Activated Clotting Time
Applications, Therapeutics and
Technologies
Marcia L. Zucker, Ph.D.
Director of Clinical Support
Response Biomedical Corporation
mzucker@responsebio.com
ITC Educational
Services, Edison, NJ
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
Time goes on…
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
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
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
Mechanical Detection
• Magnet in tube, detector in instrument
• Upon fibrin clot formation, magnet is deflected
• Clotting time displayed
Two assays for separate uses
700
Clotting Time (sec)
600
C-ACT
500
P214
400
300
200
100
CATH
ECMO
0
Dialysis 1
0
PTCA
2
CPB
3
Heparin (units/ml)
4
5
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
Lower values than CA510 –
700
675
Seconds
650
625
600
575
Hemochron
Hemotec
550
525
500
475
Pre
CPB
15
min
30
min
45
min
60
min
75
min
90
min
differences ignored by clinicians
105
min
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
– http://www.nacb.org/lmpg/poct_LMPG_draft_PDF.stm
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
Clotting Times Different
550
Jr. ACT
ACT+
450
ACT-LR
350
FTCA510
250
150
50
50
100 150 200 250 300 350 400 450 500
FTCA510 ACT
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
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
Today
•
•
•
•
•
•
•
Hemochron Response
Hemochron Signature Elite
Medtronics ACT Plus
Medtronics HMS+
Helena Actalyke XL / Mini
Gem PCL
Abbott i-STAT
Activated Clotting Time
Extrinsic Pathway
Common Pathway
CLOT
Why do we use an ACT?
• Maintain Balance
– 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
NACB Guidelines
• National Academy of Clinical Biochemistry
• Evidence Based Guidelines for POC Testing
– http://www.nacb.org/lmpg/poct_lmpg_draft.stm
• Chapter 4 – Coagulation Testing
• Caveats:
– Assume all systems equally safe / effective /
precise
– Correlation studies excluded
– Few good outcome trials
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).
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, nonrandomized 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.
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, nonrandomized 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:
– 200-300 seconds
• tirofiban:
– 250 – 300
» (Class B – Level I- at least one randomized controlled trial).
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).
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).
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
Different ACTs for each clinical setting
700
Clotting Time (sec)
C-ACT
600
K-ACT
500
ACT+
P214
400
ACT-LR
300
200
CATH
100
CCU
0
Dialysis
0
PTCA
1
2
CPB
3
Heparin (units/ml)
4
5
Clinical Applications
• Essential
– Cardiac surgery
– Percutaneous coronary intervention (PCI)
– ECMO / (Dialysis)
• Common
–
–
–
–
Critical care
Interventional radiology
Electrophysiology
Vascular surgery
• Benefits
Monitoring - ACT
– 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
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
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; 0.25 x 106
KIU/hr infusion
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
ACT Monitoring-Aprotinin Treatment
• Jones, et al. JECT. 2004;36:51–57
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
ACT Monitoring - DTIs
• Argatroban
– 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
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
900
800
ECT
y = 28.8x + 154.8
R = 0.951
700
Clotting time
600
ACTT
y = 28.4x + 224.9
R = 0.906
ACT+
y = -1.4x2 + 37.8x + 170.5
R = 0.937
500
400
Adapted from Zucker, et.al.,
JECT 2005, in press
300
200
Hemochron Celite
y = -0.68x2 + 24.4x + 149.0
R = 0.892
100
Medtronics kaolin
y = -0.64x2 + 25.0x + 160.4
R = 0.831
ACTT not yet available
0
0
5
10
Bivalirudin (ug/ml)
15
20
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
Pediatric Monitoring
Pediatric Cardiac Surgery
700
Clotting time (sec)
600
500
400
300
200
FTCA510
ACT+
100
0
baseline
post-bolus
on pump
rewarm
time during bypass
• Data from clinical evaluation, on file, ITC
post-CPB
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
Monitoring - Heparin Level
• Young: <4.5 years
• Shayevitz, JR and O’Kelly, SW Progress in Anesthesiology, vol. IX, chapter
16 1995
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
Heparin Monitoring Dilemma
ACT
Heparin
Level
Which Value Determines Response?
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
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 20 - 40% of patient population
• Response can vary up to 12 fold between patients
Protamine Dose Optimization
• Minimize protamine dose
– Reduce time for infusion
– Avoid protamine related adverse events
•
•
•
•
hypotension
shock
bleeding
platelet dysfunction
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. 1995. J Thorac Cardiovasc Surg 110: 36-45
• Reduced potential for protamine reaction
– Protamine reduced by average of 30%
– Zucker ML., et al. 1997. J Extra-Corp Tech. 29: 176-180.
• Reduced incidence of return to OR for bleeding
Economic Benefits (US$)
GROUP
N
AVERAGE
PRE / POST
1oCABG
COST PRE
NET COST
POST
AVERAGE NET
SAVINGS
151 / 139
$787
$493
$294
1o N / C
189 / 167
$849
$601
$247
ALL
REOP
28 / 34
$2,418
$1,533
$864
1oALL
CMLPX
47 / 51
$2,482
$2,133
$358
Jobes DR., et al. 1996. Cost Effective Management Of Heparin/ Protamine In
CP Bypass: Analysis By Type Of Surgery. Anesthes 85:3A.
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
– HEMOCHRON Response
– aPTT - intrinsic pathway
– HEMOCHRON tube systems
– HEMOCHRON microsample systems
Clinical Applications
• Essential
– Cardiac surgery
– Percutaneous coronary intervention (PCI)
– ECMO / (Dialysis)
• Common
–
–
–
–
Critical care
Interventional radiology
Electrophysiology
Vascular surgery
Procedures
• Diagnostic
– Catheterization
• locate and map vessel blockage(s)
• determine need for interventional procedures
– Electrophysiology
• Interventional
– Balloon angioplasty
– Atherectomy (roto-rooter)
– Stent placement
Diagnostic – Low dose heparin
• Catheterization and Electrophysiology
– 2500 - 5000 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
Interventional
• Angioplasty, Atherectomy, Stent placement
• HEMOCHRON FTCA510; HEMOCHRON Jr ACTLR; Medtronics LR-ACT or HR-ACT: Actalyke CACT, MAX-ACT; GEM PCL ACT-LR; i-STAT
ACTCelite
– 10,000 unit bolus dose or
– 2 - 2.5 mg/kg
– target ACT 300 - 350 seconds
• Target must be reduced if ReoPro Used
– ReoPro is one of 3 “GPIIb/IIIa” Inhibitors
• GPIIb/IIIa receptor critical in platelet aggregation
Novel Pharmaceuticals
• Platelet Inhibitors
– Oral
• Aspirin
• Plavix
– Parenteral
• ReoPro
• Integrilin
• Aggrastat
• Low Molecular Weight Heparins (LMWH)
– None FDA approved for interventional cardiology
– Lovenox
– Fragmin
Platelet Structure
PLAVIX
ASPIRIN
Parenteral platelet
inhibitors
Courtesy of Helena Laboratories
Intervention promotes aggregation
Picture courtesy of Reopro.com
ACT Monitoring - Platelet Inhibitors
• Aspirin
– No reported effects on ACT
– No anecdotal reports of effects on ACT
• Plavix
– No reported effects on ACT
– Anecdotal reports
• Increased bleeding at sheath pull
• ACTs don’t return to “normal” prior to sheath pull
– Plateau ~ 180 – 220 seconds
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
ACT Monitoring - LMWH
• Fragmin
– 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
Clotting Time Change (secs)
250
200
Change in APTT
Change in ACT-LR
150
Change in Hemonox CT
100
50
0
5
10
30
Time Post Bolus (min)
60
Adapted from el Rouby, et.al.,
J Thromb Thrombolys 2005, in
press
HEMONOX not yet available
Targets can change with ACT
550
450
Jr. ACT
Choose ACT by
application and
Intended Use:
ACT+
ACT-LR
350
FTCA510
250
150
50
Target
250 - 300
300 – 350
350 – 400
>400
Test
ACT-LR
LR or ACT+
ACT+ or LR
ACT+
50
100 150 200 250 300 350 400 450 500
FTCA510 ACT
Clinical Applications
• Essential
– Cardiac surgery
– Percutaneous coronary intervention (PCI)
– ECMO / (Dialysis)
• Common
–
–
–
–
Critical care
Interventional radiology
Electrophysiology
Vascular surgery
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 180 - 220 seconds
– Changing ACT requires changing target
• Target often 220-260 with ACT-LR
• Not all ACTs have low heparin indication
• Also indicated for low dose:
– GEM PCL ACT-LR; Actalyke G-ACT
Clinical Applications
• Essential
– Cardiac surgery
– Percutaneous coronary intervention (PCI)
– ECMO / (Dialysis)
• Common
–
–
–
–
Critical care
Interventional radiology
Electrophysiology
Vascular surgery
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
• HEMOCHRON FTCA510; HEMOCHRON Jr ACT-LR; Medtronics LR-ACT;
Actalyke C-ACT; GEM PCL ACT-LR
Clinical Applications
• Essential
– Cardiac surgery
– Percutaneous coronary intervention (PCI)
– ECMO / (Dialysis)
• Common
–
–
–
–
Critical care
Interventional radiology
Electrophysiology
Vascular surgery
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
Clinical Applications
• Essential
– Cardiac surgery
– Percutaneous coronary intervention (PCI)
– ECMO / (Dialysis)
• Common
–
–
–
–
Critical care
Interventional radiology
Electrophysiology
Vascular surgery
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” 80-120 sec/unit/ml blood
– ~20% patients “sensitive” >120 sec/unit/ml blood
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
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
The future of ACT?