Coagulation Testing - Point-of-care testing

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

ns th Pa y wa Monitor with aPTT or ACT H EP A R Extrinsic Pathway IN X Common Pathway Monitor with ????? WARFARIN

Xa DXaI II IIa LMWH (thrombin) Hirudin & DTI CLOT 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 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 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 Applications Operating 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

700 600 Clotting Time (sec) C-ACT 500 P214 400 300 200 100 CATH ECMO 0 Dialysis 1 0 PTCA 2

CPB 3 Heparin (units/ml) 4 5 1980s HemoTec ACT Liquid kaolin activator Different technology Different results ACT Differences Recognized in literature >20 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 Why are there so many different ACTs? Clotting Time (sec) 700 C-ACT 600 K-ACT 500

ACT+ 400 ACT-LR P214 300 200 CATH 100 CCU 0 Dialysis 0 1 PTCA 2

CPB 3 Heparin (units/ml) 4 5 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 700 675 650 Hemochron Hemotec TAS HMS Seconds 625 600 575 550 525 500 475

Pre 15 CPB min 30 min 45 min 60 min 75 min 90 min Data from Huffman, et.al. 1998 AmSECT meeting 105 min 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 C-ACT 1200 Trasylol 1000 1000 Trasylol Placebo Placebo 800

800 600 600 400 400 200 200 0 PostProt. OnPump3 OnPump2 OnPump

PostBolus2 Data from clinical evaluation, on file, ITC PostBolus PostProt. OnPump3 OnPump2 OnPump PostBolus2 PostBolus Baseline Baseline 0

ACT+ 1200 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 Applications Operating 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 aggregation Adhesion shape change release ADP release 3 sec Aggregation 10 sec Coagulation Fibrin formation 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 Applications Operating 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 120 110 y = 0.57x - 28.44 R = 0.896 aPTT (J103) (sec) 100 90 80 70 60 50 40 30 20 50 100 150

FTCA510 (sec) 200 250 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

t ri In ic ns Extrinsic Pathway th Pa y wa AP TT Common Pathway CLOT 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 underlying coagulopathy treat by giving protamine treat by giving FFP

Monitor heparin / Coumadin cross-over Heparin versus Warfarin Drug Action Direct Heparin Inhibition of Thrombin Mechanism Monitoring Effective ATIII cofactor APTT ACT Immediate

PT Delay 3-5 days Decreases Warfarin Production Vitamin K of factors Prothrombin Time t ri In ns Extrinsic Pathway ic th Pa y wa PT

Common Pathway CLOT Prothrombin Time Monitor warfarin therapy ISI Monitor heparin/warfarin crossover PTpatient INR Target times are set by PTmeannormal 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? (Probably Not) but it WILL Correlate Correlate Does Not Mean Match y = 0.737x + 22.2 R = 0.920 140 Signature APTT 120 100 80 60 40 20 0 0

50 Lab APTT 100 150 Coag is NOT Chemistry Dade Actin / MLA 70 y = 0.72x + 11.5 R = 0.883 50 40 30 20 50 40

30 20 20 30 40 lab 50 60 70 IL aPTT C / ACL #3 150.0 130.0 110.0 90.0 70.0 50.0 30.0

10.0 20 y = 0.44x + 22.2 R = 0.9533 10 30 50 70 lab 90 110 130 150

30 40 lab 50 60 70 IL aPTT SP / ACL #2 150.0 130.0 110.0 90.0 70.0 50.0 30.0 10.0 y = 0.59x + 16.0 R = 0.961

Signature Signature y = 1.02x + 4.1 R = 0.942 60 Signature Signature 60 Organon Technika / MDA 70 10 30 50

70lab 90 110 130 150 IL aPTT C /ACL #1 S ig n a tu re 60.0 40.0 40.0 20.0 0.0 0.0 lab 100

100.0 150 0 100.0 S ig n a tu re 60.0 40.0 20.0 0.0 50 lab 100 150 y = 0.59x + 16.0 R = 0.961 80.0

60.0 40.0 20.0 150 IL aPTT C / ACL #3 0 100.0 y = 0.44x + 22.2 R = 0.953 S ig n a tu re 80.0 lab 100 0.0 0

100.0 50 IL aPTT SP / ACL #2 y = 0.47x + 20.2 R = 0.942 80.0 y = 0.35x + 22.1 R = 0.928 60.0 20.0 50 IL aPTT SP / ACL #1 80.0 IL aPTT C / ACL #2

S ig n a tu re Same System / Multiple Sites y = 0.45x + 17.9 R = 0.929 80.0 0 S ig n a tu re Compare for your site. S ig n a tu re 100.0

100.0 60.0 40.0 80.0 0.0 0.0 lab 100 150 150 IL aPTT SP / ACL #3 y = 0.40x + 23.3 R = 0.912 40.0 20.0

50 lab 100 60.0 20.0 0 50 0 50 lab 100 150 Are differences important?

Sometimes no - aPTT C Signature 30 40 50 60 70 80 90 site 1 27 49 71 94 116 138 160 site 2 21 42 63

84 105 127 148 site 3 18 41 64 87 109 132 155 Sometimes VERY - aPTT SP Signature 30 40 50 60 70

80 90 site 1 23 51 80 109 138 167 196 site 2 24 41 57 74 91 108 125 site 3 33 82

130 179 >200 >200 >200 Lot to Lot Reproducibility Cuvette Lot a 80 y = 1.35x - 14.2 R=.909 70 Lab 60 50 40 30 20 20

80 70 40 60 Signature 80 Cuvette Lot b y = 1.39x - 12.8 R=0.934 La b 60 50 40 30 20 20

40 Signature 60 80 Signature 30 40 50 60 70 80 90 Lot a 26 40 53 67 80

93 107 Lot b 29 43 57 70 84 98 112 Clinical Applications Operating 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

Mean difference = 0.3 INR Difference (TPC - INN) 1 0.5 0 0 1 2 3 4 5 -0.5 -1 -1.5 Mean Innovin and TPC INR 6

7 INR Expectations INR within 0.4 of lab > 80% INR within 0.7 of lab > 90% INR within 1.0 of lab > 95% 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 % (values shown are ranges) AACC 2002 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) CPB (N=40) PVS (N=45) Median 90.0 90.0 Mean 78.5 74.0 Minimum 38.0 21.0 POC (min) All Groups Median 2.23 Minimum 0.33 Maximum 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 Whats the catch? 1. 2. Regulatory compliance 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 Doctors 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 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 [email protected] (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 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 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

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