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What is it?
Why do we need it POC?
.
Coagulation Testing
◆ Monitoring hemostasis
Bleeding Clotting
Anticoagulants
Monitor with PT
In
tri n
H Extrinsic Pathway
Monitor EP
s ic
A
Pa
with aPTT R
IN
th
or ACT
wa
y
WARFARIN
DXaI
X Xa
Common Pathway II IIa LMWH
(thrombin)
Monitor with Hirudin &
????? DTI
CLOT
Coagulation is Complex
Picture from
DiaPharma.com
Common(?) Coagulation Tests
◆ Laboratory ◆ Point of Care
PT..
aPTT
TT..
Fib. – ACT
– Anti Xa » Celite®
» Kaolin
– Anti IIa
» Glass beads
– Factor Assays » Silica
» thromboplastin
Differences in test methods
◆ Standard Laboratory ◆ Point of Care
– Platelet Poor Plasma – Whole Blood
– Sodium Citrate – No Added
Anticoagulant Anticoagulant
– 1:9 Dilution – No Dilution
– Variable Preanalytical – No Preanalytical
Delay Delay
POC Coagulation Analyzers
◆ HEMOCHRON 401 / 801 / Response
◆ HEMOCHRON Jr. Signature / Signature +
◆ ProTime / 3
◆ Medtronic HMS/HMS+/ HemoTec ACT II / ACTPlus
◆ CoaguChek / S / Pro / Pro DM
◆ i-STAT
◆ Helena Actalyke
◆ Hemosense INRatio
◆ Others?
POC Coag Analyzers Differ
◆ Test methodology
– Sample size and application
» Microliters to milliliters
– Sample measurement
» Manual vs automated
– Clot detection method
» Enzyme detection method
◆ Thrombin generation
– Reagent composition
– Results
Clinical Applications
Operating Room
– Cardiac Surgery
– Interventional Cardiology and Radiology
◆ Critical Care
◆ Satellite Sites
– Dialysis
– ECMO
– Emergency Room
– Anticoagulation Clinic
History of the ACT
◆ Lee-White clotting time
– Manual
– No activator
– Very slow
◆ 1966 –Hattersley- Activated Clotting Time
– Diatomaceous earth activator
– Operator defined mixing and clot detection
– Global assay - Contact activation of cascade
Activated
Clotting
Time
Particulate Contact Activation
◆ Initiation of intrinsic coagulation cascade
– Factor XII (Hageman factor)
– Prekallikrein (Fletcher factor)
◆ Dramatically shortens contact activation
period over Lee-White time
◆ Proposed as both screening assay for
coagulation defects and for heparin
monitoring
ACT Automation - 1969
◆ HEMOCHRON introduced
– semi-automated
– less operator dependence
– two assays
» CA510 (later FTCA510)
◆ diatomaceous earth
activated
» P214 glass bead activated
2 assays for separate applications
700
600
C-ACT
500
Clotting Time (sec)
P214
400
300
200
100 CATH
ECMO PTCA CPB
0
0
Dialysis 1 2 3 4 5
Heparin (units/ml)
1980’s HemoTec ACT
◆ Liquid kaolin activator
◆ Different technology
– Different results
ACT Differences
◆ Recognized in literature >20 years
– Clinical evaluations of Hemochron
appeared in journals mid 1970’s
– By 1981, papers appeared showing little
correlation between ACT and heparin level
– By 1988, papers clearly showed clinically
different results between Hemochron and
HemoTec
◆ Differences ignored by clinicians
Why are there so many different ACTs?
700
C-ACT
600 K-ACT
500 ACT+
Clotting Time (sec)
P214
400 ACT-LR
300
200
100 CATH
CCU PTCA CPB
0
Dialysis
0 1 2 3 4 5
Heparin (units/ml)
Monitoring - ACT
◆ Benefits
– Industry Standard Since 1970s
– Recommended as primary method in
AmSECT guidelines (perfusion)
– Easy to run
◆ Disadvantages
– Each system yields different numbers
– High sensitivity to hypothermia and
hemodilution (with exceptions)
– Little or no correlation to heparin level
» especially true for pediatric patients
Heparinized ACT - CPB
700
675
650
625 H e m o c h ro n
600 H e m o tec
Seconds
575 TA S
550 HMS
525
500
475
P re 15 30 45 60 75 90 105
C P B m in m in m in m in m in m in m in
Baseline
PostBolus
PostBolus2
OnPump
OnPump2
OnPump3
PostProt.
Baseline
PostBolus
PostBolus2
OnPump
OnPump2
OnPump3
PostProt.
Aggregation
10 sec
Coagulation
•Fibrin
formation 5 min
Need to inhibit restenosis / reocclusion
Platelet Inhibitors
◆ ReoPro
– elevates ACTs
– target time = 250 sec with ReoPro
» determined using FTCA510 tube
◆ Integrelin
– No reported clinically significant
effects on ACT
◆ Aggrastat
– No reported effects on ACT
Clinical Applications
Operating Room
– Cardiac Surgery
– Interventional Cardiology and Radiology
◆ Critical Care
◆ Satellite Sites
– Dialysis
– ECMO
– Emergency Room
– Anticoagulation Clinic
ACT or aPTT
◆ Determine when to pull the femoral sheath
– 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
◆ Must be linked to heparin sensitivity of reagent used
ACT vs aPTT
120
110 y = 0.57x - 28.44
100 R = 0.896
aPTT (J103) (sec)
90
80
70
60
50
40
30
20
50 100 150 200 250
FTCA510 (sec)
Extrinsic Pathway
AP
s ic
TT
Pa
th
wa
y
Common Pathway
CLOT
Activated Partial Thromboplastin Time
◆ NOT a PTT
– PTT is the predecessor of the aPTT
– Not used anymore
◆ Laboratory or Point of Care
◆ High APTT values
– presence of heparin
» treat by giving protamine
– underlying coagulopathy
» treat by giving FFP
◆ Monitor heparin / Coumadin® cross-over
Heparin versus Warfarin
Mechan- Moni-
Drug Action Effective
ism toring
Direct
ATIII APTT
Heparin Inhibition of Immediate
cofactor ACT
Thrombin
Decreases
Delay
Warfarin Production Vitamin K PT
3-5 days
of factors
Prothrombin Time
In
t ri
ns
ic Extrinsic Pathway
Pa
th
wa
PT
y
Common Pathway
CLOT
Prothrombin Time
◆ Monitor warfarin therapy
◆ Monitor heparin/warfarin crossover ISI
PTpatient
◆ Target times are set by INR =
PTmeannormal
International Normalized Ratio (INR)
ISI = international Sensitivity Index
– INR target ranges are specified by patient populations
» DVT, Afib, Atrial MHV: INR= 2.0 - 3.0
» Mitral mechanical heart valve: INR= 2.5 – 3.5
» Hypercoagulable disorders: INR= 1.5 – 2.5?
Will POC Results Match the Lab?
(Probably Not)
but it WILL Correlate
Correlate Does Not Mean Match
100
80
60
40
20
0
0 50 Lab APTT 100 150
Coag is NOT Chemistry
Dade Actin / MLA Organon Technika / MDA
70 70
y = 0.72x + 11.5 y = 1.02x + 4.1
60 R = 0.883 60 R = 0.942
Signature
Signature
50 50
40 40
30 30
20 20
20 30 40 lab 50 60 70 20 30 40 lab 50 60 70
Signature
90.0 90.0
70.0 70.0
50.0 50.0
30.0 30.0
10.0 10.0
10 30 50 70 90 110 130 150 10 30 50 70lab 90 110 130 150
lab
IL aPTT C /ACL #1 IL aPTT SP / ACL #1
100.0 100.0
y = 0.45x + 17.9 y = 0.35x + 22.1
80.0
Signature
80.0
Signature
Compare
R = 0.929 R = 0.928
60.0 60.0
40.0 40.0
for your
20.0 20.0
0.0 0.0
0 50 lab 100 150 0 50 lab 100 150
site. 100.0
IL aPTT C / ACL #2
y= 0.47x+ 20.2
100.0
IL aPTT SP / ACL #2
y = 0.59x + 16.0
80.0
Signature
Signature
R = 0.942 80.0 R = 0.961
60.0 60.0
Same 40.0
20.0
40.0
20.0
System /
0.0 0.0
0 50 lab 100 150 0 50 lab 100 150
Multiple
IL aPTT C / ACL #3 IL aPTT SP / ACL #3
100.0 100.0
y = 0.44x + 22.2 y = 0.40x + 23.3
80.0
Signature
80.0 R = 0.912
Signature
R = 0.953
60.0
Sites
60.0
40.0 40.0
20.0 20.0
0.0 0.0
0 50 100 150 0 50 100 150
lab lab
Are differences important?
◆ Sometimes no - aPTT C
Signature site 1 site 2 site 3
30 27 21 18
40 49 42 41
50 71 63 64
60 94 84 87
70 116 105 109
80 138 127 132
90 160 148 155
◆ Sometimes VERY - aPTT SP
Signature site 1 site 2 site 3
30 23 24 33
40 51 41 82
50 80 57 130
60 109 74 179
70 138 91 >200
80 167 108 >200
90 196 125 >200
Lot to Lot Reproducibility
Cuvette Lot a
80 Signature Lot a Lot b
70 y = 1.35x - 14.2 30 26 29
R=.909
60 40 40 43
Lab
50 50 53 57
40
60 67 70
30
70 80 84
20
20 40 60 80
80 93 98
Signature 90 107 112
Cuvette Lot b
80
y = 1.39x - 12.8
70 R=0.934
60
Lab
50
40
30
20
20 40 60 80
Signature
Clinical Applications
Operating Room
– Cardiac Surgery
– Interventional Cardiology and Radiology
◆ Critical Care
◆ Satellite Sites
– Dialysis
– ECMO
– Emergency Room
– Anticoagulation Clinic
Dialysis / ECMO
◆ ACT (or nothing in dialysis)
– Majority use P214 glass activated ACT
– Some use ACT-LR; HemoTec LR ACT
◆ Better
Control of Anticoagulation Leads to
Increased Dialyzer Reuse
– Potential for Long Term Cost Savings
– No Compromise in Dialysis Efficacy (Kt/V)
» Ouseph, R. et.al. Am J Kidney Dis 35:89-94; 2000
Emergency Room
◆ ACT; aPTT; PT; Fibrinogen
◆ Immediate Identification of Coagulopathies
– Optimization of Critical Decision Pathways
◆ ACT Allows Early Detection of Traumatic
Coagulopathy
– Allows Early Treatment Decisions
– Aids Damage Control Decisions
» Aucar, J. et.al. 1998 SW Surgeons Congress
◆ Optimize Staffing During Off Hours
Anticoagulation Clinics
◆ Results Available While Patient is Present
– Improved Anticoagulation Management
– Improved Standard of Care
– Staff Efficiency
◆ Immediate Retesting (if needed)
– Fingerstick Sampling
◆ Same System for Clinic and Home Bound
Patients
– Standardized ISI / PT normal
» Test System Specific
Anticoagulation Clinics
◆ Potential for Self-Testing
– High Risk Patients
– Patients Who Travel Frequently
– Home-Bound
– Patients in Rural Areas Far from Clinic
◆ Improved Outcomes Through More
Frequent Testing
Will POC Results Match the Lab?
◆ Lower dose?
◆ Keep same dose?
◆ Raise Dose?
◆ Test Again?
◆ Test more often?
Lab to Lab Comparison
1.5
Mean difference = 0.3 INR
1
Difference (TPC - INN)
0.5
0
0 1 2 3 4 5 6 7
-0.5
-1
-1.5
Mean Innovin and TPC INR
INR Expectations
INR within 0.4 of lab > 80%
INR within 0.7 of lab > 90%
INR within 1.0 of lab > 95%
1. Regulatory compliance
2. Connectivity
Regulatory compliance - Who sets the rules?
– JCAHO
» Joint Commission on Accreditation of Health Care Orgs
– CAP
» College of American Pathologists
– FDA
» Food and Drug Administration
» CDRH
◆ Center for Devices and Radiological Health
– CMS
» Centers for Medicare and Medicaid Services
– CDC
» Centers for Disease Control
CLIA Applies to ALL Testing Areas
◆ Central Laboratory
◆ Satellite Labs
– Critical Care
– Surgical Suite
◆ Clinics
◆ Bedside testing
◆ Doctor’s office
CLIA Regulations for Coagulation
◆ Central Laboratory can hold the CLIA license
– Satellites can have independent licensure
◆ Moderately Complex tests
– Except – ProTime, Coaguchek, INRatio are waived
◆ Requires
– Certified Laboratory Director
– Record Keeping
– Training
– Quality Policy
Implementing POC coag requires:
◆ Method Validation - accuracy
– Comparison to current standard
» NCCLS Guideline EP-09 recommends 40 samples
– Linearity may be used if no current standard
– Is assay performance appropriate to clinical needs?
◆ Precision
– Controls may be used to establish within and between run
variability
◆ Training
– Document training of all personnel
» high school equivalence or higher education level
– competency evaluations at predetermined intervals
Implementing POC coag requires:
◆ Linearity NOT required for coag
◆ Calibration “does not apply to unit test systems that
cannot be adjusted”
◆ Calibration verification
• Current assumption:
– Equivalent to CAP POC.05450
» If the laboratory has more than one method-system for performing
tests for a given analyte, are they checked against each other at least
twice a year for correlation of patient results?
– CLIA requires at least 3 point check
New CLIA Regulations
◆ Work in progress
– New rules published January 2003
– Rules in effect March 23, 2003
– Interpretive guidelines published Jan 2004
– Inspections using new regulations now
» 2 year grace period to adapt new rules
» Ends Jan 2005
◆ Quality Assessment Program - Lab Responsibilities
– Establish & follow policies/procedures addressing ongoing
QA activity.
– Take corrective actions as necessary.
» Review their effectiveness.
» Revise policies/procedures as necessary to prevent recurrence.
– Communicate to staff.
– Document all assessment activities.
New CLIA Regulations
◆ Proficiency testing
– Changed consensus for PT program grading from 90% to 80%.
◆ Quality Assessment replaces Quality Assurance.
– Quality Assessment is interspersed throughout the regulation.
– Creates one set of nonwaived QC requirements.
◆ Subpart K - Quality System for Nonwaived Testing
– Laboratory is ultimately responsible for ensuring that all
components of the analytic process are monitored.
– Each laboratory that performs nonwaived testing must meet
the applicable analytic systems requirements; unless HHS
approves a procedure, specified in the Interpretive Guidelines,
that provides equivalent quality testing
Equivalent Quality Testing
◆ Traditional:
– Testing two levels of external control materials
each day of testing
– Except coag and blood gases
» every 8 hours of use
◆ Equivalent QC Options
– #2 -Test systems with internal/procedural
controls that monitor a portion of the analytic
components, and if the lab successfully
completes a thirty day evaluation process, the
lab may reduce the frequency of external quality
control materials to once per calendar week.
Equivalent Quality Testing
◆ Option #2
– Perform the test system’s internal control procedure(s) in
accordance with the manufacturer’s instructions (but not
less frequently than once each day of testing) and test two
levels of external control material daily for 30 consecutive
days of testing.
◆ EQC AND LQC daily (NOT every 8 hours) for 30 days
– Then OK to use EQC daily, LQC weekly
» Unless manufacturer requires more
– Send comments to: Judith Yost
» Director, Division of Laboratory Services, CMS
» JYost@cms.hhs.gov
» (410) 786-3407
Routine Quality Control
◆ Instrument Performance Verification
– Electronic Quality Control with Numeric Output
– Two levels per 8 hour shift (CLIA reg)
◆ Assay Performance Verification
– Wet QC as per Manufacturer’s Recommendation
» Varies by system
◆ No external QC required for ProTime / INRatio in
most States
» Within system may vary by waived or moderate
complexity licensure
Ensuring Compliance
◆ Required identification
– Mandatory operator ID
» Password control
» Reuse IDs for some applications
– Mandatory patient ID
» Reuse IDs for some applications
◆ Lockout
– Force QC at specific times
» QC must pass to run patient samples
– Lockout non-compliant or untrained operators
– Disallow specific assays
Connectivity
◆ Multiple definitions
– Download to computer
» To LIS or to HIS or to both or to data
management software
» Real time and / or batch
» QC data, patient data, or both
Connectivity
◆ Bidirectional communication
– Send data to instrument
» Reset lockouts
» Load configurations
◆ Operator tables
◆ QC frequency
◆ QC ranges
◆ Reuse availability
◆ Oncecompliance issues
addressed –
– Improved Clinical Outcome
– Reduced LOS – Length of Stay
– Improved, timely patient care