1. Noncardiac Sources of Pain Anticoagulation in the CICU Conflict Amongst Coagulation Tests
Jonny Byrnes MD
CICU Attending
Cincinnati Children’s Hospital Medical Center
Assistant Professor
University of Cincinnati

2. I have no financial disclosures.
Antithrombin concentrates/ recombinant antithrombin is not FDA approved for the replacement on mechanical circulatory support.

3. Objectives
Review typical anticoagulation tests in context of heparin anticoagulation on MCS
Methods to resolve discrepancy between tests
Cases

4. Laboratory Monitoring
Activated partial prothrombin time
Unfractionated Heparin anti-Xa
Antithrombin
Thromboelastography

5. Activated Partial Prothrombin Time (aPTT)
Laboratory test typically used to monitor heparin therapy.
Different reagents used may influence results, so lab specific ranges.
Typically therapeutic is considered levels normal range.

6. aPTT The tube contains a calcium binder to arrest coagulation
Calcium, an activator, and a phospholipid are added to start coagulation in the lab.
The aPTT is the number of seconds it takes to initiate thrombus formation.
aPTT assays vary based on reagents used, so value can not necessarily be compared amongst labs.

7. Abnormalities of the aPTT
Shortened aPTT is typically thought to be of little consequence
Prolonged aPTT
Lupus anticoagulant/antiphospholipid antibody
Hemophilia
DIC
Factor inhibitors
Deficiency of factors VIII, IX, XI, XII

8. Unfractionated Heparin anti-Xa level
Addition of known amounts of factor Xa and antithrombin added to the sample.
UH forms an inhibitory complex with antithrombin and inactivates factor Xa.
Excess factor Xa remaining is inversely proportional to the original amount of UH.
Compared to a standard curve and a concentration of anti–factor Xa is estimated.

9. Unfractionated Heparin anti-Xa level
As described is functionally a heparin level
Since exogenous AT is added at most institutions may not represent physiologic anti-Xa level
Therapeutic ranges
UF IU/ml
Low level: consider improper collection, nontherapeutic dosing, or delay in separating plasma.
High Level: heparin contamination from line or renal impairment.

10. Unfractionated anti-Xa level
Nankervis, 2007

11. Antithrombin level
Heparin Mechanism AT
Thrombin Xa
1000 x
Heparin

12. Antithrombin Developmental variation Deficiency Replacement
Initially 40-70% in newborn period
Adult levels of % by 2 years of age
Deficiency
Congenital
Acquired: DIC, Sepsis, Protein Losing Conditions, Liver Disease
Replacement

13. TEG Technology: How It Works
Cup oscillates
Pin is attached to a torsion wire
Clot binds pin to cup
Degree of pin movement is a function of clot kinetics
Magnitude of pin motion is a function of the mechanical properties of the clot
The TEG analyzer has a sample cup that constantly oscillates at a set speed through an arc of 4°45‘; each oscillation lasts ten seconds. A whole blood sample of 360 l is placed into the cup, and a stationary pin attached to a torsion wire is immersed in the blood. When fibrin first forms, it begins to bind the cup and pin, causing the pin to oscillate in phase with the cup. The degree of pin movement is a function of the kinetics of clot development.
The torque of the rotating cup is transmitted to the immersed pin only after fibrin or fibrin-platelet bonding has linked the cup and pin together. The strength of these fibrin-platelet bonds affects the magnitude of the pin motion.
The magnitude of the output is directly related to the strength of the forming clot. As the clot retracts or lyses, the bonds between the cup and pin are broken, and the transfer of cup motion is diminished. The movement of the pin is converted by a mechanical-electrical transducer into an electrical signal, which can be monitored by a computer.
The movement of the pin generates a hemostasis profile, which is a measure of the time it takes for the first fibrin strand to form, the kinetics of clot formation, the strength of the clot (in shear elasticity units of dyn/cm2), and the dissolution of clot.
Slide courtesy of Haemoscope company

14. Thromboelastography Whole blood, POC test
Measures hemostasis – clot initiation thru lysis
Net effect of and interaction of different hemostatic components

15. Thromboelastogram LY30 α-angle Clot MA R value
Amount (%) of fibrinolysis or clot contraction occurring 30 minutes after the point of maximal amplitude
α-angle
Interaction between fibrin and platelets
Clot MA
Total clot strength, overall
platelet strength
R value
Initiation of a
white clot, can represent extrinsic, intrinsic, or common pathway 10
Nml
5-10
55-73
47-74
0-8% 20 30 40 50 60 70
R value
8.6 MA 61
α-angle 58
LY30
4.1%

16. This is your TEG This is your TEG on heparin CKH CK nml10 20 40 30 50 70 60
This is your TEG
on heparin 10 20 40 30 50 70 60
CKH CK nml
R value MA
α-angle
LY %

17. Possible Scenarios of Conflict/Disagreement
UF Heparin anti-Xa is supratherapeutic, aPTT, and
TEG are normal/subtherapeutic.
aPTT is supratherapeutic, UF Heparin anti-Xa and
TEG are therapeutic/subtherapeutic.
TEG R is supratherapeutic, aPTT and UF Heparin anti-
Xa are therapeutic/subtherapeutic.

18. Possible Scenarios of Conflict/Disagreement
aPTT and TEG R are supratherapeutic, UF Heparin
anti-Xa is therapeutic/subtherapeutic
TEG heparinase R appears short with adequate
heparin, aPTT & UF Heparin anti-Xa is therapeutic.

19. Possible Scenarios of Conflict/Disagreement
UF Heparin anti-Xa is supratherapeutic, aPTT, and
TEG are normal/subtherapeutic.
This scenario is the most straightforward and typically will be
related to contamination from the line.
In any patient on mechanical support it is useful to remove all
heparin from one of the lines for lab draws so that there is no
risk of contamination.

20. Possible Scenarios of Conflict/Disagreement
aPTT is supratherapeutic, UF Heparin anti-Xa and
TEG are therapeutic/subtherapeutic.
This could be related to a lupus “anticoagulant” or
anti-phospholipid antibody
Commonly seen after a period of turning off the heparin and
after heparin is restarted the contact system is activated within
the circuit where Factors IX, XI, XII are consumed.
- sending specific factor studies for factors IX, XI, XII
Possible reagent problem with aPTT assay

21. Possible Scenarios of Conflict/Disagreement
TEG R is supratherapeutic, aPTT and UF Heparin
anti-Xa are therapeutic/subtherapeutic.
Insufficient coagulation factor production by the liver or
consumption
- Sending factors V, VII can be helpful.
Second anticoagulant such as a direct thrombin inhibitor or
coumadin is affecting the coagulation
Possible reagent problem with TEG assay

22. Possible Scenarios of Conflict/Disagreement
aPTT and TEG are supratherapeutic, UF Heparin
anti-Xa is therapeutic/subtherapeutic
Heparinoid from the glycocalyx or from acute liver failure is
affecting aPTT and TEG
Disseminated intravascular coagulation or lack of production of
factors II, V, VII, or X in addition to a lack of factors in the
contact system.

23. Possible Scenarios of Conflict/Disagreement
TEG heparinase R appears short with adequate
heparin, aPTT & UF Heparin anti-Xa is therapeutic.
Inflammation is driving a hypercoaguable state through fibrin
and thrombin mediated thrombin generation.
- factor VIII level can be considered
- fibrinogen level will be high
- commonly associated with fevers

24. Case 1 3 month old, recent ALCAPA dx
Day 1 Transthoracic VA ECMO Day 1 for LV recovery after ALCAPA repair, MV annuloplasty
Chest tubes clearing, 1-2 cc/kg/hr, no bleeding from lines

25. Case 1 PT 9 sec aPTT 122 sec UF anti Xa 0.12 u/ml CKH TEG CK TEG
R 8 α 61 MA 62 LY30 4%
CK TEG
R 11 α 35 MA 42 LY30 8%
AT3 84%
ACT 150 sec

26. Case 1 PT 9 sec aPTT 122 sec UF anti Xa 0.12 u/ml CKH TEG CK TEG
R 8 α 61 MA 62 LY30 4%
CK TEG
R 11 α 35 MA 42 LY30 8%
AT3 84%
ACT 150 sec

27. Factor IX 32% Factor XI 16% Factor XII 50%
Case 1
Factor IX 32%
Factor XI 16%
Factor XII 50%
2 Approaches Possible
Give FFP to correct factor deficiency and turn up heparin to prevent further activation of extrinsic pathway.
Wait for liver to correct factor deficiency and turn up heparin now to prevent further activation of extrinsic pathway.

28. Case 2
4 year old, myocarditis s/p Rotaflow temporary LVAD for cardiogenic shock
MCS Day 4, hemodynamically well supported. Intermittent fevers (culture negative for the last 48 hours)
Chest tubes clearing, ~1 cc/kg/hr, no bleeding from lines.
Heparin 24 u/kg/hr

29. Case 2 PT 9 sec aPTT 70 sec UF anti Xa 0.35 u/ml CKH TEG CK TEG
R 3 α 75 MA 68 LY30 4%
CK TEG
R 16 α 35 MA 42 LY30 %
AT3 84%
ACT 170 sec
Fibrinogen 800 mg/dl
CRP 8 mg/dl WBC 27K

30. Case 2 PT 9 sec aPTT 70 sec UF anti Xa 0.35 u/ml CKH TEG CK TEG
R 3 α 75 MA 68 LY30 6%
CK TEG
R 16 α 35 MA 42 LY30 2%
AT3 84%
ACT 170 sec
Fibrinogen 800 mg/dl
CRP 8 mg/dl WBC 27K

31. Conclusions
There is no one “best” anticoagulation test for managing heparin in critically ill patients.
Specific coagulation factor testing often proves helpful.
Interdisciplinary collaboration is useful when the coagulation tests do not align.