New Oral Anticoagulants

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1 Laboratory Monitoring of New Oral Anticoagulants.....What you need to know Rita Selby MD Medical Director, Coagulation Laboratories Uniersity Health Network & Sunnybrook HSC Uniersity of Toronto The 15 th Annual Contemporary Therapeutic Issues in Cardioascular Disease April 28, 2012 New Oral Anticoagulants Brief oeriew of the chemistry of coagulation Reiew principles of routine coagulation screening tests Laboratory monitoring of NOAC Reersal strategies 1

2 New Oral Anticoagulants Brief oeriew of the chemistry of coagulation Reiew principles of routine coagulation screening tests Laboratory monitoring of NOAC Reersal strategies Old & New Oral Anticoagulants XII XI IX VIII X VII Oral Xa inhibitors riaroxaban apixaban Heparin LMWH V warfarin II I Oral IIa inhibitors dabigatran Fibrin clot 2

3 Simplified Coagulation Cascade Contact XIIa XI XIa HKa IX IXa * Platelets proide Phospholipid source TF Pathway TF-VIIa PL VIIIa * PL (Tenase) Tissue Factor + VII X Xa Va Fibrinogen Prothrombin PL Thrombin Fibrin (weak) XIII XIIIa Fibrin (strong) Coagulation Cascade Intrinsic Pathway Extrinsic Pathway Contact XIIa XI XIa HKa IX IXa TF Pathway TF-VIIa PL VIIIa Natural Anticoagulants Protein C, Protein S, Antithrombin PL + Ca (Tenase) Tissue Factor + VII X Xa Va Fibrinogen Common Pathway Prothrombin PL Thrombin Fibrin (weak) XIII XIIIa Fibrin (strong) 3

4 New Oral Anticoagulants Brief oeriew of the chemistry of coagulation Reiew principles of routine coagulation screening tests Laboratory monitoring of NOAC Reersal strategies 4

5 Common tests in use to check for anticoagulant effect in the lab 1. PT Prothrombin time 2. INR International Normalized Ratio 3. APTT Actiated Partial thromboplastin time 4. TT Thrombin time 5. Anti-Xa assays Less common: ACT Actiated Clotting time ECT Ecarin Clotting time 5

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7 Thrombin time Thrombin is added to plasma and the time taken to conert fibrinogen to fibrin is measured Thrombin time is increased when: Thrombin is inhibited by drugs (heparin, LMWH, Direct thrombin inhibitors) There is either a lack or dysfunction of fibrinogen There are degradation products of fibrinogen in the circulation 7

8 Anti-Xa assay for UFH / LMWH Principle: Plasma Sample (Xa-Hep+AT) + F Xa (excess) [Hep+AT-FXa] + F Xa (residual) F Xa (residual) + substrate = peptide + pna (paranitroaniline) pna (paranitroaniline) measured at 405 nm and reaction inersely proportional to drug concentration New Oral Anticoagulants Brief oeriew of the chemistry of coagulation Reiew principles of routine coagulation screening tests Laboratory monitoring of NOAC Reersal strategies 8

9 Situations where lab monitoring may be needed for New Oral Anticoagulants 1. A patient experiences bleeding what is the leel of anticoagulant in their blood? 2. A patient needs a procedure has the anticoagulant effect been reersed? 3. Renal dysfunction is there accumulation of drug? 4. Extremes of weight is the dose appropriate? 5. A patient has a stroke on the medication is the patient compliant with the medication? 6. Suspected drug oerdose what is the leel of anticoagulant in their blood? Monitoring Direct Thrombin Inhibitors XIIa XIa VIIa Tissue factor IXa Xa II PT aptt TT / modified TT ECT Factor IIa (thrombin) Dabigatran 9

10 Effect of dabigatran on routine coagulation tests PT/INR flat dose response - little effect at clinically releant concentrations aptt - non linear, aries with instrument reagent combinations (need to deelop institution specific cut-offs) Thrombin Time - too sensitie, aries with instrument reagent combinations Modified TT (Hemoclot ) best linearity across therapeutic range Ecarin Clotting time (ECT) good linearity, aailability, standardization and cost are limiting factors aptt s. modified Thrombin Time (Hemoclot ) for indirect assessment of dabigatran concentration Van Ryn et al. Thromb Hemost 103.6/

11 Monitoring Direct Xa inhibitors XIIa XIa IXa PT aptt Xa-inhibition assays Xa Factor II (prothrombin) VIIa Tissue factor Riaroxaban Apixaban Fibrinogen Fibrin clot Effect of riaroxaban on PT and INR PT best dose response, aries with instrument reagent combinations INR non-linear dose response, aries with instrument reagent combinations 11

12 What accounts for INR ariability? 3 ariables = PT, Mean Normal PT, ISI Manufacturer assigned ISI of PT reagents is determined from the SLOPE of the regression line when comparing the PT of: 20 plasmas from normal subjects & 60 plasmas from patients stable on OVKA determined with WHO reference thromboplastin and the working thromboplastin 7 normal plasmas spiked with a range of riaroxaban concentrations used to derie a Riaroxaban-specific ISI for 6 PT reagents When this ISI was used in the INR calculation of 3 known concentrations of Riaroxaban ariability was significantly minimized Tripodi et al, J Thromb Haemost 2011;9:

13 Anti-Xa assay for Direct Xa inhibitor Principle: Plasma Sample (Xa-inhibitor) + F Xa (excess) [Xa-inhibitor-FXa] + F Xa (residual) F Xa (residual) + substrate = peptide + pna (paranitroaniline) pna (paranitroaniline) measured at 405 nm and reaction inersely proportional to drug concentration Xa inhibition assays for monitoring Direct Oral Xa-inhibitors More specific than PT Less aailable Anti-Xa assay will need riaroxabanspecific calibration line (commercial riaroxaban calibrators) Samama et al, Thromb Haemost 2012;107: Some eidence that a specific calibration cure may not be needed for apixaban 13

14 New Oral Anticoagulants and Coagulation Monitoring : Summary Drug Coagulation assays dabigatran aptt non-linear dose response riaroxaban apixaban Thrombin time (TT) too sensitie Ecarin Clotting Time (ECT) - $$, aailability Hemoclot assay best linearity PT (INR) non-linear dose response Anti-Xa assay - with specific ria calibrator PT (INR) non-linear dose response Anti-Xa assay - with specific apixa or LMWH calibrator 14

15 New Oral Anticoagulants and Coagulation Monitoring IMPORTANT TO REMEMBER: Most of the tests proide a qualitatie assessment of coagulation No therapeutic ranges set No eidence linking plasma leels to safety of surgery or bleeding risk New Oral Anticoagulants Brief oeriew of the chemistry of coagulation Reiew principles of routine coagulation screening tests Laboratory monitoring of NOAC Reersal strategies 15

16 Guidance on the emergent reersal of oral thrombin and factor Xa inhibitors Thrombosis Hemostasis Summit of North America (THSNA) Meeting proceedings Kaatz et al - Am J Hematol 00: ,2012 Dabigatran Reersal Strategies Oral actiated charcoal - within 2 hours of ingestion > 99% adsorption in itro, boine whole blood model FFP reduced ICH but not mortality in dabi Rx mice Hemodialysis only known interention to reduce plasma dabi conc. by 68% after 4 hours dialysis 1 case series, in itro - controersial area, access to HD Procoagulant hemostatic agents (rviia, PCC) shortened bleeding time in itro and in a rat model but did not shorten PTT, ECT. 12 healthy olunteers on dabi no effect of non actiated PCC on normalizing lab tests Antidote monoclonal antibody in deelopment complete dabi inhibition in rat model 16

17 Riaroxaban Reersal Strategies Charcoal, FFP no data HD no data, highly protein bound Procoagulant hemostatic agents (rviia, PCC) shortened clotting times and bleeding times in itro and in mouse, rat, rabbit and primate models 12 healthy olunteers on ria non actiated 4 factor PCC normalized lab tests Antidote r-antidote a recombinant Xa deriatie reduction of ria induced blood loss in ASA Rx mice Patient with bleeding on dabigatran CBC, creatinine aptt If aptt >40 sec, consult Hematology Mild bleeding Moderate-seere bleeding 1 Life-threatening bleeding 1 Local hemostatic measures Hold 1 or more doses of dabigatran Supportie Care (compression, surgery) Fluid à diuresis Transfuse RBCs or platelets if needed Oral charcoal if dose <2 hrs before Supportie care Transfusion Consider tranexamic acid / VIIa Hemodialysis might be helpful 1. DO NOT TRANSFUSE FFP to reerse aptt 17

18 Thank you 18