The use of extracorporeal membrane oxygenation (ECMO), and ventricular assist devices (VADs) for both short-term and long-term management of advanced cardiac (and respiratory) failure is increasing. Both thrombotic and haemorrhagic complications are common in patients receiving mechanical support, and such complications are associated with increased morbidity and mortality. Risks of bleeding and of thrombosis vary over time, and according to technical and patient factors. Careful assessment of the risks and benefits of anticoagulation for each patient is therefore a critical component of successful mechanical support. The approach to anticoagulation for patients receiving VADs varies according to stage of recovery and device. In the immediate post-operative period, bleeding is usually a greater risk than thrombosis and a period free from anticoagulation is usually used. Subsequent initiation of anticoagulation is usually with heparin, with the introduction of warfarin and aspirin over a period of days. Current recommendations include warfarin for all continuous flow devices, usually with the addition of aspirin, and in some cases an additional antiplatelet agent. Target INR and platelet inhibition varies with device, and institution. Testing varies according to device also. Potential pitfalls and problems exist, and these will be highlighted in this session, using a case-based approach. The management of anticoagulation for patients receiving ECMO varies worldwide, and there are currently limited guidelines. Important factors in decision-making in regards to anticoagulation for ECMO include mode of ECMO, ECMO configuration, ECMO flows, and underlying patient pathology. Strategies for anticoagulation should take each of these factors into consideration. It is also important to recognise that other management techniques to avoid thrombosis are important, such as adequate intracardiac decompression, and promoting cardiac ejection to avoid stasis. Cases will be used to demonstrate important issues and practical management strategies.

1. Anticoagulation During
Mechanical Support
Sara Jane Allen
CVICU, Auckland City Hospital

5. ECMO and
Anticoagulation
• What are the current recommendations?
• Anticoagulation
• Measurement
• What are the potential problems?
• Differences between VV and VA ECMO

7. Bleeding
• Patient’s critical illness
• Surgery
• SIRS
• Activated coagulation
cascade
• Anticoagulation
Clotting
• Patient’s critical illness
• Surgery
• SIRS
• Activated coagulation
cascade
• Extracorporeal circuit and
cannula
• Underlying cardiac function

8. Bleeding
• Patient’s critical illness
• Surgery
• SIRS
• Activated coagulation
cascade
• Anticoagulation
Clotting
• Patient’s critical illness
• Surgery
• SIRS
• Activated coagulation
cascade
• Extracorporeal circuit and
cannula
• Underlying cardiac function

9. Current International
Consensus Recommendations
and Evidence

10. Current International
Consensus Recommendations
and Evidence

11. Current Evidence

12. Current Evidence

13. Current Evidence

14. Current Evidence

15. Current Evidence

16. Current Evidence

17. Current Evidence

19. Current ELSO
Recommendations
• Correct coagulopathy prior to ECMO (platelets, INR,
fibrinogen)
• Bolus heparin on cannulation/initiation of ECMO
• Heparin continuous infusion during ECMO

20. • Heparin 20-50 units/kg/hour ongoing infusion
• Aim for ACT 180-220 seconds
• Adjust doses according to clinical context (recent CPB,
bleeding, residual heparin effect)
• Individualise approach to monitoring of anticoagulation
• Use more than one method

22. • Monitor heparin with ACT *
• Consider monitoring of anti-Xa activity (gold standard of
heparin effect) and antithrombin III levels
• May use APTT
• Use of TEG beneficial to assess heparin resistance, platelet
function, components of coagulation

23. • Antithrombin III
• Optimal level of AT III activity for anticoagulation during
ECMO is unknown
• If escalating heparin doses or clear resistance, measure AT III
levels and anti-Xa activity
• Replace (AT concentrates) if < 50% activity *
• Heparinase TEG in conjunction may be useful (assess
heparin effect)

24. • Anti Xa assay
• Specific to heparin effect *
• Independent of coagulopathy, thrombocytopenia, anaemia
• May be falsely lowered by hyperlipidaemia,
hyperbilirubinaemia, haemolysis (high plasma free Hb)
• Most assays target 0.3 - 0.7 IU/mL (assay variation)
• Correlation with ACT targets on daily basis in some centres

25. • Alternatives to heparin are direct thrombin inhibitors (bivalirudin,
lepirudin, argatroban)
• Many potential advantages
• Predictable PK (independent of antithrombin, do not bind other
plasma proteins)
• Predictable dosing, monitor with APTT
• Greater reduction of thrombin generation (inhibit clot bound and
circulating thrombin)
• No reversal (major limitation!)

26. • Potential future anticoagulants
• NOACs
• Factor XIIa inhibitor
• Further circuit biocompatibility (NO, prostacyclin
releasing polymers)
• Not in clinical use at present

27. • Define a bleeding threshold (may vary between patient groups)
• Suggested targets
• Haematocrit 0.35-0.40
• INR < 1.5-2.0
• Fibrinogen > 1.0 - 1.5 g/L
• Platelets > 100 x 109/L

29. Our Practice - General
• All patients before and during ECMO
• Platelets > 80 x 109/L
• INR < 1.5
• Fibrinogen > 1.5 g/L
• Measured minimum 12 hourly
• Targets individualised (e.g., higher platelets if bleeding)

30. Our Practice - VV
• Heparin
• Bolus on cannulation
• 50-100 units per kg
• Typically 1000 - 5000 units
• Individualised for clinical context (e.g., coagulopathy,
bleeding)

31. Our Practice - VV
• Heparin
• Continuous infusion, fixed dose 10 units/kg/hour
• Commenced when ACT < 300 (or much lower!)
• Stop if excessively high ACT (>160) or bleeding
• No action if low ACT (and circuit, plasma Hb normal)
• Flows > 3 L/min

33. Our Practice - VV
• Increase heparin dose to target ACT if
• Circuit clot burden high
• Elevated plasma free Hb > 1000 mg/L
• Post oxygenator PaO2 <15 kPa (post “coughing”)
• Reducing flows for normal pump speeds
• Pressure drop across oxygenator high (>50mmHg)

34. Our Practice - VA
• Heparin
• Bolus on cannulation for ECMO
• 50-100 units per kg
• Typically 5000 units
• Individualised for clinical context (e.g., following CPB,
bleeding)

35. Our Practice - VA
• Heparin
• Continuous infusion, titrated to ACT 140-180
• Commenced when ACT < 300 *
• Flows > 3 L/min
• If bleeding, may aim for lower ACT target
• If high risk cardiac stasis, may aim for higher ACT target
• During weaning studies, aim for higher ACT target (low flows)

36. Our Practice - VA
• Post CPB
• Full heparin reversal once established on ECMO
• Allows adequate surgical haemostasis
• Restart heparin subsequently (may be 12- 48 hours
later)
• May be low dose (5-10 units/kg/hour initially)

37. Our Practice - General
• Measure plasma free Hb 12 hourly
• Use TEG to evaluate potential problems
• AT III levels and anti-Xa activity if high heparin doses (>40
units/kg/hour) or resistance concerns
• Heparin resistance (AT III < 40%, anti-Xa < 0.3 IU/mL)
treated with antithrombin concentrates and heparin dose
reduced concurrently (expected increase in heparin effect)

38. Potential Problems

39. Case One

41. • 18 year old with dilated cardiomyopathy
• Heart transplant performed
• Primary graft failure
• Central VA ECMO commenced
• Bleeding excessively
• Given multiple blood products (platelets, cryoprecipitate,
FFP)
• Bleeding ongoing

42. Problems?
• Should full protamine be given?
• Should ECMO be run with or without heparin?
• Is it safe to give factor VIIa in this circumstance?

43. • Full protamine reversal
• No heparin infusion used
• No factor VIIa used

44. 6 hours later
• Progressive hypotension
• Low flows/high pump speed
• Chatter on ECMO circuit lines
• Intermittent suckdowns
• No pulsatility on arterial line waveform

45. • Re-exploration of chest in CVICU
• Coagulation parameters normal except
• Moderate heparin effect (ACT 160s APTT 51)
• Given protamine 50mg

49. What should be done?
• Nothing - futile ongoing therapy?
• Heparinise?
• Thrombolysis?
• Return to OR?
• Thrombus excision
• Atrial septostomy?
• LV vent?

50. Taken back to OR
• Excision of clot via aorta, AV and LA
• Atrial septostomy performed
• Attempt to minimise intracardiac stasis
• Returned to ICU
• Increased inotropes (increased ejection)
• Therapeutically anticoagulated
• Flows maintained > 3 L/min

51. Progress
• Weaned from VA ECMO on day 5
• Weaned from mechanical ventilation on day 15
• Full neurological recovery
• Ongoing renal failure (CVVH/SLEDD)
• Discharged to ward on day 21 on IHD

52. Discussion
• Severe LV dysfunction is high risk for intracardiac stasis
• Can happen and progress very rapidly
• Worsened by extrinsic compression
• Higher risk in peripheral VA ECMO than central VA ECMO
• Anticoagulation balance different for these patients
• May require other interventions: ongoing inotropes,
septostomy, or LV venting (surgical or Impella)
• Can still achieve good outcomes

53. Bleeding - Early
• No heparin
• Safe for prolonged periods for VV ECMO
• Caution during VA ECMO if
• severe cardiac dysfunction (minimal ejection)
• peripheral VA cannulation (inadequate LV
decompression)
• periods of low flows or compression of cardiac chambers
(tamponade)

54. Bleeding - Early
• Normalise coagulation parameters
• Surgical haemostasis (“buy in”)
• If fibrinolysis - consider tranexamic acid
• Extreme caution with factor VIIa
• Reports of catastrophic thromboses

56. Procedures
• Higher bleeding risk than in other critically ill patients
• Even when coagulation parameters “normal”
• Avoid if at all possible
• Use oral route rather than nasal for enteral tubes
• Tracheostomies only once weaned from ECMO
• Interrupt anticoagulation if procedure necessary

57. Case Two

59. • 34 year old
• Day 16 VV ECMO for influenza A
• Stable course “single organ failure”
• Today temperature 374
• Bleeding from NJ, NG, at cannula sites (new)
• No new requirement for inotrope

60. • Platelets 96 x 109/L
• INR 1.6
• Fibrinogen 2.6 g/L

62. Problems?
• Should tranexamic acid be given?
• What else needs investigating?

63. • Tranexamic would be appropriate as the TEG is consistent
with primary fibrinolysis
• Investigate the circuit
• May indicate high clot burden in the circuit
• Plasma free haemoglobin
• Post oxygenator PaO2

65. Bleeding - Late
• Bleeding onset patient previously stable, consider
• Sepsis and DIC - no antifibrinolytic
• Circuit failure and fibrinolysis - TEG guidance
• Primary hyperfibrinolysis - fibrinolytic indicated

66. HITT
• Uncommon (<0.6% ICU patients)
• High false positive for ELISA immunoassay (PF4
antibodies)
• Pre-test probability score using “4Ts” best
• If 4T moderate or high risk and positive screen - discuss
with lab +/- haematologist
• Dilution testing
• Functional assay in some centres

67. HITT
• Requires alternative anticoagulation strategy
• No heparin
• Fondaparinux 2.5 - 5.0 mg SC daily (patient)
• Monitor anti-Xa activity
• Bivalirudin (circuit)

68. Thrombosis
• Common
• ELSO Registry thrombosis necessitating circuit change occur in
20% patients
• High incidence occult thromboembolic events in autopsy
studies (>70%)
• Increased risk with increased duration of ECMO
• Vigilance following wean and decannulation important too (limb
ischaemia or compromise)
• May need surgical intervention

69. Potential Problems
• Excessive bleeding - early and late
• Severe LV impairment
• VA versus VV ECMO
• Thromboses
• Procedures
• Fibrinolysis - sepsis
• Contraindication to heparin - HITTS

72. Ventricular Assist Devices and
Anticoagulation
• What are the current recommendations?
• Measurement
• What are the potential problems?
• Short term
• Long term
• Other factors to bear in mind

73. Recommendations
• Established by manufacturers and VAD centres
• Vary somewhat by device
• Three main devices at present
• Heart Mate II LVAD (Abbott)
• Heart Mate 3 LVAD (Abbott)
• HeartWare HVAD (Medtronic)

74. Anticoagulation - HeartWare
HVAD
• During implantation with heparin (ACT >400s)
• Full reversal protamine at completion surgery
• Normalise coagulation parameters
• Caution with factor VIIa
• Early commencement heparin (day one) if no bleeding
• Target APTT 50-80 (varies with institution)

75. Anticoagulation - HeartWare
HVAD
• Commence aspirin from day 1 if stable
• Consider platelet function TEG day 10-14
• Commencement warfarin after day 3 if stable
• INR 2.0 to 3.0

76. Problems - Bleeding
• Immediate bleeding risks post cardiac surgery
• Managed intraoperatively in standard manner
• Ongoing risk related to anti-platelet and anticoagulant
therapy
• Additional risk related to
• Acquired von Willebrand disease
• Gastrointestinal arteriovenous malformations

77. Acquired Von Willebrand
Disease

78. Acquired AVMs

79. Problems - Thrombosis

80. Case Three