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

Coagulation Testing Monitoring hemostasis Bleeding Clotting

Maintaining Hemostasis Counterbalance thrombosis with anticoagulant therapy Thrombosis

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

Components of Hemostasis Vessels Coagulation Proteins Platelets Fibrinolysis / Inhibitors

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

Components of Hemostasis Vessels Coagulation Proteins Platelets Fibrinolysis / Inhibitors

Anatomy of a Platelet

Resting Platelets

Platelet Aggregate

Hemostasis Primary hemostasis Secondary hemostasis Platelet Adhesion Coagulation Fibrin clot formation

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

Platelet Testing Peripheral smear Platelet count Platelet aggregation Bleeding time

Peripheral Blood Smear

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

Bleeding Time Cut 1 mm deep, 5 mm long Constant pressure Expected Range : 2 - 10 minutes

Components of Hemostasis Vessels Coagulation Proteins Platelets Fibrinolysis / Inhibitors

Coagulation Inactive enzyme Active enzyme Inactive enzyme

Coagulation is Complex

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

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 Usually No Added Anticoagulant No Dilution No Preanalytical Delay

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

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

Semi - Automation - 1969 HEMOCHRONOMETER (HEMOCHRON) Magnet in tube, detector in instrument Upon clot formation, magnet is deflected Clotting time displayed

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

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

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

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

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

Newer Technologies 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)

Newer Technologies Active pumping system Hemochron Jr Signature ProTime microcoagulation system

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

Activated Clotting Time Extrinsic Pathway Intrinsic Pathway ACT Common Pathway CLOT

What do we use an ACT for? Maintain Balance Heparin 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?

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

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

Heparinized ACT - CPB Data from Huffman, et.al. 1998 AmSECT meeting 17

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

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 Data from clinical evaluation, on file, ITC

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

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

Thrombin Time TT Intrinsic Pathway Extrinsic Pathway Common Pathway CLOT

Other POC in the OR Heparin Level Xa Activity Medtronic Hepcon HMS 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

Monitoring - Heparin Level Benefits Measures concentration, not activity Correlates with laboratory standards 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

Monitoring - Heparin Level Young: <4.5 years Shayevitz, JR and O’Kelly, SW Progress in Anesthesiology, vol. IX, chapter 16 1995

Other POC Coag in the OR aPTT / PT Fibrinogen Dosing Assays Pre- and post-procedural screening Fibrinogen Dosing Assays Customize heparin and protamine for each patient HEMOCHRON HRT / PRT Hepcon HMS

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 Applications Operating Room Cardiac Surgery Interventional Cardiology and Radiology

Procedures Diagnostic Interventional Catheterization Electrophysiology locate and map vessel blockage(s) determine need for interventional procedures Electrophysiology 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 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 Integrelin Aggrastat elevates ACTs target time = 250 sec with ReoPro determined using FTCA510 tube Integrelin No clinically significant effects on ACT Slight decrease in ACT observed Aggrastat No reported effects on ACT

QUESTIONS?

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

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

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

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 Extrinsic Pathway Intrinsic Pathway APTT 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 the presence of heparin underlying coagulopathy Monitor heparin / coumadin® cross-over

Heparin versus Warfarin

Prothrombin Time PT Intrinsic Pathway Extrinsic Pathway Common Pathway CLOT

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=2.5 – 3.5

Will POC Results Match the Lab? NO! (Probably Not) but it WILL Correlate

Correlate Does Not Mean Match

Coag is NOT Chemistry

Compare for your site. Same System / Multiple Sites

Are differences important? Sometimes no - aPTT C

Sometimes VERY - aPTT SP

Lot to Lot Reproducibility

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 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?

Patient Management 6.0 5.0 4.0 3.0 2.0 1.0 Target INR 3.0 Must change dose Target INR 3.0 Range 2.5 -3.5 Call Clinic May change dose Patient Management

What’s the catch? Regulatory compliance 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 CMS (formerly HCFA) Centers for Medicare & Medicaid Services CDC Centers for Disease Control

CLIAC CLIA Committee CLIA - Clinical Laboratory Improvement Act 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 / CMS / CDC complexity categories

CLIA Applies to ALL Testing Areas Central Laboratory Satellite Labs Critical Care Surgical Suite Clinics Bedside testing Doctor’s office Home Testing

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

Implementing POC coag requires: RECORD KEEPING Method Validation - accuracy comparison to current standard 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? Training competency evaluations at predetermined intervals

Routine Quality Control Instrument Performance Verification Electronic Quality Control with Numeric Output In GA, make sure state approves specific EQC 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 Multiple definitions 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 configuration, data capture, QC compliance tracking transfer to file format easily adaptable Requires independent transfer protocol e.g., ITC Configuration Manager, ReportMaker, HRDM 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

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 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

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