1. ECMO and Anticoagulation
Brian C. Bridges, MD
May 7, 2013

2. Coagulopathy
Patients frequently have clotting abnormalities prior to initiating ECLS
Disruption of hemostasis (fine balance between procoagulants and anticoagulants)
Activation of coagulation cascade requires anticoagulation to prevent thrombosis
Disruption and consumption of procoagulants requires its replacement to prevent bleeding

3. Platelets Need for platelet replacement steady for duration of ECMO
Initial target platelet > 80k
Low platelet # is a risk factor for ICH (children and adults)

4. Coagulation Monitoring
Prothrombin time (PT)
Assess the extrinsic pathway and final common pathway of clotting
Assess vitamin-K dependent factors (II,VII,IX,X)
Due to lab differences expressed as INR (international normalized ratio)
Heparin does not prolonged PT
The result (in seconds) for a prothrombin time performed on a normal individual will vary according to the type of analytical system employed. This is due to the variations between different batches of manufacturer's tissue factor used in the reagent to perform the test. The INR was devised to standardize the results.

5. Tissue factor - Vessel wall damage leads to expression of tissue factor (TF, tissue thromboplastin), an integral membrane glycoprotein [43]. Tissue factor is not normally expressed on vascular endothelial cells or monocytes but is constitutively expressed on certain biological surfaces, such as skin, organ surfaces, vascular adventitia, and many of their malignant counterparts. Normally, TF is exposed to blood flow only after endothelial damage [44].
The main role of the tissue factor pathway is to generate a "thrombin burst," a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor.･Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF) expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).･TF-FVIIa activates FIX and FX. 5

6. Coagulation Monitoring
Partial Thromboplastin Time (PTT)
Assess intrinsic and final common coagulation pathway
PTT is a plasma test activated by phospholipids which provides a measure of hemostasis in the absence of cellular components
Monitor heparin therapy
Assess only plasma component of heparin

7. The intrinsic pathway, or contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation. However, bleeding is seen with deficiency of factor XI deficiency. Intrinsic pathwayﾊﾑﾊThe initial phase of the intrinsic or contact activation pathway consists of several plasma proteins ﾑ factor XII (Hageman factor), prekallikrein (Fletcher factor) and high molecular weight kininogen (HMWK, Fitzgerald factor) - which are activated by contact with negatively charged surfaces and which initiate the following sequence: 7

8. Coagulation Monitoring
PTT levels change significantly with age as part of developmental hemostasis
PTT has poor correlation to anti-Xa levels in infants and children
PTT seems to correlate better with unfractionated heparin concentration in adults
PTT has poor correlation to anti-Xa levels in infants and children non-ECLS studies 8

9. Coagulation Monitoring
Activated Clotting Time (ACT)
Monitors coagulation of all blood components
Platelet
Plasma clotting factors
Crude method
Simple
Available at bedside
Normal ACT = 80–120 seconds
Initial ECMO standard at Vanderbilt = seconds

10. 10

11. Coagulation Parameters
Hemoglobin, hematocrit, PT, INR, PTT, fibrinogen and platelets are monitored every 6-8 hours
ACT measurements q1h at bedside
Maintain hematocrit > 30 to 40%
Maintain platelets > 80,000/mm3
INR goal depends on +/- bleeding
Maintain Fibrinogen > 150 mg/dl 11

12. Coagulation Parameters
Since September 2011, regularly following heparin assays (Anti X-a), AT3 levels QAM, and TEG PRN clotting or bleeding 12

14. TEG Analyzer

15. Thromboelastogram

18. Antithrombin
Anthrombin is the primary physiologic inhibitor of in vivo coagulation, via inactivation of thrombin, plasmin, factor IXa, Xa, XIa, and XIIa
Heparin works by potentiating the action of antithrombin III
The unfractionated heparin–antithrombin complex produces a 1000-fold increase in antithrombin inhibition of coagulation protein activity compared with antithrombin alone

19. Antithrombin
Antithrombin activity in healthy term neonates is approximately 50% of adult levels, with an increase to the normal range about 6 months after birth
Can give FFP or concentrated AT3 to correct antithrombin deficiency

20. Antithrombin There is about 1 unit of antithrombin in every ml of FFP
We currently have recombinant antithrombin available for patients who are refractory to heparin administration and have proven antithrombin deficiency

21. Antithrombin
Consider in patient with heparin resistance ( > 60 units/kg/hr of heparin, failure to achieve adequate ACT/anti-Xa level)
Side effects of antithrombin administration include bleeding
On ECMO, anticipate increased in ACTs with antithrombin administration and need to decrease heparin infusion

22. Atryn

23. Atryn (100 - baseline AT activity level) X Body Weight (kg) 2.3
* Recommend recheck of AT level two hours after dose
** This formula is not the same as for the pooled antithrombin product (Thrombate)

24. Anti-Xa Levels (Heparin Assay)
This assay measures unfractionated heparin’s antithrombin-catalyzed inhibition of factor Xa
Anti-Xa assay is commonly viewed as a heparin assay despite the fact
that it actually represents a measure of unfractionated heparin effect as opposed to a measure of unfractionated heparin concentration
Heparin inactivates factor Xa and inhibits conversion of prothrombin to thrombin

25. Anti-Xa Levels (Heparin Assay)
Our goal anti-Xa level on ECMO is 0.3 to 0.7 IU/mL
We can now get anti-Xa levels 24 hours a day, 7 days a week
Turn around time for anti-Xa levels is up to 2 hours
Currently, using anti-Xa levels to adjust patient goal ACT range
Heparin inactivates factor Xa and inhibits conversion of prothrombin to thrombin 25

26. Anticoagulation - Heparin
“gold standard” for anticoagulation
Not perfect but with wide experience
Mechanism of action
Complexes with antithrombin III (AT III) and accelerates its function x 1000
Requires presence of AT III for its action
Does not affect thrombin formation, only soluble thrombin affected
Does not inhibit thrombin already bound to fibrin
Thrombin formation late in coagulation cascade
Many factors already activated

27. Anticoagulation - Heparin
Small amount of thrombin is continuously formed in circuits despite heparin use
Heparin readily reversible with protamine
Don’t use protamine on ECMO
Heparin itself may cause:
Complement, neutrophil, and monocyte activation
Thrombocytopenia (HIT)
Thrombocytopenia and thrombosis (HITT)

28. Anticoagulation Heparin
Patients respond individually to given dose
Heparin titrated individually for every patient
Half-life time 1- 2hr
Affected by renal and hepatic function
Excreted in urine
Some amount as unchanged drug

29. Heparin Dosing
Load at cannulation time =100 U/kg (50U/kg if coagulopathic or transthoracic cannulation) – ordered by ICU team with continuous infusion 10–80 U/kg/hr to follow, after ACT < 300 seconds
Infusion titrated based on hourly ACT’s
Initial targeted ACT =
Currently, changing target ACT based on anti-Xa level

30. Heparin dosing Heparin infusion may need to be increased
During platelet infusion
During brisk diuresis
Lower ACT’s despite  heparin infusion may suggest AT III deficiency

31. Coagulation HIT
Heparin Induced Thrombocytopenia (HIT) usually occurs 4-10 days after initiation of heparin therapy – > antibodies to the heparin-platelet factor 4 complex
The antibody/antigen complex activates platelets causing further factor 4 release creating a positive feedback loop
The thrombocytopenia is rarely severe but patient refractory to platelet transfusion
Can lead to thrombosis (HITT) 31

32. HIT
HIT is the most common drug-induced thrombocytopenia in adults, complicating 1-4% of full-dose exposures to standard heparin.ﾊ Unlike other thrombocytopenias, HIT carries a high thrombotic morbidity (30-50%) and mortality (10-15%) because it is a syndrome of platelet activation.ﾊﾊ Heparin forms a complex with platelet factor 4 (PF4) which is released from platelets by platelet activation.ﾊ Antibody directed against the heparin-PF4 complex binds via its Fab region.ﾊ The antibody-heparin-PF4 immune complex binds to the Fc receptor on the surface of the platelet leading to activation of the platelet.ﾊ 32 32

33. Coagulation HIT
HIT type 1 is a less severe form of the disease, with mild, early decrease in platelet count that improves even with the ongoing heparin, thrombotic complications generally do not occur
HIT type 2 results in a more severe degree of thrombocytopenia, which does not resolve without cessation of heparin therapy and includes the potential for thrombotic complications, both the arterial and venous 33 33

34. Coagulation HIT HIT incidence is highest with unfractionated heparin
In most cases, the platelet count decreases 7–14 days after exposure to heparin, but platelet count may fall immediately on re-exposure to heparin If circulating antiheparin IgG antibody present from a previous exposure 34 34

35. Coagulation HIT
Antibody (PF4) ELISAs are sensitive but not specific, high false positive rate
Functional assays based on in vitro heparin-dependent platelet activation (14C serotonin release, heparin-dependent platelet aggregation, lumi- aggregometry) are more specific for clinical HIT
Functional assays are less sensitive and often negative or indeterminate in the first hours of HIT
Both assays usually become negative in about 3 weeks, making it difficult to diagnose previous HIT 35 35

36. HIT
Heparin-Induced Thrombocytopenia Syndrome Bullous Lesions Treated with Trypsin-Balsam of Peru-Castor Oil Ointment: A Case Study

37. Argatroban Alternative to heparin Direct thrombin inhibitor
Goal = PTT
INR may be falsely elevated

38. Coagulation Circuit DIC
Represents a consumptive coagulopathy caused by clot within the circuit
Consistently abnormal clotting profile (low plts/fibrinogen) unresponsive to frequent blood product transfusions
Increasing D-dimer levels
Resolves with a change of circuit 38

39. Future Directions for Vanderbilt…
Study of heparin use, blood product administration, and bleeding/clotting complications since start of coagulation lab protocol
Heparin assay protocol specific to ECMO for the bedside specialist
Decreasing the other coagulation labs (PTT, ACT)

40. Future of ECMO Hemostasis
More bio-friendly surface circuit materials
Heparin coated
New polymers
New anticoagulants
Direct thrombin inhibitors (argatroban, hirudin, bivalirudin)
Nafamostat mesilate
NO in sweep gases
Regional Citrate Anticoagulation
Nafamostat -> kallikrein (cali-cre-in) inhibitor

41. Questions?