Helene Maltz, B.S., Pharm.D. PGY 2 Pharmacy Resident Internal Medicine Kingsbrook Jewish Medical Center Department of Pharmacy Clinical Assistant Professor of Pharmacy Practice Arnold & Marie Schwartz College of Pharmacy and Health Sciences Long Island University Brooklyn, New York January 20, 2013 None to disclose 2 Explain the mechanism of action of select antiplatelet and anticoagulant agents Outline a treatment plan for bleeding complications associated with antiplatelet agents including aspirin, clopidogrel, prasugrel, and ticagrelor Describe potential reversal options for anticoagulation with warfarin, heparin, low molecular weight heparins, fondaparinux, dabigatran, rivaroxaban, and apixaban 3 1
Explain the mechanism of action of select antiplatelet and anticoagulant agents Outline a treatment plan for bleeding complications associated with antiplatelet and anticoagulant agents 4 Primary hemostasis at endothelial damage site Platelet adhesion Thrombin burst via extrinsic pathway Immediate seal formation Secondary hemostasis Thrombin activation of intrinsic pathway Fibrin generation Fully developed clot 5 INDICATIONS AND USAGE Up to 2% of developed world population Uses Atrial fibrillation Venous thromboembolism Post MI Post PCI Ischemic stroke AVAILABLE CLASSES Vitamin K antagonists (VKA) Unfractionated heparin (UFH) Low molecular weight heparins (LMWH) Pentasaccharides (FXa inhibitor) Oral direct thrombin inhibitors (DTI) Dabigatran Factor Xa inhibitors (oral) Rivaroxaban Apixaban Vigue B. Critical Care. 2009;13:209 (doi:10.1186/cc7001 Levi MM, et al. Neth J Med. 2010;68:68 76 6 2
Vitamin K antagonists Factor Xa inhibitors Direct thrombin inhibitors Low molecular weight heparins Unfractionated heparin http://www.cancerthrombosis.org/content/modules/2/articlefigures/mod02new_fig02.jpg 7 INDICATIONS Primary CAD/CVA prophylaxis Secondary CAD/CVA prophylaxis Peripheral vascular disease Post stent placement AVAILABLE AGENTS Aspirin ADP P2Y 12 inhibitors Clopidogrel Prasugrel Ticagrelor Ticlopidine Phosphodiesterase inhibitors Cilostazol Dipyridamole GP IIb/IIIa antagonists 8 Normal platelet effects: Seal microscopic gaps in endothelium Activated platelets recruit additional platelets through secretion of ADP, histamine, serotonin, thromboxane A 2 (TXA 2 ) and growth factor Adherence surface for coagulation factors http://numob.files.wordpress.com/2009/08/mech_antiplatelet.gif?w=544 9 3
Worse than non anticoagulant associated bleeds Major bleeding Critical locations: intracranial, retroperitoneal, gastrointestinal, genitourinary Associated with intensity of anticoagulation and combination with antiplatelet agents Predictor of mortality: 5 fold increased risk of death within 30 days of bleed Outcomes improved if rapid reversal of anticoagulation Risk/benefit balance must be favorable for use Vigue B. Critical Care. 2009;13:209 (doi:10.1186/cc7001) Levi MM, et al. Neth J Med. 2010;68:68 76 Levi M, et al. J Thromb Haemostas. 2011;9:1705 12 Kalyanasundaram A, et al. Nat Rev Cardiol.2011;8:592 600 10 Scheduled versus urgent Antiplatelet/anticoagulant indication Cardiovascular events: low versus high risk Time since stent placement and stent type Thromboembolic complications (mechanical valves, atrial fibrillation, VTE): low versus high risk Procedure type/location Minor dental or dermatologic versus cataract Cardiac Gastrointestinal, genitourinary Weigh thrombosis risk (ex. antithrombotic indication, CHADS 2 ) versus bleeding risk (ex. HAS BLED) Levi MM, et al. Neth J Med. 2010;68:68 76 Ortel TL. Hematology Am Soc Hematol Educ Program. 2012;529 35. doi: 10.1182/asheducation 2012.1.529 11 Assess whole patient Consider drug half life Determine goal Complete reversal Return to therapeutic anticoagulation Create protocols for institution Remain vigilant with new agents 12 4
Supportive Care Removal of Drug Antidotes Replacement Therapy Discontinue drug Activated charcoal Protamine sulfate Platelet infusions Fluid resuscitation Hemodialysis Vitamin K Fresh frozen plasma (FFP) Blood Identification and control of bleeding source Hemostasis agents: Aminocaproic acid Tranexamic acid Hemoperfusion with charcoal Investigational: Factor Xa antidote Monoclonal antibodies Avidin neutralization Prothrombin complex concentrates (PCC) Recombinant factor VIIa (rfviia) Desmopressin 13 1 unit single donor platelets (5 6 units multiple donor) 30 x 10 9 /L platelet count increase Immediate restoration of platelet activity Nishijima DK, et al. J Trauma Acute Care Surg. 2012;72:1658 63 Blood bank product 22ºC incubator, agitator Blood typing required Administration Filter Infuse over 30 minutes Use within 4 hours Potential risks Infection ABO mismatch Alloimmunization Refractoriness 14 Replaces all coagulation factors at 1 unit/ml Dose: 10 15 ml/kg Blood bank product Requires blood typing Requires thawing time Administration Blood giving set (filter) Use within 4 hours of thaw Infuse each unit over 30 minutes Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Beshay JE, et al. J Neurosug. 2010;112:307 18 Lexi Comp Online TM Lexi Comp, Inc.; Accessed January 4, 2013. Limitations Fluid overload Cannot fully replete factors at tolerable volume Freezing reduces factor concentration Delays in procurement Allergic reactions Transfusion related acute lung injury Cost ~$60 per unit (200 ml) ~$360 per treatment (80 kg) 15 5
MOA: Replaces factors II, IX, X resulting in thrombin formation and hemostasis Indications Labeled: Factor IX deficiency Unlabeled: warfarin coagulopathy Dosed by FIX activity Profilnine (25% greater activity): 1 unit/kg raises plasma factor IX level by 1% Pharmacy product Refrigerated; bring to room temp, reconstitute, and use within 3 hours No thawing required Lower volume than FFP Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119 S126 Lexi Comp Online TM ; Accessed January 4, 2013. Administration IV infusion Bebulin: <2 ml/minute Profilnine: <10 ml/minute 24 hour intervals Half life: ~24 hours Limitations No FVII Adverse reactions Flushing, rash Nausea, vomiting Thrombosis Cost ~$0.97 per unit ~$1,940 per treatment (warfarin reversal: 25 U/kg for 80 kg) 16 Replaces factors II, VII, IX, X, proteins C and S resulting in thrombin formation and hemostasis Labeled indication: VKA coagulopathy Not available in US Dose by initial INR: max 120 ml Pharmacy product Refrigerated; bring to room temp, reconstitute, and use immediately No thawing required Product is light blue Lower volume than FFP Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119 S126 Lexi Comp Online TM. Lexi Comp, Inc.; Accessed January 4, 2013. Administration IV infusion Initial: 1 ml/minute If no significant tachycardia, can increase to 2 3 ml/minute Onset: within 10 minutes Duration Half life FII: 48 72 hour FVII: 1.5 6 hour FIX: 20 24 hour FX: 24 48 hour Adverse reactions Hypertension Headache Elevated LFTs Hypersensitivity reactions 6 8 hours 17 Replaces activated factors II, VII, IX, X (and protein C) resulting in thrombin formation and hemostasis Indications Labeled: bleeding or surgery in hemophilia A/B Unlabeled: rivaroxaban reversal BOXED WARNING: thromboembolic events Dose: 50 100 unit/kg; based on FVIII bypassing activity Pharmacy product Room temp storage, reconstitute, and use within 3 hours Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119 S126 Lexi Comp Online TM Lexi Comp, Inc.; Accessed January 4, 2013. Administration IV infusion 2 units/kg/minute Onset: within 15 30 minutes Half life Duration FII: 48 72 hour FVII: 1.5 6 hour 8 12 hours FIX: 20 24 hour FX: 24 48 hour Adverse reactions Hypotension Thrombosis Rash and allergic reactions Cost ~$1.70 per unit $10,227 per treatment (75 unit/kg for 80 kg) 18 6
Replaces FVIIa Binds to tissue factor (TF) on subendothelial cells TF VIIa complex activates FIX and FX Thrombin generated (small amount) Thrombin activates platelets, FV and FVIII Thrombin burst and fibrin clot formation Indications Labeled: bleeding due to hemophilia A/B, acquired hemophilia, factor VII deficiency Unlabeled: warfarin related ICH BOXED WARNING: off label use, monitor for thrombosis Pharmacy product Refrigerated; bring to room temp, reconstitute, and use within 3 hours Dosage: 10 100 mcg/kg Administration IV bolus over 2 5 minutes Redose at 2 6 hour intervals Limitations Half life: ~2.3 hours Only contains FVIIa Adverse reactions Thrombosis risk (hemophilia dosing) Hypertension, bradycardia Fever, headache Rash, allergic reactions Cost ~$1,400 per 1 mg ~$4,480 $10,000 per treatment (40 mcg/kg for warfarin reversal and 90 mcg/kg for fondaparinux reversal per 80 kg) Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119 S126 Lexi Comp Online TM Lexi Comp, Inc.; Accessed January 4, 2013. 19 Increases plasma levels of von Pharmacy product Willebrand (VW) factor, factor Refrigerated VIII, and tpa to correct platelet Dilute in 10 50 ml NS dysfunction Onset: 0.5 hr; Peak: 1.5 2 hr Indications Half life: 3 hr; Duration: 6 14 hr Labeled: diabetes insipidus, Adverse reactions hemophilia A bleeding (FVIII activity >5%), VW s disease (type I), primary Vasoconstriction, hypertension nocturnal enuresis Headache, GI upset Unlabeled: uremic bleeding (in renal Hyponatremia failure), prevention of surgical Allergic reactions bleeding in uremia Thrombosis Dosage and administration Cost VW s disease, pre surgery: ~$59.30 per 4 mcg vial 0.3 mcg/kg IVPB over 15 30 minutes ~$355.80 per treatment (at 0.3 Uremic bleeding: 0.4 mcg/kg IVPB over 10 minutes mcg/kg for 80 kg for aspirin reversal) Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119 S126 Lexi Comp Online TM Lexi Comp, Inc.; Accessed January 4, 2013. 20 Irreversible inhibition of thromboxane A 2 (TXA 2 ) production causes platelet inactivation Half life: 10 20 minutes Duration of effect: 5 10 days Recovery of TXA 2 production takes ~4 days Platelet turnover: 10% per day Requires production of 40% non ASA platelets TXA 2 from non ASA platelets can activate ASA platelets Longer if used with clopidogrel Platelet transfusion for intracranial hemorrhage 1 unit single donor or 5 pooled concentrates Properly timed platelet transfusions prior to procedures Desmopressin (0.3 mcg/kg) May correct platelet dysfunction No large studies done rfviia Reversal of ASA antiaggregation effect Studied in healthy individuals Li C, et al. J Thromb Haemost. 2012;10:521 8 Campbell PG, et al. World Neurosurg. 2010;74:279 85 21 7
CLOPIDOGREL/PRASUGREL Irreversible inhibition of ADPinduced platelet aggregation Recovery takes >7 10 days 90% platelet turnover required Inhibited platelets cannot aggregate in response to ADP Platelet transfusions* 10 12 pooled concentrates Up to 4 5 days after last dose because of active metabolites Desmopressin rfviia (possibly) TICAGRELOR Reversible ADP inhibition Shorter acting than clopidogrel or prasugrel Requires 3 5 days for reversal due to strong antiplatelet effect Platelet transfusions may be required for severe bleeding Clopidogrel Prasugrel Ticagrelor Half life 6 hours 7 hours 7 hours Duration 7 10 days 5 9 days 3 5 days *PI suggestion Li C, et al. J Thromb Haemost. 2012;10:521 8 Campbell PG, et al. World Neurosurg. 2010;74:279 85 22 TRUE or FALSE: The reversibility and short half life of ticagrelor allow for its discontinuation the evening before major surgical procedures. 1. TRUE 2. FALSE 23 Risk of intracranial hemorrhage doubles for every 0.5 INR increase over 4.5 Reversal involves de novo synthesis of affected factors Watch for long duration of warfarin effect Half life: ~40 hours Duration of effect: 2 5 days FVII replenished before FII Vigue B. Critical Care. 2009;13:209 (doi:10.1186/cc7001) Rolfe S, et al. J Pharm Practice.2010;23:217 25 Leissinger CA, et al. Am J Hematol.2008;83:137 43 Chapman SA, et al. Ann Pharmacother. 2011;45:869 75 Beshay JE, et al. J Neurosug. 2010;112:307 18 24 8
Vitamin K* Route dependent (PO, SQ, IVPB) timing of INR decrease Artificial: reflects primarily FVII increase, requires factor supplementation until FII recovery FFP*: historically used but significant limitations PCC* (with rfviia* 20 60 mcg/kg if 3 factor) Provides all factors for rapid INR reversal Doses used: 20 50 U/kg Concern over hypercoagulable state *PI suggestion Vigue B. Critical Care. 2009;13:209 (doi:10.1186/cc7001) Rolfe S, et al. J Pharm Practice.2010;23:217 25 Leissinger CA, et al. Am J Hematol.2008;83:137 43 Chapman SA, et al. Ann Pharmacother. 2011;45:869 75 Beshay JE, et al. J Neurosug. 2010;112:307 18 25 Guyatt GH, et al.chest; 2012;141:7S 47 Chest Guidelines, 2012 INR/bleeding status Treatment 4.5 10 AND no bleeding No vitamin K > 10 AND no bleeding Oral vitamin K Any INR AND major bleeding Vitamin K 5 10 mg IVPB + 4 factor PCC INR as surrogate for clinical outcome Levi M, et al. J Thromb Haemost. 2011;9:1705 12. Guyatt GH, et al.chest; 2012;141:7S 47 26 What would you recommend for a 45 year old male (80 kg) on warfarin 2 mg daily for MVR and INR of 2.7 who requires emergency exploratory laparotomy following a motor vehicle accident with crushing injuries and internal bleeding? 1. Vitamin K 5 mg PO, 2 units FFP, and rfviia 2,400 mg 2. Vitamin K 10 mg IM and Octaplex 120 ml 3. Vitamin K 10 mg IVPB and Octaplex 120 ml 4. Vitamin K 10 mg IVPB, Profilnine SD 2,000 U, and rfviia 2.4 mg 27 9
Stop infusion (heparin) Protamine sulfate* (partial antidote for LMWH) Consider half life Err towards lower dosage Time since bolus Time since infusion stopped Protamine dose (cumulative) e <30 minutes 1 hour 1 mg/100 units UFH Heparin 30 minutes 1 hour 1 2 hours 0.5 mg/100 units UFH >2 hours 2 hours 0.25 0.375mg/100 units UFH LMWH < 8 hours n/a 1 mg/unit; redose as needed Consider FFP (but may potentiate antithrombin), PCC, rfviia *PI suggestion Rolfe S, et al. J Pharm Practice.2010;23:217 25. Beshay JE, et al. J Neurosug. 2010;112:307 18 28 Major bleeding 1 2.2% Long half life: 17 21 hr No antidote Protamine sulfate ineffective Avidin biotin complex? Dialysis* removes 20% Potential role for rfviia at 30 90 mcg/kg *PI suggestion Case series, N=8, 2011 Major, symptomatic bleeding with detectable anti Xa activity 5/8 with ASA/clopidogrel rfviia 90 mcg/kg with PRBC Assessed for clinical bleeding control (4/8) and thrombotic complications (0/8) If abnormal, aptt and INR normalized Anti Xa gradually decreased: ineffective with high baseline anti Xa activity Rolfe S, et al. J Pharm Practice.2010;23:217 25 Luporsi P, et al. Acute Card Care. 2011;13:93 8 29 85 yo M atrial fibrillation (CHADS2 score: 5) on dabigatran 150 mg BID; also ASA 325 mg Hemorrhagic shock following upper GI bleed Treatment: 22 U/kg 3 factor PCC and FFP over 4 days Result: stabilization of hemoglobin, aptt; however, patient died from multi organ failure Low dose PCC used, 3 factor PCC used, concomitant ASA not addressed Dumkow LE, et al. Am J Health Syst Pharm.2012;69:1646 50 30 10
Oral DTI Appropriate use: no increase ICH or GI bleed compared with warfarin Indication Age Renal function CrCl (ml/min) T1/2 (hr) >80 13 50 80 K 15 30 50 18 15 30 27 http://www.fda.gov/drugs/drugsafety/ucm326580.htm Miyares MA, et al. Am J Health Syst Pharm. 2012;69:1473 84 Siegal D, et al. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs 408 Kaatz S, et al. Am J Hematol. 2012;87:S141 45 No antidote: investigational monoclonal antibody (clone 22) < 2 hours: activated charcoal Major bleeding Supportive care: PRBCs, FFP and platelet concentrates if thrombocytopenic or antiplatelet drugs used Consider hemodialysis* 60% removal in 2 3 hours Watch for rebound apcc: some in vitro effects at 75 80 U/kg PCC: Single healthy human study did not reverse aptt elevation rfviia: no effect *PI suggestion 31 12 healthy males Rivaroxaban 20 mg BID Dabigatran 150 mg BID 4 factor PCC placebo with Lab monitoring Dabigatran 150 mg BID Rivaroxaban 20 mg BID 4 factor PCC placebo with Lab monitoring 2.5 days 11 day washout 2.5 days Dabigatran: aptt, ecarin clotting time, thrombin time, endogenous thrombin potential Rivaroxaban: PT, endogenous thrombin potential RESULTS: Dabigatran: NO EFFECT Rivaroxaban: normalized PT and endogenous thrombin potential Eerenberg ES, et al. Circulation. 2011;124:1573 9 32 10 healthy males Rivaroxaban 20 mg Dabigatran 150 mg 4 factor PCC apcc rfviia Lab monitoring Dabigatran 150 mg Rivaroxaban 20 mg 4 factor PCC apcc rfviia Lab monitoring 1 dose Blood draw after 2 hr 1 dose Blood draw after 2 hr Lab monitoring of thrombin generation: endogenous thrombin potential, peak thrombin generation, lag time, time to peak thrombin Dabigatran: 4 factor PCC and rviia: inconsistent effect on lab values apcc: some effect Marlu R, et al. Thromb Hemost. 2012;108:217 24 Rivaroxaban: 4 factor PCC and rviia: inconsistent effect on lab values apcc: consistent reversal effect 33 11
Oral FXa inhibitors No specific antidote: rfxa? Activated charcoal* Not dialyzable Major bleeding Supportive care, FFP 4 factor PCC (50 U/kg) may reverse PT elevation FEIBA: some in vitro effects at 75 80 U/kg rfviia: no effect Miyares MA, et al. Am J Health Syst Pharm. 2012;69:1473 84 Kaatz S, et al. Am J Hematol. 2012;87:S141 45 Peacock WF, et al. Clin Cardiol.2012; DOI:10.1002/clc.22037 Siegal D, et al. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs 408 Rivaroxaban Apixaban Half life 5 9 hours ~12 hours Duration 12 hours No data *PI suggestion 34 Assess: hemodynamic stability bleeding source time since last dose renal function Minor Bleeding Local hemostasis Weigh risk/benefit of holding anticoagulant Siegal D, et al. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs 408 Moderate Bleeding Hold anticoagulant Compression Hemodynamic monitoring Volume replacement Surgical intervention Administer: PRBC FFP Platelets if concomitant antiplatelet agents Severe Bleeding As per moderate plus ICU Vasopressor agents Prohemostatic agents (PCC FXa inhibitors, apcc DTI) Adjunctive therapy: Activated charcoal Hemodialysis (dabigatran) Desmopressin Antifibrinolytic agents 35 Antiplatelets Half life Duration of effect Pre procedure management Reversal agent Aspirin 20 min 5 10 7 10 days Platelets, DDAVP days Clopidogrel 6 hr 7 10 5 10 days Platelets, DDAVP days Prasugrel 7 hr 5 9 days 5 7 days Platelets, DDAVP Ticagrelor 7 hr 3 5 days > 5 days Aminocaproic acid, tranexamic acid, rfviia Levi MM, et al. Neth J Med. 2010;68:68 76 Lexi Comp Online TM.; Accessed November 20, 2012. 36 12
Anticoagulants VKAs (warfarin) Half life Duration of effect Pre procedure management Reversal agent 40 hr 60 80 hr 5 days Vitamin K, PCC (+ rfviia), FFP Heparin 1.5 hr 3 4 hr Discontinue Protamine sulfate LMWHs ~5 6 hr 12 24 hr 12 hours Protamine sulfate Fondaparinux 17 21 hr 24 30hr Consider rfviia Rivaroxaban 5 9 hr ~12 hr > 1 day Consider PCC, rfviia Apixaban ~12 hr no information Consider FFP, rfviia Dabigatran 12 17 hr ~12 hr Clcr > 50: 1 2 days Clcr < 50: 3 5 days Consider PCC, FFP, rfviia Dialysis Levi MM, et al. Neth J Med. 2010;68:68 76 Lexi Comp Online TM. Lexi Drugs Online TM, Hudson, Ohio: Lexi Comp, Inc.; Accessed January 4, 2013. 37 Which approach/agent would you select for the treatment of bleeding related to factor Xa inhibitor use? (More than one choice may be selected) 1. Hemodialysis 2. FFP 3. FEIBA 4. rfviia 5. 4 factor PCC 38 Due to their mechanisms of action, the major risk of antiplatelet and anticoagulant agents is bleeding Reversal agents and procedures include vitamin K, protamine sulfate, FFP, PCCs, rfviia, and dialysis Some older agents, including warfarin and heparin, have antidotes Many newer agents, including dabigatran, rivaroxaban and apixaban, do not have clear reversal agents or protocols at this time 39 13
40 Bauer KA. Reversal of antithrombotic agents. Am J Hematol. 2012;87:S119 26. Beshay JE, MorganH, Madden C, Yu W, Sarode R. Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients. J Neurosurg. 2010;112:307 18. Campbell PG, Sen A, Yadla S, Jabbour P, Jallo J. Emergency reversal of antiplatelet agents in patients presenting with an intracranial hemorrhage: a clinical review. World Neurosurg. 2010;74:279 85. Chapman SA, Irwin ED, Beal AL, Kulinski NM, Hutson KE, Thorson MAL. Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011;45:869 75. De Lemos JA, Brilakis ES. No free lunches: balancing bleeding and efficacy with ticagrelor. Eur Heart J. 2011;32:2919 21. doi: 10.1093/eurheartj/ehr424. Epub 2011 Nov 17. Dumkow LE, Voss Jr, Peters M, Jennings DL. Reversal of dabigatran induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm. 2012;69:1646 50. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo controlled, crossover study in healthy subjects. Circulation. 2011;124:1573 9. FDA Drug Safety Communication: Safety review of post market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate), U.S. Food and Drug Administration. Available at: http://www.fda.gov/drugs/drugsafety/ucm326580.htm Accessed January 3, 2013. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schunemann HJ. Executive summary: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians evidence based clinical practice guidelines. Chest. 2012;141:7S 47S. Kalyanasundaram A, Lincoff AM. Managing adverse effects and drug drug interactions of antiplatelet agents. Nat Rev Cardiol.2011;8:592 600. Kaatz S, Kouides PA, Garcia, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87:S141 45. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol.2008;83:137 43. 41 Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011;9:1705 12. Levi MM, Eerenberg E, Lowenberg E, Kamphuisen PW. Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management. Neth J Med. 2010;68:68 76. Li C, Hirsh J, Xie C, Johnston MA, Eikelboom JW. Reversal of the anti platelet effects of aspirin and clopidogrel. J Thromb Haemost. 2012;10:521 8. Luporsi P, Chopard R, Janin S, et al. Use of recombinant factor VIIa (NovoSeven) in 8 patients with ongoing life threatening bleeding treated with fondaparinux. Acute Cardiac Care. 2011;13:93 8. Marietta M, Pedrazzi, Luppi M. Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal: what are we really looking for? Blood Transfus. 2011;9:469. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217 24. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm. 2012;69:1473 84. Nishijima DK, Zahtabchi S, Berrong J, Legome E. Utility of platelet transfusion in adult patients with traumatic intracranial hemorrhage and preinjury antiplatelet use: a systematic review. J Trauma Acute Care Surg. 2012;72:1658 63. OrtelTL. Perioperative management of patients on chronic antithrombotic therapy. Hematology Am Soc Hematol Educ Program. 2012;2012:529 35. doi: 10.1182/asheducation 2012.1.529. Peacock WF, Gearheart MM, Mills RM. Clin Cardiol. 2012. DOI:10.1002/clc.22037. Rolfe S, Papadopoulos S, Cabral KP. Controversies of anticoagulation reversal in life threatening bleeds. J Pharm Practice.2010;23:217 25. Siegal D, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs 408. Vigue B. Bench to bedside review: optimizing emergency reversal of vitamin K antagonists in severe haemorrhage from theory to practice. Critical Care. 2009;13:209 (doi:10.1186/cc7001). 42 14