NIH Public AccessAuthor ManuscriptBrain Res. Author manuscript; available in PMC 2013 August 01. NIH-PA Author Manuscript Published in final edited form as: Brain Res. 2013 June 13; 1514: 12–17. doi:10.1016/j.brainres.2013.04.011. Rationale and Design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective Sub
Guidelines for the Management of Anticoagulant and Anti-Platelet Agent Associated Bleeding Complications in Purpose: To be used as a common tool for all practitioners involved in the care of patients
who present with bleeding problems related to use of anticoagulant and anti-platelet agents.
The guidelines were developed to represent available evidence from the literature. It is
recognized that there may be instances where interventions not identified in these guidelines
may be indicated. These guidelines are not meant to supersede the clinical judgment of the
treating physician. For purposes of organization, the guidelines are arranged in a linear order
from initial interventions through definitive care. The clinician should recognize that treatment
phases may overlap and interventions will occur concurrently.
Quick Index to Reversal Recommendations
Vitamin K Antagonists
Standard Unfractionated Heparin
Low Molecular Weight Heparin (LMWH)
Direct Thrombin Inhibitors (DTI)
Direct Factor Xa Inhibitors
Other Platelet Inhibitors
GP IIb/IIIa Inhibitors
General Principles of Management of Anticoagulant-Associated Bleeding
Hold further doses of anticoagulant (or anti-platelet agent)
Investigate for bleeding source
volume resuscitation, inotropes as needed optimize oxygenation Consider Antidote (e.g. Vitamin K, protamine)
Local or topical agents (fibrin glue, sealants, hemostatic agents, topical aminocaproic acid or tranexamic acid) Systemic hemostatic measures (intravenous tranexamic acid) Surgical intervention Interventional radiology (e.g. embolization) Red cells, platelets, FFP, cryo as indicated Factor concentrates: Prothrombin Complex Concentrate (PCC), Factor VIIa, FEIBA Comments
Infusion reactions rare (anaphylaxis): administer over 30 min not SQ or IM
Takes 6 hrs (IV) to 24 hrs (PO) to reverse warfarin Large doses can cause warfarin resistance on resumption Use smaller doses if mechanical heart valve (1 -2 mg) Protamine sulfate 12.5-50 mg IV
Full reversal of unfractionated heparin Heparin: 1mg for every 100 units of heparin remaining Dalteparin: 1mg for every 100 anti-Xa international units of dalteparin Enoxaparin: 1mg for every 1mg of enoxaparin given in previous 8 hrs Tinzaparin: 1mg for every 100 anti-Xa international units of tinzaparin 60-80% reversal of LMWH No reversal for fondaparinux May require repeat dose after a few hours Platelets
1 apheresis unit Raise platelet count by 10-30 x 109/L Frozen Plasma
Replaces all coagulation factors, but cannot fully correct (1 unit = 250ml) o Hemostasis usually requires factor levels 30% o Factor IX may only reach 20% Risk of acute lung injury and circulatory overload Large volume, takes hours to thaw and infuse, must be type specific May need repeat dose after 6 hours Prothrombin Complex Concentrates (PCC): 3-Factor (Profilnine) or 4-Factor (Kcentra)
30-50 units/kg IV Consider 4-Factor PCC (Kcentra) – see below Not currently on formulary here at McLaren – Lapeer Region 3-Factor PCC Content: 500 units of Factor IX contains: Factor II: 750 units Factor VII: 175 units (non-therapeutic levels) Factor X: 500 units No protein C and S
4- Factor PCC
Approved for rapid reversal of warfarin in bleeding patients. INR 2-3.9: 25 units/kg Must be given with IV Vitamin K concurrently when used for warfarin preferred (max of 2500 units) + Vitamin K 2.5mg IVPB Do NOT give repeat dose. INR 4-6: 35 units/kg (max Risk of thrombosis is low. of 3500 units) + Vitamin K Contraindicated in active HIT with thrombosis. 5mg IVPB 4-Factor Content: 500 units of Factor IX contains: Factor II: 380-800 units INR>6: 50 units/kg (max of Factor VII: 200-500 units 5000 units) + Vitamin K Factor X: 500-1020 units Prothrombin Complex Concentrates (PCC): 3-Factor (Profilnine) or 4-Factor (Kcentra) cont.
4- Factor PCC
Rate of infusion: Dose is based on patient's weight and pre-dose INR Measure INR prior to treatment close to the time of dosing (Pharmacy preferred ( 3 units/kg/min) up to must verify INR before dispensing) – stored in pharmacy Correction of Vitamin K antagonist- impairment of hemostasis is reached at the latest 30 min after the injection and will persist for 6-8 hrs. ( 210 units/min) However, the effect of vitamin K (if given simultaneously) is usually achieved within 4-6 hrs. Thus, repeat treatment with human PCC is NOT usually required when vitamin K has been given. Monitoring of INR during treatment is mandatory. The following may ONLY to be used at the direction of Hematology
FEIBA (not currently 50 units/kg
Small volume infusion (20-50mls), 20/kg/min stocked)
No clinical trials for this off-label use High dose (100u/kg) & repeat doses within 12 hours should be avoided Aminocaproic acid
4-5 grams over one Loading dose 4-5 grams over one hour. (Amicar)
Followed by 1 gram/hr IV infusion for 8 hrs or until bleeding is controlled (max of 30 grams/day) Tranexamic Acid
10-30 mg/kg Loading dose: 1 gram over 10min followed by maintenance dose of 1 gram over next 8 hrs (125 mg/hr) Infuse over 30 minutes in 50 ml saline Recombinant factor 15-30 units/kg
Infusion of small volume over 10-20 minutes (may require multiple small VIIa (rFVIIa)
infusions to make total dose) NovoSeven ®
Trauma dose: 100-200 mcg/kg x 1 dose Rapid INR correction due to warfarin, but may not correct bleeding because only restores Factor VIIa Unknown value in correcting bleeding with DTI's, anti- Xa inhibitors, clopidogrel and related drugs Risk of thrombosis 5-10% with higher doses
Studies fail to show mortality benefit If patient still bleeding, may consider dose increase to 30-60 units/kg, if dose is to be repeated. May need repeat dose after 2 hours Definitions Used for Reversal Situations
Reversal is elective (procedures > 12-24 hours)
Urgent (without bleeding):
Reversal needed within hours (6-12 hours)
Emergency Reversal (< 6 hours)
Reversal of Warfarin (Coumadin)
Emergent (Major bleeding or Urgent (No Major Bleeding) surgery for life threatening condition within 6 hours) Stop warfarin 5 days prior to procedure If procedure can be delayed 6-24 Check INR 1-2 days prior hours, vitamin K 1.25-10mg PO or Give Vitamin K and/or FFP – If INR greater than 1.9 low-dose vitamin K 1-2mg IV or Kcentra if pt not a administer Vitamin K 1.25- Higher doses of vitamin K 5-10 mg IV candidate for FFP or life- may be needed depending on initial threatening bleed For supra-therapeutic INR, INR results and post-reversal INR High dose vitamin K 5-10 consider Vitamin K 5-10 mg which is checked 24 hrs after dose mg IV; repeat every 12 Higher doses of vitamin K may Consult cardiology if patient increase need to and duration of Higher doses of vitamin K has mechanical heart valve bridging therapy (e.g. enoxaparin, IV may increase need to and (high risk of thrombosis) heparin) if warfarin is to be restarted duration of bridging Consider 1-2 units of FFP for INR therapy (e.g. enoxaparin, IV greater than 4.9. Repeat every 6-12 heparin) if warfarin is to be hours until 2 successive INR results are at desired target. Consider 2-4 units of FFP Consult cardiology if patient has depending on urgency of mechanical heart valve (high risk of situation; recheck INR in 8 4-Factor PCC ( Kcentra). USE DOSING PROTOCOL
PER PHARMACY (page 4-
Do not repeat dose of Kcentra. Consult cardiology if patient has mechanical heart valve (high risk of thrombosis) Reversal of Heparin
Protamine sulfate is used to reverse the effects of Heparin:
o Heparin (half life of 1-2 hrs): 1mg of protamine sulfate for every 100 units of IV heparin remaining (infused
in last 2-3 hrs)
Example: 20-30mg if heparin infused at 1000 units/hr
Check PTT in 2 hrs and consider more protamine if still prolonged
** Half-life is longer with subcutaneous administration for all agents so may require monitoring with PTT (heparin) every 3 hrs with repeat
protamine (decrease dose to 0.5mg increments though) for heparin if bleeding continues. **
Emergent (Major bleeding/surgery for Urgent (No Major Bleeding) life threatening condition within 6 hrs) Hold 4 hrs prior to Wait 2-4 hrs if possible Consider protamine sulfate if delay Protamine sulfate (e.g. 1mg for not possible for high bleeding risk every 100 units of IV heparin procedures – will reverse 60% of remaining/infused in last 2-3 activity (e.g. 1mg for every 100 units of IV heparin remaining/infused in No proven role for rVIIa or PCC. No role for Frozen Plasma (FFP) Reversal of LMWH (Enoxaparin, Dalteparin, Tinzaparin) and Fondaparinux+
Protamine sulfate is used to reverse the effects of LMWH:
o Enoxaparin (half-life of 4.5 hrs): 1mg of protamine sulfate for every 1mg of Enoxaparin given in previous
o Dalteparin (half-life of 2.2 hrs): 1mg of protamine sulfate for every 100 units of Dalteparin given in
previous 8 hrs
o Tinzaparin (half-life of 3.9 hrs): 1mg of protamine sulfate for every 100 units of Tinzaparin given in
previous 8 hrs
** Half-life is longer with subcutaneous administration for all agents so may require monitoring with anti-Xa level (LMWH) every 3 hrs with
repeat protamine (decrease dose to 0.5mg increments though) for LMWH if bleeding continues. **
Enoxaparin (Lovenox); Dalteparin (Fragmin); Tinzaparin (Innohep)
Emergent (Major bleeding/surgery for Urgent (No Major Bleeding) life threatening condition within 6 hrs) Hold day of procedure Wait 12-24 hours if possible Once-daily regimens Consider protamine sulfate if Protamine sulfate (e.g. 1mg for o May consider ½ dose delay not possible for high every 1 mg of enoxaparin given day prior to procedure bleeding risk procedures – in previous 8 hrs) Twice-daily regimens will reverse 60% of activity No proven role for rVIIa or PCC. o Hold evening dose (e.g. 1mg for every 1 mg No role for Frozen Plasma (FFP) enoxaparin given in previous +Fondaparinux has no specific antidote. Consider Factor VIIa 30 µg/kg for life-threatening bleeding (BUT NO proven
benefit). Hematology consultation required.
Reversal of Bivalirudin (Angiomax) and Argatroban
Urgent (No Major Emergent (Major bleeding or surgery for life threatening condition within 6 hours) Short half-life (25 min) Cleared by the kidneys If procedure can Stop drug (no antidote) (20%) and by proteolytic be delayed, delay Drug may be removed by hemodialysis but generally not indicated due to short half-life Consider rFVIIa (no proven benefit Time (ACT) return though) only for life- threatening intracranial hemorrhage Consider Frozen Plasma (FFP) to competitively antagonize thrombin inhibition – Hematology Consultation required. Reversal of Dabigatran (Pradaxa)
Emergent (Major bleeding or Urgent (No Major Bleeding) surgery for life threatening condition within 6 hours) Creatinine Clearance > 50 ml/min: Hold drug and may check PTT Hold drug and check PTT Treat with activated charcoal if < 2 hrs Treat with activated charcoal if since last dose b < 2 hrs since last dose b - Hold drug x 2 days prior to Optimize renal function with IV fluids to Optimize renal function with IV maintain diuresis c fluids to maintain diuresis c Creatinine Clearance 30-50 ml/min: If PTT is normal: unlikely that If PTT is normal: unlikely that - Hold drug x 2 days prior to dabigatran is contributing to bleeding dabigatran is contributing to - Reassess patient - Hold drug x 4 days prior to - Repeat coagulation tests - Reassess patient - Repeat coagulation tests If PTT is elevated: dabigatran may be If PTT is elevated: dabigatran may Creatinine Clearance < 30 ml/min: contributing to bleeding (no antidote) be contributing to bleeding: - Hold drug x 4 days prior to - Consider prolonged hemodialysis - No antidote available but may - Hold drug x 6 days prior to consider the following: - Reassess patient - PCC (4 factor)d – Kcentra - Repeat abnormal coagulation tests - Use prolonged hemodialysis - Reassess patient. - Repeat abnormal coagulation May consider TEG to further assess May consider TEG (thromboelastography) to further Normal R-time may signify lower assess bleeding risk – not done bleeding risk even if TT mildly here at McLaren-Lapeer though Normal R-time may signify lower bleeding risk even if TT mildly prolonged a May consider longer hold times for major surgery, placement of spinal or epidural catheter or mediport.
b Contraindicated in setting of GI bleeding .
c Dabigatran is primarily excreted in the urine; therefore, need adequate diuresis.
d PCC may not lower PTT.
Reversal of Rivaroxaban (Xarelto)
Urgent (No Major Bleeding) Emergent (Major bleeding or surgery for life threatening condition within 6 hours) Creatinine Clearance > 50 ml/min: Hold drug and may check PT/INR and anti Hold drug and check PT/INR and Xa level (sent out) anti Xa level (sent out) Treat with activated charcoal if < 2 hrs Treat with activated charcoal if < 2 - Hold drug x 2 days prior to since last dose b hrs since last dose b major surgery Creatinine Clearance 30-50 ml/min: If PT/INR or anti Xa level is normal: unlikely If PT/INR or anti Xa level is normal: - Hold drug x 1-2 days prior to that rivaroxaban is contributing to unlikely that rivaroxaban is contributing to bleeding - Hold drug x 3-4 days prior to - Reassess patient - Reassess patient - Repeat coagulation tests - Repeat coagulation tests If PTT is elevated: rivaroxaban may be If PTT is elevated: rivaroxaban may Creatinine Clearance < 30 ml/min: contributing to bleeding be contributing to bleeding: - Hold drug x 2 days prior to - No antidote available - No antidote available but may - Hold drug x 4 days prior to - Reassess patient. consider the following: - Repeat abnormal coagulation - PCC (4 factor) – Kcentra - Reassess patient. - Repeat abnormal coagulation tests. a May consider longer hold times for major surgery, placement of spinal or epidural catheter or mediport.
b Contraindicated in setting of GI bleeding .
Reversal of Apixaban (Eliquis)
Urgent (No Major Bleeding) Emergent (Major bleeding or surgery for life threatening condition within 6 Creatinine Clearance > 50 ml/min: Hold drug and may check PT/INR and Hold drug and check PT/INR and anti Xa anti Xa level (sent out) level (sent out) Treat with activated charcoal if < 2 hrs Treat with activated charcoal if < 2 hrs - Hold drug x 2 days prior to since last dose b since last dose b major surgery Creatinine Clearance 30-50 ml/min: If PT/INR or anti Xa level is normal: If PT/INR or anti Xa level is normal: unlikely - Hold drug x 1-2 days prior to unlikely that apixaban is contributing to that apixaban is contributing to bleeding - Reassess patient - Hold drug x 3-4 days prior to - Reassess patient - Repeat coagulation tests - Repeat coagulation tests If PTT is elevated: apixaban may be If PTT is elevated: apixaban may be Creatinine Clearance < 30 ml/min: contributing to bleeding contributing to bleeding: - Hold drug x 2 days prior to - No antidote available - No antidote available but may - Hold drug x 4 days prior to - Reassess patient. consider the following: - Repeat abnormal coagulation - PCC (4 factor) – Kcentra - Reassess patient. - Repeat abnormal coagulation a May consider longer hold times for major surgery, placement of spinal or epidural catheter or mediport.
b Contraindicated in setting of GI bleeding .
Antiplatelet Agent Reversal
*** Consult Cardiology for All Patients with Stents ***
COX-1 Inhibitors: Aspirin, Aspirin/Dipyridamole (Aggrenox), Dipyridamole (Persantine)
P2Y12 Inhibitors: Clopidogrel (Plavix), Ticlopidine (Ticlid), Prasugrel (Effient), Ticagrelor (Brilinta)
GPIIbIIIa Inhibitors: Eptifibatide (Integrilin), Tirofiban (Aggrastat)
1. Cardiology Consultation Must consider indication for use in decision to reverse. a. Consult cardiology for ALL patients with coronary stents b. Risk of coronary stent occlusion (which can be fatal) within 3 months of bare metal stent Period of risk is likely longer for drug-eluting stents, perhaps up to one year. c. Risk of reversal in some cases may be worse than risk of bleeding. 2. Half-lives a. Clopidogrel, ticlopidine, dipyridamole, prasugrel, ticagrelor: 7-10 hours b. Low-dose aspirin (150 mg daily): 2-4.5 hours c. Overdose aspirin (greater than 4,000 mg): 15-30 hours 3. Reversibility of anti-platelet effect a. Aspirin, clopidogrel, ticlopidine, and prasugrel inhibit platelet function for lifetime of platelet. Inhibition takes 7-10 days to resolve as new platelets are generated. b. Ticagrelor is a reversible inhibitor, so platelet function normalizes after drug clearance. Half- life is 7-9 hours for drug and its active metabolite. 4. Circulating drug or active metabolites can inhibit transfused platelets.
5. Platelet function testing is recommended prior to procedure.
6. Please see separate recommendations for patients on dual antiplatelet therapy (DAPT) with bare metal
(BMS) or drug-eluting stents (DES). Reversal of Aspirin and Aspirin/Dipyridamole (Aggrenox)
Emergent (Bleeding or surgery Urgent (Not Bleeding) Discontinue drug 2 days prior Laboratory testing to evaluate platelet function (e.g. Platelet factor assay) Laboratory testing to evaluate platelet function Do NOT discontinue in (e.g. Platelet factor assay) patients treated for coronary Consider platelet transfusion or cerebrovascular disease – (1 unit) for critical cardiology consult neurosurgery/eye surgery recommended for these ONLY; usually not necessary Recommend hematology consult Reversal of P2Y12 Inhibitors (Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor)
Emergent (Bleeding or surgery Urgent (Not Bleeding) Discontinue drug 5-10 days Laboratory testing to evaluate platelet prior to procedure Laboratory testing to Consider platelet transfusion (1 unit) if evaluate platelet function > 40% inhibited prior to high risk bleeding Platelet transfusion (1 unit) if > 40% inhibited; 2 units if Recommend hematology consult critical neurosurgery/eye Recommend cardiology consult surgery or if dual agent therapy Recommend hematology Recommend cardiology consult Reversal of GP IIb/IIIa Inhibitors (Eptifibatide and Tirofiban)
Emergent (Bleeding or surgery Urgent (Not Bleeding) Discontinue drug; short half- Wait 2-4 hours for elimination of drug lives so drug will be cleared in If platelet count < 20,000/µl, consider Platelet transfusion (1 unit) if transfusion of 1 unit of platelets intervention is truly emergent (Eptifibatide rarely associated with or serious bleeding thrombocytopenia) Recommend hematology Recommend hematology consult Recommend cardiology consult Recommend cardiology consult Anticoagulant Conversion Chart
Anticoagulant to be Discontinue warfarin and start dabigatran when INR is less than 2. CrCl greater than 50 ml/min: start warfarin 3 day before stopping dabigatran CrCL 31-50 ml/min: start warfarin 2 days before stopping dabigatran CrCL 15-30 ml/min: start warfarin 1 day before stopping dabigatran CrCl less than 15 ml/min: no recommendation Start dabigatran when the next dose of LMWH, fondaparinux, I V fondaparinux or heparin would have been due. Start dabigatran at same time as discontinuation of heparin infusion. CrCL greater than 30 ml/min: start 12 hours after last dose of fondaparinux, I V CrCL less than 30 ml/min: start 24 hours after last dose of dabigatran (not fondaparinux) Discontinue warfarin Start rivaroxaban/apixaban when the INR is less than 3 to avoid periods of inadequate anticoagulation. Stop rivaroxaban/apixaban and start warfarin with a full anticoagulant bridging dose of LMWH or fondaparinux. Continue both warfarin and anticoagulant bridge for a minimum of 5 days and until the INR is within the desired therapeutic range. Start rivaroxaban/apixaban when the next dose of LMWH, fondaparinux, I V fondaparinux or heparin would have been due. Start rivaroxaban/apixaban at same time as discontinued of heparin infusion. Start LMWH, fondaparinux or heparin when the next dose of fondaparinux, I V rivaroxaban/apixaban would have been due. Abbreviations: CrCl – creatinine clearance; INR international normalized ratio, LMWH = low-molecular-weight-heparin Warfarin (Coumadin); Dabigatran (Pradaxa); Rivaroxaban (Xarelto); Apixaban (Eliquis); Fondaparinux (Arixtra) References:
1. Chest websit2. ASH website:3. For further information, contact the ASH Department of Government Relations, Practice, & Scientific
Affairs at 202-776-0544 4. American Society of Hematology Guide 2011. 5. Levi M, et al. Bleeding Risk and Reversal Strategies for old and new anticoagulants and antiplatelet agents. Journal of Thrombosis and Haemostasis, 9:1705-1712. 6. Sarode R. How do I transfuse platelets (PLTs) to reverse anti-PLT drug effect? Transfusion 2012; 52:695- 7. Kaatz S. et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Amer J Hematology 2012; THSNA Meeting Proceedings, DOI: 10.1002/ajh.2320 8. Bauer KA. Reversal of antithrombotic agents. Amer J Hematology, DOI:10.1002/ajh.23165 9. Bracey A et al. How do we manage patients treated with antithrombolytic therapy in the perioperative interval? Transfusion 2011; 51:2066-2077. 10. Sarode R et al. Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding.Circulation, 2013; 128: 1234- 1243. 11. Quinlan d et al. Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding (editorial). Circulation, 2013; 128: 1179-1181. 12. Nutescu E et al. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health-Syst Pharm, 2013; 70: e82-e97.
ZUSAMMENFASSUNG DER MERKMALE DES ARZNEIMITTELS BEZEICHNUNG DES ARZNEIMITTELS Pravafenix 40 mg/160 mg Hartkapseln 2. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG Jede Hartkapsel enthält 40 mg Pravastatin-Natrium und 160 mg Fenofibrat. Sonstiger Bestandteil: Jede Hartkapsel enthält 19 mg Lactose. Die vollständige Auflistung der sonstigen Bestandteile siehe Abschnitt 6.1.