Transcript Coagulation Testing

Coagulation Testing
What is it?
Why do we need it POC?
Marcia L. Zucker, Ph.D.
Director of Clinical Research
Educational Services,
Edison, NJ
Coagulation Testing
 Monitoring
hemostasis
Bleeding
Clotting
Anticoagulants
Monitor with PT
Extrinsic Pathway
Monitor
with aPTT
or ACT
WARFARIN
X
Common Pathway
Monitor with
?????
Xa
DXaI
II
IIa LMWH
(thrombin) Hirudin &
DTI
CLOT
Coagulation is Complex
Picture from
DiaPharma.com
Common(?) Coagulation Tests
 Point
 Laboratory
PT..
aPTT
TT..
Fib.
– Anti Xa
– Anti IIa
– Factor Assays
of Care
– ACT
» Celite®
» Kaolin
» Glass beads
» Silica
» thromboplastin
Differences in test methods
Standard
Laboratory
– Platelet Poor Plasma
– Sodium Citrate
Anticoagulant
– 1:9 Dilution
– Variable Preanalytical
Delay
Point
of Care
– Whole Blood
– No Added
Anticoagulant
– No Dilution
– No Preanalytical
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
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
 Liquid
kaolin activator
 Different technology
– Different results
700
675
Seconds
650
625
600
575
Hemochron
Hemotec
550
525
500
475
Pre 15
CPB min
30
min
45
min
60
min
75
min
90
min
105
min
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
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
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
Seconds
650
Hemochron
Hemotec
TAS
HMS
625
600
575
550
525
500
475
Pre 15
CPB min
30
min
45
min
60
min
75
min
90
min
Data from Huffman, et.al. 1998 AmSECT meeting
105
min
Pharmaceutical Intervention
Amicar
or Tranexamic Acid
– No effect on standard celite ACT
Aprotinin
– Significant elevation of celite ACT
– Two dosing regimens
» Full or Half Hammersmith
» Both independent of patient size
ACT Monitoring-Aprotinin Treatment
 Celite ACT
– Not recommended
– Still used with target times of >750 seconds
 Kaolin ACT
– Unaffected by moderate doses of aprotinin
– Used with target times of > 480 seconds
 ACT+
– Unaffected by ALL doses of aprotinin
– Used with target times of > 400 seconds
Monitoring in CPB - Aprotinin
C-ACT
ACT+
1200
1200
Trasylol
1000
1000
Trasylol
Placebo
Placebo
800
800
600
600
400
400
200
200
0
PostProt.
OnPump3
OnPump2
OnPump
PostBolus2
Data from clinical evaluation, on file, ITC
PostBolus
PostProt.
OnPump3
OnPump2
OnPump
PostBolus2
PostBolus
Baseline

Baseline
0
Other POC Coag in the OR
 aPTT /
PT
– Pre- and post-procedural screening
 Fibrinogen
– Pre- and post-procedural screening
 Dosing Assays
– Customize heparin and protamine for each patient
» HEMOCHRON HRT / PRT
» Hepcon HMS
– Measure heparin level
» Relationship to coagulation status unclear
Other POC Coag in the OR
Heparin
neutralization verification
– Ensure complete removal of circulating
heparin
» aPTT
» PDA-O - ACT based
» TT / HNTT - Thrombin Time based
» heparinase ACT
Outcome studies - POC in OR
 Reduced
Blood Loss/Transfusion
– Use of HRT and PRT (RxDx System)
 Reduced
Cost Resulting from Use of POC Assays
– RxDx combined with TT / HNTT
 Reduced
Complication Rates
– TT / HNTT
– Re-Exploration for Bleeding Reduced from 2.5% to
1.1%
– Re-Exploration for Coagulopathy Reduced from
1.0% to 0.0.
Clinical Applications
Operating Room
– Cardiac Surgery
– Interventional Cardiology and Radiology
Critical
Care
Satellite Sites
–
–
–
–
Dialysis
ECMO
Emergency Room
Anticoagulation Clinic
Procedures
Diagnostic
– Catheterization
» locate and map vessel blockage(s)
» determine need for interventional procedures
– Electrophysiology
– Interventional Radiology
Interventional
– Balloon angioplasty
– Atherectomy (roto-rooter)
Diagnostic – Low dose heparin
Catheterization
and Electrophysiology
– 2500 - 5000 unit bolus dose
– frequently not monitored
– if monitored –
» ACT
» aPTT
Interventional – Moderate dose
 Angioplasty
and Atherectomy
– Heparin
» 10,000 unit bolus dose or
» 2 - 2.5 mg/kg
» target ACT 300 - 350 seconds

200 – 300 in presence of ReoPro
– Angiomax (bivalirudin)
» ACT >300

Hemochron (ACT-LR or FTCA510) trials
» Measure post-bolus to ensure drug on board
» Required in patients with renal impairment
Why use platelet inhibitors?
 Angioplasty
Adhesion
•shape change
• release
promotes aggregation
ADP release
3 sec
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
R = 0.896
aPTT (J103) (sec)
100
90
80
70
60
50
40
30
20
50
100
150
FTCA510 (sec)
200
250
Single site comparison, ACT tube vs HE Jr Sig aPTT
ACT or aPTT
Monitor
heparin therapy
– Target times determined by each facility
– APTT outcome study
» Reduce time to result (112 vs <5 minute)
» Reduce time to stabilization
» Reduce dose adjustments
» Reduce length of stay
» By using POC aPTT instead of lab
 Poster
at AACC 2000 – Staikos, et.al.
Activated Partial Thromboplastin Time
Extrinsic Pathway
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
»
–
underlying coagulopathy
»

treat by giving protamine
treat by giving FFP
Monitor heparin / Coumadin® cross-over
Heparin versus Warfarin
Drug
Action
Direct
Heparin Inhibition of
Thrombin
Mechanism
Monitoring
Effective
ATIII
cofactor
APTT
ACT
Immediate
PT
Delay
3-5 days
Decreases
Warfarin Production Vitamin K
of factors
Prothrombin Time
Extrinsic Pathway
PT
Common Pathway
CLOT
Prothrombin Time
 Monitor
warfarin therapy
 Monitor heparin/warfarin crossover
 PTpatient
INR  
 Target times are set by


PT

meannormal 
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?
ISI
Will POC Results Match the Lab?
(Probably Not)
but it WILL Correlate
Correlate Does Not Mean Match
y = 0.737x + 22.2
R = 0.920
140
Signature APTT
120
100
80
60
40
20
0
0
50
Lab APTT
100
150
Coag is NOT Chemistry
Dade Actin / MLA
70
y = 0.72x + 11.5
R = 0.883
50
40
50
40
30
30
20
20
20
30
40
lab 50
60
70
IL aPTT C / ACL #3
150.0
130.0
110.0
90.0
70.0
50.0
30.0
10.0
y = 1.02x + 4.1
R = 0.942
60
Signature
Signature
60
20
y = 0.44x + 22.2
R = 0.9533
10
30
50
70
lab
90
110
130
150
30
40
lab 50
60
70
IL aPTT SP / ACL #2
150.0
130.0
110.0
90.0
70.0
50.0
30.0
10.0
y = 0.59x + 16.0
R = 0.961
Signature
Signature
Organon Technika / MDA
70
10
30
50
70lab 90
110
130
150
IL aPTT C /ACL #1
IL aPTT SP / ACL #1
100.0
Signature
60.0
40.0
60.0
40.0
20.0
20.0
0.0
0.0
50
lab 100
150
0
100.0
Signature
y = 0.47x + 20.2
R = 0.942
60.0
40.0
20.0
150
y = 0.59x + 16.0
R = 0.961
80.0
60.0
40.0
0.0
0
50
lab 100
150
0
IL aPTT C / ACL #3
y = 0.44x + 22.2
R = 0.953
60.0
40.0
80.0
0.0
0.0
lab 100
150
150
y = 0.40x + 23.3
R = 0.912
40.0
20.0
50
lab 100
60.0
20.0
0
50
IL aPTT SP / ACL #3
100.0
Signature
80.0
lab 100
20.0
0.0
100.0
50
IL aPTT SP / ACL #2
100.0
80.0
y = 0.35x + 22.1
R = 0.928
80.0
IL aPTT C / ACL #2
Signature
Same
System /
Multiple
Sites
y = 0.45x + 17.9
R = 0.929
80.0
0
Signature
Compare
for your
site.
Signature
100.0
0
50
lab
100
150
Are differences important?
Sometimes
Signature
30
40
50
60
70
80
90
site 1
27
49
71
94
116
138
160
no - aPTT C
site 2
21
42
63
84
105
127
148
site 3
18
41
64
87
109
132
155
Sometimes
Signature
30
40
50
60
70
80
90
VERY - aPTT SP
site 1
23
51
80
109
138
167
196
site 2
24
41
57
74
91
108
125
site 3
33
82
130
179
>200
>200
>200
Lot to Lot Reproducibility
Cuvette Lot a
80
y = 1.35x - 14.2
R=.909
70
Lab
60
50
40
30
20
20
40
60
80
Signature
Cuvette Lot b
80
70
y = 1.39x - 12.8
R=0.934
Lab
60
50
40
30
20
20
40
Signature
60
80
Signature
30
40
50
60
70
80
90
Lot a
26
40
53
67
80
93
107
Lot b
29
43
57
70
84
98
112
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?
(It will be a lot closer than for aPTT)
but it WILL Correlate
How to Compare INR Results
 Lower
dose?
 Keep same dose?
 Raise Dose?
 Test Again?
 Test
more often?
Lab to Lab Comparison
1.5
Mean difference = 0.3 INR
Difference (TPC - INN)
1
0.5
0
0
1
2
3
4
5
-0.5
-1
-1.5
Mean Innovin and TPC INR
6
7
INR Expectations
INR within 0.4 of lab > 80%
INR within 0.7 of lab > 90%
INR within 1.0 of lab > 95%
(values shown are
ranges)
AACC 2002
Pairs within
0.4 INR
Pairs within
0.7 INR
Lab to Lab
85.4 – 97.9 %
94.8 – 99.0 %
POC to Lab
74.7 – 89.9 %
87.9 – 99.0 %
POC to POC
89.9 – 94.9 %
97.0 – 99.5 %
Why Bother with POC Coag?
Improved
TAT - Turn Around Time
– Defined from the Clinician, not Lab view
– When is Turn Around Important
» Emergency Room
» ICU/CCU Dose Adjustments
» Operating Room / Cath Lab
– STAT Testing Turn Around
STAT Testing TAT
Lab (min) CPB (N=40) PVS (N=45)
Median
90.0
90.0
Mean
78.5
74.0
Minimum
38.0
21.0
POC (min)
All Groups
Median
2.23
Minimum
0.33
Maximum
6.97
Fitch, et.al, J. Clin Monit & Comput. 1999. 15:197-204
Standardized Clinical Interpretation
 Defined Assay
Sensitivity
– Requires Lot to Lot Reproducibility
 Defined
Reagent Variability
– Identical Instrumentation and Reagents at All
Testing Sites
 Defined
Critical Clinical Decision Points
– No Change of Normal Ranges or Target Times
Between Lots of Test Reagents or Testing
Locations
What’s the catch?
1.
2.
Regulatory compliance
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
» [email protected]
» (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
» Vary configuration by clinical setting
Solutions
 System
specific configuration
– e.g. HCM for Signature+
HRDM for Response
 System
specific data management
– e.g. ReportMaker for Signature / +
HRDM for Response
RapidLink for Bayer RapidPoint
DataCare for Roche CoaguChek / S / DM / Pro
 Link
to systems designed for glucose
– Abbott and Roche state they will connect with any POC
instrumentation
Solutions
 Manufacturer
neutral interface
– MAS RALS-plus
– Telcor Quick Serv
– Manufacturer works with interface supplier to
ensure compatibility
– Interface supplier works with LIS / HIS
supplier to ensure compatibility
– Likely more options as CIC guidelines
implemented (NCCLS POCT1-A)
Why Bother with POC Coag?
Once
compliance issues
addressed –
–Improved Clinical Outcome
–Reduced LOS – Length of Stay
–Improved, timely patient care