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Coagulation Testing

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Title: Coagulation Testing


1
Coagulation Testing
  • What is it?
  • Why do we need it POC?

Marcia L. Zucker, Ph.D. Director of Clinical
Research
2
Coagulation Testing
  • Monitoring hemostasis

Bleeding
Clotting
3
Maintaining Hemostasis
Counterbalance thrombosis with anticoagulant
therapy
Thrombosis
4
Maintaining Hemostasis
Counterbalance bleeding by correcting defect
(i.e., neutralize heparin, transfuse blood
product)
Bleeding
5
Components of Hemostasis
Vessels
Coagulation Proteins
Platelets
Fibrinolysis / Inhibitors
6
Vascular System
Basement membrane
Endothelial cells
Red blood cells Platelets
White blood cells
7
Components of Hemostasis
Vessels
Coagulation Proteins
Platelets
Fibrinolysis / Inhibitors
8
Anatomy of a Platelet
9
Resting Platelets
10
Platelet Aggregate
11
Hemostasis
  • Primary hemostasis
  • Platelet Adhesion
  • Secondary hemostasis
  • Coagulation
  • Fibrin clot formation

12
(No Transcript)
13
Platelet Function
  • Platelet Adhesion
  • shape change
  • release

3 sec 10 sec 5 min
ADP release
Platelet Aggregation
  • Coagulation
  • Fibrin formation

14
Platelet Testing
  • Peripheral smear
  • Platelet count
  • Platelet aggregation
  • Bleeding time

15
Peripheral Blood Smear
16
Platelet Aggregation

Aggregate Clumping
Platelet Rich Plasma (PRP)
Aggregating Agent
Baseline Light Transmission
Increased Light Transmission
17
Bleeding Time
  • Cut 1 mm deep, 5 mm long
  • Constant pressure
  • Expected Range 2 - 10 minutes

18
Components of Hemostasis
Vessels
Coagulation Proteins
Platelets
Fibrinolysis / Inhibitors
19
Coagulation
Inactive enzyme
Active enzyme
Inactive enzyme
Active enzyme
20
Coagulation is Complex
21
Coagulation Testing
22
Common(?) Coagulation Tests
  • Laboratory
  • PT..
  • aPTT
  • TT..
  • Fib.
  • Anti Xa
  • Anti IIa
  • Factor Assays
  • Point of Care
  • ACT
  • Celite
  • Kaolin
  • Glass beads
  • Silica
  • thromboplastin

23
Differences 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

24
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

25
POC Coag Analyzers Differ
  • Test methodology
  • Sample size and application
  • Sample measurement
  • Clot detection method
  • Enzyme detection method
  • Reagent composition
  • Results

26
Semi - Automation - 1969
  • HEMOCHRONOMETER (HEMOCHRON)
  • Magnet in tube, detector in instrument
  • Upon clot formation, magnet is deflected
  • Clotting time displayed

27
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

28
1980s
  • 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

29
Medtronics test menu
  • ACT (kaolin)
  • Empty cartridge for aPTT
  • PT (look up conversion)
  • Heparinase ACT
  • HMS Dosing Assays
  • HDR, HPT

30
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

31
Test 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

32
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)

33
Newer Technologies
  • Active pumping system
  • Hemochron Jr Signature
  • ProTime microcoagulation system

34
Test 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

35
Activated Clotting Time
Extrinsic Pathway
Intrinsic Pathway
ACT
Common Pathway
CLOT
36
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

37
Why are there so many different ACTs?
38
Monitoring - ACT
  • Benefits
  • Industry Standard Since 1970s
  • Recommended as primary method in AmSECT
    guidelines (perfusion)
  • Easy to run

39
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

40
Clinical Applications
  • Operating Room
  • Cardiac Surgery
  • Interventional Cardiology and Radiology
  • Critical Care
  • Satellite Sites
  • Dialysis
  • ECMO
  • Emergency Room

41
Heparinized ACT - CPB
Data from Huffman, et.al. 1998 AmSECT meeting
42
Monitoring in CPB - ACT
  • Data from clinical evaluation, on file, ITC

43
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

44
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

45
ACT 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

46
ACT Monitoring -Aprotinin Treatment
Data from clinical evaluation, on file, ITC
47
Non-ACT Monitoring - Aprotinin
  • HiTT - High Dose Thrombin Time

Adapted from Huyzen, et. al. J.CardioThorac.
Vasc. Anesth. 8153, 1994
48
Alternative Monitoring - Aprotinin
  • Adapted from Huyzen, et. al. J.CardioThorac.Vasc.A
    nesth. 8153, 1994

49
Thrombin Time
Extrinsic Pathway
Intrinsic Pathway
Common Pathway
TT
CLOT
50
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

51
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

52
Monitoring - Heparin Level
  • Young lt4.5 years
  • Shayevitz, JR and OKelly, SW Progress in
    Anesthesiology, vol. IX, chapter 16 1995

53
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

54
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

55
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.

56
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.

57
Clinical Applications
  • Operating Room
  • Cardiac Surgery
  • Interventional Cardiology and Radiology

58
Procedures
  • Diagnostic
  • Catheterization
  • locate and map vessel blockage(s)
  • determine need for interventional procedures
  • Electrophysiology
  • Interventional
  • Balloon angioplasty
  • Atherectomy (roto-rooter)

59
Diagnostic Low dose heparin
  • Catheterization and Electrophysiology
  • 2500 - 5000 unit bolus dose
  • frequently not monitored
  • if monitored
  • ACT
  • aPTT

60
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

61
Why use platelet inhibitors?
62
Angioplasty promotes aggregation
63
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64
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

65
QUESTIONS?
66
Coagulation Testing
  • What is it?
  • Why do we need it POC?

PART 2
67
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

68
STAT Testing TAT
  • Fitch, et.al, J. Clin Monit Comput. 1999.
    15197-204

69
Clinical Applications
  • Operating Room
  • Cardiac Surgery
  • Interventional Cardiology and Radiology
  • Critical Care
  • Satellite Sites
  • Dialysis
  • ECMO
  • Emergency Room
  • Anticoagulation Clinic

70
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

71
ACT 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.

72
What 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

73
Activated Partial Thromboplastin Time
Extrinsic Pathway
Intrinsic Pathway
APTT
Common Pathway
CLOT
74
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
  • the presence of heparin
  • underlying coagulopathy
  • Monitor heparin / coumadin cross-over

75
Heparin versus Warfarin
76
Prothrombin Time
Extrinsic Pathway
Intrinsic Pathway
PT
Common Pathway
CLOT
77
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 INR2.5 3.5

78
Will POC Results Match the Lab?
NO!
  • (Probably Not)
  • but it WILL Correlate

79
Correlate Does Not Mean Match
80
Coag is NOT Chemistry
81
Compare for your site. Same System / Multiple
Sites
82
Are differences important?
  • Sometimes no - aPTT C

83
  • Sometimes VERY - aPTT SP

84
Lot to Lot Reproducibility
85
Clinical Applications
  • Operating Room
  • Cardiac Surgery
  • Interventional Cardiology and Radiology
  • Critical Care
  • Satellite Sites
  • Dialysis
  • ECMO
  • Emergency Room
  • Anticoagulation Clinic

86
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 3589-94 2000

87
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

88
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

89
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

90
How to compare INR differences
  • Has the Hemostatic Balance been Upset?
  • Is the Clinical Response Different?

91
(No Transcript)
92
Whats the catch?
  1. Regulatory compliance
  2. Connectivity

93
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

94
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

95
CLIA Applies to ALL Testing Areas
  • Central Laboratory
  • Satellite Labs
  • Critical Care
  • Surgical Suite
  • Clinics
  • Bedside testing
  • Doctors office
  • Home Testing

96
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

97
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

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

99
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

100
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
    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

102
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

103
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

104
Why Bother with POC Coag?
  • Improved Clinical Outcome
  • Reduced LOS Length of Stay
  • Improved, timely patient care
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