Best Evidence for Antithrombotic Agent Reversal in Bleeding

3/16/2021

JAMES H. PAXTON, MD

• DIRECTOR OF CLINICAL RESEARCH • DETROIT RECEIVING HOSPITAL (DRH), DEPARTMENT OF EMERGENCY MEDICINE, WAYNE STATE UNIVERSITY • ATTENDING PHYSICIAN • SINAI-GRACE HOSPITAL (SGH) • DETROIT RECEIVING HOSPITAL (DRH)

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DISCLOSURES

• FUNDED RESEARCH SPONSORED BY: TELEFLEX INC, 410 MEDICAL, HOSPI CORP.

OBJECTIVES •AT THE CONCLUSION OF THIS LECTURE, THE LEARNER WILL: • RECOGNIZE COMMON ANTITHROMBOTIC MEDICATIONS ASSOCIATED WITH BLEEDING EMERGENCIES • BE ABLE TO EXPLAIN THE MECHANISMS OF ACTION FOR COMMON ANTITHROMBOTIC MEDICATIONS • UNDERSTAND THE EVIDENCE FOR RAPID REVERSAL OF ANTITHROMBOTIC MEDICATIONS, INCLUDING CONTROVERSIES AND BEST PRACTICES

HAVE FEWER NIGHTMARES ABOUT SCENES LIKE THE ONE ON THE NEXT SLIDE?

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BLEEDING IS BAD

WHEN TO REVERSE?

• WHEN RISK OF BLEEDING OUTWEIGHS RISK OF REVERSAL: • INTRACRANIAL HEMORRHAGE (ICH) • OTHER CNS HEMATOMA (E.G., INTRAOCULAR, SPINAL) • EXSANGUINATING GASTROINTESTINAL (GI) BLEED • UNCONTROLLED RETROPERITONEAL BLEED • HEMORRHAGE INTO EXTREMITY WITH COMPARTMENT SYNDROME • CONSIDER IN POSTERIOR EPISTAXIS, HEMOTHORAX, PERICARDIAL TAMPONADE

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ANTITHROMBOTIC AGENTS

•ANTI-PLATELET DRUGS •ANTI-COAGULANTS •FIBRINOLYTICS

THROMBOGENESIS

• Primary component in arterial thrombosis (“white clot”)

• Target for antiplatelet drugs

• Primary component in venous thrombosis (“red clot”) • Aggregated platelets + • Target for anticoagulants fibrin mesh

• Target for fibrinolytics

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PLATELET AGGREGATION

Antiplatelet Drugs Mechanism

Aspirin* Inhibit TXA2 synthesis Clopidogrel (Plavix)* Inhibit ADP receptor Prasugrel (Effient)* “-grel” activation Ticagrelor (Brillinta) Dipyridamole (Persantine) Lower Ca++ by elevating “-ol” Cilostazol (Pletal) cAMP Abciximab (ReoPro) Block GPIIb/IIIa receptors Tirofiban (Aggrestat) “-fib / -mab” Eptifibatide (Integrilin) * Permanent inhibition PLATELET LIFESPAN IS ∼8-10 DAYS!

REVERSAL OF ANTIPLATELET AGENTS

• ACTIVATED CHARCOAL • IF INGESTION IS WITHIN 2-3 HRS (E.G., OVERDOSE), INTUBATED PATIENT • PLATELETS • THROMBOELASTOGRAPHY (TEG) MAY BE USEFUL – LIMITED EVIDENCE • DO NOT TRANSFUSE PLATELETS FOR ICH IF NO SURGICAL INTERVENTION IS PLANNED • CONSIDER 1 UNIT (6-10 PACKS) IF PFA-PLAVIX ASSAY IS POSITIVE (< 194 PRU) • DESMOPRESSIN (DDAVP) • CONSIDER SINGLE IV DOSE FOR INTRACRANIAL HEMORRHAGE • DOSE = 0.3-0.4 MCG/KG IV (NO MAX DOSE) • DECREASED LIKELIHOOD OF HEMATOMA EXPANSION IN FIRST 24 HRS (FELDMAN 2019)

THERE IS NO EVIDENCE TO SUPPORT REVERSING ASPIRIN ALONE

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COAGULATION CASCADE

Oral Anticoagulants Warfarin (Coumadin) Inhibits SYNTHESIS of multiple factors ANTICOAGULANTS Dabigatran (Pradaxa) Inhibits ACTIVITY of Factor IIa Rivaroxaban (Xarelto) Inhibits ACTIVITY of Factor Xa Apixaban (Eliquis) Edoxaban (Savaysa) Betrixaban (Bevyxxa)

Parenteral Anticoagulants Heparin Inhibits ACTIVITY of multiple factors LMWH: Inhibits ACTIVITY of Factors Xa & IIa Enoxaparin (Lovenox) Dalteparin (Fragmin) Fondaparinux (Arixtra) Inhibits ACTIVITY of Factor Xa Bivalirudin (Angiomax) Inhibits ACTIVITY of Factor IIa

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Factor Synonyms Source I Fibrinogen Liver CLOTTING II Prothrombin Liver (Vit K-dependent) III Tissue Factor, or Tissue Thromboplastin Liver FACTORS IV Calcium Liver V Labile Factor, or Proaccelerin Liver VI Accelerin Liver VII Stable Factor, or Proconvertin Liver (Vit K-dependent) VIII Antihemophilic Factor A Endothelium IX Christmas Factor, or Plasma Thromboplastin Liver (Vit K-dependent) Component (PTC), or Antihemophilic Factor B X Stuart-Prower Factor Liver (Vit K-dependent) XI Plasma Thromboplastin Antecedent (PTA) Liver XII Hageman Factor, or Glass Factor Liver XIII Fibrin Stabilizing Factor, or Laki-Lorand Factor Liver VITAMIN K-DEPENDENT FACTORS = “2 + 7 = 9, NOT 10”

• ACTS IN THE LIVER ONLY WARFARIN EFFECTS • COMPROMISES CARBOXYLATION, PREVENTING PRODUCTION OF GAMMA-CARBOXYGLUTAMIC ACID (GLA) RESIDUES • FACTORS THAT ENTER CIRCULATION WITH GLA RESIDUES ARE UNAFFECTED • PROTEIN C / S ALSO INHIBITED (8 HR / ??)

Factor Synonyms Plasma Half-Life II Prothrombin 70 hours VII Stable Factor, or Proconvertin 3-6 hours IX Christmas Factor, or Plasma Thromboplastin 18-24 hours Component (PTC), or Antihemophilic Factor B X Stuart-Prower Factor 40 hours

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WARFARIN REVERSAL

• LONG-ACTING DRUG • TERMINAL ½ LIFE AFTER SINGLE DOSE = 1 WEEK; EFFECTIVE ½ LIFE = 20-60 HOURS (MEAN ∼ 40 HOURS) • METABOLIZED IN THE LIVER (CYP2C9 ALLELE FOR P450 ENZYME) > KIDNEY; DRUG-DRUG INTERACTIONS • TREATMENT • WITHHOLD DRUG, CONSERVATIVE MANAGEMENT, SUPPORTIVE THERAPIES • RESERVE REPLETION OF VIT K-DEPENDENT FACTORS FOR LIFE-THREATENING EVENTS (E.G., EXSANGUINATION, ICH) • RISK FROM BASELINE PROTHROMBOTIC STATE, OR “OVERSHOOT” THROMBOEMBOLIC COMPLICATIONS WITH REPLETION

WARFARIN REVERSAL • VITAMIN K • GRADUAL EFFECT OVER HOURS TO DAYS – INEFFECTIVE FOR LIFE-THREATENING BLEEDS (AS MONOTHERAPY) • NECESSARY TO GIVE IF GIVING FFP OR PCC, TO AVOID REBOUND INR ELEVATIONS • DOSE = 10 MG (FOR LIFE-THREATENING BLEED); “CONSIDER 5-10 MG” IF HEMODYNAMICALLY STABLE • IV GIVEN OVER > 20 MIN TO AVOID ANAPHYLACTOID REACTION; ONSET = 1-2 HRS, PEAK = 4-6 HRS • ANAPHYLACTOID REACTION (NON-IGE-MEDIATED) • THOUGHT TO BE DUE TO POLYETHOXYLATED CASTOR OIL DILUENT (NO LONGER USED) (MI 2014) • SEEN IN <0.03% OF CASES (RIEGERT-JOHNSON 2002) • DO NOT GIVE SQ / IM • CONSIDER RE-DOSING (10 MG IV) FOR ICH IF INR > 1.4 AFTER 24-48 HRS (FRONTERA 2016)

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WARFARIN REVERSAL • FRESH FROZEN PLASMA (FFP) • INCLUDES ALL FACTORS, PROTEIN C, VWF • DOSE = 10-15 ML/KG; 1 UNIT = 200-250 ML • LIMITED BY TIME THAWING, CROSS-MATCHING, CONCERNS OF VOLUME OVERLOAD, POOR EFFICACY, TRALI, TACO • INTRINSIC INR = 1.5 (NO PROVEN BENEFIT FOR INR < 1.7) • NOT RECOMMENDED FOR REVERSAL A/W INTRACRANIAL HEMORRHAGE (FRONTERA 2016) • RECOMBINANT FACTOR VIIA (NOVOSEVEN®) • 100 U/KG @ $1.94/U = $15,000 / DOSE • MORE PRO-THROMBOTIC IN VITRO THAN PCC; UNCOMMONLY USED FOR WARFARIN REVERSAL • LOW-DOSE (1000-1200 MCG) MORE EFFECTIVE THAN 3FPCC (20 IU/KG) IN REDUCING INR (CHAPMAN 2014)

WARFARIN REVERSAL

• PROTHROMBIN COMPLEX CONCENTRATE (PCC) • POOLED, VIRUS-INACTIVATED CONCENTRATES OF HUMAN CLOTTING FACTORS • SUPERIOR TO FFP IN WARFARIN-ASSOCIATED INTRACRANIAL HEMORRHAGE (STEINER 2016) • MORE THROMBOEMBOLIC COMPLICATIONS (5-10%, DOSE-DEPENDENT) THAN FFP (DENTALI 2011, MILLING 2016) • THREE-FACTOR PCC (3FPCC) = FACTORS II, IX, X (AND VERY LOW LEVELS OF VII) • PROFILNINE ® / BEBULIN ® • CAN BE COMBINED WITH RECOMBINANT FACTOR VIIA – LIMITED DATA ON EFFICACY

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WARFARIN REVERSAL • FOUR-FACTOR PROTHROMBIN COMPLEX CONCENTRATE (4FPCC) = ADDS FACTOR VII, PROTEIN C/S • COST = $1.65 / IU = $6,600 FOR 50 IU/KG @ 80 KG • KCENTRA® • BEST EVIDENCE SUPPORTS FIXED DOSING (1,000-1,500 IU; MORE FOR OBESE, ICH, INR>4) (RHONEY 2020) • LEXI-COMP: 25 IU/KG (INR 2 TO <4), 35 IU/KG (INR 4-6), 50 IU/KG (INR >6) • INR CORRECTION FASTER THAN 3PCC, W/SIMILAR MORTALITY, LOS, THROMBOSES, BLOOD USE (HOLT 2018; DEANGELO 2018) • 3.6-8% THROMBOSIS RATES @ 30 DAYS (MAJEED 2017, SCHULMAN 2018) VS. 7.8% FFP (SARODE 2013) • FACTOR EIGHT INHIBITOR BYPASSING ACTIVITY (FEIBA®) = ACTIVATED PCC (APCC) • USED FOR HEMOPHILIA FOR DECADES; DOSE = 50-100 U/KG Q 6-12 HRS UNTIL RESOLUTION • HAS ACTIVATED FACTOR VII, AND NO HEPARIN (UNLIKE KCENTRA®)

FACTOR VII = SHORT ½ LIFE, INITIATES EXTR. PATHWAY = MORE PROTHROMBOTIC

SOURCE: FRONTERA 2016

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REBOUND AFTER WARFARIN REVERSAL

IF INR > 1.4 AFTER 24-48 HRS FOLLOWING PCC, CONSIDER FFP / RE-DOSING VIT K

DIRECT ORAL ANTICOAGULANTS (DOACS)

Drug Factor Inhibited Cmax (Hrs) Half-Life (Hrs) Reversal Agents Dabigatran (Pradaxa) Factor IIa 2 12-17 Idarucizumab (Praxbind), PCC Rivaroxaban (Xarelto) 2-4 5-9 Apixaban (Eliquis) 1-3 12 Factor Xa Andexanet Alfa (Andexxa), PCC Edoxaban (Savaysa) 1-2 10-14 Betrixaban (Bevyxxa) 3-4 19-27

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DABIGATRAN (PRADAXA) REVERSAL • IDARUCIZUMAB (PRAXBIND) • HUMANIZED MONOCLONAL ANTIBODY FRAGMENT (BINDS DABIGATRAN) • 350X HIGHER AFFINITY TO DABIGATRAN THAN THROMBIN • ONLY FDA-APPROVED REVERSAL AGENT FOR DABIGATRAN • RE-VERSE AD TRIAL (POLLACK 2015) • ONSET IN MINUTES, CLINICAL HEMOSTASIS ∼ 11.4 HRS • 6.3% THROMBOEMBOLIC EVENTS @ 90 DAYS (90% IN PTS NOT RE-INITIATED ON ANTICOAGULATION) • DOSE = 5 GM IV, ADMINISTERED IN TWO 2.5 GM DOSES • COST = $3,600 / 5-GM DOSE • PCC MAY BE USED (MARLU 2012, SCHULMAN 2017), BUT LIMITED EVIDENCE OF EFFICACY

FACTOR XA INHIBITOR REVERSAL • ANDEXANET ALFA (ANDEXXA) • RECOMBINANT, MODIFIED FACTOR XA MOLECULE (“FACTOR XA DECOY”) – FDA APPROVED 2018 • HIGH AFFINITY FOR ALL FACTOR XA INHIBITORS • DOSING • EDOXABAN / BETRIXABAN = 800 MG IV BOLUS @ 30 ML/MIN, THEN 8 MG/MIN FOR UP TO 120 MIN (HIGH DOSE) • APIXABAN / RIVAROXABAN = 400 MG IV BOLUS @ 30 ML/MIN, THEN 4 MG/MIN FOR UP TO 120 MIN (LOW DOSE) OR HIGH DOSE (DEPENDS ON AMOUNT AND TIMING OF LAST DOSE) • COST = $22,000 / DOSE • 10% THROMBOTIC RATE, 82% ACHIEVED GOOD CONTROL OF HEMORRHAGE (CONNOLLY 2019)

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FACTOR XA INHIBITOR REVERSAL • ANDEXANET ALFA (ANDEXXA) • ONLY REVERSES INHIBITION EFFECT DURING THE ACTUAL 2-HOUR INFUSION (REBOUND @ 4 HRS) • THEORY = ALLOWS A HEMOSTATIC PLUG TO FORM BEFORE REBOUND • ANNEXA-4 TRIAL (CONNOLLY 2019) • HETEROGENEOUS POPULATION, 352 PTS (64% ICH, 26% GIB), WITHIN 18 HRS OF LAST DOSE • MOSTLY APIXABAN (55%) > RIVAROXABAN (36%) > ENOXAPARIN (6%), EDOXABAN (3%) • 92% REDUCTION IN ANTI-FACTOR XA ACTIVITY W/ DOACS; 75% REDUCTION W/ENOXAPARIN • LACK OF CONTROL GROUP • ONLY 58% OF PATIENTS IN THE UPDATE WERE ELIGIBLE FOR EFFICACY ANALYSIS • EXCLUDED PATIENTS WITH ANTICIPATED POOR PROGNOSIS

Exclusion Criteria (ANNEXA-4) Planned surgery within 12 hrs of Andexanet (excl. minor procedures) ICH with GCS < 7 or hematoma volume > 60 cc Expected survival < 1 month Thrombotic event in last 2 weeks Use of (in last 7 days): Vit K antagonist, Dabigatran, PCC, rFVIIa, whole blood, plasma

MEDIAN NIH SCORE = 8 FOR DOAC-RELATED ICH (INOHARA 2018)

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FACTOR XA INHIBITOR REVERSAL • 4FPCC (50 U/KG) IV REMAINS RECOMMENDED BY MOST MAJOR GUIDELINES • ACC EXPERT CONSENSUS (TOMASELLI 2020) – ANDEXANET ALSO CLASS 2 RECOMMENDATION • NEUROCRITICAL CARE SOCIETY AND SOCIETY OF CRITICAL CARE MEDICINE (FRONTERA 2016) • EHRA PRACTICAL GUIDE ON USE OF NON-VITAMIN K ANTAGONISTS IN NVAF (HEIDBUCHEL 2015) • AMERICAN SOCIETY OF HEMATOLOGY HAS NO PREFERENCE FOR PCC VS. ANDEXANET (WITT 2018) • IF 4FPCC UNAVAILABLE, CONSIDER APCC (FEIBA) 50 U/KG IV • RECOMBINANT FACTOR VIIA (90 MCG/KG) CONSIDERED LAST LINE, DUE TO THROMBOTIC RISK / EXPENSE

PROTAMINE SULFATE • USED FOR UNFRACTIONATED HEPARIN / LMWH • BINDS TO HEPARIN TO FORM A SALT; ONSET 5 MIN; DURATION 2 HOURS • 1 MG NEUTRALIZES 100 U • HALF-LIVES OF HEPARIN (90 MIN) AND LMWH (4-7 HOURS) BOTH LONGER THAN PROTAMINE (7-MIN) • FULL-DOSE GIVEN IF < 60 MIN SINCE HEPARIN BOLUS, OR < 8 HRS SINCE LMWH DOSE • HALF-DOSE IF LATER • CONSIDER RE-DOSING IF APTT / ANTI-XAASSAYS REMAINS ELEVATED 2-4 HRS AFTER FIRST DOSE • PROBABLY NOT HELPFUL IF LAST HEPARIN DOSE > 12 HOURS AGO

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CIRAPARANTAG

• BINDS NONCOVALENTLY TO HEPARIN, LOW-MOLECULAR-WEIGHT HEPARIN, AND ALL DOACS (ANSELL 2021) • COST = $50,000 / DOSE?

FIBRINOLYTICS

TPA IS THE MOST COMMONLY-ENCOUNTERED FIBRINOLYTIC AGENT

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FIBRINOLYTICS

• CATALYZE CONVERSION OF FIBRIN-BOUND PLASMINOGEN TO PLASMIN. PLASMIN EXERTS ADDITIONAL PROTEOLYTIC EFFECTS, INCLUDING CLEAVAGE OF PLATELET GPIIIA AND GP1B CAUSING INHIBITION OF PLATELET FUNCTION. • NON-SELECTIVE (UROKINASE / STREPTOKINASE) = DEGRADE BOTH FIBRINOGEN AND FIBRIN = MORE BLEEDING • SELECTIVE: Agent Elimination Serum Half-Life Terminal Half-Life Alteplase (Activase) Hepatic 3-6 min 26-77 min Reteplase (Retevase) Renal 13-16 min UNK Tenecteplase (TNKase) Hepatic 11-24 min 90-138 min

TENECTEPLASE HAS 14-FOLD GREATER FIBRIN SPECIFICITY THAN ALTEPLASE

FIBRINOLYTICS • SYMPTOMATIC INTRAPARENCHYMAL HEMORRHAGE WITH MASS EFFECT OCCURS IN APPROXIMATELY 2– 7 % OF PATIENTS WITH ISCHEMIC STROKE WHO RECEIVE IV ALTEPLASE (FRONTERA 2016) • HEMATOMA EXPANSION OCCURS IN UP TO 40 % OF PATIENTS; MORTALITY IS 9-61 % @ 3 MONTHS • MUCH LOWER RISK (0.4-0.9%) IN NON-CVA INDICATIONS • SINCE TERMINAL HALF-LIFE IS QUITE LONG, CONSIDER REVERSAL IF < 24 HRS • FIBRINOGEN LEVEL < 150 MG/DL IS THE ONLY SIGNIFICANT FACTOR A/W HEMATOMA EXPANSION (YAGHI 2015)

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FIBRINOLYTIC REVERSAL

• CRYOPRECIPITATE = CONTAINS FIBRINOGEN (200 MG/UNIT), FACTOR VIII, FIBRONECTIN, FACTOR XIII, AND VON WILLEBRAND FACTOR • 10 UNITS OF CRYOPRECIPITATE RAISE FIBRINOGEN LEVELS BY ∼70 MG/DL (@70 KG PATIENT) • TARGET FIBRINOGEN LEVEL > 150 MG/DL • ANTIFIBRINOLYTICS (E-AMINOCAPROIC ACID, TRANEXAMIC ACID) = COMPETITIVELY BIND TO PLASMINOGEN AND BLOCK ITS CONVERSION TO PLASMIN, THEREBY INHIBITING FIBRIN DEGRADATION. • TRANEXAMIC ACID (10–15 MG/KG IV OVER 20 MIN) OR E-AMINOCAPROIC ACID (4–5 G IV) • FFP & PLATELET TRANSFUSION = LITTLE EVIDENCE, POSSIBLY HELPFUL

PLATELETS MAY ACTUALLY ACCELERATE HEMATOMA EXPANSION (YOGHI 2015)

REVERSAL WITH DIALYSIS? • NOT USUALLY HELPFUL • CONSIDER IN • DABIGATRAN (57% REMOVED OVER 4 HRS) • ARGATROBAN (20% OVER 4 HRS) • BIVALIRUDIN / DESIRUDIN / LEPIRUDIN • FONDAPARINUX (20%) • ASPIRIN • EPTIFIBATIDE (73-83% AFTER 1 HR) • TIROFIBAN

SOURCE: FRONTERA 2016

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SUMMARY

• WARFARIN • 4FPCC (25-50 IU/KG) + IV VIT K (5-10 MG) • DABIGATRAN • IDARUCIZUMAB 5 MG IV • RIVAROXABAN / APIXABAN • ≥ 8 HRS = LOW-DOSE ANDEXANET, OR PCC • < 8 HRS = LOW-DOSE ANDEXANET (IF ≤ 10 MG RIVAROXABAN, ≤ 5 MG APIXABAN), OR PCC • USE HIGH-DOSE IF > 10 MG RIVAROXABAN OR > 5 MG APIXABAN (OR DOSE UNKNOWN) • EDOXABAN / BETRIXABAN • HIGH-DOSE ANDEXANET OR PCC

PEARLS

• BALANCE THE RISK OF REVERSAL WITH THE RISK OF CONTINUED BLEEDING • DECISION TO REVERSE SHOULD BE GUIDED BY BLEEDING (ICH, MAJOR BLEED), NOT BY LAB VALUES • CONSIDER ACTIVATED CHARCOAL IF < 2 HRS SINCE LAST DOSE, AND LOW RISK FOR ASPIRATION • NOT ALL REVERSAL AGENTS ARE AVAILABLE AT ALL INSTITUTIONS • CONSIDER THE LIMITATIONS OF PREVIOUS STUDIES IN APPLYING EVIDENCE TO YOUR PATIENT • THIS IS AN EVOLVING LANDSCAPE – NEW EVIDENCE / AGENTS WILL CONTINUE TO APPEAR

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QUESTIONS? [email protected]

REFERENCES

• STEINER T, POLI S, GRIEBE M, ET AL. FRESH FROZEN PLASMA VERSUS PROTHROMBIN COMPLEX CONCENTRATE IN PATIENTS WITH INTRACRANIAL HAEMORRHAGE RELATED TO VITAMIN K ANTAGONISTS (INCH): A RANDOMISED TRIAL. LANCET NEUROL. 2016;15(6):566-573. • DEANGELO J, JARRELL D, ET AL. COMPARISON OF 3-FACTOR VERSUS 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE WITH REGARD TO WARFARIN REVERSAL, BLOOD PRODUCT USE, AND COSTS. AM J THER. 2018 MAY-JUN;25(3):E326-E332. • HOLT T, TAYLOR S, ABRAHAM P, ET AL. THREE- VERSUS FOUR-FACTOR PROTHROMBIN COMPLEX CONCENTRATE FOR THE REVERSAL OF WARFARIN-INDUCED BLEEDING. INT J CRIT ILLN INJ SCI. 2018 JAN-MAR;8(1):36-40. • CHAPMAN SA,, IRWIN ED, ET AL. COMPARISON OF 3-FACTOR PROTHROMBIN COMPLEX CONCENTRATE AND LOW-DOSE RECOMBINANT FACTOR VIIA FOR WARFARIN REVERSAL. WORLD J EMERG SURG. 2014;9:27. • RHONEY DH, CHESTER KW, DARSEY DA. OPTIMAL DOSAGE AND ADMINSTRATION PRACTICES FOR VITAMIN K ANTAGONIST REVERSAL WITH 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE. CLIN APPL THROMB HEMOST. 2020 JAN-DEC;26.

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REFERENCES

• FELDMAN EA, MEOLA G, ET AL. RETROSPECTIVE ASSESSMENT OF DESMOPRESSIN EFFECTIVENESS AND SAFETY IN PATIENTS WITH ANTIPLATELET-ASSOCIATED INTRACRANIAL HEMORRHAGE. CRIT CARE MED. 2019 DEC;47(12):1759-1765. • DENTALI F, MARCHESI C, ET AL. SAFETY OF PROTHROMBIN COMPLEX CONCENTRATES FOR RAPID ANTICOAGULATION REVERSAL OF VITAMIN K ANTAGONISTS. A META-ANALYSIS. THROMB HAEMOST. 2011 SEP;106(3):429-438. • MILLING TJ, REFAAI MA, ET AL. THROMBOEMBOLIC EVENTS AFTER VITAMIN K ANTAGONIST REVERSAL WITH 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE;EXPLORATORY ANALYSES OF TWO RANDOMIZED, PLASMA-CONTROLLED STUDIES. ANN EMERG MED. 2016 JAN;67(1):96-105. • POLLACK CV, REILLY PA, ET AL. IDARUCIZUMAB FOR DABIGATRAN REVERSAL. N ENGL J MED. 2015;373(6):511-520. • MARLU R, HODAJ E, ET AL. 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 AUG;108(2):217- 224.

REFERENCES

• SCHULMAN S, RITCHIE B, ET AL. REVERSAL OF DABIGATRAN-ASSOCIATED MAJOR BLEEDING WITH ACTIVATED PROTHORMBIN CONCENTRATE: A PROSPECTIVE COHORT STUDY. THROMB RES. 2017;152:144-148. • TOMASELLI G, MAHAFFEY K, ET AL. 2017 ACC EXPERT CONSENSUS DECISION PATHWAY ON MANAGEMENT OF BLEEDING IN PATIENTS ON ORAL ANTICOAGULANTS. J AM COLL CARDIOL. 2017;70:3042-3067. • FRONTERA JA, LEWIN JJ, ET AL. GUIDELINE FOR REVERSAL OF ANTITHROMBOTICS IN INTRACRANIAL HEMORRHAGE. NEUROCRIT CARE. 2016;24:6-46. • HEIDBUCHEL H, VERHAMME P, ET AL. UPDATED EUROPEAN HEART RHYTHM ASSOCIATION PRACTICAL GUIDE ON THE USE OF NON- VITAMIN K ANTAGONIST ANTICOAGULANTS IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION. EUROPACE. 2015;17:1467- 1507. • CONNOLLY SJ, CROWTHER M, ET AL. FULL STUDY REPORT OF ANDEXANET ALFA FOR BLEEDING ASSOCIATED WITH FACTOR XA INHIBITORS. N ENGL J MED. 2019 APR;380:1326-1335.

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REFERENCES

• ANSELL J, LAULICHT BE, ET AL. CIRAPARANTAG, AN ANTICOAGULANT REVERSAL DRUG: MECHANISM OF ACTION, PHARMACOKINETICS, AND REVERSAL OF ANTICOAGULANTS. BLOOD. 2021 JAN;137(1):115-125. • SARODE R, MILLING TJ, ET AL. EFFICACY AND SAFETY OF A 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE IN PATIENTS ON VITAMIN K ANTAGONISTS PRESENTING WITH MAJOR BLEEDING: A RANDOMIZED, PLASMA-CONTROLLED, PHASE IIIB STUDY. CIRCULATION. 2013;128(11):1234-43. • MAJEED A, AGREN A, ET AL. MANAGEMENT OF RIVAROXABAN- OR APIXABAN-ASSOCIATED MAJOR BLEEDING WITH PROTHROMBIN COMPLEX CONCENTRATES: A COHORT STUDY. BLOOD. 2017;130(15):1706-1712. • INOHARA T, XIAN Y, ET AL. ASSOCIATION OF INTRACEREBRAL HEMORRHAGE AMONG PATIENTS TAKING NON-VITAMIN K ANTAGONIST VS VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS WITH IN-HOSPITAL MORTALITY. JAMA. 2018;319:463–73. • WITT D, NIEUWLAAT R, ET AL. AMERICAN SOCIETY OF HEMATOLOGY 2018 GUIDELINES FOR MANAGEMENT OF VENOUS THROMBOEMBOLISM: OPTIMAL MANAGEMENT OF ANTICOAGULATION THERAPY. BLOOD ADV. 2018;2(22):3257–91

REFERENCES

• RIEGERT-JOHNSON DL, VOLCHECK GW. THE INCIDENCE OF ANAPHYLAXIS FOLLOWING INTRAVENOUS PHYTONADIONE (VITMAIN K1): A 5-YEAR RETROSPECTIVE REVIEW. ANN ALLERGY ASTHMA IMMUNOL. 2002 OCT;89(4):400-406. • MI Y-N, PING N-N, ET AL. THE SEVERE ADVERSE REACTION TO VITAMIN K1 INJECTION IS ANAPHYLACTOID REACTION BUT NOT ANAPHYLAXIS. PLOS ONE. 2014 MAR;9(3);E90199. • YAGHI S, BOEHME AK, ET AL. TREATMENT AND OUTCOME OF THROMBOLYSIS-RELATED HEMORRHAGE: A MULTICENTER RETROSPECTIVE STUDY. JAMA NEUROL. 2015;26:1–7.