1. 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

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 Secondary hemostasis Platelet Adhesion
Coagulation
Fibrin clot formation

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 : minutes

18. Components of Hemostasis
Vessels
Coagulation Proteins
Platelets
Fibrinolysis / Inhibitors

19. Coagulation Inactive enzyme Active enzyme Inactive enzyme

20. Coagulation is Complex

21. Coagulation Testing Heparin Coumadin Thrombolytics Monitor with
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT / aPTT
Monitor with PT
Thrombolytics
TT / Fibrinogen

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
Standard Laboratory
Platelet Poor Plasma
Sodium Citrate Anticoagulant
1:9 Dilution
Variable Preanalytical Delay
Point of Care
Whole Blood
Usually No Added Anticoagulant
No Dilution
No 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 aPTT and PT Thrombin time based assays
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. 1980’s HemoTec (later ACTII) Medtronics HMS uses same technology
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 CoaguChek / S Bayer RapidPoint ACT PT (FWB)
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
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 HEMOCHRON Jr Signature PT only CLIA waived ACT
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

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

36. What do we use an ACT for? Maintain Balance Heparin
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 AmSECT meeting 17

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; x 106 KIU/hr infusion
Half Hammersmith
1 x 106 KIU loading dose; 1 x 106 KIU pump prime; x 106 KIU/hr infusion

45. 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

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. 8:153, 1994

48. Alternative Monitoring - Aprotinin
Adapted from Huyzen, et. al. J.CardioThorac.Vasc.Anesth. 8:153, 1994

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

50. Other POC in the OR Heparin Level Xa Activity Medtronic Hepcon HMS
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

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: <4.5 years
Shayevitz, JR and O’Kelly, SW Progress in Anesthesiology, vol. IX, chapter

53. Other POC Coag in the OR aPTT / PT Fibrinogen Dosing Assays
Pre- and post-procedural screening
Fibrinogen
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., J.Thorac.Cardiovasc.Surg.
Reduced Cost
Resulting from POC Assays
RxDx combined with TT / HNTT
Jobes, D. et. al., 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 Interventional Catheterization Electrophysiology
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
unit bolus dose
frequently not monitored
if monitored –
ACT
aPTT

60. Interventional – Moderate dose
Angioplasty and Atherectomy
10,000 unit bolus dose or
mg/kg
target ACT seconds
unless platelet inhibitors used
200 – 300 in presence of ReoPro

61. Why use platelet inhibitors?

62. Angioplasty promotes aggregation

64. Platelet Inhibitors ReoPro Integrelin Aggrastat 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. What is it? Why do we need it POC?
Coagulation Testing
What is it?
Why do we need it POC?
PART 2
ITC Educational Services, Edison, NJ

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 :

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 <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.

72. 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

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 PT Intrinsic Pathway Extrinsic Pathway 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=
artificial heart valve: INR=2.5 – 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 35:89-94; 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 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. Patient Management 6.0 5.0 4.0 3.0 2.0 1.0 Target INR 3.0
Must change dose
Target INR 3.0
Range
Call Clinic
May change dose
Patient Management

92. What’s the catch?
Regulatory compliance
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 CLIA - Clinical Laboratory Improvement Act
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
Doctor’s 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 Manufacturer’s Recommendation
Two levels for each box of reagent when opened

99. Connectivity Everyone wants it Multiple definitions
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 manufacturer’s 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