Minimal clinical evidence exists to support the efficacy of nonspecific procoagulant therapies that promote thrombin formation and antifibrinolytics in the setting of antithrombotic-related bleeding. Hemostatic products are associated with a risk of thrombosis and should be reserved for use in life-threatening bleeding when the potential benefit of their use outweighs the associatied risk. Maximum supportive therapy should be initiated as indicated, including volume resuscitation, inotropes, optimization of oxygenation, and blood product transfusion. HEPARINS Unfractionated heparin (UFH) partial 30-90 minutes (dosedependent) Protamine sulfate 1mg of protamine sulfate will neutralize every 100 units of UFH Due to the short half-life of UFH, the dose of protamine depends on the time elapsed since UFH administration Time elapsed since UFH administration Protamine dose (mg) per 100 units of UFH given over the last 3 Immediate 1 mg 1.5mg 30 min 2 0.5mg -0.75mg > 2 0.25mg -0.375mg Maximum protamine dose is 50mg. Subcutaneously administered UFH in treatment doses: Half-life is longer with subcutaneous UFH administration. Monitor aptt every 3 with repeat protamine (0.5mg per 100 units UFH administered) if bleeding continues. aptt 2 after protamine administration Consider additional dose of protamine if aptt is still prolonged. Surgery: Hold UFH 4-6 prior to surgery. Obtain aptt to ensure return to baseline. Contraindicated during therapeutic UFH anticoagulation. SUBQ UFH in doses >5000 units or IV UFH (therapeutic dosing), DC UFH and aptt < 33 secs prior to any neuraxial Minimum time between UFH and spinal injection is 4 (IV) and 8-10 (subq). Minimum time between catheter removal and restarting UFH is 2. Time to resume may be up to 24 with traumatic puncture. IF SUBQ UFH 5000 units (prophylactic dosing) administered, hold 8-10 prior to neuraxial procedures and 2 post removal Prophylactic doses of SUBQ UFH are not considered to increase hemorrhagic risk. Rapid administration of protamine can cause hypotension and/or anaphylaxis. Excessive protamine doses can increase bleeding risk. Hypersensitivity to protamine is more common in patients with fish allergy and in patients sensitized to protamine (via protamine-containing insulins). Premedicate with: Diphenhydramine 50mg IVP x 1 Hydrocortisone 100mg IVP x 1 Protamine Administration: IV push or IVPB at a maximum rate of 5 mg/min. Incompatible with other medications. Administer through a dedicated IV line. Monitor for hypotension and bradycardia. 1
HEPARINS - continued Low-molecular weight heparin (LMWH) Enoxaparin (Lovenox ) 2-8 Protamine sulfate Only partially reverses enoxaparin effect. Maximum reversal of anti-xa factor activity is 60-75% Time elapsed since enoxaparin administration Initial dose of protamine (mg) per 1 mg enoxaparin < 8 1mg 8-12 0.5mg Maximum protamine dose is 50mg. LMWH level (anti-xa level) Surgery: Hold enoxaparin 12-24 prior to surgery At least 24 should elapse after the last dose of enoxaparin 1mg/kg Q 12 or 1.5mg/kg daily before neuraxial procedures can be performed. Minimum time between catheter removal and next LMWH dose is 24 hrs At least 12 should elapse after the last dose of prophylactic enoxaparin before neuraxial procedures can be performed Minimum time between catheter removal and next LMWH dose is 4-24 hrs depending on bleeding risk of procedure Rapid administration of protamine can cause hypotension and/or anaphylaxis. Excessive protamine doses can increase bleeding risk. Hypersensitivity to protamine is more common in patients with fish allergy and in patients sensitized to protamine (via protamine-containing insulins) Premedicate with: Diphenhydramine 50mg IVP x 1 Hydrocortisone 100mg IVP x 1 Protamine Administration: IV push or IVPB at a maximum rate of 5 mg/min. Incompatible with other medications. Administer through a dedicated IV line. Monitor for hypotension and bradycardia. DIRECT THROMBIN INHIBITORS (DTI) Argatroban 20% 39-51 minutes; Hepatic impairment > 181 minutes. No antidote available DiSUBQontinuation of DTI is the primary means of attenuating bleed Support with crystalloid and blood products to facilitate rapid renal clearance aptt returns to baseline in 2-4 Surgery: Hold argatroban for at least 4 before any invasive procedure Obtain aptt to ensure return to baseline. Contraindicated while on argatroban Argatroban must be discontinued and aptt < 33 seconds prior to neuraxial Minimum time to hold prior to spinal injection or catheter placement is 4 ; minimum time to restart after removal is 2 Reported cases of argatroban overdoses have not resulted in bleeding complications even though coagulation parameters may remain elevated for some time. 2
DIRECT THROMBIN INHIBITORS (DTI) - continued Bivalirudin (Angiomax ) 25% Dabigatran (Pradaxa ) approximately 60% within 2. Longer sessions (i.e. 6 ) may be required. 25 minutes; up to 60 minutes with renal impairment CrCl> 50 ml/min: 16 CrCl 31-49: 18 CrCl < 30: 27 Elderly: 14-17 No antidote available Discontinuation of DTI is the primary means of attenuating bleed Support with crystalloid and blood products to facilitate rapid renal clearance For urgent reversal of life threatening bleed or emergency surgery/procedure: Idarucizumab (Praxbind) 5g total dose (2 consecutive infusions of 2.5g IV over 10 minutes; no longer than 15 minutes in between doses). Flush with at least 50mL NS after complete. If ingested within 2, administer activated charcoal orally (1 gm/kg) aptt or ACT returns to baseline in 1-2 DABIG assay, TT, aptt, CBC, SCr DABIG assay on admission and w/in 24 hrs after Praxbind infusion. Dabigatran levels < 0.03 mcg/ml are considered normal (no dabigatran activity) TT is useful in confirming presence of dabigatran with respect to trending (TT not indicative of how much dabigatran is present) Normal TT = 15-21 sec (baseline and f/u are used to see trending (ACL Labs: final within 24 ) n/a Minor surgery: For minor surgery with low bleeding risk, consider risk of holding vs risk of VTE. May hold x 24 hrs prior to Timing of Last Dose Before Surgery/Neuraxial Procedure CrCl est Low Med or High >50 24 2-3 days ml/min 31-49 2-3 days 4-5 days <30 ml/min 4-5 days 6 days Neuraxial procedures are contraindicated while patient is fully anticoagulated with dabigatran. If patient risk of VTE is high, a LMWH bridge therapy may be used while dabigatran is being held. LMWH should be held 24 prior to Oral charcoal should not be used in patients with nonfunctioning gastrointestinal tract, uncontrolled vomiting, unprotected airway, or if there has been co-ingestion of hydrocarbons. aptt has negative predictive value: normal value (< 33) suggests little anticoagulant present. PT/INR is not sensitive and not recommended. Minimum time between spinal injection or catheter removal and next dabigatran dose is 24. If VTE risk is very high, can give half the usual dabigatran dose 12 hrs after removal. 3
FACTOR Xa INHIBITORS Apixaban (Eliquis ) Not Dialyzable Fondaparinux (Arixtra ) 20% Dosedependent: 2.5mg 8 with repeated dosing 5mg single dose: 15 17-21 ; Longer with renal impairment No specific antidote is available If within 2 of ingestion, give oral activated charcoal with sorbitol 50g orally x 1 dose 4-Factor Prothrombin Complex Concentrate (4-F PCC, Kcentra ) 50 units Factor IX per kg maximum dose 5000 units. Contraindications to the use of 4-F PCC (Kcentra ): heparin allergy or history of heparin-induced thrombocytopenia, disseminated intravascular coagulation (DIC). Kcentra contains heparin. Heparin allergy or history of heparin-allergy: Consider FEIBA (50 units Factor IX per kg slow IV push at max rate of 2 units/kg/min) No antidote available FEIBA 20 units factor IX per kg OR Recombinant Activated Factor VII (rfviia, NovoSeven ) 90mcg/kg IV push over 2-5 minutes Prolongs INR, aptt, and anti-factor Xa activity. High degree of variability and not useful for monitoring. Anticoagulant effects can persist for approximately 24 FONDA level (anti- Xa activity) Drawn 3-4 hrs postdose: Prophylaxis peak: 0.2 0.4 anti-xa units/ml Treatment peak: 0.5-1.5 anti-xa units/ml Minor surgery: For minor surgery with low bleeding risk, consider risk of holding vs risk of VTE. May hold x 24 hrs prior to Timing of Last Dose Before Surgery/Neuraxial Procedure Low Med-High At least 24 3-5 days prior prior to to surgery surgery Minimum time between spinal injection or catheter removal and next apixaban dose is 24. If VTE risk is very high, can give half the usual apixaban dose 12 hrs after removal. Low bleed risk surgery: Hold fondaparinux for 2 days prior to surgery Med-High risk surgery: Hold fondaparinux for 3-4 days prior to Minimum time between last dose of fondaparinux and when spinal injection or catheter placement can occur (prolonged in renal impairment): Fondaparinux < 2.5mg SUBQ daily (prophylaxis dose): 2 days Fondaparinux 5-10mg SUBQ daily (full dose): 3-4 days rfviia is associated with thrombotic risk. Minimum time between spine injection or catheter removal and next dose of 4
fondaparinux: 24 FACTOR Xa INHIBITORS - continued Rivaroxaban (Xarelto ) Healthy: 5-9 Elderly: 11-13 No specific antidote is available. If last dose given < 2, give activated charcoal 1 g/kg 4-Factor Prothrombin Complex Concentrate (4-F PCC, Kcentra ) 50 units Factor IX per kg maximum dose 5000 units. Contraindications to the use of 4-F PCC (Kcentra ): heparin allergy or history of heparin-induced thrombocytopenia, disseminated intravascular coagulation (DIC). Kcentra contains heparin. Heparin allergy or history of heparin-allergy: Consider FEIBA (50 units Factor IX per kg slow IV push at max rate of 2 units/kg/min) Rivaroxaban (RIVAR assay) may be used to detect the presence of rivaroxaban. Draw on admission and 24 after KCentra administered. Rivaroxaban levels < 21 ng/ml are considered undetectable PT is somewhat sensitive and may be prolonged with rivaroxaban use. Minor surgery: For minor surgery with low bleeding risk, consider risk of holding vs risk of VTE. May hold x 24 hrs prior to Timing of Last Dose Before Surgery/Neuraxial Procedure CrCl Low Med- High > 30 24 3 days ml/min 15-30 ml/min 2 days 4 days Time between rivaroxaban dose and placement of epidural catheter is dependent on CrCl The next rivaroxaban dose is not to be administered earlier than 24 after the removal of the catheter. If VTE risk is very high, can give half the usual rivaroxaban dose 12 hrs after removal. 5
VITAMIN K ANTAGONIST Warfarin (Coumadin ) 36 at steadystate Use 4-factor prothrombin complex concentrate (4-F PCC, Kcentra ) AND vitamin K 10mg IVPB. Do not repeat KCentra dose. Pre-treatment INR Dose of Kcentra (units of Factor IX per kg actual body weight) Maximum dose (units of Factor IX) 2 to 3.9 4 to 6 >6 25 35 50 Not to exceed 2500 units Not to excee d 3500 units Not to exceed 5000 units Contraindications to the use of 4-F PCC (Kcentra ): heparin allergy or history of heparin-induced thrombocytopenia, disseminated intravascular coagulation (DIC). Kcentra contains heparin. Heparin allergy or history of heparin-allergy: Consider FEIBA (50 units Factor IX per kg slow IV push at max rate of 2 units/kg/min) or fresh frozen plasma (15ml/kg at 10ml/min). Reversal for life-threatening bleeding must include administration of IV vitamin K. INR 30 minutes after administration. KCentra effect persists for 6-8. The effect of simultaneously administered IV vitamin K is seen within 4-6. Repeat treatment with PCC has not been studied. Monitoring of INR during treatment is mandatory. Reversal for non-emergent, major surgery (goal INR < 1.5): Elective surgery: Hold warfarin for 5 days prior to medium-high risk bleeding surgery. Consider bridging with parenteral LMWH anticoagulant until surgery in patients at high risk for thrombosis. Repeat INR prior to surgery. Surgery within 24-48 : Administer 2.5mg to 10mg oral vitamin K depending on degree of INR elevation and warfarin dose requirement. Repeat INR 24 after vitamin K dose. Minor surgery: For minor surgery with low bleeding risk, consider risk of holding vs risk of VTE. Majority of minor procedures may be performed when INR < 3 Neuraxial procedures are contraindicated in patients therapeutically anticoagulated with warfarin. Minimum time between spinal injection or catheter removal and next warfarin dose is 24. Prothrombin complex concentrates (KCentra, FEIBA) are associated with thrombotic events. Prophylactic anticoagulation should be started when possible after warfarin reversal. Kcentra Dosing: Kcenta potency is defined by Factor IX content. The range of Factor IX units per vial is 400-620 units. When reconstituted using the 20ml diluent provided, the final concentration of drug product in Factor IX units will be in a range from 20-31 units/ml. KCentra administration: Do not mix with other products and administer through a separate infusion line at a maximum rate of 8.4 ml/min. 6
Drug Half-life Emergent Reversal for Life-threatening Monitoring Periprocedural Management Comments ANTIPLATELETS Aspirin 50-100% Clopidogrel (Plavix ) Half-life is dose dependent Low-dose: 2-4.5 Overdose: 15-30 Platelet inhibition for ~ 3-5 days after last dose Half-life 7-10 Platelet inhibition for ~ 5 days after last dose No antidote available DDAVP (desmopressin) 0.3 mcg/kg IV in 50 ml NS x 1 over 30 minutes Caution: Serial doses associated with tachyphylaxis, hyponatremia, and seizures. May need platelet transfusion to attenuate bleeding. Aspirin Response (ASARES) (VerifyNow) Platelet function Screen (PFS) on PFA100 Platelet Function P2Y12 (VerifyNow) Minor surgery/low bleeding risk: Consider continuation of antiplatelet based on physician discretion. Do not discontinue in patients treated for coronary or cerebrovascular disease. Major surgery / Discontinue agent for the duration of platelet inhibition (6 days); however, continuation of aspirin is recommended for most surgeries, including coronary artery bypass graft (CABG), depending on indication for aspirin use. Aspirin is generally held for spine, neurosurgical and some ophthalmological surgeries Major surgery: Discontinue 5-7 days prior to procedure or 24 prior to urgent CABG. The decision to hold should take into consideration the risk of thromboembolic events and bleeding risks. A shared assessment, risk stratisfication, and management decision should occur in conjunction with pertinent physicians Discuss risk vs benefit of discontinuing antiplatelet therapy with cardiologist due to increased risk of thrombotic events after discontinuation Repeated doses of DDAVP can result in tachyphylaxis Circulating drug or active metabolites can inhibit transfused platelets. Irreversible platelet inhibitor Given the active metabolite of clopidogrel, platelet transfusion every 12 for up to 48 may be needed in life-threatening bleeds. Prasugrel (Effient ) No Dialyzable 7-10 Platelet inhibition for ~ 7 days after last dose 7 Platelet Function P2Y12 (VerifyNow) Med-High bleed: Hold for at least 7 days prior and 12 after the removal of epidural catheter or injection (24 hrs if loading dose). If at high risk for VTE, can hold for 5 days; if available, platelet function tests may be performed Major surgery (med-high bleed risk): Discontinue 7-10 days prior to procedure Hold for at least 7-10 days prior to placement and 24 after the removal of epidural catheter or injection. Irreversible platelet inhibitor Ticagrelor Parent drug: ~ 7 Platelet Function Major surgery (med-high bleed risk): Reversible platelet inhibitor
(Brilinta ) Active metabolite: ~9 Platelet inhibition for ~ 3 days after last dose P2Y12 (VerifyNow) Discontinue 5 days prior to procedure or 24 prior to urgent CABG Hold for at least 5 days prior to placement and 24 after the removal of epidural catheter or injection. Drug Half-life Emergent Reversal for Life-threatening Monitoring Periprocedural Management Comments GLYCOPROTEIN IIb IIIa INHIBITORS Abciximab (ReoPro ) Eptifibitide (Integrelin ) Tirofiban (Aggrastat ) 30 min 2.5 hrs RTB 4 hrs 2 hrs No specific antidote available Discontinue infusion Administer platelets to attenuate bleeding DDAVP 0.3 mcg/kg IV in 50 ml NS over 30 minutes x 1 Caution: Serial doses associated with tachyphylaxis, hyponatremia, and seizures n/a Neuraxial Procedures: Abciximab Eptifibatide Tirofiban Prior to catheter placement 48 (low risk) 5 days (med-high) 8 (low) 24 hrs (med-high) 8 (low) 24 hrs (med-high) After catheter removal 8-12 8-12 8-12 Primarily urinary excretion. Significant renal impairment may alter clearance. THROMBOLYTICS t-pa alteplase (Activase ) Half-life: 26-46 minutes 80% cleared within 10 minutes No specific antidote available There is no evidence that administration of clotting factors has a favorable effect on clinical or radiologic outcomes. Tranexamic acid 1gm loading dose in 50 ml NS over 10 minutes followed by 1gm in 250 ml NS infused over the next 8 Minimal effect of tpa on coagulation and no predictive value of laboratory coagulation assays for a bleeding event caused by tpa Neuraxial Procedures: Hold 48 prior to catheter placement Restart 48 after catheter removal Fibrinogen levels will return to normal within 24 of tpa administration Advocate P&T Approval: March 2014, January 2016 Revision date: 1/18/16 8
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