Bleeding in a NOVAL World EVALUATION AND MANAGEMENT OF BLEEDING IN AN ERA OF NOVEL ORAL ANTICOAGULANTS
NEIL KUMAR, MD UNIVERSITY OF ROCHESTER MEDICAL CENTER Disclosures
I have no financial disclosures
I am NOT A HEMATOLOGIST Outline
Review of hemostasis and coagulation
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 Fibrinolysis 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 platelets 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 heparin used TT
Thrombin Time
Measures conversion of fibrinogen to fibrin.
Take plasma and add thrombin Reptilase Time
Reptilase is secreted by vipers and catalyzes fibrinogen to fibrin
Related to Thrombin Time
Except, since it not mammalian, it doesn’t adhere to normal human homeostatic feedback mechanisms Ecarin Clotting Time
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 warfarin 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