Coagulation Testing

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Coagulation Testing

• What is it?
• Why do we need it POC?

Marcia L. Zucker, Ph.D. Director of Clinical
Research
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Coagulation Testing

• Monitoring hemostasis

Bleeding
Clotting
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Anticoagulants
Monitor with PT
Extrinsic Pathway
Monitor with aPTT or ACT
Intrinsic Pathway
HEPARIN
WARFARIN
DXaI
X Xa
LMWH
Common Pathway
II IIa (thrombin)
Hirudin DTI
Monitor with ?????
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Coagulation is Complex
Picture from DiaPharma.com
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Common(?) Coagulation Tests

• Laboratory
• PT..
• aPTT
• TT..
• Fib.
• Anti Xa
• Anti IIa
• Factor Assays

• Point of Care
• ACT
• Celite
• Kaolin
• Glass beads
• Silica
• thromboplastin

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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
• 19 Dilution
• Variable Preanalytical Delay

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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?

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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

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Clinical Applications

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

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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

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Activated Clotting Time
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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

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ACT Automation - 1969

• HEMOCHRON introduced
• semi-automated
• less operator dependence
• two assays
• CA510 (later FTCA510)
• diatomaceous earth activated
• P214 glass bead activated

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2 assays for separate applications
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1980s HemoTec ACT

• Liquid kaolin activator
• Different technology
• Different results

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ACT Differences

• Recognized in literature gt20 years
• Clinical evaluations of Hemochron appeared in
  journals mid 1970s
• 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

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Why are there so many different ACTs?
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Monitoring - ACT

• Benefits
• 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

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Heparinized ACT - CPB
Data from Huffman, et.al. 1998 AmSECT meeting
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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

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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

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Monitoring in CPB - Aprotinin

• Data from clinical evaluation, on file, ITC

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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
• Measure heparin level
• Relationship to coagulation status unclear

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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

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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.

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Clinical Applications

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

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Procedures

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

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Diagnostic Low dose heparin

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

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Interventional Moderate dose

• Angioplasty and Atherectomy
• Heparin
• 10,000 unit bolus dose or
• 2 - 2.5 mg/kg
• target ACT 300 - 350 seconds
• 200 300 in presence of ReoPro
• Angiomax (bivalirudin)
• ACT gt300
• Hemochron (ACT-LR or FTCA510) trials
• Measure post-bolus to ensure drug on board
• Required in patients with renal impairment

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Why use platelet inhibitors?

• Angioplasty promotes aggregation

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Need to inhibit restenosis / reocclusion
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Platelet Inhibitors

• ReoPro
• 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

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Clinical Applications

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

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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

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

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

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Heparin versus Warfarin
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Prothrombin Time
Extrinsic Pathway
Intrinsic Pathway
PT
Common Pathway
CLOT
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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 2.0 - 3.0
• Mitral mechanical heart valve INR 2.5 3.5
• Hypercoagulable disorders INR 1.5 2.5?

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Will POC Results Match the Lab?
NO!

• (Probably Not)
• but it WILL Correlate

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Correlate Does Not Mean Match
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Coag is NOT Chemistry
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Compare for your site. Same System / Multiple
Sites
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Are differences important?

• Sometimes no - aPTT C

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• Sometimes VERY - aPTT SP

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Lot to Lot Reproducibility
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Clinical Applications

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

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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 3589-94 2000

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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

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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

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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

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Will POC Results Match the Lab?
NOT Necessarily

• (It will be a lot closer than for aPTT)
• but it WILL Correlate

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How to Compare INR Results

• Lower dose?
• Keep same dose?
• Raise Dose?
• Test Again?
• Test more often?

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Lab to Lab Comparison
Mean difference 0.3 INR
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INR Expectations
INR within 0.4 of lab gt 80 INR within 0.7 of lab
gt 90 INR within 1.0 of lab gt 95
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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

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STAT Testing TAT

• Fitch, et.al, J. Clin Monit Comput. 1999.
  15197-204

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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

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Whats the catch?

1. Regulatory compliance
2. Connectivity

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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

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CLIA Applies to ALL Testing Areas

• Central Laboratory
• Satellite Labs
• Critical Care
• Surgical Suite
• Clinics
• Bedside testing
• Doctors office

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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

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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

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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

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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.

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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

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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.

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Equivalent Quality Testing

• Option 2
• Perform the test systems internal control
  procedure(s) in accordance with the
  manufacturers 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
• JYost_at_cms.hhs.gov
• [phone]

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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 Manufacturers Recommendation
• Varies by system
• No external QC required for ProTime / INRatio in
  most States
• Within system may vary by waived or moderate
  complexity licensure

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Ensuring Compliance

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

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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

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Connectivity

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

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Solutions

• System specific configuration
• e.g. HCM for Signature
• HRDM for Response
• System specific data management
• e.g. ReportMaker for Signature /
• HRDM for Response
• 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

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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)

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Why Bother with POC Coag?

• Once compliance issues addressed
• Improved Clinical Outcome
• Reduced LOS Length of Stay
• Improved, timely patient care