1. Direct Oral Anticoagulants
Allison Paroskie, MD

2. Outline Anticoagulation Review of New Direct Oral Anticoagulants
Laboratory Testing
Reversal / Techniques with Bleeding

3. Anticoagulants Heparin Warfarin: vitamin K antagonist
Unfractionated & low molecular weight
Factors II and X
Warfarin: vitamin K antagonist
Factors II, VII, IX, X
New oral anticoagulants
Direct thrombin inhibitors
Dabigatran
Xa inhibitors
Rivaroxaban, apixaban, betrixaban, edoxaban

5. “Ideal” Oral Anticoagulant
Antithrombotic effect without bleeding
Predictable dose response
No need for routine monitoring
Reduced need for dose adjustment
No food interaction
Limited drug interactions

6. Direct Oral Anticoagulants

8. Direct Oral Anticoagulants Thrombus

9. Direct Oral Anticoagulants Bleeding
Increased GI bleeding in DTI’s
Reduction in ICH
Trend towards reduced major bleeding
Otherwise no clear increased bleeding for any of the new ODI (“clear” because it is difficult to compare bleeding between studies thus a direct comparison has not been made)

10. Direct Oral Anticoagulants
Dabigatran
Rivaroxaban
Direct specific competitive inhibitor of free and fibrin-bound thrombin
Renal clearance
½ life: 11 hours
Extended if poor renal function
No adjustment if kg
Food has no significant effect
Direct specific competitive inhibitor of Xa
Limits thrombin generation in a dose dependent manner
Metabolized in liver
½ life: 7 – 11 hours
No adjustment if kg
Food increases absorption

11. Direct Oral Anticoagulants Drug Interactions

12. Warfarin Drug Interactions

13. Laboratory Testing

14. Useful Timing for Testing
Baseline
Assessment for bleeding diathesis: CBC, PT, aPTT
Preoperatively
Concern of delayed clearance
Adverse events (thrombosis or hemorrhage)
Assessment for under- or over-anticoagulation
May require reversal
Assessment of adherence
Dose adjustments if extreme body weight and/or known drug-to-drug interactions

15. Laboratory Assessment

16. Direct Thrombin Inhibitors
Ecarin Clotting Time (ECT)
Thrombin Time (TT)
Snake venom that converts FII to meizothrombin; DTI inhibition of meizothrombin can be measured
Linear and dose dependent
3 x baseline
Measurement of plasma clotting time after adding thrombin
Linear and dose dependent
Excessive response
10 x baseline
Normal result rules out anticoagulant effect
No reflection of drug concentration
Dilute TT
Activated Partial Thromboplastin Time (aPTT)
1.7 x baseline
Not linearly related
Between–reagent variability

17. Direct Xa Inhibitors Anti-Xa Prothrombin Time (PT)
Measurement of residual Xa with synthetic substrates upon mixing plasma with Xa
Responsive to Xa
Linear dose response
1.5 x baseline
Varies based on reagents

18. Other Helpful Lab Tidbits
Antithrombin activity can be overestimated
Fibrinogen activity can be underestimated
Factor XIII activity can be underestimated
Activated protein C resistance may be affected
Protein C & S levels, and lupus anticoagulant testing can be affected

19. Summary of Laboratory Testing

20. Reversal / Treatment with Bleeding

21. Supportive Measures Discontinuation of medication
Oral activated charcoal
Recent intake / overdose
Local / mechanical control
Dialysis – dabigatran

22. Supportive Medications
Antifibrinolytic agents
No studies
Safety demonstrated in surgical and traumatic bleeding
Desmopressin
Stimulates release of VWF & FVIII from vascular endothelium (primary hemostasis)
Reduced skin bleeding in animals anticoagulated with thrombin inhibitors
Topical thrombin

23. Supportive Blood Products
pRBCs
Volume expansion
Improvement of symptomatic anemia
Platelets
Correction of thrombocytopenia
Perhaps beneficial if anti-platelet agents are also used
Fresh Frozen Plasma
Dilutional coagulopathy
No role in reversal of oral agents
Cryoprecipitate

24. Reversal of DTI Activated prothrombin complex concentrate
Factors II, IX, X, VII
Reduction in bleeding time in mice
Reversal of impaired thrombin generation (ex-vivo)
Associated increased risk of thromboembolic complications

25. Reversal of DTI Inactive factor prothrombin complex concentrate
Factors II, IX, X, (VII)
Animal models resulted in limited hemorrhage
Inability to reverse thrombin generation in ex-vivo studies
Case series: 4 patients with excessive levels (renal impairment)
pRBC, FFP, PCC, rFVIIa

26. Reversal of DTI Recombinant FVIIa
Does not reverse thrombin generation in ex-vivo studies
Not effective in minimizing clinical bleeding

27. Reversal of DTI Monoclonal antibodies
Humanized, highly selective antibody is in development
Rapid dose dependent decrease in experimentally induced blood loss
Clinical studies in

28. Reversal of DXI Prothrombin complex concentrates
Shortened the aPTT and clotting time (TEG), but no change in clinical bleeding
Normalizes PT in healthy controls

29. Reversal of DXI Recombinant VIIa
Normalizes PT and bleeding time in animal models, but no effect on blood loss (supratherapeutic doses)

30. Reversal of DXI PRT4445 Universal reversal agent for Xa inhibitors
Recombinant protein that binds Xa inhibitors
Pre-clinical data shows reversal in fondaparinux and enoxaparin
Health controls: tolerated with no safety concerns

31. Conclusions Non-inferior / equivalent anti-coagulation to warfarin
Bleeding risks are equivocal
Improved pharmacodynamics and pharmacokinetics
Moderately helpful monitoring
Minimal reversal techniques

32. References
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