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
Educational Services, Edison, NJ

2. Coagulation Testing
Monitoring hemostasis
Bleeding Clotting

3. Anticoagulants Monitor with PT Extrinsic Pathway
Monitor with aPTT or ACT
Intrinsic Pathway
HEPARIN
WARFARIN
DXaI
X Xa
LMWH
Common Pathway
II IIa (thrombin)
Monitor with ?????
Hirudin & DTI
CLOT

4. Coagulation is Complex
Picture from DiaPharma.com

5. Common(?) Coagulation Tests
Laboratory
PT..
aPTT
TT..
Fib.
Anti Xa
Anti IIa
Factor Assays
Point of Care
ACT
Celite®
Kaolin
Glass beads
Silica
thromboplastin

6. Differences in test methods
Standard Laboratory
Platelet Poor Plasma
Sodium Citrate Anticoagulant
1:9 Dilution
Variable Preanalytical Delay
Point of Care
Whole Blood
No Added Anticoagulant
No Dilution
No Preanalytical Delay

7. POC Coagulation Analyzers
HEMOCHRON 401 / 801 / Response
HEMOCHRON Jr. Signature / Signature +
ProTime / 3
Medtronic HMS/HMS+/ HemoTec ACT II / ACTPlus
CoaguChek / S / Pro / Pro DM
i-STAT
Helena Actalyke
Hemosense INRatio
Others?

8. POC Coag Analyzers Differ
Test methodology
Sample size and application
Microliters to milliliters
Sample measurement
Manual vs automated
Clot detection method
Enzyme detection method
Thrombin generation
Reagent composition
Results

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

10. History of the ACT Lee-White clotting time
Manual
No activator
Very slow
1966 –Hattersley- Activated Clotting Time
Diatomaceous earth activator
Operator defined mixing and clot detection
Global assay - Contact activation of cascade

11. Activated Clotting Time

12. Particulate Contact Activation
Initiation of intrinsic coagulation cascade
Factor XII (Hageman factor)
Prekallikrein (Fletcher factor)
Dramatically shortens contact activation period over Lee-White time
Proposed as both screening assay for coagulation defects and for heparin monitoring

13. ACT Automation - 1969 HEMOCHRON introduced semi-automated
less operator dependence
two assays
CA510 (later FTCA510)
diatomaceous earth activated
P214 glass bead activated

14. 2 assays for separate applications

15. 1980’s HemoTec ACT Liquid kaolin activator Different technology
Different results

16. ACT Differences Recognized in literature >20 years
Clinical evaluations of Hemochron appeared in journals mid 1970’s
By 1981, papers appeared showing little correlation between ACT and heparin level
By 1988, papers clearly showed clinically different results between Hemochron and HemoTec
Differences ignored by clinicians

17. Why are there so many different ACTs?

18. Monitoring - ACT Benefits Disadvantages Industry Standard Since 1970s
Recommended as primary method in AmSECT guidelines (perfusion)
Easy to run
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

19. Heparinized ACT - CPB
Data from Huffman, et.al AmSECT meeting 17

20. Pharmaceutical Intervention
Amicar or Tranexamic Acid
No effect on standard celite ACT
Aprotinin
Significant elevation of celite ACT
Two dosing regimens
Full or Half Hammersmith
Both independent of patient size

21. 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

22. Monitoring in CPB - Aprotinin
Data from clinical evaluation, on file, ITC

23. 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
Measure heparin level
Relationship to coagulation status unclear

24. 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

25. Outcome studies - POC in OR
Reduced Blood Loss/Transfusion
Use of HRT and PRT (RxDx System)
Reduced Cost Resulting from Use of POC Assays
RxDx combined with TT / HNTT
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.

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

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

28. Diagnostic – Low dose heparin
Catheterization and Electrophysiology
unit bolus dose
frequently not monitored
if monitored –
ACT
aPTT

29. Interventional – Moderate dose
Angioplasty and Atherectomy
Heparin
10,000 unit bolus dose or
mg/kg
target ACT seconds
200 – 300 in presence of ReoPro
Angiomax (bivalirudin)
ACT >300
Hemochron (ACT-LR or FTCA510) trials
Measure post-bolus to ensure drug on board
Required in patients with renal impairment

30. Why use platelet inhibitors?
Angioplasty promotes aggregation
Adhesion
shape change
release
ADP release
Aggregation
Coagulation
Fibrin formation
3 sec
10 sec
5 min

31. Need to inhibit restenosis / reocclusion

32. Platelet Inhibitors ReoPro Integrelin Aggrastat elevates ACTs
target time = 250 sec with ReoPro
determined using FTCA510 tube
Integrelin
No reported clinically significant effects on ACT
Aggrastat
No reported effects on ACT

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

34. 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
Must be linked to heparin sensitivity of reagent used

35. ACT vs aPTT
Single site comparison, ACT tube vs HE Jr Sig aPTT

36. 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.

37. Activated Partial Thromboplastin Time
Extrinsic Pathway
Intrinsic Pathway
APTT
Common Pathway
CLOT

38. 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
presence of heparin
treat by giving protamine
underlying coagulopathy
treat by giving FFP
Monitor heparin / Coumadin® cross-over

39. Heparin versus Warfarin

40. Prothrombin Time PT Intrinsic Pathway Extrinsic Pathway Common Pathway
CLOT

41. 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
DVT, Afib, Atrial MHV: INR=
Mitral mechanical heart valve: INR= 2.5 – 3.5
Hypercoagulable disorders: INR= 1.5 – 2.5?

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

43. Correlate Does Not Mean Match

44. Coag is NOT Chemistry

45. Compare for your site.
Same System / Multiple Sites

46. Are differences important?
Sometimes no - aPTT C

47. Sometimes VERY - aPTT SP

48. Lot to Lot Reproducibility

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

50. Dialysis / ECMO ACT (or nothing in dialysis)
Majority use P214 glass activated ACT
Some use ACT-LR; HemoTec LR ACT
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

51. 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

52. 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

53. 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

54. Will POC Results Match the Lab?
NOT Necessarily
(It will be a lot closer than for aPTT)
but it WILL Correlate

55. How to Compare INR Results
Lower dose?
Keep same dose?
Raise Dose?
Test Again?
Test more often?

56. Lab to Lab Comparison
Mean difference = 0.3 INR

57. (values shown are ranges)
INR Expectations
INR within 0.4 of lab > 80%
INR within 0.7 of lab > 90%
INR within 1.0 of lab > 95%
(values shown are ranges)
AACC 2002
Pairs within 0.4 INR
Pairs within 0.7 INR
Lab to Lab
85.4 – 97.9 %
94.8 – 99.0 %
POC to Lab
74.7 – 89.9 %
87.9 – 99.0 %
POC to POC
89.9 – 94.9 %
97.0 – 99.5 %

58. 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

59. STAT Testing TAT
Fitch, et.al, J. Clin Monit & Comput :

60. 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
NEED TWO COPIES OF THIS SLIDE

61. What’s the catch?
Regulatory compliance
Connectivity

62. Regulatory compliance - Who sets the rules?
JCAHO
Joint Commission on Accreditation of Health Care Orgs
CAP
College of American Pathologists
FDA
Food and Drug Administration
CDRH
Center for Devices and Radiological Health
CMS
Centers for Medicare and Medicaid Services
CDC
Centers for Disease Control

63. CLIA Applies to ALL Testing Areas
Central Laboratory
Satellite Labs
Critical Care
Surgical Suite
Clinics
Bedside testing
Doctor’s office

64. CLIA Regulations for Coagulation
Central Laboratory can hold the CLIA license
Satellites can have independent licensure
Moderately Complex tests
Except – ProTime, Coaguchek, INRatio are waived
Requires
Certified Laboratory Director
Record Keeping
Training
Quality Policy

65. Implementing POC coag requires:
Method Validation - accuracy
Comparison to current standard
NCCLS Guideline EP-09 recommends 40 samples
Linearity may be used if no current standard
Is assay performance appropriate to clinical needs?
Precision
Controls may be used to establish within and between run variability
Training
Document training of all personnel
high school equivalence or higher education level
competency evaluations at predetermined intervals

66. Implementing POC coag requires:
Linearity NOT required for coag
Calibration “does not apply to unit test systems that cannot be adjusted”
Calibration verification
Current assumption:
Equivalent to CAP POC.05450
If the laboratory has more than one method-system for performing tests for a given analyte, are they checked against each other at least twice a year for correlation of patient results?
CLIA requires at least 3 point check

67. New CLIA Regulations Work in progress
New rules published January 2003
Rules in effect March 23, 2003
Interpretive guidelines published Jan 2004
Inspections using new regulations now
2 year grace period to adapt new rules
Ends Jan 2005
Quality Assessment Program - Lab Responsibilities
Establish & follow policies/procedures addressing ongoing QA activity.
Take corrective actions as necessary.
Review their effectiveness.
Revise policies/procedures as necessary to prevent recurrence.
Communicate to staff.
Document all assessment activities.

68. New CLIA Regulations Proficiency testing
Changed consensus for PT program grading from 90% to 80%.
Quality Assessment replaces Quality Assurance.
Quality Assessment is interspersed throughout the regulation.
Creates one set of nonwaived QC requirements.
Subpart K - Quality System for Nonwaived Testing
Laboratory is ultimately responsible for ensuring that all components of the analytic process are monitored.
Each laboratory that performs nonwaived testing must meet the applicable analytic systems requirements; unless HHS approves a procedure, specified in the Interpretive Guidelines, that provides equivalent quality testing

69. Equivalent Quality Testing
Traditional:
Testing two levels of external control materials each day of testing
Except coag and blood gases
every 8 hours of use
Equivalent QC Options
#2 -Test systems with internal/procedural controls that monitor a portion of the analytic components, and if the lab successfully completes a thirty day evaluation process, the lab may reduce the frequency of external quality control materials to once per calendar week.

70. Equivalent Quality Testing
Option #2
Perform the test system’s internal control procedure(s) in accordance with the manufacturer’s instructions (but not less frequently than once each day of testing) and test two levels of external control material daily for 30 consecutive days of testing.
EQC AND LQC daily (NOT every 8 hours) for 30 days
Then OK to use EQC daily, LQC weekly
Unless manufacturer requires more
Send comments to: Judith Yost
Director, Division of Laboratory Services, CMS
(410)

71. Routine Quality Control
Instrument Performance Verification
Electronic Quality Control with Numeric Output
Two levels per 8 hour shift (CLIA reg)
Assay Performance Verification
Wet QC as per Manufacturer’s Recommendation
Varies by system
No external QC required for ProTime / INRatio in most States
Within system may vary by waived or moderate complexity licensure

72. Ensuring Compliance Required identification Lockout
Mandatory operator ID
Password control
Reuse IDs for some applications
Mandatory patient ID
Lockout
Force QC at specific times
QC must pass to run patient samples
Lockout non-compliant or untrained operators
Disallow specific assays

73. Connectivity Multiple definitions Download to computer
To LIS or to HIS or to both or to data management software
Real time and / or batch
QC data, patient data, or both

74. Connectivity Bidirectional communication Send data to instrument
Reset lockouts
Load configurations
Operator tables
QC frequency
QC ranges
Reuse availability
Vary configuration by clinical setting

75. Solutions System specific configuration
e.g. HCM for Signature+
HRDM for Response
System specific data management
e.g. ReportMaker for Signature / +
RapidLink for Bayer RapidPoint
DataCare for Roche CoaguChek / S / DM / Pro
Link to systems designed for glucose
Abbott and Roche state they will connect with any POC instrumentation

76. Solutions Manufacturer neutral interface MAS RALS-plus
Telcor Quick Serv
Manufacturer works with interface supplier to ensure compatibility
Interface supplier works with LIS / HIS supplier to ensure compatibility
Likely more options as CIC guidelines implemented (NCCLS POCT1-A)

77. Why Bother with POC Coag?
Once compliance issues addressed –
Improved Clinical Outcome
Reduced LOS – Length of Stay
Improved, timely patient care