Bleeding in a NOVAL World EVALUATION AND MANAGEMENT OF BLEEDING IN AN ERA OF NOVEL ORAL

NEIL KUMAR, MD UNIVERSITY OF ROCHESTER MEDICAL CENTER Disclosures

 I have no financial disclosures

 I am NOT A HEMATOLOGIST Outline

 Review of hemostasis and

 Discuss laboratory markers for coagulopathy

 Discuss new oral anticoagulants

 Options for evaluation and management of the bleeding patient Outline

 Review of hemostasis and coagulation

 Discuss laboratory markers for coagulopathy

 Discuss new oral anticoagulants

 Options for evaluation and management of the bleeding patient Coagulation

 Coagulation is the process in which blood clots  is the process in which clot dissolves  Hemostasis is the stopping of bleeding or hemorrhage.  Ideally, hemostasis is a balance between coagulation and fibrinolysis Coagulation (classic pathways)

Michael G. Crooks Simon P. Hart Eur Respir Rev 2015;24:392-399 Coagulation (another view)

Gando, S. et al. (2016) Disseminated intravascular coagulation Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37 Coagulation (yet another view)

 Inflammation and coagulation intersect with in the middle

 An example of this is Disseminated Intravascular Coagulation.

Gando, S. et al. (2016) Disseminated intravascular coagulation Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37 Outline

 Review of hemostasis and coagulation

 Discuss laboratory markers for coagulopathy

 Discuss new oral anticoagulants

 Options for evaluation and management of the bleeding patient PT / INR

 Test of Extrinsic Pathway

 Take plasma (blood without cells) and re-add calcium

 Calcium was removed with citrate in tube

 Add tissue factor

 See how long it takes to clot and normalize PT to get INR Coagulation (classic pathways)

Michael G. Crooks Simon P. Hart Eur Respir Rev 2015;24:392-399 aPTT

 Activated Partial Thromboplastin Time  Test of Intrinsic Pathway  Take plasma (blood without cells) and re-add calcium  Calcium was removed with citrate in tube  Add “partial thromboplastin”  Thromboplastin is a lab surrogate for tissue factor. It Is actually phospholipid and tissue factor  Add negative charged particle (usually kaolin or silica)  Negative charged particle in the vessel is collagen exposed by vessel injury

 See how long it takes to clot Coagulation (classic pathways)

Michael G. Crooks Simon P. Hart Eur Respir Rev 2015;24:392-399 ACT

 Test of entire coagulation cascade, except fibrinolysis

 Take whole blood and mix with glass beads or kaolin

 See how long clot will take to form

 Most commonly used in cardiac bypass due to extreme amounts of used TT

Time

 Measures conversion of to fibrin.

 Take plasma and add thrombin

 Reptilase is secreted by vipers and catalyzes fibrinogen to fibrin

 Related to

 Except, since it not mammalian, it doesn’t adhere to normal human homeostatic feedback mechanisms

 Ecarin is from venom and activates prothrombin

 Bypasses extrinsic and intrinsic pathways TEG / ROTEM

 Both are commercial types of viscoelastic tests.

 TEG, the cup moves. ROTEM, the pin moves

 It shows interaction of platelets with the coagulation cascade TEG / ROTEM

Gregory Semon, Michael Cheatham. TEG in Trauma http://www.surgicalcriticalcare.net/Guidelines/TEG%202014.pdf TEG / ROTEM TEG / ROTEM

The Lancet Neurology 2017 16, 630-647DOI: (10.1016/S1474-4422(17)30197-7) Outline

 Review of hemostasis and coagulation

 Discuss laboratory markers for coagulopathy

 Discuss new oral anticoagulants

 Options for evaluation and management of the bleeding patient NOACs

 Direct Thrombin Inhibitor  Dabigatron (Pradaxa)

 Factor Xa Inhibitor  Rivaroxaban (Xarelto)  Apixaban (Eliquis)  Edoxaban (Savaysa) NOACs

 Direct Thrombin Inhibitor  Dabigatron (Pradaxa)

 Factor Xa Inhibitor  RivaroXAban (Xarelto)  ApiXAban (Eliquis)  EdoXAban (Savaysa) NOACs NOACs Pharmacology

Key Points Dabigatran Apixaban Edoxaban Rivaroxaban

Mechanism Direct thrombin Factor Xa Factor Xa Factor Xa action inhibitor inhibitor inhibitor inhibitor

Time to peak 1 h 3-4 h 1-2 h 2-4 h

Half life 12-17 h 12 h 10-14 h 5-9 h

Bioavailability 3%-7% 50% 62% 66%

Hepatic glucouronidatio Minimal CYP n to active CYP 3A4/5 and CYP 3A4/5 and Metabolism 3A4 and P-gp metabolites P-gp substrate P-gp substrate substrate and P-gp substrate

Excretion Renal 80% Renal 27% Renal 50% Renal 36%

Rachel Rosovsky, Geno Merli, Anticoagulation in Pulmonary Embolism: Update in the Age of Direct Oral Anticoagulants, Techniques in Vascular and Interventional Radiology, Volume 20, Issue 3,2017, NOACs

 Effective in reducing stroke risk in atrial fibrillation when compared against  Effective in reducing recurrent VTE when compared against warfarin NOACs

Xiaoxi Yao et al. J Am Heart Assoc 2016;5:e003725 NOACs

 There is a real bleeding risk, but what to do and how to evaluate these patients. Outline

 Review of hemostasis and coagulation

 Discuss laboratory markers for coagulopathy

 Discuss new oral anticoagulants

 Options for evaluation and management of the bleeding patient NOACs

 There is a real bleeding risk, but what to do and how to evaluate these patients. Dabigatron

 Evaluation  aPTT, PT, TT  Normal aPTT or TT likely excludes therapeutic levels of dabigatron  Prolonged aPTT likely indicates anticoagulation, but does indicate degree of effect  Normal PT likely does not exclude therapeutic levels  Quantitative assessment may be possible with ecarin based assays Dabigatron

 Management  If recent major ingestion, can consider activated charcoal  Hemodialysis may remove 50% within 4 hours  Antidote is idarucizumab (Praxbind)  Case reports with FFP, recombinant Factor VII activated, PCCs, fibrinogen, platelets with mixed results Rivaroxaban

 Evaluation  ACT, anti-Factor Xa  Undetectable anti-Xa activity likely excludes clinically relevant drug levels.  Prolonged PT with no other explanation in patient known to be taking rivaroxaban likely indicates drug presence.  Normal PT does not exclude drug presence or greater concentrations, so not useful Rivaroxaban

 Management  If recent major ingestion, can consider activated charcoal  Hemodialysis not useful  Antidote is andexanet alfa (in testing)  4F PCC led to normalization of PT and endogenous thrombin potential in volunteers  In vitro data suggests that recombinant Factor VII activated may be superior than 4F PCC  Case reports using FFP or PCC show success in correcting laboratory coagulation parameters. Apixaban

 Evaluation  Similar to Rivaroxaban (anti-Xa likely most useful)  PT and aPTT are not useful Apixaban

 Management  Similar to Rivaroxaban  Interim analysis of Andexanet Alfa shows 93% reduction in anti-Factor Xa activity and 80% with good or excellent clinical hemostasis Edoxaban

 Evaluation  Similar to Rivaroxaban (anti-Xa likely most useful)  PT is more sensitive than aPTT  Prolonged PT with no other explanation in patient known to be taking edoxaban likely indicates drug presence.  Normal PT does not exclude drug presence or greater concentrations, so, again, not useful Edoxaban

 Management  Similar to Rivaroxaban  4F PCC showed dose dependent reversal with complete reversal of bleeding duration after skin punch biopsy Conclusion

Amish N. Raval et al. Circulation. 2017;135:e604-e633 Conclusion

 Hemostasis is the interplay between coagulation and fibrinolysis

 Laboratory evaluation is not perfect

 NOACs aren’t really that new anymore and we should be prepared to treat the bleeding patient with a normal PT/INR

 References

 Amish N. Raval et al. Circulation. 2017;135:e604-e633

 Rachel Rosovsky et al. Techniques in Vascular and Interventional Radiology. 2017; 20,3:141-151