Activation of - PowerPoint Presentation

Slide1

Activation of

the Hemostatic System During

Cardiopulmonary BypassSlide2

Normal hemostasisSlide3

circulating platelets adhere to the

subendothelium

that is exposed when the

vascular lining

is broken

.

Adhesion of platelets to the endothelial bed is mediated

through the

surface proteins that are produced and stored in platelets and endothelial cells such

as von

Willebrand

Factor (VWF

).

*** Leads to:

platelet shape

changes

Assembly of

the glycoprotein

IIb

/

IIIa

(

GPIIb

/IIIA)

receptor

release

of secondary aggregators as

ADP and thromboxane

A2.Slide4

At the same time of platelet plug formation, the coagulation system is activated.Slide5

Anticoagulant mechanisms

tissue factor pathway inhibitor (TFPI

)

inactivates factor

VIIa

bound to tissue factor

antithrombin

III

It neutralizes factor

Xa

, thrombin (factor

IIa

), factor

IXa

and factor

VIIa

bound to

tissue factor.

All these actions are thought to be accelerated when

antithrombin

is bound to

heparin or

vascular heparin-like proteoglycans.

protein C anticoagulant pathway

inactivates factors

Va

and

VIIIa

.Slide6

Cardiopulmonary bypass (CPB)

 is a technique that temporarily takes over the function of the 

heart

 and 

lungs

 during 

surgery

, maintaining the circulation of blood and the oxygen content of the patient's body.

The

CPB pump itself is often referred to as a 

heart–lung machine

.

R

esults

in widespread activation of the hemostatic system. However, surgery also results in normal increases in coagulation activation, platelet activation, and fibrinolysis that are associated with normal wound hemostasis.Slide7
Slide8
Slide9

MECHANISMS OF ACTIVATION

Hemostatic system activation occurs via

several mechanisms including:

Activation of

coagulation

fibrinolysis

,

inflammation,

platelets.Slide10
Slide11

Activation of coagulation

it has been thought that contact activation via factor XII was the trigger

for extensive

activation of the hemostatic system during CPB

.

Factor XII becomes activated

when blood

interacts with a foreign surface, such as the CPB circuit, thus activating the

intrinsic clotting

pathway

.

Boisclair

et al. showed no change in factor

XIIa

levels during

CPB, despite

significant thrombin generation, indicating that contact activation was not the

initial trigger

for coagulation

.Slide12

This suggests a role for the extrinsic pathway

as the

primary stimulus with subsequent activation of factor IX and the intrinsic system via

the extrinsic

pathway

.

TF is released by the endothelial cells

due to

the surgical trauma and the

retransfusion

of pericardial blood and TF-expression on

the surface

of activated monocytes are also sources for

VIIa

/TF activation during CPB

.

Together, the

contact activation and tissue factor pathway result in the immense formation of

thrombin during

CPB.Slide13

The

Fibrinolytic

System

Activation of fibrinolysis occurs simultaneously and by several

mechanisms.

t-PA

release contributes to fibrinolysis and is promoted

by:

CPB-mediated

contact activation

of factor XII

Thrombin

Hypothermia

traumatized

endothelial

cells

returned

blood from

the

cardiotomy

suction.Slide14

The activation of these cascades may lead to a consumptive

coagulopathy

Thrombin

mediates the

conversion of fibrinogen to fibrin, and also activates factor V, VII, XIII, and platelets.

It also

activates complement in the inflammatory system, which may further enhance

coagulation activation.

thrombin also

downregulates

hemostasis by releasing TFPI

and in

combination with

thrombomodulin

, it activates protein C, which inhibits the

previously generated

factors

Va

and

VIIIa

Thrombin also initiates fibrinolysis by mediating release of

t-PA which

activates plasmin

.

If the effects of thrombin and plasmin are not

attenuated, unrestricted thrombin

and plasmin activity will lead

to consumption

of coagulation factors and platelets (

i.e. a

disseminated intravascular coagulation state during CPB) and this may result in both

bleeding and

thrombo

-embolic complications.Slide15

Inflammation

A sepsis-like clinical picture that often results

from CPB

, termed the systemic inflammatory response

syndrome, can

be linked to “crosstalk” with the

coagulation system.

Leukocytes, including neutrophils and monocytes,

bind to

and are activated by the surface of the bypass circuit

,

which leads to an increase in TF

expression,

procoagulant

activation, and thrombin generation on

these cells.

Shed blood contains increased numbers

of activated

leukocytes and levels of TF bound to cells

and

microparticles

, as well as soluble TF.Slide16

Platelet

CPB activates platelets with resultant structural

and biochemical

changes

.

These include physical factors (

such as

hypothermia and high shear stresses), exposure to artificial surfaces, the use of

exogenous drugs

(such as heparin and protamine), and the release of endogenous chemical mediators (

such as

thrombin, complement, cytokines and adrenaline

)Slide17

several platelet surface molecules such as

GPIb

and

GPIIb

/

IIIa

are

downregulated

during

CPB.

expression of P-

selectin

is increased by activated platelets

All these changes can lead to both the formation of platelet conjugates by activated platelets and hemostatic defects due to impaired platelet function.

Thrombocytopenia.Slide18

Use of heparin and protamine

To prevent thromboembolic complications due tot the use of CPB, heparin is administered

before

the patient is connected to the CPB system. Heparin binds to

the enzyme

inhibitor

antithrombin

III (AT-III) causing rapid interaction

with thrombin.

Next

to the neutralization of thrombin, heparin also leads to increased plasmin generation.

This results

in increased fibrinolysis and also platelet activation, as plasmin binds to their surface

.

protamine sulfate is used for reversal of

heparin anticoagulation The administration

of protamine may also cause a transient thrombocytopenia, which is

associated with

platelet activation and the formation of transient aggregates that appear to sequestrate

in the

lungs.Slide19

Strategies to attenuate hemostatic activation during cardiac surgery

Pharmacological

strategies

Platelet

inhibition:

Aspirin,

Clopidogrel

,

dipyridamole

,

short-acting

GPIIb

/

IIIa

antagonist

Fibrinolysis

inhibitors:

Tranexaminic

acid (TA),

ε-

aminocaproic

acid (EACA) and

aprotinine

Thrombin

inhibitors:

Several newly developed antithrombotic agents have been studied as alternatives to

heparin when

heparin cannot be used (

eg

, heparin-induced thrombocytopenia with thrombosis)Slide20

Non-pharmacological strategies

Heparin-coated CPB

circuit

Cardiotomy

suction:

blood in the pericardial cavity is highly activated and contains

high concentrations

of thrombin and plasmin

.

This blood is usually collected by

cardiotomy

suction and

rerouted to the patient without processing

.

Normothermia

:

platelet aggregation

and endothelial

cell related

coagulation

Plasma levels of

soluble

thrombomodulin

were more increased in hypothermic than in

normothermic

more extensive endothelial damage or activationSlide21

References

S.F. KHURI

, et al.:

EFFECTS OF CARDIOPULMONARY BYPASS ON

HEMOSTASIS,1997

Roman M.

Sniecinski

, et al.:

Activation of the Hemostatic System

During Cardiopulmonary Bypass,2011

A Practical Approach to Cardiac

Anesthesia,2007,

Chapter twoSlide22