Title: Coagulation Testing
1Coagulation Testing
- What is it?
- Why do we need it POC?
Marcia L. Zucker, Ph.D. Director of Clinical
Research
2Coagulation Testing
Bleeding
Clotting
3Maintaining Hemostasis
Counterbalance thrombosis with anticoagulant
therapy
Thrombosis
4Maintaining Hemostasis
Counterbalance bleeding by correcting defect
(i.e., neutralize heparin, transfuse blood
product)
Bleeding
5Components of Hemostasis
Vessels
Coagulation Proteins
Platelets
Fibrinolysis / Inhibitors
6Vascular System
Basement membrane
Endothelial cells
Red blood cells Platelets
White blood cells
7Components of Hemostasis
Vessels
Coagulation Proteins
Platelets
Fibrinolysis / Inhibitors
8Anatomy of a Platelet
9Resting Platelets
10Platelet Aggregate
11Hemostasis
- Primary hemostasis
- Platelet Adhesion
- Secondary hemostasis
- Coagulation
- Fibrin clot formation
12(No Transcript)
13Platelet Function
- Platelet Adhesion
- shape change
- release
3 sec 10 sec 5 min
ADP release
Platelet Aggregation
- Coagulation
- Fibrin formation
14Platelet Testing
- Peripheral smear
- Platelet count
- Platelet aggregation
- Bleeding time
15Peripheral Blood Smear
16Platelet Aggregation
Aggregate Clumping
Platelet Rich Plasma (PRP)
Aggregating Agent
Baseline Light Transmission
Increased Light Transmission
17Bleeding Time
- Cut 1 mm deep, 5 mm long
- Constant pressure
- Expected Range 2 - 10 minutes
18Components of Hemostasis
Vessels
Coagulation Proteins
Platelets
Fibrinolysis / Inhibitors
19Coagulation
Inactive enzyme
Active enzyme
Inactive enzyme
Active enzyme
20Coagulation is Complex
21Coagulation Testing
22Common(?) Coagulation Tests
- Laboratory
- PT..
- aPTT
- TT..
- Fib.
- Anti Xa
- Anti IIa
- Factor Assays
- Point of Care
- ACT
- Celite
- Kaolin
- Glass beads
- Silica
- thromboplastin
23Differences in test methods
- Point of Care
- Whole Blood
- Usually No Added Anticoagulant
- No Dilution
- No Preanalytical Delay
- Standard Laboratory
- Platelet Poor Plasma
- Sodium Citrate Anticoagulant
- 19 Dilution
- Variable Preanalytical Delay
24POC 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
25POC Coag Analyzers Differ
- Test methodology
- Sample size and application
- Sample measurement
- Clot detection method
- Enzyme detection method
- Reagent composition
- Results
26Semi - Automation - 1969
- HEMOCHRONOMETER (HEMOCHRON)
- Magnet in tube, detector in instrument
- Upon clot formation, magnet is deflected
- Clotting time displayed
27HEMOCHRON 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
281980s
- 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
29Medtronics test menu
- ACT (kaolin)
- Empty cartridge for aPTT
- PT (look up conversion)
- Heparinase ACT
- HMS Dosing Assays
- HDR, HPT
30Newer 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
31Test Menu
- CoaguChek ProDM
- ACT
- Tissue factor activated
- PT (FWB)
- aPTT (FWB)
- CoaguChek / S
- Detection as per RapidPoint
- PT only
- CLIA waived
- Bayer 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
32Newer 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)
33Newer Technologies
- Active pumping system
- Hemochron Jr Signature
- ProTime microcoagulation system
34Test Menu
- ProTime
- PT only
- CLIA waived
- Home use approved
- Integral Controls
- Meet CLIA and CAP requirement for daily QC testing
- HEMOCHRON Jr Signature
- ACT
- ACT, ACT-LR
- PT
- Fresh or citrated WB
- aPTT
- Fresh or citrated WB
35Activated Clotting Time
Extrinsic Pathway
Intrinsic Pathway
ACT
Common Pathway
CLOT
36What 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
37Why are there so many different ACTs?
38Monitoring - ACT
- Benefits
- Industry Standard Since 1970s
- Recommended as primary method in AmSECT
guidelines (perfusion) - Easy to run
39Monitoring - 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
40Clinical Applications
- Operating Room
- Cardiac Surgery
- Interventional Cardiology and Radiology
- Critical Care
- Satellite Sites
- Dialysis
- ECMO
- Emergency Room
41Heparinized ACT - CPB
Data from Huffman, et.al. 1998 AmSECT meeting
42Monitoring in CPB - ACT
- Data from clinical evaluation, on file, ITC
43Pharmaceutical 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
44Pharmaceutical 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
45ACT Monitoring-Aprotinin Treatment
- Celite ACT
- Not recommended
- Still used with target times of gt750 seconds
- Kaolin ACT
- Unaffected by moderate doses of aprotinin
- Used with target times of gt 480 seconds
- ACT
- Unaffected by ALL doses of aprotinin
- Used with target times of gt 400 seconds
46ACT Monitoring -Aprotinin Treatment
Data from clinical evaluation, on file, ITC
47Non-ACT Monitoring - Aprotinin
- HiTT - High Dose Thrombin Time
Adapted from Huyzen, et. al. J.CardioThorac.
Vasc. Anesth. 8153, 1994
48Alternative Monitoring - Aprotinin
- Adapted from Huyzen, et. al. J.CardioThorac.Vasc.A
nesth. 8153, 1994
49Thrombin Time
Extrinsic Pathway
Intrinsic Pathway
Common Pathway
TT
CLOT
50Other 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
51Monitoring - 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
52Monitoring - Heparin Level
- Young lt4.5 years
- Shayevitz, JR and OKelly, SW Progress in
Anesthesiology, vol. IX, chapter 16 1995
53Other 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
54Other 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
55Outcome 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.
56Outcome 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.
57Clinical Applications
- Operating Room
- Cardiac Surgery
- Interventional Cardiology and Radiology
58Procedures
- Diagnostic
- Catheterization
- locate and map vessel blockage(s)
- determine need for interventional procedures
- Electrophysiology
- Interventional
- Balloon angioplasty
- Atherectomy (roto-rooter)
59Diagnostic Low dose heparin
- Catheterization and Electrophysiology
- 2500 - 5000 unit bolus dose
- frequently not monitored
- if monitored
- ACT
- aPTT
60Interventional 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
61Why use platelet inhibitors?
62Angioplasty promotes aggregation
63(No Transcript)
64Platelet 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
65QUESTIONS?
66Coagulation Testing
- What is it?
- Why do we need it POC?
PART 2
67Why 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
68STAT Testing TAT
- Fitch, et.al, J. Clin Monit Comput. 1999.
15197-204
69Clinical Applications
- Operating Room
- Cardiac Surgery
- Interventional Cardiology and Radiology
- Critical Care
- Satellite Sites
- Dialysis
- ECMO
- Emergency Room
- Anticoagulation Clinic
70ACT 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
71ACT or aPTT
- Monitor heparin therapy
- Target times determined by each facility
- APTT outcome study
- Reduce time to result (112 vs lt5 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.
72What did it say?
- Mean time to lab result 112 min
- Mean time to POC result lt5 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
73Activated Partial Thromboplastin Time
Extrinsic Pathway
Intrinsic Pathway
APTT
Common Pathway
CLOT
74Activated Partial Thromboplastin Time
- NOT a PTT
- PTT is the predecessor of the aPTT
- Not used anymore
- Laboratory or Point of Care
- High APTT values
- the presence of heparin
- underlying coagulopathy
- Monitor heparin / coumadin cross-over
75Heparin versus Warfarin
76Prothrombin Time
Extrinsic Pathway
Intrinsic Pathway
PT
Common Pathway
CLOT
77Prothrombin 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 INR2.5 3.5
78Will POC Results Match the Lab?
NO!
- (Probably Not)
- but it WILL Correlate
79Correlate Does Not Mean Match
80Coag is NOT Chemistry
81Compare for your site. Same System / Multiple
Sites
82Are differences important?
83 84Lot to Lot Reproducibility
85Clinical Applications
- Operating Room
- Cardiac Surgery
- Interventional Cardiology and Radiology
- Critical Care
- Satellite Sites
- Dialysis
- ECMO
- Emergency Room
- Anticoagulation Clinic
86Dialysis / 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 3589-94 2000
87Emergency 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
88Anticoagulation 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
89Anticoagulation 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
90How to compare INR differences
- Has the Hemostatic Balance been Upset?
- Is the Clinical Response Different?
91(No Transcript)
92Whats the catch?
- Regulatory compliance
- Connectivity
93Regulatory 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
94CLIAC
- 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
95CLIA Applies to ALL Testing Areas
- Central Laboratory
- Satellite Labs
- Critical Care
- Surgical Suite
- Clinics
- Bedside testing
- Doctors office
- Home Testing
96CLIA 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
97Implementing 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
98- 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 Manufacturers Recommendation
- Two levels for each box of reagent when opened
99Connectivity
- 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
100Short 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
manufacturers instrumentation - e.g., Abbott Lifescan
- Manufacturer ensures system compatibility
101- 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
102Long 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
103Why 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
104Why Bother with POC Coag?
- Improved Clinical Outcome
- Reduced LOS Length of Stay
- Improved, timely patient care