COAGULATION ISSUES ON ECMO 2010

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

Incidence of bleeding (ELSO 1998)

CLOTS IN CIRCUIT BLEEDING

29% of neonates 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 activation Contact activation Thrombin generation despite heparin Plasminogen activation Continued thrombotic stimulus

Clotting cascade

Fibrinogen adsoprtion on circuit

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

factor 12 + fibrinogen

Cytokines platelets

Contact PATHWA Y

Platelet activation

Activated platelet

Platelet (non activated)

Thrombin binding site Fibrinogen

CYTOKINES Endothelium

Thrombin generation
ANTICOAGULANT PRO-COAGULANT

Antithrombin Protein C Protein S Tissue factor inhibitor heparin Anticoag

Thrombin

platelet

thrombin

Fibrin formation via thrombin (PROCOAGULANT)

1.Platelets Thrombin

2. Factor X111

Fibrinogen A

3. Fibrin

crosslinked

Insoluble fibrin

4. tPA can dissolve

Fibrinogen / platelet mesh

Action of Heparin as ANTICOAGULANT

Procoagulant surface overwhelming

heparin

Heparin unable to get into monolayer Accelerates antithrombin x 1000 No effect on platelets

Heparin thrombin interaction

ANTICOAGULANT S Antithrombin III Protein C Protein S Tissue factor inhibitor

Thrombin

Procoag

fibrin

Thrombin activated

History ECMO

Clot formation
Thrombogenic surface Protein C Protein S Tissue factor inhibitor Thrombin

Heparin

fibrinogen

Antithrombin

platelets CLOT

fibrin

Action of Heparin: Clotting cascade

Clot formation

Heparin does not dissolve clots

Anticoagulants

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

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 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

Wide variation between ACTs And heparin delivery between Patients and in same patient

ASAIO Journal 2007; 53:111-114 Ann Thorac Surg 2007;83:91220

ACT vs Anti Xa levels with heparin

ACTs do NOT reflect anticoagulation cascade with accuracy DO NOT interpret in isolation Always recheck abnormal values

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

Standard ACT target 160 to 180 sec Bleeding (reduce heparin) 140 to 160 sec Major Bleeding add Tranexamic acid Microdose heparin dont use ACT 10 u/kg/hr

Tranexamic acid

Reduced surgical bleeding

o o

(57 v 390 mL, P = .005) (1.13 v 2.95 mL/kg/h, P = .03).

Lower RBC transfusion 2 patients with severe thrombotic complications Dose

o o

bolus 4 mg/kg 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

Clot formation: Patient or circuit

If ECMO flow stopped for > 5 minutes: consider thrombus risk