nature. 1964;202:498-499.
Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting.
Science. 1964;145:1310-1312
The Coagulation Cascade
aPTT
Intrinsic Pathway
PT
Extrinsic Pathway
FXII/HMK/PK
Factor XI
Factor IX
Factor XIa
Factor VIIa
Tissue Factor
Lipid
Factor IXa
Factor VIIIa
Lipid
Factor X
Prothrombin
Factor Xa
Factor Va
Lipid
Factor X
Thrombin
Fibrinogen
Fibrin
The “cascade” was intended
as a model of how the
coagulation proteins interact
biochemically, not how
hemostasis works in the body
It IS a good model of what happens
in the PT and aPTT assays
Intrinsic Pathway
Prolonged aPTT only
Factor XII/HMK/PK
Factor XI
Factor IX
Factor XIa
Prolonged aPTT
Variable bleeding
Factor IXa
Factor VIIIa
Factor X
Prolonged aPTT
Severe bleeding
Factor Xa
Factor Va
Prothrombin
Thrombin
Fibrinogen
Fibrin
Can putting the cells back in
the model explain some
clinical phenomena that the
“protein-centered” cascade
model cannot?
Cell-based experimental model
cells
monocytes (TF)
platelets
1 pM TF
15/uL
100,000/uL
proteins
prothrombin
factor VII
factor IX
factor X
factor XI
factor V
factor VIII
1400 nM
10 nM
70 nM
135 nM
30 nM
20 nM
0.3 nM
100 ug/mL
0.5 ug/mL
4 ug/mL
8 ug/mL
5 ug/mL
7 ug/mL
0.1 ug/mL
inhibitors
antithrombin
TFPI
3000 nM
3 nM
200 ug/mL
0.1 ug/mL
Cell-based conceptual model Hemostasis occurs on two surfaces:
TF-bearing cells and platelets
1.Initiation
IIa
2.Amplification
3.Propagation
IIa
X
TF
VIIa
TF VIIa
Xa
II
Initiation
Va
IIa
TF-Bearing Cell
TF
IX
VIIa
IXa
Hoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas, 85:958-65, 2001
X
TF
VIIa
TF VIIa
II
Amplification
VIII/vWF
Xa
Va
IIa
V
TF-Bearing Cell
Priming Amount
of Thrombin
TF
VIIa
XIa
VIIIa + vWF
Platelet
V
Va
XI
XIa
VIIIa
Va
Activated Platelet
Hoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas, 85:958-65, 2001
Propagation
TFPI
Xa
VIIa
TF
VIIa
TF
VIII/vWF
Xa
VIIIa + vWF
Va
IIa
V
TF-Bearing Cell
Platelet
V
Va
XI
XIa
TF
IX
IX
VIIa
X
IXa
XIa VIIIa
II
Large amount
of thrombin
Xa
IIa
Va
Activated Platelet
Hoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas, 85:958-65, 2001
A Cell-Based Model of
Hemostasis
II
X
TF VIIa
Xa
Va
IIa
VIII/vWF
VIIIa
TF-Bearing Cell
TF
IXa
XIa
VIIa
V
IX
Platelet
II
X
IXa VIIIa
XI
Va
Xa
Va
Activated Platelet
IIa
IX
Hoffman M, et al. Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65.
XIa
There Really Are “Intrinsic”
and “Extrinsic” Pathways
 They are not redundant - they operate
on different cellular surfaces to fill
different roles
 The “extrinsic” or TF pathway works on
the initiating cells
 The “intrinsic” pathway works on platelets
to produce the thrombin “burst”
The extrinsic pathway acts in vivo
to initiate coagulation
PT Assay
in vivo
Adapted from: Monroe DM and Hoffman, M: What does it take to make the perfect clot?
Arterio Thromb Vasc Biol 26:41-48, 2006
The intrinsic pathway acts on
platelet surfaces to generate large
amounts of thrombin
aPTT
in vivo
Adapted from: Monroe DM and Hoffman, M: What does it take to make the perfect clot?
Arterio Thromb Vasc Biol 26:41-48, 2006
Why do previously normal
patients bleed?
 Anatomic defects - “surgical” bleeding
 Microvascular bleeding
 Dilution or depletion of coagulation
factors and platelets
 Hyperfibrinolysis
 Hypothermia
 Acidosis
 ?
Good News!
The tests we have are fine for
evaluating the cause of bleeding
 The PT and aPTT are useful if we have a
bleeding patient and we want to figure out if a
factor deficiency is responsible
The tests we have are also fine
for directing component therapy
 Prolonged PT or aPTT = plasma
 Low fibrinogen = cryoprecipitate
 Low platelet count or defect on platelet
function testing = platelet concentrates
The whole idea is to get a
stable platelet/fibrin clot
IIa
Fibrinogen
Fibrin assembly can be a race
against plasmin degradation
Blood component therapy does
not always stop the bleeding
 Component therapy is generally intended to
replace deficient factors/platelets
 Replacement doesn’t always work
 FFP is always somewhat diluted
 Platelets have a “storage defect”
 Even if we apparently restore “normal” levels,
bleeding may not stop
 Can exacerbate acidosis, hypocalcemia,
hyperkalemia and hypothermia
What else can we do for
microvascular bleeding?
 Blood component replacement
 Anti-fibrinolytics
 Effective in some settings
 Coagulation factor concentrates - can achieve
supra-normal levels of factors
 Recombinant FVIIa
 Fibrinogen concentrate
 Prothrombin complex concentrates
Fibrin clot structure depends on
the amount/rate of thrombin
generation and the amount of
fibrinogen incorporated
Higher levels of each give more
structurally stable clots
More thrombin gives a more
tightly packed clot
We can enhance thrombin
generation by:
 Replacing deficient factors or platelets
 Should return thrombin generation to “normal”
 Might not be enough to maintain hemostasis
 Administration of rFVIIa
 (note that this is an off-label use)
 Probably can get thrombin generation higher than
“normal” in non-hemophilic patients
 This can be both good and bad
Higher levels of fibrinogen
produce more tightly packed
and stable fibrin clots in vitro
and
increase fibrin content of clots
and resistance to lysis in vivo
Machlus et al. Blood 2011, 117:4953-63
Higher pre-op fibrinogen
associated with less bleeding
after CPB
and
Fibrinogen concentrate
reduced bleeding compared to
historical controls
Ucar et al. Preoperative fibrinogen levels as a predictor of postoperative bleeding after open
heart surgery. Heart SurgForum. 2007;10(5):E392-6.
Rahe-Meyer et al. Bleeding management with fibrinogen concentrate targeting a high-normal
plasma fibrinogen level: a pilot study. Br J Anaesth.2009;102(6):785-92.
We can increase fibrinogen with:
 Cryoprecipitate
 Concentrated form of fibrinogen as well as FVIII/vWF
 Might enhance platelet adhesion as well as increase fibrinogen
 Administration of fibrinogen concentrate
 (note that this is an off-label use)
 Infectious disease risk probably less than cryo
 Can give a known dose of fibrinogen
What is the best thing to do
for a bleeding patient?





Blood components/FVIIa/fibrinogen?
What strategy is most effective?
What tests can we use to guide therapy?
What should our targets be?
What are the risks of thrombosis?
 Immediately? Several days post-op?
Take-home messages
 The cascade model helps us interpret the
PT and aPTT tests
 A cell-based model gives us insight into
hemostatic mechanisms in vivo
 The PT and aPTT give information about
procoagulant levels, but do not
necessarily reflect bleeding risk
 Clot stability in a bleeding patient can be
enhanced by increasing thrombin
generation or increasing the fibrin
content of the clot
Questions
To maintain hemostasis a
sufficiently stable clot must
be formed
 Primary hemostasis via platelet plug
 Stabilized by a meshwork of fibrin due to
platelet surface thrombin generation
 Final clot must resist mechanical and
enzymatic disruption until healing occurs
This is what happens to thrombin generation
when you dilute all of the proteins
If both pro- and anti-coagulant
factors are reduced, the ability
to generate thrombin is
preserved