Coagulation Testing for POCC

Coagulation TestingWhat is it?

Why do we need it POC?

.

Coagulation Testing

Monitoring hemostasis

Bleeding Clotting

CLOT

Anticoagulants

Intrinsic Pathway

Extrinsic Pathway

Common PathwayX Xa

II IIa (thrombin)

HEPARIN

WARFARIN

LMWH

Hirudin & DTI

DXaI

Monitor with aPTT or ACT

Monitor with PT

Monitor with ?????

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

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

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 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 ApplicationsOperating Room

– Cardiac Surgery– Interventional Cardiology and Radiology

Critical Care Satellite Sites

– Dialysis– ECMO– Emergency Room– Anticoagulation Clinic

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

Activated Clotting Time

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

HEMOCHRON introduced– semi-automated

– less operator dependence

– two assays » CA510 (later FTCA510)

diatomaceous earth activated

» P214 glass bead activated

2 assays for separate applications

0

100

200

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500

600

700

0 1 2 3 4 5

Heparin (units/ml)

Clo

ttin

g T

ime

(sec

)

C-ACT

P214

ECMO Dialysis

CATHPTCA CPB

1980’s HemoTec ACT Liquid kaolin activator Different technology

– Different results

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

Why are there so many different ACTs?

0

100

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700

0 1 2 3 4 5

Heparin (units/ml)

Clo

ttin

g T

ime

(sec

)

C-ACT

K-ACT

ACT+

P214

ACT-LR

CCUDialysis

CATHPTCA CPB

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

475

500

525

550

575

600

625

650

675

700

PreCPB

15min

30min

45min

60min

75min

90min

105min

Seco

nds

Hemochron

Hemotec

TAS

HMS

Heparinized ACT - CPB

Data from Huffman, et.al. 1998 AmSECT meeting

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 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

Monitoring in CPB - Aprotinin

Data from clinical evaluation, on file, ITC

C-ACT

0

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1200

Baselin

e

PostB

olu

s

PostB

olu

s2

OnP

um

p

OnP

um

p2

OnP

um

p3

PostP

rot.

Trasylol

Placebo

ACT+

0

200

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600

800

1000

1200

Baseline

PostB

olus

PostB

olus2

OnP

ump

OnP

ump2

OnP

ump3

PostP

rot.

Trasylol

Placebo

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 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 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 ApplicationsOperating Room

– Cardiac Surgery– Interventional Cardiology and Radiology

Critical Care Satellite Sites

– Dialysis– ECMO– Emergency Room– Anticoagulation Clinic

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

Catheterization and Electrophysiology– 2500 - 5000 unit bolus dose

– frequently not monitored

– if monitored – » ACT» aPTT

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? Angioplasty promotes aggregationAdhesion

•shape change • release

ADP release

Aggregation

Coagulation

•Fibrin formation

3 sec

10 sec

5 min

Need to inhibit restenosis / reocclusion

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 ApplicationsOperating Room

– Cardiac Surgery– Interventional Cardiology and Radiology

Critical Care Satellite Sites

– Dialysis– ECMO– Emergency Room– Anticoagulation Clinic

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

y = 0.57x - 28.44R = 0.896

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50 100 150 200 250FTCA510 (sec)

aP

TT

(J1

03)

(se

c)

Single site comparison, ACT tube vs HE Jr Sig aPTT

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

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

APTT

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

Activated Partial Thromboplastin Time

Heparin versus Warfarin

Drug ActionMechan-

ismMoni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

Prothrombin Time

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

PT

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?

ISI

meannormal

patient

PT

PTINR

Will POC Results Match the Lab?

(Probably Not)

but it WILL Correlate

Correlate Does Not Mean Match

y = 0.737x + 22.2R = 0.920

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0 50 100 150Lab APTT

Sig

na

ture

AP

TT

Coag is NOT Chemistry

y = 0.4493x + 17.898y = 0.4723x + 20.24y = 0.4374x + 22.173

IL C

Dade Actin / MLA

y = 0.72x + 11.5R = 0.883

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60

70

20 30 40 50 60 70lab

Sig

na

ture

IL aPTT SP / ACL #2

y = 0.59x + 16.0R = 0.961

10.0

30.050.0

70.090.0

110.0130.0

150.0

10 30 50 70 90 110 130 150lab

Sig

na

ture

IL aPTT C / ACL #3y = 0.44x + 22.2

R = 0.9533

10.0

30.050.0

70.090.0

110.0130.0

150.0

10 30 50 70 90 110 130 150lab

Sig

na

ture

Organon Technika / MDA

y = 1.02x + 4.1R = 0.942

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70

20 30 40 50 60 70lab

Sig

na

ture

y = 0.4493x + 17.898y = 0.4723x + 20.24y = 0.4374x + 22.173

IL C

IL SP

IL aPTT C /ACL #1

y = 0.45x + 17.9R = 0.929

0.0

20.0

40.0

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100.0

0 50 100 150lab

Sig

na

ture

IL aPTT SP / ACL #1

y = 0.35x + 22.1R = 0.928

0.0

20.0

40.0

60.0

80.0

100.0

0 50 100 150lab

Sig

na

ture

IL aPTT C / ACL #2

y = 0.47x + 20.2R = 0.942

0.0

20.0

40.0

60.0

80.0

100.0

0 50 100 150lab

Sig

na

ture

IL aPTT SP / ACL #3

y = 0.40x + 23.3R = 0.912

0.0

20.0

40.0

60.0

80.0

100.0

0 50 100 150lab

Sig

na

ture

IL aPTT C / ACL #3

y = 0.44x + 22.2R = 0.953

0.0

20.0

40.0

60.0

80.0

100.0

0 50 100 150lab

Sig

na

ture

IL aPTT SP / ACL #2

y = 0.59x + 16.0R = 0.961

0.0

20.0

40.0

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80.0

100.0

0 50 100 150lab

Sig

na

ture

Compare for your site.

Same System / Multiple Sites

Are differences important?

Sometimes no - aPTT C

Signature site 1 site 2 site 330 27 21 1840 49 42 4150 71 63 6460 94 84 8770 116 105 10980 138 127 13290 160 148 155

Sometimes VERY - aPTT SPSignature site 1 site 2 site 3

30 23 24 3340 51 41 8250 80 57 13060 109 74 17970 138 91 >20080 167 108 >20090 196 125 >200

Lot to Lot ReproducibilitySignature

30405060708090

Cuvette Lot a

y = 1.35x - 14.2R=.909

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80

20 40 60 80Signature

La

b

Cuvette Lot b

y = 1.39x - 12.8R=0.934

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20 40 60 80Signature

La

b

Signature Lot a Lot b30 26 2940 40 4350 53 5760 67 7070 80 8480 93 9890 107 112

Clinical ApplicationsOperating Room

– Cardiac Surgery– Interventional Cardiology and Radiology

Critical Care Satellite Sites

– Dialysis– ECMO– Emergency Room– Anticoagulation Clinic

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 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 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 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 Lab?

(It will be a lot closer than for aPTT)

but it WILL Correlate

How to Compare INR Results

Lower dose? Keep same dose? Raise Dose?

Test Again? Test more often?

Lab to Lab Comparison

-1.5

-1

-0.5

0

0.5

1

1.5

0 1 2 3 4 5 6 7

Mean Innovin and TPC INR

Dif

fere

nce

(T

PC

- I

NN

)

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 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? 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

Lab (min) Median

CPB (N=40)90.0

PVS (N=45)90.0

Mean 78.5 74.0Minimum 38.0 21.0

POC (min)Median

All Groups2.23

Minimum 0.33Maximum 6.97

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

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?

1. Regulatory compliance

2. Connectivity

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

Central Laboratory Satellite Labs

– Critical Care

– Surgical Suite Clinics Bedside testing Doctor’s office

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: 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 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

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 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 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 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 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 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 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

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 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

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 Coag?

Once compliance issues addressed ––Improved Clinical Outcome

–Reduced LOS – Length of Stay

–Improved, timely patient care