activated clotting time applications, therapeutics and technologies itc educational services,...
TRANSCRIPT
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Activated Clotting TimeApplications, Therapeutics and
Technologies
ITC Educational Services, Edison, NJ
Marcia L. Zucker, Ph.D.Director of Clinical Support
Response Biomedical [email protected]
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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
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Time goes on…
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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
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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
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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
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Mechanical Detection• Magnet in tube, detector in instrument• Upon fibrin clot formation, magnet is deflected• Clotting time displayed
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Two assays for separate uses
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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
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Lower values than CA510 –
differences ignored by clinicians
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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
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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
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Clotting Times Different
50
150
250
350
450
550
50 100 150 200 250 300 350 400 450 500FTCA510 ACT
Jr.
AC
T
ACT+
ACT-LR
FTCA510
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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
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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
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Today• Hemochron Response
• Hemochron Signature Elite
• Medtronics ACT Plus
• Medtronics HMS+
• Helena Actalyke XL / Mini
• Gem PCL
• Abbott i-STAT
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Activated Clotting Time
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
ACT
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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
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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
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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).
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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.
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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:
– 200-300 seconds
• tirofiban: – 250 – 300
» (Class B – Level I- at least one randomized controlled trial).
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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).
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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).
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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
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Different ACTs for each clinical setting
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Clinical Applications
• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)
• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery
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Monitoring - ACT• Benefits
– 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
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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
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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
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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
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ACT Monitoring-Aprotinin Treatment
• Jones, et al. JECT. 2004;36:51–57
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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
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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
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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
ACTTy = 28.4x + 224.9
R = 0.906
ECTy = 28.8x + 154.8
R = 0.951
Hemochron Celitey = -0.68x2 + 24.4x + 149.0
R = 0.892
ACT+y = -1.4x2 + 37.8x + 170.5
R = 0.937
Medtronics kaoliny = -0.64x2 + 25.0x + 160.4
R = 0.831
0
100
200
300
400
500
600
700
800
900
0 5 10 15 20
Bivalirudin (ug/ml)
Clo
ttin
g t
ime
Adapted from Zucker, et.al., JECT 2005, in press
ACTT not yet available
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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
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Pediatric MonitoringPediatric Cardiac Surgery
0
100
200
300
400
500
600
700
baseline post-bolus on pump rewarm post-CPB
time during bypass
Clo
ttin
g tim
e (s
ec)
FTCA510
ACT+
• Data from clinical evaluation, on file, ITC
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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
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Monitoring - Heparin Level
• Young: <4.5 years• Shayevitz, JR and O’Kelly, SW Progress in Anesthesiology, vol. IX, chapter 16 1995
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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
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Heparin Monitoring Dilemma
ACT HeparinLevel
Which Value Determines Response?
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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
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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
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• Minimize protamine dose– Reduce time for infusion
– Avoid protamine related adverse events• hypotension
• shock
• bleeding
• platelet dysfunction
Protamine Dose Optimization
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Clinical Benefits• Individualize heparin dose
• Reduce blood products needed for post-operative transfusions– i.e. red blood cells, platelets, fresh frozen plasma and
cryoprecipitateJobes 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
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Economic Benefits (US$)GROUP N
PRE / POSTAVERAGE
COST PRENET COST
POSTAVERAGE NET
SAVINGS
1oCABG 151 / 139 $787 $493 $294
1oN / C 189 / 167 $849 $601 $247
ALLREOP
28 / 34 $2,418 $1,533 $864
1oALLCMLPX
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.
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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
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Clinical Applications
• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)
• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery
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Procedures• Diagnostic
– Catheterization• locate and map vessel blockage(s)• determine need for interventional procedures
– Electrophysiology
• Interventional– Balloon angioplasty– Atherectomy (roto-rooter)– Stent placement
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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
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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– 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
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Novel Pharmaceuticals• Platelet Inhibitors
– Oral• Aspirin• Plavix
– Parenteral• ReoPro• Integrilin• Aggrastat
• Low Molecular Weight Heparins (LMWH)– None FDA approved for interventional cardiology– Lovenox– Fragmin
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Platelet Structure
Courtesy of Helena Laboratories
PLAVIX
ASPIRIN
Parenteral platelet inhibitors
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Intervention promotes aggregation
Picture courtesy of Reopro.com
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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
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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
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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
0
50
100
150
200
250
5 10 30 60Time Post Bolus (min)
Clo
ttin
g T
ime
Ch
an
ge
(s
ec
s)
Change in APTT
Change in ACT-LR
Change in Hemonox CT
Adapted from el Rouby, et.al., J Thromb Thrombolys 2005, in pressHEMONOX not yet available
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Targets can change with ACT
50
150
250
350
450
550
50 100 150 200 250 300 350 400 450 500FTCA510 ACT
Jr. A
CT
ACT+
ACT-LR
FTCA510
Choose ACT by application and Intended Use:
Target Test 250 - 300 ACT-LR 300 – 350 LR or ACT+
350 – 400 ACT+ or LR
>400 ACT+
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Clinical Applications
• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)
• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery
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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
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Clinical Applications
• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)
• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery
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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
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Clinical Applications
• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)
• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery
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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
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Clinical Applications
• Essential– Cardiac surgery– Percutaneous coronary intervention (PCI)– ECMO / (Dialysis)
• Common– Critical care– Interventional radiology– Electrophysiology– Vascular surgery
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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
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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
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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
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The future of ACT?
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