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Coagulation Testing What is it? Why do we need it POC? Marcia L. Zucker, Ph.D. Director of Clinical Research Educational Services, Edison, NJ.

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Presentation on theme: "Coagulation Testing What is it? Why do we need it POC? Marcia L. Zucker, Ph.D. Director of Clinical Research Educational Services, Edison, NJ."— Presentation transcript:

1 Coagulation Testing What is it? Why do we need it POC? Marcia L. Zucker, Ph.D. Director of Clinical Research Educational Services, Edison, NJ

2 Coagulation Testing u Monitoring hemostasis Bleeding Clotting

3 CLOT Anticoagulants Intrinsic Pathway Extrinsic Pathway Common Pathway X Xa II IIa (thrombin) HEPARIN WARFARIN LMWH Hirudin & DTI DXaI Monitor with aPTT or ACT Monitor with PT Monitor with ?????

4 Coagulation is Complex Picture from

5 Common(?) Coagulation Tests u Laboratory PT.. aPTT TT.. Fib. –Anti Xa –Anti IIa –Factor Assays u Point of Care –ACT »Celite ® »Kaolin »Glass beads »Silica »thromboplastin

6 Differences in test methods u Point of Care –Whole Blood –No Added Anticoagulant –No Dilution –No Preanalytical Delay u Standard Laboratory –Platelet Poor Plasma –Sodium Citrate Anticoagulant –1:9 Dilution –Variable Preanalytical Delay

7 POC Coagulation Analyzers u HEMOCHRON 401 / 801 / Response u HEMOCHRON Jr. Signature / Signature + u ProTime / 3 u Medtronic HMS/HMS+/ HemoTec ACT II / ACTPlus u CoaguChek / S / Pro / Pro DM u i-STAT u Helena Actalyke u Hemosense INRatio u Others?

8 POC Coag Analyzers Differ u Test methodology –Sample size and application »Microliters to milliliters –Sample measurement »Manual vs automated –Clot detection method »Enzyme detection method u Thrombin generation –Reagent composition –Results

9 Clinical Applications Operating Room –Cardiac Surgery –Interventional Cardiology and Radiology u Critical Care u Satellite Sites –Dialysis –ECMO –Emergency Room –Anticoagulation Clinic

10 History of the ACT u Lee-White clotting time –Manual –No activator –Very slow u 1966 –Hattersley- Activated Clotting Time –Diatomaceous earth activator –Operator defined mixing and clot detection –Global assay - Contact activation of cascade

11 Activated Clotting Time

12 Particulate Contact Activation u Initiation of intrinsic coagulation cascade –Factor XII (Hageman factor) –Prekallikrein (Fletcher factor) u Dramatically shortens contact activation period over Lee-White time u Proposed as both screening assay for coagulation defects and for heparin monitoring

13 ACT Automation u HEMOCHRON introduced –semi-automated –less operator dependence –two assays »CA510 (later FTCA510) u diatomaceous earth activated »P214 glass bead activated

14 2 assays for separate applications

15 1980s HemoTec ACT u Liquid kaolin activator u Different technology –Different results

16 ACT Differences u 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 u Differences ignored by clinicians

17 Why are there so many different ACTs?

18 Monitoring - ACT u Benefits –Industry Standard Since 1970s –Recommended as primary method in AmSECT guidelines (perfusion) –Easy to run u 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

19 Heparinized ACT - CPB Data from Huffman, AmSECT meeting

20 Pharmaceutical Intervention u Amicar or Tranexamic Acid –No effect on standard celite ACT u Aprotinin –Significant elevation of celite ACT –Two dosing regimens »Full or Half Hammersmith »Both independent of patient size

21 ACT Monitoring-Aprotinin Treatment u Celite ACT –Not recommended –Still used with target times of >750 seconds u Kaolin ACT –Unaffected by moderate doses of aprotinin –Used with target times of > 480 seconds u ACT+ –Unaffected by ALL doses of aprotinin –Used with target times of > 400 seconds

22 Monitoring in CPB - Aprotinin u Data from clinical evaluation, on file, ITC

23 Other POC Coag in the OR u aPTT / PT –Pre- and post-procedural screening u Fibrinogen –Pre- and post-procedural screening u Dosing Assays –Customize heparin and protamine for each patient »HEMOCHRON HRT / PRT »Hepcon HMS –Measure heparin level »Relationship to coagulation status unclear

24 Other POC Coag in the OR u Heparin neutralization verification –Ensure complete removal of circulating heparin »aPTT »PDA-O - ACT based »TT / HNTT - Thrombin Time based »heparinase ACT

25 Outcome studies - POC in OR u Reduced Blood Loss/Transfusion –Use of HRT and PRT (RxDx System) u Reduced Cost Resulting from Use of POC Assays –RxDx combined with TT / HNTT u 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.

26 Clinical Applications Operating Room –Cardiac Surgery –Interventional Cardiology and Radiology u Critical Care u Satellite Sites –Dialysis –ECMO –Emergency Room –Anticoagulation Clinic

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

28 Diagnostic – Low dose heparin u Catheterization and Electrophysiology – unit bolus dose –frequently not monitored –if monitored – »ACT »aPTT

29 Interventional – Moderate dose u Angioplasty and Atherectomy –Heparin »10,000 unit bolus dose or » mg/kg »target ACT seconds u 200 – 300 in presence of ReoPro –Angiomax (bivalirudin) »ACT >300 u Hemochron (ACT-LR or FTCA510) trials »Measure post-bolus to ensure drug on board »Required in patients with renal impairment

30 Why use platelet inhibitors? u Angioplasty promotes aggregation Adhesion shape change release ADP release Aggregation Coagulation Fibrin formation 3 sec 10 sec 5 min

31 Need to inhibit restenosis / reocclusion

32 Platelet Inhibitors u ReoPro –elevates ACTs –target time = 250 sec with ReoPro »determined using FTCA510 tube u Integrelin –No reported clinically significant effects on ACT u Aggrastat –No reported effects on ACT

33 Clinical Applications Operating Room –Cardiac Surgery –Interventional Cardiology and Radiology u Critical Care u Satellite Sites –Dialysis –ECMO –Emergency Room –Anticoagulation Clinic

34 ACT or aPTT u 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 u Must be linked to heparin sensitivity of reagent used

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

36 ACT or aPTT u 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 u Poster at AACC 2000 – Staikos,

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

38 u NOT a PTT –PTT is the predecessor of the aPTT –Not used anymore u Laboratory or Point of Care u High APTT values –presence of heparin »treat by giving protamine –underlying coagulopathy »treat by giving FFP u Monitor heparin / Coumadin ® cross-over Activated Partial Thromboplastin Time

39 Heparin versus Warfarin

40 Prothrombin Time Intrinsic Pathway Extrinsic Pathway Common Pathway CLOT PT

41 Prothrombin Time u Monitor warfarin therapy u Monitor heparin/warfarin crossover u 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= »Mitral mechanical heart valve: INR= 2.5 – 3.5 »Hypercoagulable disorders: INR= 1.5 – 2.5?

42 Will POC Results Match the Lab? (Probably Not) but it WILL Correlate

43 Correlate Does Not Mean Match

44 Coag is NOT Chemistry

45 Compare for your site. Same System / Multiple Sites

46 Are differences important? u Sometimes no - aPTT C

47 u Sometimes VERY - aPTT SP

48 Lot to Lot Reproducibility

49 Clinical Applications Operating Room –Cardiac Surgery –Interventional Cardiology and Radiology u Critical Care u Satellite Sites –Dialysis –ECMO –Emergency Room –Anticoagulation Clinic

50 Dialysis / ECMO u ACT (or nothing in dialysis) –Majority use P214 glass activated ACT –Some use ACT-LR; HemoTec LR ACT u Better Control of Anticoagulation Leads to Increased Dialyzer Reuse –Potential for Long Term Cost Savings –No Compromise in Dialysis Efficacy (Kt/V) »Ouseph, R. Am J Kidney Dis 35:89-94; 2000

51 Emergency Room u ACT; aPTT; PT; Fibrinogen u Immediate Identification of Coagulopathies –Optimization of Critical Decision Pathways u ACT Allows Early Detection of Traumatic Coagulopathy –Allows Early Treatment Decisions –Aids Damage Control Decisions »Aucar, J. SW Surgeons Congress u Optimize Staffing During Off Hours

52 Anticoagulation Clinics u Results Available While Patient is Present –Improved Anticoagulation Management –Improved Standard of Care –Staff Efficiency u Immediate Retesting (if needed) –Fingerstick Sampling u Same System for Clinic and Home Bound Patients –Standardized ISI / PT normal »Test System Specific

53 Anticoagulation Clinics u Potential for Self-Testing –High Risk Patients –Patients Who Travel Frequently –Home-Bound –Patients in Rural Areas Far from Clinic u Improved Outcomes Through More Frequent Testing

54 Will POC Results Match the Lab? (It will be a lot closer than for aPTT) but it WILL Correlate

55 How to Compare INR Results u Lower dose? u Keep same dose? u Raise Dose? u Test Again? u Test more often?

56 Lab to Lab Comparison Mean difference = 0.3 INR

57 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%

58 Why Bother with POC Coag? u 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

59 STAT Testing TAT Fitch,, J. Clin Monit & Comput :

60 Standardized Clinical Interpretation u Defined Assay Sensitivity –Requires Lot to Lot Reproducibility u Defined Reagent Variability –Identical Instrumentation and Reagents at All Testing Sites u Defined Critical Clinical Decision Points –No Change of Normal Ranges or Target Times Between Lots of Test Reagents or Testing Locations

61 Whats the catch? 1. Regulatory compliance 2. Connectivity

62 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 u Center for Devices and Radiological Health –CMS »Centers for Medicare and Medicaid Services –CDC »Centers for Disease Control

63 CLIA Applies to ALL Testing Areas u Central Laboratory u Satellite Labs –Critical Care –Surgical Suite u Clinics u Bedside testing u Doctors office

64 CLIA Regulations for Coagulation u Central Laboratory can hold the CLIA license –Satellites can have independent licensure u Moderately Complex tests –Except – ProTime, Coaguchek, INRatio are waived u Requires –Certified Laboratory Director –Record Keeping –Training –Quality Policy

65 Implementing POC coag requires: u 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? u Precision –Controls may be used to establish within and between run variability u Training –Document training of all personnel »high school equivalence or higher education level –competency evaluations at predetermined intervals

66 Implementing POC coag requires: u Linearity NOT required for coag u Calibration does not apply to unit test systems that cannot be adjusted u Calibration verification Current assumption: –Equivalent to CAP POC »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

67 New CLIA Regulations u 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 u 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.

68 New CLIA Regulations u Proficiency testing –Changed consensus for PT program grading from 90% to 80%. u Quality Assessment replaces Quality Assurance. –Quality Assessment is interspersed throughout the regulation. –Creates one set of nonwaived QC requirements. u 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

69 Equivalent Quality Testing u Traditional: –Testing two levels of external control materials each day of testing –Except coag and blood gases »every 8 hours of use u 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.

70 Equivalent Quality Testing u 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. u 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 »(410)

71 Routine Quality Control u Instrument Performance Verification –Electronic Quality Control with Numeric Output –Two levels per 8 hour shift (CLIA reg) u Assay Performance Verification –Wet QC as per Manufacturers Recommendation »Varies by system u No external QC required for ProTime / INRatio in most States »Within system may vary by waived or moderate complexity licensure

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

73 Connectivity u 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

74 Connectivity u Bidirectional communication –Send data to instrument »Reset lockouts »Load configurations u Operator tables u QC frequency u QC ranges u Reuse availability »Vary configuration by clinical setting

75 Solutions u System specific configuration –e.g. HCM for Signature+ HRDM for Response u System specific data management –e.g. ReportMaker for Signature / + HRDM for Response RapidLink for Bayer RapidPoint DataCare for Roche CoaguChek / S / DM / Pro u Link to systems designed for glucose –Abbott and Roche state they will connect with any POC instrumentation

76 Solutions u 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)

77 Why Bother with POC Coag? u Once compliance issues addressed – –Improved Clinical Outcome –Reduced LOS – Length of Stay –Improved, timely patient care

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