Reversal of Antithrombotics in Intracranial Hemorrhage
Recommendations
VKA Reversal
(1) We recommend discontinuing vitamin K antagonists when intracranial hemorrhage is present or suspected.
(GPS, )(2) We recommend urgent reversal of vitamin K antagonists in patients with intracranial hemorrhage with the following considerations:
(S, M)(b) We recommend assessing risks and benefits when considering VKA reversal in intracranial hemorrhage patients with concurrent symptomatic or life-threatening thrombosis, ischemia, heparin-induced thrombocytopenia, or DIC.
(3) We recommend administration of Vitamin K to ensure durable reversal of INR following VKA-associated intracranial hemorrhage. Vitamin K should be dosed as soon as possible or concomitantly with other reversal agents.
(S, M)(a) We suggest one dose of Vitamin K 10 mg IV. Subsequent treatment should be guided by follow-up INR.
(b) If repeat INR is still elevated≥1.4 within the first 24–48 h after reversal agent administration, we suggest redosing with vitamin K 10 mg IV.
(GPS, )(4) We recommend administering 3-factor or 4-factorprothrombin complex concentrates (PCC) rather than fresh frozen plasma (FFP) to patients with VKA-associated intracranial hemorrhage and INR ≥1.4.
(S, M)(a) We suggest the use of 4-factor PCC over 3-factor PCC.
(b) We suggest initial reversal with PCC alone (either 3- or 4- factor) rather than combined with FFP or rFVIIa.
(C, L)(c) We recommend that PCC dosing should be weight-based and vary according to admission INR and type of PCC used.
(d) We recommend repeating INR testing soon after PCC administration (15–60 min), and serially every 6–8 h for the next 24–48 h. Subsequent treatment should be guided by follow-up INR, with consideration given to the fact that repeat PCC dosing may lead to increased thrombotic complications and risk of DIC.
(e) If the repeat INR is still elevated ≥1.4 within the first 24–48 h after initial PCC dosing, we suggest further correction with FFP.
(C, L)(5) We recommend against administration of rFVIIa for the reversal of VKA.
(S, L)(6) If PCCs are not available or contraindicated, alternative treatment is recommended over no treatment.
(S, M)(a) Treatment with FFP and Vitamin K is recommended over no treatment.
(S, M)(b) We suggest dosing FFP at 10–15 ml/kg IV along with one dose of vitamin K 10 mg IV.
(C, L)Oral Direct Factor Xa Inhibitors Reversal
(1) We recommend discontinuing factor Xa inhibitors when intracranial hemorrhage is present or suspected.
(GPS, )(2) We recommend obtaining information on the time elapsed since the last dose of direct factor Xa inhibitor and possible medication interactions to assist in estimating the degree of anticoagulation exposure.
(GPS, )(3) We suggest that pharmacological reversal of oral factor Xa inhibitors should be guided primarily by bleeding (major or intracranial) and not primarily by laboratory testing.
(C, L)(4) We suggest administration of activated charcoal (50 g) to intubated intracranial hemorrhage patients with enteral access and/or those at low risk of aspiration who present within 2 h of ingestion of an oral direct factor Xa inhibitor.
(C, VL)(5) We suggest administering a 4-factor PCC (50 U/kg) or activated PCC (50 U/kg) if intracranial hemorrhage occurred within 3–5 terminal half-lives of drug exposure or in the context of liver failure.
(C, L)(6) We suggest administering 4-factor PCC or activated PCC over rFVIIa because of the lower risk of adverse thrombotic events.
(C, L)Direct Thrombin Inhibitor Reversal
(1) We recommend discontinuing direct thrombin inhibitors when intracranial hemorrhage is present or suspected.
(GPS, )(2) We recommend assessing the time and amount of the last ingested dose, renal function, and possible medication interactions to assist in estimating the degree of anticoagulation exposure.
(GPS, )(3) We suggest that pharmacological reversal of direct thrombin inhibitors should be guided primarily by bleeding (major or intracranial) and not primarily by laboratory testing.
(C, L)(4) We suggest administering activated charcoal (50 g) to intubated intracranial hemorrhage patients with enteral access and/or those at low risk of aspiration who present within 2 h of ingestion of an oral direct thrombin inhibitor.
(C, VL)(5) We recommend administering idarucizumab (5 g IV in two divided doses) to patients with intracranial hemorrhage associated with dabigatran if:
(a) the dabigatran was administered within a period of 3–5 half-lives and there is no evidence of renal failure or
(b) there is renal insufficiency leading to continued drug exposure beyond the normal 3–5 half-lives.
(6) We suggest administering aPCC (50 units/kg) or 4-factor PCC (50 units/kg) to patients with intracranial hemorrhage associated with direct thrombin inhibitors if idarucizumab is not available or if the hemorrhage is associated with a DTI other than dabigatran if:
(a) the direct thrombin inhibitor was administered within a period of 3–5 half-lives and there is no evidence of renal failure or
(b) there is renal insufficiency leading to continued drug exposure beyond the normal 3–5 half-lives.
(7) In patients with dabigatran-associated intracranial hemorrhage and renal insufficiency or dabigatran overdose, we suggest hemodialysis if idarucizumab is not available.
(C, L)(8) In patients with dabigatran-associated intracranial hemorrhage who have already been treated with idarucizumab, PCC, or aPCC, with ongoing evidence of clinically significant bleeding, we suggest consideration of redosing idarucizumab and/or hemodialysis.
(C, L)(9) We recommend against administration of rFVIIa or FFP in direct thrombin inhibitor-related intracranial hemorrhage.
(S, L)Unfractionated Heparin Reversal
(1) We recommend discontinuing heparin infusions when intracranial hemorrhage is present or suspected.
(GPS, )(2) We recommend urgently reversing anticoagulation in patients who develop intracranial hemorrhage during full dose heparin infusion.
(GPS, )(3) We do not recommend routinely reversing prophylactic subcutaneous heparin.
(GPS, )(a) We suggest considering reversal of prophylactic subcutaneous heparin if the aPTT is significantly prolonged.
(4) We recommend administering intravenous protamine sulfate to reverse heparin in the context of intracranial hemorrhage.
(S, M)(a) We recommend dosing protamine according to the dose of heparin infused over the preceding 2–3 h.
(b) We recommend dosing protamine sulfate at 1 mg for every 100 units of heparin given in the previous 2–3 h with a maximum single dose of 50 mg.
(S, M)(c) If the aPTT remains elevated, we suggest repeat administration of protamine at a dose of 0.5 mg protamine per 100 units of UFH.
(C, L)Low-Molecular Weight Heparin Reversal
(1) We recommend discontinuing LMWH when intracranial hemorrhage is present or suspected.
(GPS, )(2) We recommend reversing LMWH in patients with intracranial hemorrhage receiving therapeutic doses of LMWH.
(S, M)(3) We recommend protamine administration by slow intravenous injection over a period of about 10 min according to the following dosing:
(a) For enoxaparin: If enoxaparin was given within 8 h, protamine sulfate should be administered at a dose of 1 mg per 1 mg of enoxaparin administered (up to a maximum single dose of 50 mg). If enoxaparin was given within 8–12 h, a dose of 0.5 mg of protamine per 1 mg of enoxaparin should be administered. After 3–5 half-lives have elapsed, protamine is probably not needed.
(b) For dalteparin, nadroparin, and tinzaparin: Dose protamine at 1 mg per 100 anti-Xa units of LMWH administered in the past 3–5 half-lives of the drug, up to a maximum single dose of 50 mg.
(c) If life-threatening bleeding persists, or the patient has renal insufficiency, we suggest redosing protamine (0.5 mg of protamine per 100 anti-Xa units or per 1 mg of enoxaparin).
(4) We suggest considering recombinant Factor VIIa (90 mcg/kg IV) if protamine is contraindicated.
(C, VL)(5) We recommend against the reversal of LMWH in patients with intracranial hemorrhage receiving prophylactic dosing of LMWH.
(GPS, )(6) We suggest against reversing danaparoid with protamine.
(C, L)(7) We suggest reversing danaparoid with recombinant Factor VIIa (90 mcg/kg IV once) in the context of intracranial hemorrhage.
(C, VL)(8) We suggest against using FFP, PCC, or aPCC to reverse LMWH.
(C, L)Pentasaccharide Reversal
(1) We recommend discontinuing pentasaccharides when intracranial hemorrhage is present or suspected.
(GPS, )(2) We suggest reversing pentasaccharides in patients with intracranial hemorrhage receiving full therapeutic doses.
(GPS, )(a) We suggest administration of aPCC (20 IU/kg) for reversal of pentasaccharides.
(b) If aPCC is contraindicated or not available, we suggest administration of rFVIIa (90 mcg/kg).
(C, L)(c) We recommend against protamine for reversal of pentasaccharides.
(3) In intracranial hemorrhage patients receiving pentasaccharides for venous thromboembolism prophylaxis, we suggest against reversal unless there is evidence of bioaccumulation or impaired clearance.
(GPS, )Thrombolytic Reversal
(1) We recommend discontinuing thrombolytic agents when intracranial hemorrhage is present or suspected.
(GPS, )(2) We suggest using cryoprecipitate (10 units initial dose) in patients with thrombolytic agent-related symptomatic intracranial hemorrhage who have received a thrombolytic agent in the previous 24 h.
(C, L)(3) In cases where cryoprecipitate is contraindicated or not available in a timely manner, we suggest using an antifibrinolytic agent (tranexamic acid 10–15 mg/kg IV over 20 min or ε-aminocaproic acid 4–5 g IV) as an alternative to cryoprecipitate.
(C, VL)(4) We suggest checking fibrinogen levels after administration of reversal agents. If the fibrinogen is less than 150 mg/dL, we suggest administration of additional cryoprecipitate.
(C, VL)Antiplatelet Agent Reversal
(1) We recommend discontinuing antiplatelet agents when intracranial hemorrhage is present or suspected.
(GPS, )(2) We suggest against platelet transfusion for patientswith antiplatelet-associated intracranial hemorrhage who will not undergo a neurosurgical procedure, regardless of the type of platelet inhibitor, platelet function testing, hemorrhage volume, or neurological exam.
(C, L)(3) We suggest platelet transfusion for patients with aspirin- or ADP inhibitor- associated intracranial hemorrhage who will undergo a neurosurgical procedure.
(C, M)(a) We recommend platelet function testing prior to platelet transfusion if possible.
(b) When platelet function testing is not readily available, empiric platelet transfusion may be reasonable.
(C, L)(c) We recommend against platelet transfusion for patients with laboratory documented platelet function within normal limits or documented antiplatelet resistance.
(S, M)(4) We suggest against platelet transfusion in NSAID or GP IIb/IIIa inhibitor-related intracranial hemorrhage, even in the context of neurosurgical intervention.
(C, VL)(5) In candidates for platelet transfusion, we suggest an initial dose of one single-donor apheresis unit of platelets. Platelet testing is suggested prior to repeat platelet transfusion, if available and repeat transfusion should be used only for those with persistently abnormal platelet function tests and/or ongoing bleeding.
(C, M)(6) We suggest consideration of a single dose of desmopressin (DDAVP) in intracranial hemorrhage (0.4 mcg/kg IV) associated with aspirin/COX-1 inhibitors or ADP receptor inhibitors. In patients deemed appropriate (e.g., those undergoing a neurosurgical procedure), DDAVP can be used in addition to platelet transfusion.
(C, L)Recommendation Grading
Overview
Title
Reversal of Antithrombotics in Intracranial Hemorrhage
Authoring Organizations
Neurocritical Care Society
Society of Critical Care Medicine
Publication Month/Year
December 1, 2015
Last Updated Month/Year
May 31, 2023
Supplemental Implementation Tools
Document Type
Guideline
External Publication Status
Published
Country of Publication
US
Target Patient Population
Adult patients with intracranial hemorrhage
Target Provider Population
These guidelines are intended for use by all clinicians providing care to intracranial hemorrhage patients exposed to antithrombotic agents.
Inclusion Criteria
Female, Male, Adult, Older adult
Health Care Settings
Ambulatory, Emergency care, Hospital, Medical transportation, Operating and recovery room
Intended Users
Physician, paramedic emt, nurse, nurse practitioner, physician assistant
Scope
Management, Treatment
Diseases/Conditions (MeSH)
D020300 - Intracranial Hemorrhages, D046648 - Hematoma, Subdural, Intracranial
Keywords
warfarin, intracerebral hemorrhage, subarachnoid hemorrhage (SAH), tpa, intracranial hemorrhages, Reversal of Antithrombotics, Intraparenchymal hemorrhage, Subdural hematoma, Coumadin, Factor Xa inhibitor, Prothrombin complex concentrates, Heparinoid