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COAGULATION ISSUES ON ECMO 2010
COAGULATION ISSUES ON ECMO 2010

Endothelial activation Thrombin / clot formation Action of heparin Bleeding protocol Clinical relevance

Incidence of bleeding (ELSO 1998)
Incidence of bleeding (ELSO 1998)

CLOTS IN CIRCUIT

• 29% of neonates

BLEEDING

• 41% of neonates

• 28% of children

• 45% of cardiac patients

• 47% of adults

Why does blood clot when exposed to an ECMO circuit? • Fibrinogen adsorption • Platelet

Why does blood clot when exposed to an ECMO circuit?

• Fibrinogen adsorption

• Platelet activation

• Contact activation

• Thrombin generation despite heparin

• Plasminogen activation

• Continued thrombotic stimulus

Clotting cascade
Clotting cascade
Clotting cascade
Fibrinogen adsoprtion on circuit
Fibrinogen adsoprtion on circuit
Protein monolayer Activates contact pathway factor 12
Protein monolayer
Activates
contact
pathway
factor 12

• Any foreign surface is thrombogenic

• Fibrinogen coats foreign surface or damaged endothelium

• Occurs in thick dense MOLOLAYER (1000 x concentration of plasma)

• Process is unpredicatble: different tissues / different time period

“Contact Activation”
“Contact Activation”
“Contact Activation” factor 12 + fibrinogen Cytokines platelets Contact PATHWA Y
factor 12
factor 12

+

fibrinogen
fibrinogen
Cytokines platelets Contact PATHWA
Cytokines
platelets
Contact
PATHWA

Y

Platelet activation
Platelet activation
Activated platelet Platelet (non activated) Fibrinogen CYTOKINES Endothelium
Activated platelet
Platelet
(non activated)
Fibrinogen
CYTOKINES
Endothelium

Thrombin binding site

Thrombin generation
Thrombin generation

ANTICOAGULANT

PRO-COAGULANT

Antithrombin Protein C Protein S Tissue factor inhibitor
Antithrombin
Protein C
Protein S
Tissue factor inhibitor
Antithrombin Protein C Protein S Tissue factor inhibitor h e p a r i n Thrombin
Antithrombin Protein C Protein S Tissue factor inhibitor h e p a r i n Thrombin

heparin

Thrombin

Anticoag

Antithrombin Protein C Protein S Tissue factor inhibitor h e p a r i n Thrombin

platelet

thrombin

Fibrin formation via thrombin (PROCOAGULANT)
Fibrin formation via thrombin (PROCOAGULANT)
1.Platelets Thrombin 2. Factor X111 Fibrinogen 3. Fibrin A crosslinked B Insoluble fibrin 4. tPA
1.Platelets
Thrombin
2. Factor X111
Fibrinogen
3. Fibrin
A
crosslinked
B
Insoluble fibrin
4. tPA can dissolve

Fibrinogen / platelet mesh

Fibrinogen / platelet mesh
Action of Heparin as ANTICOAGULANT
Action of Heparin as ANTICOAGULANT

Procoagulant surface overwhelming

heparin
heparin

• Heparin unable to get into monolayer

• Accelerates antithrombin x 1000

• No effect on platelets

Heparin thrombin interaction
Heparin thrombin interaction

ANTICOAGULANT

S

Antithrombin III Protein C Protein S Tissue factor inhibitor
Antithrombin III
Protein C
Protein S
Tissue factor inhibitor
ANTICOAGULANT S Antithrombin III Protein C Protein S Tissue factor inhibitor Thrombin Procoag fibrin Thrombin activated
Thrombin
Thrombin

Procoag

fibrin
fibrin

Thrombin activated

History ECMO
History ECMO

Clot formation

Protein C Protein S Tissue factor inhibitor

Thrombogenic

surface

C Protein S Tissue factor inhibitor Thrombogenic surface Thrombin fibrinogen CLOT fibrin Heparin Antithrombin
C Protein S Tissue factor inhibitor Thrombogenic surface Thrombin fibrinogen CLOT fibrin Heparin Antithrombin

Thrombin

C Protein S Tissue factor inhibitor Thrombogenic surface Thrombin fibrinogen CLOT fibrin Heparin Antithrombin platelets

fibrinogen

C Protein S Tissue factor inhibitor Thrombogenic surface Thrombin fibrinogen CLOT fibrin Heparin Antithrombin platelets

CLOT

fibrin
fibrin

Heparin

C Protein S Tissue factor inhibitor Thrombogenic surface Thrombin fibrinogen CLOT fibrin Heparin Antithrombin platelets

Antithrombin

platelets

Action of Heparin: Clotting cascade
Action of Heparin: Clotting cascade
Clot formation
Clot formation
Clot formation Heparin does not dissolve clots

Heparin does not dissolve clots

Anticoagulants
Anticoagulants
HEPARIN ANTICOAGULATION
HEPARIN ANTICOAGULATION

• Massive tissue factor release on ECMO

• Overwhelming procoagulant state

• Platelets and thrombin activated

• Fibrinogen meshwork forms

• HEPARIN DOES NOT DISSOLVE CLOTS

• HEPARIN PREVENTS NEW CLOTS FORMING

Heparin
Heparin

1 unit of heparin (the "Howell Unit") is an amount required to keep 1 mL of cat's blood fluid for 24 hours at 0°C.

Standard Heparin Anticoagulation
Standard Heparin Anticoagulation

• Standard unfractionated heparin will be used for routine anticoagulation for all children on ECMO

• Standard concentration of 1ml = 20u/kg/hr (20 x wt x 50u Heparin in 50ml 0.9% saline)

• Heparin dose at cannulation = 75u/kg (on surgeons instructions)

• Start infusion of 20 u/kg/hr when ACT < 300

• Maintain ACT between 160-180 seconds and monitor and record ACT's HOURLY

Ann Thorac Surg 2007;83:912–20 Wide variation between ACT’s And heparin delivery between Patients and in

Ann Thorac Surg 2007;83:912–20

Wide variation between ACT’s And heparin delivery between Patients and in same patient
Wide variation between ACT’s
And heparin delivery between
Patients and in same patient

ASAIO Journal 2007; 53:111-114

Wide variation between ACT’s And heparin delivery between Patients and in same patient ASAIO Journal 2007;
ACT vs Anti Xa levels with heparin
ACT vs Anti Xa levels with heparin
ACT’s do NOT reflect anticoagulation cascade with accuracy DO NOT interpret in isolation Always recheck
ACT’s do NOT reflect
anticoagulation cascade with
accuracy
DO NOT interpret in isolation
Always recheck abnormal values
Targeting Heparin effect with ACT
Targeting Heparin effect with ACT

Increasing heparin to target value

Bolus 25u/kg and escalate dose by 5u/kg/hr until target ACT reached

• Measure ACT every 15 min till ACT Target achieved

• If > 50ug/kg/hr heparin is needed then check antithrombin level

• Platelet transfusions may increase requierments for ECMO Decreasing heparin to target value

• Reduce by 5u/kg/hr until target ACT reached.

• Measure ACT every 15 min until Target reached

• DO NOT STOP HEPARIN regardless of ACT (see bleeding protocol and discuss with ECMO lead)

Bleeding protocol
Bleeding protocol

• Standard ACT target 160 to 180 sec

• Bleeding (reduce heparin) 140 to 160 sec

• Major Bleeding add Tranexamic acid

Microdose heparin don’t use ACT 10 u/kg/hr

(reduce heparin) 140 to 160 sec • Major Bleeding add Tranexamic acid Microdose heparin don’t use
Tranexamic acid
Tranexamic acid

• Reduced surgical bleeding

o (57 v 390 mL, P = .005)

• Lower RBC transfusion

o (1.13 v 2.95 mL/kg/h, P = .03).

• 2 patients with severe thrombotic complications

• Dose

o

bolus 4 mg/kg

o

infusion of 1 mg/kg/h

van der Staak,F.H. et al J Ped Surg 1997;32(4):594-599

Bleeding protocol: Last resort: Factor 7
Bleeding protocol: Last resort: Factor 7
Bleeding protocol: Last resort: Factor 7
Clot formation: Patient or circuit
Clot formation: Patient or circuit
Clot formation: Patient or circuit If ECMO flow stopped for > 5 minutes: consider thrombus risk
If ECMO flow stopped for > 5 minutes: consider thrombus risk
If ECMO flow stopped for > 5 minutes: consider thrombus risk