Coagulation Testing What is it? Why do we need it POC? ITC Educational Services, Edison, NJ Marcia...
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Transcript of Coagulation Testing What is it? Why do we need it POC? ITC Educational Services, Edison, NJ Marcia...
Coagulation TestingWhat is it?
Why do we need it POC?
ITC Educational Services, Edison, NJ
Marcia L. Zucker, Ph.D.Director of Clinical Research
Coagulation Testing
Monitoring hemostasis
Bleeding Clotting
Coagulation Testing Monitoring therapy
Intrinsic PathwayExtrinsic Pathway
Common Pathway
CLOT
Heparin CoumadinMonitor with
ACT / aPTT Monitor with PT
Thrombolytics Monitor with
TT / Fibrinogen
Coagulation is ComplexPlatelet Adhesion
•shape change • release
ADP release
PlateletAggregation
Coagulation
•Fibrin formation
3 sec
10 sec
5 min
Coagulation is Complex
Common(?) Coagulation Tests Laboratory
PT..
aPTT
TT..
Fib.– Anti Xa– Anti IIa– Factor Assays
Point of Care
– ACT» Celite®
» Kaolin» Glass beads» Silica» thromboplastin
Differences in test methods
Point of Care– Whole Blood
– No Added Anticoagulant
– No Dilution
– No Preanalytical Delay
Standard Laboratory– Platelet Poor Plasma
– Sodium Citrate Anticoagulant
– 1:9 Dilution
– Variable Preanalytical Delay
POC Coagulation Analyzers HEMOCHRON 401 / 801 / Response HEMOCHRON Jr. Signature ProTime Medtronic HMS / HemoTec ACT II CoaguChek / CoaguChek Pro DM Bayer RapidPoint i-STAT Others
POC Coag Analyzers Differ
Test methodology– Sample size and application
– Sample measurement
– Clot detection method» Enzyme detection method
– Reagent composition
– Results
Clinical ApplicationsOperating Room
– Cardiac Surgery– Interventional Cardiology and Radiology
Critical Care Satellite Sites
– Dialysis– ECMO– Emergency Room– Anticoagulation Clinic
Activated Clotting Time
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
ACT
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?
0
100
200
300
400
500
600
700
0 1 2 3 4 5
Heparin (units/ml)
Clo
ttin
g T
ime
(sec
)
C-ACT
K-ACT
ACT+
P214
ACT-LR
CCUDialysis
CATHPTCA CPB
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
475
500
525
550
575
600
625
650
675
700
PreCPB
15min
30min
45min
60min
75min
90min
105min
Seco
nds
Hemochron
Hemotec
TAS
HMS
Heparinized ACT - CPB
Data from Huffman, et.al. 1998 AmSECT meeting
Monitoring in CPB - ACT
Data from clinical evaluation, on file, ITC
0
100
200
300
400
500
600
700
800
900
1000
Clo
ttin
g T
ime
Kaolin ACT
Celite ACT
ACT+
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
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
– 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
0
200
400
600
800
1000
1200
Baseline PostBolus PostBolus2 OnPump OnPump2 OnPump3 PostProt.
Clo
ttin
g T
ime
.
Kaolin ACT
Celite ACT
ACT+
Data from clinical evaluation, on file, ITC
Alternative Monitoring - Aprotinin HiTT - High Dose Thrombin Time
Control Patients
0
200
400
600
800
1000
Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine
Clot
ting
Tim
e
Celite
Kaolin
HiTT
Aprotinin Patients
0
200
400
600
800
1000
Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine
Clot
ting
Tim
e
Celite
Kaolin
HiTT
Adapted from Huyzen, et. al. J.CardioThorac. Vasc. Anesth. 8:153, 1994
Alternative Monitoring - Aprotinin
Kaolin ACT
0
200
400
600
800
1000
Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine
Clot
ting
Tim
e
Aprotinin
Placebo
HiTT
0
50
100
150
200
250
Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine
Clot
ting T
ime
Aprotinin
Placebo
Adapted from Huyzen, et. al. J.CardioThorac.Vasc.Anesth. 8:153, 1994
Thrombin Time
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOTTT
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» RapidPoint
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 ApplicationsOperating 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
– Balloon angioplasty
– Arthrectomy (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 Arthrectomy– 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 reported effects on ACT
Aggrastat– No reported effects on ACT
Clinical ApplicationsOperating 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
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
APTT
NOT a PTT– PTT is the predecessor of the aPTT– Not used anymore
Laboratory or Point of Care High APTT values
1. the presence of heparin
2. underlying coagulopathy Monitor heparin / coumadin® cross-over
Activated Partial Thromboplastin Time
Heparin versus Warfarin
Drug ActionMechan-
ismMoni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
Prothrombin Time
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
PT
Prothrombin Time Monitor warfarin therapy Monitor heparin/warfarin crossover Target times are set by
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=3.0 - 4.0
ISI
meannormal
patient
PT
PTINR
Will POC Results Match the Lab?
(Probably Not)
but it WILL Correlate
Correlate Does Not Mean Match
y = 0.737x + 22.2R = 0.920
0
20
40
60
80
100
120
140
0 50 100 150Lab APTT
Sig
na
ture
AP
TT
Coag is NOT Chemistry
y = 0.4493x + 17.898y = 0.4723x + 20.24y = 0.4374x + 22.173
IL C
Dade Actin / MLA
y = 0.72x + 11.5R = 0.883
20
30
40
50
60
70
20 30 40 50 60 70lab
Sig
na
ture
IL aPTT SP / ACL #2
y = 0.59x + 16.0R = 0.961
10.0
30.050.0
70.090.0
110.0130.0
150.0
10 30 50 70 90 110 130 150lab
Sig
na
ture
IL aPTT C / ACL #3y = 0.44x + 22.2
R = 0.9533
10.0
30.050.0
70.090.0
110.0130.0
150.0
10 30 50 70 90 110 130 150lab
Sig
na
ture
Organon Technika / MDA
y = 1.02x + 4.1R = 0.942
20
30
40
50
60
70
20 30 40 50 60 70lab
Sig
na
ture
y = 0.4493x + 17.898y = 0.4723x + 20.24y = 0.4374x + 22.173
IL C
IL SP
IL aPTT C /ACL #1
y = 0.45x + 17.9R = 0.929
0.0
20.0
40.0
60.0
80.0
100.0
0 50 100 150lab
Sig
na
ture
IL aPTT SP / ACL #1
y = 0.35x + 22.1R = 0.928
0.0
20.0
40.0
60.0
80.0
100.0
0 50 100 150lab
Sig
na
ture
IL aPTT C / ACL #2
y = 0.47x + 20.2R = 0.942
0.0
20.0
40.0
60.0
80.0
100.0
0 50 100 150lab
Sig
na
ture
IL aPTT SP / ACL #3
y = 0.40x + 23.3R = 0.912
0.0
20.0
40.0
60.0
80.0
100.0
0 50 100 150lab
Sig
na
ture
IL aPTT C / ACL #3
y = 0.44x + 22.2R = 0.953
0.0
20.0
40.0
60.0
80.0
100.0
0 50 100 150lab
Sig
na
ture
IL aPTT SP / ACL #2
y = 0.59x + 16.0R = 0.961
0.0
20.0
40.0
60.0
80.0
100.0
0 50 100 150lab
Sig
na
ture
Compare for your site.
Same System / Multiple Sites
Are differences important?
Sometimes no - aPTT C
Signature site 1 site 2 site 330 27 21 1840 49 42 4150 71 63 6460 94 84 8770 116 105 10980 138 127 13290 160 148 155
Sometimes VERY - aPTT SPSignature site 1 site 2 site 3
30 23 24 3340 51 41 8250 80 57 13060 109 74 17970 138 91 >20080 167 108 >20090 196 125 >200
Lot to Lot ReproducibilitySignature
30405060708090
Cuvette Lot a
y = 1.35x - 14.2R=.909
20
30
40
50
60
70
80
20 40 60 80Signature
La
b
Cuvette Lot b
y = 1.39x - 12.8R=0.934
20
30
40
50
60
70
80
20 40 60 80Signature
La
b
Signature Lot a Lot b30 26 2940 40 4350 53 5760 67 7070 80 8480 93 9890 107 112
Clinical ApplicationsOperating 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
5.0
4.0
3.0
2.0
1.0
Must change dose
Target INR 3.0Range 2.5 -3.5
Must change dose
Call Clinic
May change dose
May change dose
Call Clinic
Patient Management
What’s the catch?
1. Regulatory compliance
2. 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
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 complexity categories
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 and Coaguchek are waived Requires
– Certified Laboratory Director– Record Keeping– Training– Quality Policy
Implementing POC coag requires:RECORD KEEPING
Method Validation - accuracy– comparison to current standard
Linearity Assessment – Also used for ACT “calibration/ verification”– Is assay performance appropriate to clinical needs? – Does linear range span clinical range?
Training – competency evaluations at predetermined intervals
Routine Quality Control– Instrument Performance Verification
» Electronic Quality Control with Numeric Output » 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 data capture, QC compliance tracking– transfer to file format easily adaptable
» Requires independent transfer protocol
» e.g., ITC ReportMaker
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
Telcor concept
Quick Serv (DM)
LIS/HIS
Quick Script or Quick EDI
Quick Linc
ITC Dawning box
Data translation
Via hospital Ethernet
OR
Cath lab
CCU
Quick-Multi-Linc (QML)
Blood Gas
Co-ox
Coagulation
Glucose
Chemistry
I M P O R T
Snapshot
Exception Management
Quality Control
Operator Management
Device Management
Statistics
Manual Result Entry
Configuration
Result Management
Windows 2000 SP1 Workstation
Data Management Configuration
Output Management
Quick-Script
Quick-EDI
or
Interface Management
LIS / HIS Host
System
POC
Vend
or’s
Dat
a
Com
mun
icat
ion
& Se
t-U
p
Output
Cardiac Marker
Urinalysis
Terminal Emulation
Host EDI
RALS plus concept
LIS
Results that meet user-defined criteria are transferred to the LIS for placement
on the patient’s permanent medical record
HIS
RALS-ADT gathers demographic data to enable patient verification
Test results are transferred from a RALS-Plus Test Station to the RALS-Plus Core System (RCS)
Glucose
ICU
RALS Dataport
TM
MAS
RALS DATA PO RT®
Coagulation
ERRALS Plus Test
Station
Glucose
Urinalysis
9 WestRALS Remote
ConnectHospital Client PC
POCC’s can view, analyze, or edit results using the RALS-Plus IMS (Information Management System)
RALS-IMS
RALS-Core System (RCS)Located in the Hospital Data Center
Coagulation Coagulation
Glucose
Blood Gas
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
– 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) Median
CPB (N=40)90.0
PVS (N=45)90.0
Mean 78.5 74.0Minimum 38.0 21.0
POC (min)Median
All Groups2.23
Minimum 0.33Maximum 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
Why Bother with POC Coag?
Improved Clinical Outcome Reduced LOS – Length of Stay Improved, timely patient care