Coagulation TestingWhat is it?

Why do we need it POC?

ITC Educational Services, Edison, NJ

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

Coagulation Testing

Monitoring hemostasis

Bleeding Clotting

Coagulation Testing Monitoring therapy

Intrinsic PathwayExtrinsic Pathway

Common Pathway

CLOT

Heparin CoumadinMonitor with

ACT / aPTT Monitor with PT

Thrombolytics Monitor with

TT / Fibrinogen

Coagulation is ComplexPlatelet Adhesion

•shape change • release

ADP release

PlateletAggregation

Coagulation

•Fibrin formation

3 sec

10 sec

5 min

Coagulation is Complex

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 ProTime Medtronic HMS / HemoTec ACT II CoaguChek / CoaguChek Pro DM Bayer RapidPoint i-STAT Others

POC Coag Analyzers Differ

Test methodology– Sample size and application

– Sample measurement

– Clot detection method» Enzyme detection method

– Reagent composition

– Results

Clinical ApplicationsOperating Room

– Cardiac Surgery– Interventional Cardiology and Radiology

Critical Care Satellite Sites

– Dialysis– ECMO– Emergency Room– Anticoagulation Clinic

Activated Clotting Time

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

ACT

What do we use an ACT for? Maintain Balance

– Bleeding Thrombosis Heparin

– Rapid Anticoagulant Effect» Individual sensitivities vary significantly» Potency differences

Source: Bovine or Porcine Lot to Lot variability

– Rapidly Reversible with Protamine

Why are there so many different ACTs?

0

100

200

300

400

500

600

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

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

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

Monitoring in CPB - ACT

Data from clinical evaluation, on file, ITC

0

100

200

300

400

500

600

700

800

900

1000

Clo

ttin

g T

ime

Kaolin ACT

Celite ACT

ACT+

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

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; 0.5 x 106 KIU/hr infusion

» Half Hammersmith 1 x 106 KIU loading dose; 1 x 106 KIU pump prime;

0.25 x 106 KIU/hr infusion

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

ACT Monitoring -Aprotinin Treatment

0

200

400

600

800

1000

1200

Baseline PostBolus PostBolus2 OnPump OnPump2 OnPump3 PostProt.

Clo

ttin

g T

ime

.

Kaolin ACT

Celite ACT

ACT+

Data from clinical evaluation, on file, ITC

Alternative Monitoring - Aprotinin HiTT - High Dose Thrombin Time

Control Patients

0

200

400

600

800

1000

Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine

Clot

ting

Tim

e

Celite

Kaolin

HiTT

Aprotinin Patients

0

200

400

600

800

1000

Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine

Clot

ting

Tim

e

Celite

Kaolin

HiTT

Adapted from Huyzen, et. al. J.CardioThorac. Vasc. Anesth. 8:153, 1994

Alternative Monitoring - Aprotinin

Kaolin ACT

0

200

400

600

800

1000

Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine

Clot

ting

Tim

e

Aprotinin

Placebo

HiTT

0

50

100

150

200

250

Baseline Post-Bolus CPB 1 CPB 2 Post-Protamine

Clot

ting T

ime

Aprotinin

Placebo

Adapted from Huyzen, et. al. J.CardioThorac.Vasc.Anesth. 8:153, 1994

Thrombin Time

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOTTT

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» RapidPoint

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)» Jobes, D. et. al., 1995. J.Thorac.Cardiovasc.Surg.

Reduced Cost– Resulting from POC Assays– RxDx combined with TT / HNTT

» Jobes, D. et. al., 1996. Am Soc Anesth Mtg.

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.

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

– Balloon angioplasty

– Arthrectomy (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 Arthrectomy– 10,000 unit bolus dose or

– 2 - 2.5 mg/kg

– target ACT 300 - 350 seconds » unless platelet inhibitors used

200 – 300 in presence of ReoPro

Why use platelet inhibitors?

Angioplasty promotes aggregation

Platelet Inhibitors ReoPro

– elevates ACTs

– target time = 250 sec with ReoPro» determined using FTCA510 tube

Integrelin– No reported 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

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.

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

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

1. the presence of heparin

2. underlying coagulopathy 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

» prophylactic therapy for DVT: INR= 2.0 - 3.0

» artificial heart valve: INR=3.0 - 4.0

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

0

20

40

60

80

100

120

140

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

20

30

40

50

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

20

30

40

50

60

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

60.0

80.0

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

60.0

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

20

30

40

50

60

70

80

20 40 60 80Signature

La

b

Cuvette Lot b

y = 1.39x - 12.8R=0.934

20

30

40

50

60

70

80

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 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

How to compare INR differences

Has the Hemostatic Balance been Upset? Is the Clinical Response Different?

6.0

5.0

4.0

3.0

2.0

1.0

Must change dose

Target INR 3.0Range 2.5 -3.5

Must change dose

Call Clinic

May change dose

May change dose

Call Clinic

Patient Management

What’s the catch?

1. Regulatory compliance

2. Connectivity

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

CLIAC CLIA Committee

– 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 complexity categories

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 and Coaguchek are waived Requires

– Certified Laboratory Director– Record Keeping– Training– Quality Policy

Implementing POC coag requires:RECORD KEEPING

Method Validation - accuracy– comparison to current standard

Linearity Assessment – Also used for ACT “calibration/ verification”– Is assay performance appropriate to clinical needs? – Does linear range span clinical range?

Training – competency evaluations at predetermined intervals

Routine Quality Control– Instrument Performance Verification

» Electronic Quality Control with Numeric Output » 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

Connectivity

Everyone wants it– 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

Short term solutions

Interim programs for data capture, QC compliance tracking– transfer to file format easily adaptable

» Requires independent transfer protocol

» e.g., ITC ReportMaker

Dedicated interface specific to one manufacturer’s instrumentation

» e.g., Abbott; Lifescan

» Manufacturer ensures system compatibility

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

Telcor concept

Quick Serv (DM)

LIS/HIS

Quick Script or Quick EDI

Quick Linc

ITC Dawning box

Data translation

Via hospital Ethernet

OR

Cath lab

CCU

Quick-Multi-Linc (QML)

Blood Gas

Co-ox

Coagulation

Glucose

Chemistry

I M P O R T

Snapshot

Exception Management

Quality Control

Operator Management

Device Management

Statistics

Manual Result Entry

Configuration

Result Management

Windows 2000 SP1 Workstation

Data Management Configuration

Output Management

Quick-Script

Quick-EDI

or

Interface Management

LIS / HIS Host

System

POC

Vend

or’s

Dat

a

Com

mun

icat

ion

& Se

t-U

p

Output

Cardiac Marker

Urinalysis

Terminal Emulation

Host EDI

RALS plus concept

LIS

Results that meet user-defined criteria are transferred to the LIS for placement

on the patient’s permanent medical record

HIS

RALS-ADT gathers demographic data to enable patient verification

Test results are transferred from a RALS-Plus Test Station to the RALS-Plus Core System (RCS)

Glucose

ICU

RALS Dataport

TM

MAS

RALS DATA PO RT®

Coagulation

ERRALS Plus Test

Station

Glucose

Urinalysis

9 WestRALS Remote

ConnectHospital Client PC

POCC’s can view, analyze, or edit results using the RALS-Plus IMS (Information Management System)

RALS-IMS

RALS-Core System (RCS)Located in the Hospital Data Center

Coagulation Coagulation

Glucose

Blood Gas

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

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

Why Bother with POC Coag?

Improved Clinical Outcome Reduced LOS – Length of Stay Improved, timely patient care