Transcript Coagulation Testing What is it? Why do we need it POC?

Coagulation Testing
What is it?
Why do we need it POC?
Marcia L. Zucker, Ph.D.
Director of Clinical Research
ITC Educational
Services, Edison, NJ
Coagulation Testing
 Monitoring
hemostasis
Bleeding
Clotting
Maintaining Hemostasis
Counterbalance
thrombosis with
anticoagulant therapy
Thrombosis
Maintaining Hemostasis
Counterbalance bleeding
by correcting defect
(i.e., neutralize heparin,
Bleeding
transfuse blood product)
Components of Hemostasis
Vessels
Coagulation
Proteins
Platelets
Fibrinolysis / Inhibitors
Vascular System
Basement membrane
Endothelial cells
Red blood cells
Platelets
White blood cells
Components of Hemostasis
Vessels
Coagulation
Proteins
Platelets
Fibrinolysis / Inhibitors
Anatomy of a Platelet
Resting Platelets
Platelet Aggregate
Hemostasis
 Primary
hemostasis
– Platelet Adhesion
 Secondary
hemostasis
– Coagulation
– Fibrin clot formation
Platelet Function
Platelet Adhesion
•shape change
• release
ADP release
3 sec
Platelet
Aggregation
10 sec
Coagulation
•Fibrin
formation
5 min
Platelet Testing
 Peripheral
smear
 Platelet count
 Platelet aggregation
 Bleeding time
Peripheral Blood Smear
Platelet Aggregation
Platelet Rich
Plasma (PRP)
+
Aggregating
Aggregate
Agent
Clumping
Baseline Light
Increased Light
Transmission
Transmission
Bleeding Time
•Cut 1 mm deep, 5 mm long
•Constant pressure
•Expected Range : 2 - 10 minutes
Components of Hemostasis
Vessels
Coagulation
Proteins
Fibrinolysis / Inhibitors
Platelets
Coagulation
Inactive enzyme
Active enzyme
Inactive enzyme
Active enzyme
Coagulation is Complex
Coagulation Testing
Heparin
Coumadin
Monitor with
ACT / aPTT
Monitor with PT
Extrinsic
Pathway
Common Pathway
Thrombolytics
CLOT
Monitor with
TT / Fibrinogen
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
Point
– Platelet Poor Plasma
– Sodium Citrate
Anticoagulant
– 1:9 Dilution
– Variable Preanalytical
Delay
of Care
– Whole Blood
– Usually No Added
Anticoagulant
– No Dilution
– No Preanalytical
Delay
POC Coagulation Analyzers
 HEMOCHRON
401 / 801 / Response
 HEMOCHRON Jr. Signature/ Signature+
 ProTime
 Medtronic HMS/ HMS+ / HemoTec ACT II
 CoaguChek/ S / CoaguChek Pro/ Pro DM
 Bayer RapidPoint
 i-STAT
 Helena Actalyke
 Others
POC Coag Analyzers Differ
Test
methodology
– Sample size and application
– Sample measurement
– Clot detection method
» Enzyme detection method
– Reagent composition
– Results
Semi - Automation - 1969
 HEMOCHRONOMETER
(HEMOCHRON)
– Magnet in tube, detector in instrument
– Upon clot formation, magnet is deflected
– Clotting time displayed
HEMOCHRON Test Menu
 ACT
– FTCA510, FTKACT, P214
 aPTT and
PT
– Fresh or citrated whole blood
 Thrombin
time based assays
– TT, HNTT, HiTT
 Fibrinogen
 Dosing Assays
– HRT, PRT, PDAO
» Celite and kaolin
1980’s
 HemoTec
(later ACTII)
– Smaller sample volume
– Mechanical detection
» Flag moves up and down
» As clot forms, motion slows
» Instrument displays clotting
time
 Medtronics
HMS uses
same technology
Medtronics test menu
 ACT
(kaolin)
 Empty cartridge for aPTT
 PT (look up conversion)
 Heparinase ACT
 HMS Dosing Assays
– HDR, HPT
Newer technologies
Sample
introduction by capillary action
CoaguChek Pro/ DM
– Time to when
capillary flow stops
determines
endpoint
Bayer RapidPoint
– Sample mixes with
magnetic particles
– Pulsating magnetic field
– Motion detected
optically
Test Menu
 CoaguChek
ProDM
 Bayer
– ACT
» Tissue factor activated
– PT (FWB)
– aPTT (FWB)
 CoaguChek
/S
– Detection as per
RapidPoint
– PT only
– CLIA waived
RapidPoint
– HMT
– aPTT
» F & C WB and plasma
– PT
» F & C WB and plasma
– ECT (ecarin time)
» Compassionate use only
– ENOX
– Accent Dosing
» HTT, PRT
Newer Technologies
 Chemical
endpoint detection
– i-STAT – Abbott
» Synthetic thrombin substrate
» Electro-active compound formed and
detected amperometrically
– Coagulation Test Menu
» ACT (Celite®)
» PT (cleared but not yet introduced)
Newer Technologies
 Active
pumping system
– Hemochron Jr Signature
– ProTime microcoagulation
system
Test Menu
 HEMOCHRON
Jr
Signature
– ACT
» ACT+, ACT-LR
– PT
» Fresh or citrated WB
– aPTT
» Fresh or citrated WB
 ProTime
–
–
–
–
PT only
CLIA waived
Home use approved
Integral Controls
» Meet CLIA and CAP
requirement for daily
QC testing
Activated Clotting Time
Extrinsic Pathway
Common Pathway
CLOT
What do we use an ACT for?
Maintain
Balance
– Bleeding
Thrombosis
Heparin
– Rapid Anticoagulant Effect
» Individual sensitivities vary significantly
» Potency differences
 Source:
Bovine or Porcine
 Lot to Lot variability
– Rapidly Reversible with Protamine
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
Monitoring - ACT
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
Clinical Applications
Operating Room
– Cardiac Surgery
– Interventional Cardiology and Radiology
Critical
Care
Satellite Sites
– Dialysis
– ECMO
– Emergency Room
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
Monitoring in CPB - ACT
Clotting Time
1000
900
Kaolin ACT
800
Celite ACT
700
ACT+
600
500
400
300
200
100

Data from clinical evaluation, on file, ITC
Po
st
Pr
ot
.
p3
O
nP
um
p2
O
nP
um
p
nP
um
O
Po
st
Bo
lus
Po
st
Bo
lus
2
Ba
se
lin
e
0
Pharmaceutical Intervention
Amicar
or Tranexamic Acid
– No effect on standard celite ACT
– Continued debate on efficacy
»Multiple reports
Reduction
in post-operative blood loss
Reduced transfusion requirements
Pharmaceutical Intervention
Aprotinin
– Significant elevation of celite ACT
– Two dosing regimens
» Full Hammersmith
x 106 KIU loading dose; 2 x 106 KIU pump prime;
0.5 x 106 KIU/hr infusion
2
» Half Hammersmith
x 106 KIU loading dose; 1 x 106 KIU pump prime;
0.25 x 106 KIU/hr infusion
1
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
ACT Monitoring -Aprotinin Treatment
1200
1000
Kaolin ACT
Celite ACT
800
Clotting Time
.
ACT+
600
400
200
0
Baseline
PostBolus
PostBolus2
OnPump
Data from clinical evaluation, on file, ITC
OnPump2
OnPump3
PostProt.
Non-ACT Monitoring - Aprotinin
HiTT
Control Patients
600
1000
Celite
Kaolin
HiTT
Clotting Time
Clotting Time
1000
800
- High Dose Thrombin Time
400
200
800
600
Aprotinin Patients
Celite
Kaolin
HiTT
400
200
0
0
Baseline Post-Bolus
CPB 1
CPB 2
PostProtamine
Baseline Post-Bolus
CPB 1
CPB 2
PostProtamine
Adapted from Huyzen, et. al. J.CardioThorac. Vasc. Anesth. 8:153, 1994
Alternative Monitoring - Aprotinin
Kaolin ACT
HiTT
800
250
Aprotinin
Placebo
Clotting Time
Clotting Time
1000
600
400
200
200
150
100
50
Aprotinin
Placebo
0
0
Baseline Post-Bolus CPB 1
CPB 2
PostProtamine
Baseline Post-Bolus
CPB 1
CPB 2
PostProtamine
Adapted from Huyzen, et. al. J.CardioThorac.Vasc.Anesth. 8:153, 1994
Thrombin Time
Extrinsic Pathway
Common Pathway
CLOT
TT
Other POC in the OR
 Heparin
Level
– Xa Activity
» laboratory only, impractical
– Medtronic Hepcon HMS
» indirect measure of protamine reversible heparin
activity in whole blood
» correlates with Xa and IIa activity
– HEMOCHRON PRT
» ACT based protamine titration
– HEMOCHRON HiTT
» unaffected by hemodilution, hypothermia
» insensitive to aprotinin
» correlates with Xa and IIa activity
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
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
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)
» Jobes, D. et. al., 1995. J.Thorac.Cardiovasc.Surg.
 Reduced
Cost
– Resulting from POC Assays
– RxDx combined with TT / HNTT
» Jobes, D. et. al., 1996. Am Soc Anesth Mtg.
Outcome studies - POC in OR
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%
»
Jobes, et.al. 1997, NACB Presentation, Phila.
Clinical Applications
Operating Room
– Cardiac Surgery
– Interventional Cardiology and Radiology
Procedures
Diagnostic
– Catheterization
» locate and map vessel blockage(s)
» determine need for interventional procedures
– Electrophysiology
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
– 10,000 unit bolus dose or
– 2 - 2.5 mg/kg
– target ACT 300 - 350 seconds
» unless platelet inhibitors used
 200
– 300 in presence of ReoPro
Why use platelet inhibitors?
Angioplasty promotes aggregation
Platelet Inhibitors
ReoPro
– elevates ACTs
– target time = 250 sec with ReoPro
» determined using FTCA510 tube
Integrelin
– No clinically significant effects on ACT
» Slight decrease in ACT observed
Aggrastat
– No reported effects on ACT
QUESTIONS?
Coagulation Testing
What is it?
Why do we need it POC?
PART 2
ITC Educational
Services, Edison, NJ
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
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
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.
What did it say?
 Mean
time to lab result = 112 min
– Mean time to POC result <5 min
 Fewer
dose adjustments needed in
POC group to reach therapeutic level
 Shorter time required to reach
therapeutic level in POC group
 Fewer dose changes in POC group
Activated Partial Thromboplastin Time
Extrinsic Pathway
Common Pathway
CLOT
Activated Partial Thromboplastin Time

NOT a PTT
–
–


Laboratory or Point of Care
High APTT values
–
–

PTT is the predecessor of the aPTT
Not used anymore
the presence of heparin
underlying coagulopathy
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
» prophylactic therapy for DVT: INR= 2.0 - 3.0
» artificial heart valve: INR=2.5 – 3.5
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
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
How to compare INR differences
 Has
the Hemostatic Balance been Upset?
 Is the Clinical Response Different?
6.0
Call Clinic
5.0
Must change dose
4.0
May change dose
3.0
Target INR 3.0
Range 2.5 -3.5
2.0
May change dose
Must change dose
Call Clinic
1.0
Patient Management
What’s the catch?
1.
2.
Regulatory compliance
Connectivity
Regulatory compliance
 Who
sets the rules?
– JCAHO
» Joint Commission on Accreditation of Health Care
Organizations
– CAP
» College of American Pathologists
– FDA
» Food and Drug Administration
– CMS (formerly HCFA)
» Centers for Medicare & Medicaid Services
– CDC
» Centers for Disease Control
CLIAC
CLIA Committee
– Define and interpret CLIA regulations
CLIA - Clinical Laboratory Improvement Act
– Designed to ensure accuracy of results from
clinical laboratories
– Compliance required to pass
» JCAHO and / or CAP inspections
– CLIA defines regulations for each test
» CDC / FDA / CMS / CDC complexity categories
CLIA Applies to ALL Testing Areas
Central
Laboratory
Satellite Labs
– Critical Care
– Surgical Suite
Clinics
Bedside
testing
Doctor’s office
Home Testing
CLIA Regulations for Coagulation
 Central
Laboratory can hold the CLIA license
– Satellites can have independent licensure
 Moderately
Complex tests
– Except - ProTime and Coaguchek / S are waived
 Requires
–
–
–
–
Certified Laboratory Director
Record Keeping
Training
Quality Policy
Implementing POC coag requires:
RECORD KEEPING
 Method
Validation - accuracy
– comparison to current standard
 Performance
Range Assessment
– “Linearity” often used
» Calibration/ verification NOT required for coag
– Is assay performance appropriate to clinical needs?
– Does dose responsiveness span clinical range?
 Training
– competency evaluations at predetermined intervals
Routine
Quality Control
– Instrument Performance Verification
» Electronic Quality Control with Numeric Output
 In
GA, make sure state approves specific EQC
» Two levels per 8 hour shift
– Assay Performance Verification
» Wet QC as per Manufacturer’s Recommendation
» Two levels for each box of reagent when opened
Connectivity
Everyone
wants it
– Almost no one is ready to implement
Multiple
definitions
– Download to computer
» To LIS or to HIS or to both or to data
management software
» Real time or batch
» QC data, patient data, or both
Short term solutions
 Interim
programs for configuration, data
capture, QC compliance tracking
– transfer to file format easily adaptable
» Requires independent transfer protocol
» e.g., ITC Configuration Manager, ReportMaker, HRDM
 Dedicated
interface specific to one
manufacturer’s instrumentation
» e.g., Abbott; Lifescan
» Manufacturer ensures system compatibility
 Instrument
manufacturer neutral interface
– RALS-plus
– Telcor
– Manufacturer works with interface supplier to
ensure compatibility
– Interface supplier works with LIS / HIS
supplier to ensure compatibility
Long term Solutions
 POC
Connectivity Industry Consortium
– Accepted as NCCLS document POCT1-A
– sections of the CIC specification approved by:
» IEEE
» HL7
– Standardization of POC connectivity:
» Messages
» Protocols
» Technologies
Why Bother with POC Coag?
 Improved TAT
- Turn Around Time
 Standardized Clinical Interpretation
– Defined Assay Sensitivity
» Requires Lot to Lot Reproducibility
– Defined Reagent Variability
» Identical Instrumentation /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
Why Bother with POC Coag?
Improved
Clinical Outcome
Reduced LOS – Length of Stay
Improved, timely patient care