DOAC s and Implications on Laboratory Results. Kandice Kottke-Marchant, MD, PhD Cleveland Clinic

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1 DOAC s and Implications on Laboratory Results Kandice Kottke-Marchant, MD, PhD Cleveland Clinic

2 Anticoagulants Heparin Low Molecular Weight Heparins enoxaparin, fragmin Heparin pentasaccharide - fondaparinux Intravenous IIa inhibitors bivalirudin Vitamin K antagonists - warfarins Direct Oral Anticoagulants (DOAC) Thrombin inhibitors - dabigatran Xa inhibitors rivaroxaban, apixaban, edoxaban

3 Use of DOAC s Prevention of strokes Prevention of systemic thromboemboli In patients with nonvalvular atrial fibrilation

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5 DOAC s and the Laboratory Assessment of anticoagulant activity Interference with other coagulation tests

6 Assessment of Anticoagulant Activity Dabigatran APTT more sensitive than PT Rivaroxaban PT more sensitive than APTT Apixaban little effect on PT and APTT However, response variable between PT and APTT reagents Reagent sensitivity: in vitro drug concentration required to double baseline value

7 Dabigatran ISTH Recommendation APTT can be used to determine relative intensity of anticoagulation (variability of reagents) Labs should be aware of the sensitivity of their APTT reagents to dabigatran Normal TT indicates a very low dabigatran level Dilute TT in combination with dabigatran calibrant can determine drug level Baglin T, et al. ISTH SSC Guidelines; J Thromb Haemst 2013: 11: 756

8 Rivaroxaban ISTH Laboratory Guidelines PT with a plain thromboplastin can be used to assess relative intensity of anticoagulation Each lab should be aware of the sensitivity of their PT assay to rivaroxaban Anti-Xa assays, with rivaroxaban calibrants, can be used to determine drug level Baglin T, et al. ISTH SSC Guidelines; J Thromb Haemst 2013: 11: 756

9 Concentrations to Double PT and APTT Test Dabigatran (Peak ug/l) Rivaroxaban (therapeutic ug/l) Apixaban (therapeutic 200 ug/l) PT ug/l Quick Type: ug/l Owren Type: ug/l ug/l APTT ug/l ug/l ug/l Lindahl, Thr Haemost 2011: 105: 371 Hillarp, JTH 2011; 9: 133 Hillarp JTH :1545

10 What effect do DTI s have on other laboratory tests? PT/INR, APTT prolonged, remain prolonged in mix Acts like an inhibitor in clotting-time assays, under-estimating results Fibrinogen falsely low C & S, overestimated ATIII - has anti-thrombin activity Walenga, J., (2006) Direct Thrombin Inhibitors & Laboratory Monitoring Issues, Coagulation Symposium, Indianpolis, May 5.

11 How Common is DOAC interference with Thrombophilia Testing?

12 Percentage of Panels with Drug Interference Year Hyper Panel (total) % Drug Effect Lupus Panel (total) % Drug Effect

13 Percentage of Panels with Anti- Xa Drug Effect Year Hyper Panel (Total) %XADI Lupus Panel (Total) % XADI

14 Laboratory Strategy for Thrombophilia Testing in the DOAC Era Identify interfering anticoagulants Heparin and LMWH Anti-Xa Anti-IIa Screen samples with PT, APTT, TT and anti-xa Utilize heparin neutralization (Heparinase) to distinguish

15 Test UFH (Xa:IIa 1:1) LMWH (Xa>IIa) Anti-Xa Anti-IIa PT NL NL NL Elev APTT Elev Mildly Elevated TT Very Elev (>80 sec) Slightly Elevated Often NL Anti-Xa U/ml U/ml Usually >1.0 U/ml TT + HZ Anti-Xa +HZ NL (or near normal) <0.1 U/ml (neutralized) Elev NL Very Elev (>80 sec) NEGATIVE NL NL Very Elev (>80 sec) (Not Neutralized) Usually >0.1 U/ml (incomplete neutralization) Not changed NEGATIVE

16 Tailor Panel to Intefering Drug Heparin (<1.0 U/ml) Neutralize heparin and proceed with testing High Heparin (>1.0 U/ml) Do not do lupus testing Anti-IIa and anti-xa Do not do lupus testing, VIII, APC-R or protein S clottable Add FVL and protein S antigen

17 Summary DOAC s present laboratory challenges for assessment of anticoagulant effect DOAC s interfere with many laboratory tests, especially clot-based assays and lupus anticoagulant testing Thrombophilia testing is increasingly affected by patients on DOAC therapy Laboratory strategies exist to detect and modify panels for heparin, anti-iia and anti-xa drugs