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Educational Services, Edison, NJ. Coagulation Testing. What is it? Why do we need it POC?. Marcia L. Zucker, Ph.D. Director of Clinical Research. Coagulation Testing. Monitoring hemostasis. Bleeding Clotting. CLOT. Anticoagulants. Monitor with PT.

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coagulation testing

Educational Services, Edison, NJ

Coagulation Testing

What is it?

Why do we need it POC?

Marcia L. Zucker, Ph.D.

Director of Clinical Research

coagulation testing2
Coagulation Testing
  • Monitoring hemostasis

Bleeding Clotting

anticoagulants

CLOT

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

coagulation is complex
Coagulation is Complex

Picture from DiaPharma.com

common coagulation tests
Laboratory

PT..

aPTT

TT..

Fib.

Anti Xa

Anti IIa

Factor Assays

Point of Care

ACT

Celite®

Kaolin

Glass beads

Silica

thromboplastin

Common(?) Coagulation Tests
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

1:9 Dilution

Variable Preanalytical Delay

Differences in test methods
poc coagulation analyzers
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?
poc coag analyzers differ
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
clinical applications
ClinicalApplications
  • Operating Room
    • Cardiac Surgery
    • Interventional Cardiology and Radiology
  • Critical Care
  • Satellite Sites
    • Dialysis
    • ECMO
    • Emergency Room
    • Anticoagulation Clinic
history of the act
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
particulate contact activation
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
act automation 1969
ACT Automation - 1969
  • HEMOCHRON introduced
    • semi-automated
    • less operator dependence
    • two assays
      • CA510 (later FTCA510)
        • diatomaceous earth activated
      • P214 glass bead activated
1980 s hemotec act
1980’s HemoTec ACT
  • Liquid kaolin activator
  • Different technology
    • Different results
act differences
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
monitoring act
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
heparinized act cpb
Heparinized ACT - CPB

Data from Huffman, et.al. 1998 AmSECT meeting

pharmaceutical intervention
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
act monitoring aprotinin treatment
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
other poc coag in the or
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
other poc coag in the or24
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
outcome studies poc in or
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.
clinical applications26
ClinicalApplications
  • Operating Room
    • Cardiac Surgery
    • Interventional Cardiology and Radiology
  • Critical Care
  • Satellite Sites
    • Dialysis
    • ECMO
    • Emergency Room
    • Anticoagulation Clinic
procedures
Procedures
  • Diagnostic
    • Catheterization
      • locate and map vessel blockage(s)
      • determine need for interventional procedures
    • Electrophysiology
    • Interventional Radiology
  • Interventional
    • Balloon angioplasty
    • Atherectomy (roto-rooter)
diagnostic low dose heparin
Diagnostic – Low dose heparin
  • Catheterizationand Electrophysiology
    • 2500 - 5000 unit bolus dose
    • frequently not monitored
    • if monitored –
      • ACT
      • aPTT
interventional moderate dose
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 >300
        • Hemochron (ACT-LR or FTCA510) trials
      • Measure post-bolus to ensure drug on board
      • Required in patients with renal impairment
why use platelet inhibitors

Adhesion

    • shape change
    • release

3 sec

10 sec

5 min

ADP release

Aggregation

  • Coagulation
    • Fibrin formation
Why use platelet inhibitors?
  • Angioplasty promotes aggregation
platelet inhibitors
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
clinical applications33
ClinicalApplications
  • Operating Room
    • Cardiac Surgery
    • Interventional Cardiology and Radiology
  • Critical Care
  • Satellite Sites
    • Dialysis
    • ECMO
    • Emergency Room
    • Anticoagulation Clinic
act or aptt
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
act vs aptt
ACT vs aPTT

Single site comparison, ACT tube vs HE Jr Sig aPTT

act or aptt36
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.
activated partial thromboplastin time
Activated Partial Thromboplastin Time

Extrinsic Pathway

Intrinsic Pathway

APTT

Common Pathway

CLOT

activated partial thromboplastin time38
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
prothrombin time
Prothrombin Time

Extrinsic Pathway

Intrinsic Pathway

PT

Common Pathway

CLOT

prothrombin time41
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?
will poc results match the lab
Will POC Results Match the Lab?

NO!

(Probably Not)

but it WILL Correlate

slide45

Compare for your site.

Same System / Multiple Sites

are differences important
Are differences important?
  • Sometimes no - aPTT C
clinical applications49
ClinicalApplications
  • Operating Room
    • Cardiac Surgery
    • Interventional Cardiology and Radiology
  • Critical Care
  • Satellite Sites
    • Dialysis
    • ECMO
    • Emergency Room
    • Anticoagulation Clinic
dialysis ecmo
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
emergency room
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
anticoagulation clinics
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
anticoagulation clinics53
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
will poc results match the lab54
Will POC Results Match the Lab?

NOT Necessarily

(It will be a lot closer than for aPTT)

but it WILL Correlate

how to compare inr results
How to Compare INR Results
  • Lower dose?
  • Keep same dose?
  • Raise Dose?
  • Test Again?
  • Test more often?
lab to lab comparison
Lab to Lab Comparison

Mean difference = 0.3 INR

inr expectations

(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 %

INR Expectations

INR within 0.4 of lab > 80%

INR within 0.7 of lab > 90%

INR within 1.0 of lab > 95%

why bother with poc coag
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
stat testing tat
STAT Testing TAT

Fitch, et.al, J. Clin Monit & Comput. 1999. 15:197-204

standardized clinical interpretation
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
what s the catch
What’s the catch?
  • Regulatory compliance
  • Connectivity
regulatory compliance who sets the rules
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
clia applies to all testing areas
CLIA Applies to ALL Testing Areas
  • Central Laboratory
  • Satellite Labs
    • Critical Care
    • Surgical Suite
  • Clinics
  • Bedside testing
  • Doctor’s office
clia regulations for coagulation
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
implementing poc coag requires
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
implementing poc coag requires66
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 CAPPOC.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
new clia regulations
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.
new clia regulations68
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
equivalent quality testing
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.
equivalent quality testing70
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
      • JYost@cms.hhs.gov
      • (410) 786-3407
routine quality control
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
ensuring compliance
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
connectivity
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
connectivity74
Connectivity
  • Bidirectional communication
    • Send data to instrument
      • Reset lockouts
      • Load configurations
        • Operator tables
        • QC frequency
        • QC ranges
        • Reuse availability
      • Vary configuration by clinical setting
solutions
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
solutions76
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)
why bother with poc coag77
Why Bother with POC Coag?
  • Once compliance issues addressed –
    • Improved Clinical Outcome
    • Reduced LOS – Length of Stay
    • Improved, timely patient care