1. Activated Clotting Time
Applications, Therapeutics and Technologies
Marcia L. Zucker, Ph.D.
Director of Clinical Support
Response Biomedical Corporation
ITC Educational Services, Edison, NJ

3. There was….. The Lee-White clotting time
Add blood to glass tube, shake
No activator
Manual
Place in heat block
Examine for clot every 30 seconds
Very slow
Subjective clot detection

4. Time goes on…

5. 1966 - Hattersley Activated Clotting Time
Add blood to glass tube with dirt, shake
Diatomaceous earth activator
Still manual
Place in heat block
Visual clot detection
Subjective clot detection

6. Particulate Contact Activation
Initiation of intrinsic coagulation cascade
Factor XII (Hageman factor)
Prekallikrein (Fletcher factor)
Shortens contact activation period
Proposed as both screening assay for coagulation defects and for heparin monitoring
Critical fibrin clot endpoint

7. Semi - Automation - 1969 HEMOCHRONOMETER Later - HEMOCHRON
Add blood to tube, shake
Manual sample treatment
Place in test well
Automated heating
Objective fibrin clot detection
two different activators
CA510 (later FTCA510)
diatomaceous earth
P214 glass bead

8. Mechanical Detection Magnet in tube, detector in instrument
Upon fibrin clot formation, magnet is deflected
Clotting time displayed

9. Two assays for separate uses

10. 1980’s HemoTec ACT (later Medtronics ACTII)
Add blood to dual cartridge
Liquid kaolin activator
Place in instrument
Automated mixing
Objective clot detection
Flag moves up and down
As fibrin forms, motion slows
Mechanical clot detection
Instrument displays clotting time

11. Lower values than CA510 –
differences ignored by clinicians

12. 1980’s - ACT Differences Reported in literature >20 years
Clinical evaluations of Hemochron - mid 1970’s
By 1981 –
poor correlation between ACT and heparin level
By 1988
Hemochron and HemoTec clinically different
Early ’80’s to Present
Improved clinical outcome with ACT use
Reviewed: Draft NACB Laboratory medicine practice guideline for point of care coagulation testing

13. 1990’s Microsample ACTs - Hemochron Jr
Add blood to sample well, press start
Silica, kaolin and phospholipid (ACT+)
Diatomaceous earth (ACT-LR)
Automated sample measurement
Automated mixing
Objective clot detection
Sample pumped across restriction
Flow slows with clot formation
Optics measure motion
Clotting time displayed

14. Clotting Times Different

15. 2000 Abbott - i-STAT Add blood to cartride, press start
Diatomaceous earth or kaolin
Insert into instrument
Automated mixing
No clot detection
Synthetic thrombin substrate
Electro-active compound formed and detected amperometrically
“Clotting time” reported

16. Clotting Times Likely Different
i-STAT ACT Package Insert
Used to monitor moderate- and high-level heparin
Prewarmed vs. non-prewarmed calibration modes
Good correlation with Hemochron (Celite below)
Intercept varied by site (+4 to -73 sec)
Slope range 0.85 – 1.19
Few publications
All show wide scatter vs Hemochron or Medtronics

17. Today Hemochron Response Hemochron Signature Elite Medtronics ACT Plus
Medtronics HMS+
Helena Actalyke XL / Mini
Gem PCL
Abbott i-STAT

18. Activated Clotting Time
Extrinsic Pathway
Intrinsic Pathway
ACT
Common Pathway
CLOT

19. Why do we use an ACT? Maintain Balance Point of Care
Bleeding Thrombosis
Point of Care
Immediate turn around
Rapidly adjust anticoagulant dosing as needed
Heparin – half life varies by patient
Dose required varies by patient
Potency varies by lot
Direct thrombin inhibitors – very short half life
Require immediate intervention
No antidote available

20. NACB Guidelines National Academy of Clinical Biochemistry
Evidence Based Guidelines for POC Testing
Chapter 4 – Coagulation Testing
Caveats:
Assume all systems equally safe / effective / precise
Correlation studies excluded
Few good outcome trials

21. NACB Guidelines
Is there evidence of improved clinical outcome using ACT testing? In cardiovascular surgery?
Is there evidence for optimal target times to be used with ACT monitoring?
Strongly recommend ACT monitoring of heparin anticoagulation and neutralization in cardiac surgery.
(Class A, Level I at least one randomized controlled trial, Level II–1 - small randomized controlled trials, non-randomized controlled trials).
Insufficient evidence to recommend specific target times for use during cardiovascular surgery.
(Class I – conflicting evidence across clinical trials).

22. NACB Guidelines
Is there evidence of improved clinical outcome using ACT testing? In interventional cardiology?
Is there evidence for optimal target times to be used with ACT monitoring?
Strongly recommend ACT monitoring of heparin anticoagulation in interventional cardiology.
(Class A, Level II–1 - small randomized controlled trials, non-randomized controlled trials, Level II-2 – Case controlled analytic studies from more than one center or research group).
Recommend target times specific to ACT system
Targets differ if specific platelet inhibitors are used concurrently with heparin.

23. NACB Guidelines Target Times: Without intravenous platelet inhibitors:
>250 seconds using the Medtronics ACTII
>300 seconds using the HEMOCHRON FTCA510 tube
(Class B – Level II–1 - small randomized controlled trials, non-randomized controlled trials, Level II-2 – Case controlled analytic studies from more than one center or research group).
With the intravenous platelet inhibitors:
abciximab or eptifibatide:
seconds
tirofiban:
250 – 300
(Class B – Level I- at least one randomized controlled trial).

24. NACB Guidelines
Is there evidence of improved clinical outcome using ACT testing? In ECMO?
Is there evidence for optimal target times to be used with ACT monitoring?
ExtraCorporeal Membrane Oxygenation
Strongly recommend ACT monitoring to control heparin anticoagulation during ECMO.
(Class A – Level III – opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees).
Target times for ECMO based on the ACT system.
(Class B – Level III – opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees).

25. NACB Guidelines
Is there evidence of improved clinical outcome using ACT testing? In other applications (e.g. vascular surgery, intravenous heparin therapy, dialysis, neuroradiology, etc.)?
Is there evidence for optimal target times to be used with ACT monitoring?
There is insufficient evidence to recommend for or against ACT monitoring in applications other than cardiovascular surgery, interventional cardiology or extracorporeal oxygenation.
(Class I).

26. ACT - Clinical Applications
Essential - outcome studies show evidence
Cardiac surgery
Percutaneous coronary intervention (PCI)
ECMO / (Dialysis)
Common – insufficient evidence for “essential”
Critical care
Interventional radiology
Electrophysiology
Vascular surgery

27. Different ACTs for each clinical setting

28. Clinical Applications
Essential
Cardiac surgery
Percutaneous coronary intervention (PCI)
ECMO / (Dialysis)
Common
Critical care
Interventional radiology
Electrophysiology
Vascular surgery

29. Monitoring - ACT Benefits Disadvantages Industry Standard Since 1970s
Recommended as 1o method in AmSECT guidelines
ACT improves outcome in CPB, PCI
NACB draft LMPG for POC coagulation
Easy to run
Disadvantages
Each system yields different numbers
Most sensitive to hypothermia and hemodilution
Little or no correlation to heparin level
especially true for pediatric patients

30. When to choose which ACT?
Different pharmaceutical interventions
Antifibrinolytics
Novel anticoagulants
Different patient populations
Especially pediatric patients
Different monitoring preferences
Heparin Level
Need for specialty assays
Dosing
Fibrinogen

31. Pharmaceutical Intervention
Amicar or Tranexamic Acid
No effect on standard celite ACT
Continued debate on efficacy
Multiple reports of reduction in post-operative blood loss and reduced transfusion requirements
Aprotinin
Significant elevation of Celite ACT
Two dosing regimens – Patient size independent
Full Hammersmith
2 x 106 KIU loading dose; 2 x 106 KIU pump prime; 0.5 x 106 KIU/hr infusion
Half Hammersmith
1 x 106 KIU loading dose; 1 x 106 KIU pump prime; x 106 KIU/hr infusion

32. ACT Monitoring-Aprotinin Treatment
Celite® ACT
HEMOCHRON FTCA510; Actalyke C-ACT; i-STAT ACTCelite
Not recommended
Still used with target times of >750 seconds
Kaolin ACT
HEMOCHRON FTKACT; Actalyke K-ACT; i-STAT ACTKaolin; Medtronics HR-ACT
Unaffected by moderate doses of aprotinin
Used with target times of > 480 seconds
Combination ACT reagents
HEMOCHRON Jr ACT+; Actalyke MAX-ACT; GEM PCL ACT
Unaffected by ALL doses of aprotinin
Used with target times of > 400 seconds

33. ACT Monitoring-Aprotinin Treatment
Jones, et al. JECT. 2004;36:51–57

34. Novel Pharmaceuticals
None FDA approved for cardiac surgery
Direct thrombin inhibitors (DTIs)
Used if patient at risk for HIT
Heparin induced thrombocytopenia
“Heparin allergy”
Argatroban
Refludan
Angiomax

35. ACT Monitoring - DTIs Argatroban Refludan
Synthetic analog of L-arginine
Reversible binding to thrombin
PCI monitoring: ACT 300 – 450
Papers state standard ACT targets for CPB
Refludan
Recombinant hirudin
Irreversible inhibition of thrombin
Routine monitoring with aPTT
No recent reports in CPB
Original studies used ECT - No longer available

36. ACT Monitoring - DTIs Angiomax Synthetic analog hirudin
Reversible binding to thrombin
PCI monitoring: HEMOCHRON ACT-LR >300
Papers state standard ACT not appropriate for CPB
Adapted from Zucker, et.al., JECT 2005, in press
ACTT not yet available

37. Patient populations Pediatric Patients are NOT little adults
Reports of both shorter and longer heparin half life
Pediatric Patients are NOT all the same
In neonates, coagulation factor levels confound dilutional effects
Once patient exceeds 2 years of age, only dilutional effects need to be considered
These can be very important
Test volume is critical

38. Pediatric Monitoring
Data from clinical evaluation, on file, ITC

39. Monitoring - Heparin Level
Benefits
Measures concentration, not activity
Correlates with laboratory standards
Disadvantages
Each system yields different numbers
apples and oranges do not compare
Correlation to anticoagulation status is still disputed
Target for neonate, pediatric and adult patients may differ

40. Monitoring - Heparin Level
Young: <4.5 years
Shayevitz, JR and O’Kelly, SW Progress in Anesthesiology, vol. IX, chapter

41. Monitoring - Heparin Level
αXa / αIIa Activity - laboratory only, impractical
Not available with microsample systems
Medtronic Hepcon HMS
Indirect measure of protamine reversible heparin activity
Thromboplastin based
HEMOCHRON PRT
ACT based protamine titration
HEMOCHRON HiTT
unaffected by hemodilution, hypothermia
insensitive to aprotinin
Thrombin Time based
Correlates with αXa and αIIa activity

42. Heparin Monitoring Dilemma
Level
ACT
Which Value Determines Response?

43. More reasons for selecting a system
Heparin and Protamine Dose Optimization
In vitro dosing systems
Not available on microsample systems
Hemochron RxDx
Heparin Response Time (HRT)
Protamine Response Time (PRT)
PDAO
HMS
HDR
HPT

44. Heparin Dose Optimization
Traditional dosing regimens recommend fixed drug doses by body weight.
Regimen does not account for patients whose response to heparin is different than the average “normal” patient.
Patients differ in their response to heparin; may be resistant or sensitive to heparin
Can represent % of patient population
Response can vary up to 12 fold between patients

45. Protamine Dose Optimization
Minimize protamine dose
Reduce time for infusion
Avoid protamine related adverse events
hypotension
shock
bleeding
platelet dysfunction

46. Clinical Benefits Individualize heparin dose
Reduce blood products needed for post-operative transfusions
i.e. red blood cells, platelets, fresh frozen plasma and cryoprecipitate
Jobes DR, et al J Thorac Cardiovasc Surg 110: 36-45
Reduced potential for protamine reaction
Protamine reduced by average of 30%
Zucker ML., et al J Extra-Corp Tech. 29:
Reduced incidence of return to OR for bleeding

47. Economic Benefits (US$)
Jobes DR., et al Cost Effective Management Of Heparin/ Protamine In CP Bypass: Analysis By Type Of Surgery. Anesthes 85:3A.

48. Heparin neutralization verification
Test Options
ACT - global indicator of coagulation
PDAO /ACT – protamine titration
HEMOCHRON Response
Heparinase ACT – enzymatic confirmation
Medtronics ACTPlus
Thrombin time – highly sensitive to heparin
TT/HNTT – protamine titration
aPTT - intrinsic pathway
HEMOCHRON tube systems
HEMOCHRON microsample systems

49. Clinical Applications
Essential
Cardiac surgery
Percutaneous coronary intervention (PCI)
ECMO / (Dialysis)
Common
Critical care
Interventional radiology
Electrophysiology
Vascular surgery

50. Procedures Diagnostic Interventional Catheterization Electrophysiology
locate and map vessel blockage(s)
determine need for interventional procedures
Electrophysiology
Interventional
Balloon angioplasty
Atherectomy (roto-rooter)
Stent placement

51. Diagnostic – Low dose heparin
Catheterization and Electrophysiology
unit bolus dose
frequently not monitored
if monitored –
ACT
HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR; Medtronics LR-ACT: Actalyke C-ACT; GEM PCL ACT-LR
Targets ~ 200 seconds
aPTT

52. Interventional Angioplasty, Atherectomy, Stent placement
HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR; Medtronics LR-ACT or HR-ACT: Actalyke C-ACT, MAX-ACT; GEM PCL ACT-LR; i-STAT ACTCelite
10,000 unit bolus dose or
mg/kg
target ACT seconds
Target must be reduced if ReoPro Used
ReoPro is one of 3 “GPIIb/IIIa” Inhibitors
GPIIb/IIIa receptor critical in platelet aggregation

53. Novel Pharmaceuticals
Platelet Inhibitors
Oral
Aspirin
Plavix
Parenteral
ReoPro
Integrilin
Aggrastat
Low Molecular Weight Heparins (LMWH)
None FDA approved for interventional cardiology
Lovenox
Fragmin

54. Platelet Structure PLAVIX ASPIRIN Parenteral platelet inhibitors
Courtesy of Helena Laboratories

55. Intervention promotes aggregation
Picture courtesy of Reopro.com

56. ACT Monitoring - Platelet Inhibitors
Aspirin
No reported effects on ACT
No anecdotal reports of effects on ACT
Plavix
Anecdotal reports
Increased bleeding at sheath pull
ACTs don’t return to “normal” prior to sheath pull
Plateau ~ 180 – 220 seconds

57. ACT Monitoring - Platelet Inhibitors
ReoPro
elevates ACTs
Study used FTCA510 and Medtronics HR-ACT
target time = 250 sec with ReoPro
determined using FTCA510 tube
Integrelin
No reported clinically significant effects on ACT
Slight decrease in ACT
Study used FTCA510 and ACT-LR
Aggrastat
No reported effects on ACT

58. ACT Monitoring - LMWH Fragmin Lovenox
Reports of efficacy of ACT monitoring during PCI
Studies used FTCA510; ACT-LR; HR-ACT; LR-ACT
Lovenox
Reports that ACT not useful for monitoring in PCI
Adapted from el Rouby, et.al., J Thromb Thrombolys 2005, in press
HEMONOX not yet available

59. Targets can change with ACT
Choose ACT by application and Intended Use:

60. Clinical Applications
Essential
Cardiac surgery
Percutaneous coronary intervention (PCI)
ECMO / (Dialysis)
Common
Critical care
Interventional radiology
Electrophysiology
Vascular surgery

61. ECMO (Dialysis) ACT used to monitor low dose heparin
P214 glass activated ACT has been the “standard”
HemoTec HR and LR also used
Targets generally seconds
Changing ACT requires changing target
Target often with ACT-LR
Not all ACTs have low heparin indication
Also indicated for low dose:
GEM PCL ACT-LR; Actalyke G-ACT

62. Clinical Applications
Essential
Cardiac surgery
Percutaneous coronary intervention (PCI)
ECMO / (Dialysis)
Common
Critical care
Interventional radiology
Electrophysiology
Vascular surgery

63. ACT or aPTT Determine when to pull the femoral sheath
HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR; Medtronics LR-ACT; Actalyke C-ACT; GEM PCL ACT-LR
Premature sheath pull can lead to bleeding.
Delayed removal can increase time in CCU.
Target set at each site.
ACT targets range from 150 – 220 seconds
aPTT targets range from 40 – 70 seconds
Monitor heparin therapy
Target times determined by each facility

64. Clinical Applications
Essential
Cardiac surgery
Percutaneous coronary intervention (PCI)
ECMO / (Dialysis)
Common
Critical care
Interventional radiology
Electrophysiology
Vascular surgery

65. Low dose heparin Interventional Radiology Targets generally ~250 - 300
Sometimes target “twice baseline”
Twice baseline can differ by ACT heparin sensitivity
More centers targeting “increase from baseline”
e.g. >130 second increase from baseline

66. Clinical Applications
Essential
Cardiac surgery
Percutaneous coronary intervention (PCI)
ECMO / (Dialysis)
Common
Critical care
Interventional radiology
Electrophysiology
Vascular surgery

67. Low dose heparin Vascular Surgery and Electrophysiology
Targets generally ~200 – 250
frequently no monitoring
Change from baseline is critical factor
Is heparin having an effect?
Is patient responding “normally”?
~20% patients “resistant” <80 sec/unit/ml blood
~60% patients “normal” sec/unit/ml blood
~20% patients “sensitive” >120 sec/unit/ml blood

68. Summary ACT is NOT a standardized test
Each assay yields different results
Activator differences
Endpoint detection differences
Current targets developed on Hemochron
First available non-manual system
Targets must be adjusted for other systems

69. Summary While all systems correlate, they yield different results
Targets may need to be adjusted by clinical application
Inter-operator differences minimized with microcoagulation technology

70. The future of ACT?