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

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

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

2 Coagulation Testing u Monitoring hemostasis Bleeding Clotting

3 Maintaining Hemostasis Counterbalance thrombosis with anticoagulant therapy Thrombosis

4 Maintaining Hemostasis Counterbalance bleeding by correcting defect (i.e., neutralize heparin, transfuse blood product) Bleeding

5 Coagulation Proteins Platelets Fibrinolysis / Inhibitors Vessels Components of Hemostasis

6 Vascular System Basement membrane Endothelial cells Red blood cells Platelets White blood cells

7 Coagulation Proteins Platelets Fibrinolysis / Inhibitors Vessels Components of Hemostasis

8 Anatomy of a Platelet

9 Resting Platelets

10 Platelet Aggregate

11 Hemostasis u Primary hemostasis –Platelet Adhesion u Secondary hemostasis –Coagulation –Fibrin clot formation

12

13 Platelet Function Platelet Adhesion shape change release ADP release Platelet Aggregation Coagulation Fibrin formation 3 sec 10 sec 5 min

14 Platelet Testing u Peripheral smear u Platelet count u Platelet aggregation u Bleeding time

15 Peripheral Blood Smear

16 Platelet Aggregation Baseline Light Transmission Platelet Rich Plasma (PRP) + Aggregating Agent Aggregate Clumping Increased Light Transmission

17 Bleeding Time Cut 1 mm deep, 5 mm long Constant pressure Expected Range : minutes

18 Coagulation Proteins Platelets Fibrinolysis / Inhibitors Vessels Components of Hemostasis

19 Coagulation Inactive enzyme Active enzyme Inactive enzyme

20 Coagulation is Complex

21 Coagulation Testing Intrinsic Pathway Extrinsic Pathway Common Pathway CLOT Heparin Coumadin Monitor with ACT / aPTT Monitor with PT Thrombolytics Monitor with TT / Fibrinogen

22 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

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

24 POC Coagulation Analyzers u HEMOCHRON 401 / 801 / Response u HEMOCHRON Jr. Signature/ Signature+ u ProTime u Medtronic HMS/ HMS+ / HemoTec ACT II u CoaguChek/ S / CoaguChek Pro/ Pro DM u Bayer RapidPoint u i-STAT u Helena Actalyke u Others

25 POC Coag Analyzers Differ u Test methodology –Sample size and application –Sample measurement –Clot detection method »Enzyme detection method –Reagent composition –Results

26 Semi - Automation u HEMOCHRONOMETER (HEMOCHRON) –Magnet in tube, detector in instrument –Upon clot formation, magnet is deflected –Clotting time displayed

27 HEMOCHRON Test Menu u ACT –FTCA510, FTKACT, P214 u aPTT and PT –Fresh or citrated whole blood u Thrombin time based assays –TT, HNTT, HiTT u Fibrinogen u Dosing Assays –HRT, PRT, PDAO »Celite and kaolin

28 1980s u HemoTec (later ACTII) –Smaller sample volume –Mechanical detection »Flag moves up and down »As clot forms, motion slows »Instrument displays clotting time u Medtronics HMS uses same technology

29 Medtronics test menu u ACT (kaolin) u Empty cartridge for aPTT u PT (look up conversion) u Heparinase ACT u HMS Dosing Assays –HDR, HPT

30 Newer technologies CoaguChek Pro/ DM –Time to when capillary flow stops determines endpoint Bayer RapidPoint –Sample mixes with magnetic particles –Pulsating magnetic field –Motion detected optically u Sample introduction by capillary action

31 Test Menu u CoaguChek ProDM –ACT »Tissue factor activated –PT (FWB) –aPTT (FWB) u CoaguChek / S –Detection as per RapidPoint –PT only –CLIA waived u Bayer RapidPoint –HMT –aPTT »F & C WB and plasma –PT »F & C WB and plasma –ECT (ecarin time) »Compassionate use only –ENOX –Accent Dosing »HTT, PRT

32 Newer Technologies u Chemical endpoint detection –i-STAT – Abbott »Synthetic thrombin substrate »Electro-active compound formed and detected amperometrically –Coagulation Test Menu »ACT (Celite®) »PT (cleared but not yet introduced)

33 Newer Technologies u Active pumping system –Hemochron Jr Signature –ProTime microcoagulation system

34 Test Menu u HEMOCHRON Jr Signature –ACT »ACT+, ACT-LR –PT »Fresh or citrated WB –aPTT »Fresh or citrated WB u ProTime –PT only –CLIA waived –Home use approved –Integral Controls »Meet CLIA and CAP requirement for daily QC testing

35 Activated Clotting Time Intrinsic Pathway Extrinsic Pathway Common Pathway CLOT ACT

36 What do we use an ACT for? u Maintain Balance –Bleeding Thrombosis u Heparin –Rapid Anticoagulant Effect »Individual sensitivities vary significantly »Potency differences u Source: Bovine or Porcine u Lot to Lot variability –Rapidly Reversible with Protamine

37 Why are there so many different ACTs?

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

39 Monitoring - ACT 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

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

41 Heparinized ACT - CPB Data from Huffman, et.al AmSECT meeting

42 Monitoring in CPB - ACT u Data from clinical evaluation, on file, ITC

43 Pharmaceutical Intervention u Amicar or Tranexamic Acid –No effect on standard celite ACT –Continued debate on efficacy »Multiple reports u Reduction in post-operative blood loss u Reduced transfusion requirements

44 Pharmaceutical Intervention u Aprotinin –Significant elevation of celite ACT –Two dosing regimens »Full Hammersmith u 2 x 10 6 KIU loading dose; 2 x 10 6 KIU pump prime; 0.5 x 10 6 KIU/hr infusion »Half Hammersmith u 1 x 10 6 KIU loading dose; 1 x 10 6 KIU pump prime; 0.25 x 10 6 KIU/hr infusion

45 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

46 ACT Monitoring -Aprotinin Treatment Data from clinical evaluation, on file, ITC

47 Non-ACT Monitoring - Aprotinin u HiTT - High Dose Thrombin Time Adapted from Huyzen, et. al. J.CardioThorac. Vasc. Anesth. 8:153, 1994

48 Alternative Monitoring - Aprotinin Adapted from Huyzen, et. al. J.CardioThorac.Vasc.Anesth. 8:153, 1994

49 Thrombin Time Intrinsic Pathway Extrinsic Pathway Common Pathway CLOT TT

50 Other POC in the OR u Heparin Level – Xa Activity »laboratory only, impractical –Medtronic Hepcon HMS »indirect measure of protamine reversible heparin activity in whole blood »correlates with Xa and IIa activity –HEMOCHRON PRT »ACT based protamine titration –HEMOCHRON HiTT »unaffected by hemodilution, hypothermia »insensitive to aprotinin »correlates with Xa and IIa activity

51 Monitoring - Heparin Level u Benefits –Measures concentration, not activity –Correlates with laboratory standards u Disadvantages –Each system yields different numbers »apples and oranges do not compare –Correlation to anticoagulation status is still disputed –Target for neonate, pediatric and adult patients may differ

52 Monitoring - Heparin Level u Young: <4.5 years u Shayevitz, JR and OKelly, SW Progress in Anesthesiology, vol. IX, chapter

53 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

54 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

55 Outcome studies - POC in OR u Reduced Blood Loss/Transfusion –Use of HRT and PRT (RxDx System) »Jobes, D. et. al., J.Thorac.Cardiovasc.Surg. u Reduced Cost –Resulting from POC Assays –RxDx combined with TT / HNTT »Jobes, D. et. al., Am Soc Anesth Mtg.

56 Outcome studies - POC in OR 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% » Jobes, et.al. 1997, NACB Presentation, Phila.

57 Clinical Applications Operating Room –Cardiac Surgery –Interventional Cardiology and Radiology

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

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

60 Interventional – Moderate dose u Angioplasty and Atherectomy –10,000 unit bolus dose or – mg/kg –target ACT seconds »unless platelet inhibitors used u 200 – 300 in presence of ReoPro

61 Why use platelet inhibitors?

62 Angioplasty promotes aggregation

63

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

65 QUESTIONS?

66 Coagulation Testing What is it? Why do we need it POC? ITC Educational Services, Edison, NJ PART 2

67 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

68 STAT Testing TAT Fitch, et.al, J. Clin Monit & Comput :

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

70 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

71 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, et.al.

72 What did it say? u Mean time to lab result = 112 min –Mean time to POC result <5 min u Fewer dose adjustments needed in POC group to reach therapeutic level u Shorter time required to reach therapeutic level in POC group u Fewer dose changes in POC group

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

74 u NOT a PTT –PTT is the predecessor of the aPTT –Not used anymore u Laboratory or Point of Care u High APTT values –the presence of heparin –underlying coagulopathy u Monitor heparin / coumadin ® cross-over Activated Partial Thromboplastin Time

75 Heparin versus Warfarin

76 Prothrombin Time Intrinsic Pathway Extrinsic Pathway Common Pathway CLOT PT

77 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 »prophylactic therapy for DVT: INR= »artificial heart valve: INR=2.5 – 3.5

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

79 Correlate Does Not Mean Match

80 Coag is NOT Chemistry

81 Compare for your site. Same System / Multiple Sites

82 Are differences important? u Sometimes no - aPTT C

83 u Sometimes VERY - aPTT SP

84 Lot to Lot Reproducibility

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

86 Dialysis / ECMO u ACT (or nothing in dialysis) –Majority use P214 glass activated ACT –Some use ACT-LR; HemoTec 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. et.al. Am J Kidney Dis 35:89-94; 2000

87 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. et.al SW Surgeons Congress u Optimize Staffing During Off Hours

88 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

89 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

90 How to compare INR differences â Has the Hemostatic Balance been Upset? â Is the Clinical Response Different?

91 Must change dose Target INR 3.0 Range Must change dose Call Clinic May change dose Call Clinic Patient Management

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

93 Regulatory compliance u Who sets the rules? –JCAHO »Joint Commission on Accreditation of Health Care Organizations –CAP »College of American Pathologists –FDA »Food and Drug Administration –CMS (formerly HCFA) »Centers for Medicare & Medicaid Services –CDC »Centers for Disease Control

94 CLIAC u CLIA Committee –Define and interpret CLIA regulations u 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 / CMS / CDC complexity categories

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

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

97 Implementing POC coag requires: RECORD KEEPING u Method Validation - accuracy –comparison to current standard u Performance Range Assessment –Linearity often used »Calibration/ verification NOT required for coag –Is assay performance appropriate to clinical needs? –Does dose responsiveness span clinical range? u Training –competency evaluations at predetermined intervals

98 u Routine Quality Control –Instrument Performance Verification »Electronic Quality Control with Numeric Output u In GA, make sure state approves specific EQC »Two levels per 8 hour shift –Assay Performance Verification »Wet QC as per Manufacturers Recommendation »Two levels for each box of reagent when opened

99 Connectivity u Everyone wants it –Almost no one is ready to implement u 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

100 Short term solutions u Interim programs for configuration, data capture, QC compliance tracking –transfer to file format easily adaptable »Requires independent transfer protocol »e.g., ITC Configuration Manager, ReportMaker, HRDM u Dedicated interface specific to one manufacturers instrumentation »e.g., Abbott; Lifescan »Manufacturer ensures system compatibility

101 u 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

102 Long term Solutions u 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

103 Why Bother with POC Coag? u Improved TAT - Turn Around Time u Standardized Clinical Interpretation –Defined Assay Sensitivity »Requires Lot to Lot Reproducibility –Defined Reagent Variability »Identical Instrumentation /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

104 Why Bother with POC Coag? u Improved Clinical Outcome u Reduced LOS – Length of Stay u Improved, timely patient care


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