7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Reversal of anticoagulation in intracranial hemorrhage : W David Freeman, MD, Jeffrey I Weitz, MD : Lawrence LK Leung, MD, Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA, Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 17, 2023. INTRODUCTION Intracranial hemorrhage, which includes intracerebral, intraventricular, subarachnoid, subdural, and epidural bleeding, is a potentially devastating occurrence associated with anticoagulant therapy. Reversal of anticoagulation in patients with anticoagulant-associated intracranial hemorrhage is a medical emergency, as anticoagulation is associated with greater hematoma growth, neurologic deterioration, and increased risk of death and major disability compared with no anticoagulation. This topic discusses the reversal of anticoagulation in patients with anticoagulant-associated intracranial hemorrhage. Other aspects of the management and prevention of intracranial hemorrhage are presented separately. Risks and prevention (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Risk of recurrence'.) Management https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 1/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Intracerebral hemorrhage (ICH) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Intraventricular hemorrhage (IVH) (See "Intraventricular hemorrhage", section on 'Management'.) Subarachnoid hemorrhage (SAH) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Subdural hematoma (SDH) (See "Subdural hematoma in adults: Management and prognosis".) Epidural hematoma (EDH) (See "Intracranial epidural hematoma in adults", section on 'Management'.) TERMINOLOGY The following terms are used herein: Intracranial hemorrhage Intracranial hemorrhage is the broadest term for bleeding; it includes bleeding anywhere inside the skull, including intracerebral, intraventricular, subarachnoid, and subdural hemorrhage. Intracerebral hemorrhage Intracerebral hemorrhage (ICH) is bleeding in the brain parenchyma. Intraventricular hemorrhage Intraventricular hemorrhage refers to bleeding within the ventricular system in the brain. Subarachnoid hemorrhage Subarachnoid hemorrhage is bleeding directly adjacent to the brain in the subarachnoid space (between the pia mater and arachnoid membrane); most of these are caused by ruptured saccular aneurysms. Subdural hematoma Subdural hematoma is bleeding outside the subarachnoid space directly beneath the dura mater. Epidural hematoma Epidural hematoma is bleeding in the potential space between the dura mater and the skull or in the epidural space in the spinal canal. URGENT EVALUATION The goal of the evaluation is to document as rapidly as possible, with brain imaging, whether the patient's symptoms are due to intracranial bleeding rather than another cause, such as https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 2/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate poisoning (related to a suicide attempt or other toxic exposure), encephalopathy, or ischemia; to document that the patient is in fact anticoagulated; and to confirm which anticoagulant is responsible. This information determines whether a reversal agent is needed, and if so, the specific agent. We request urgent evaluation by neurology and/or neurosurgery (and stroke team where available) when a patient presents with a suspected intracranial hemorrhage. Laboratory testing for anticoagulation status and brain imaging should be obtained immediately, notifying the laboratory and the radiology department of the emergency nature of the testing and imaging. Patient history can be obtained while the patient is being examined and blood for laboratory testing is being drawn. Often, the neurologist or stroke team can meet the patient in the radiology department and see the images as they are being obtained or review them immediately after. Rapid clinical assessment We rapidly obtain the relevant history, which includes the onset of symptoms, major neurologic abnormalities, which anticoagulant and dose the patient is taking and for what indication, and when they took the most recent dose. Presenting symptoms Patients with symptomatic intracranial hemorrhage generally present with acute onset of neurologic impairment consistent with stroke, although some patients with subarachnoid hemorrhage (SAH) may be neurologically intact and present with isolated sudden-onset, severe headache (ie, thunderclap headache). Subdural hematoma in the setting of anticoagulation may present with acute neurologic deterioration or milder symptoms initially, depending on the size and acuity. Clinical manifestations of epidural hematoma (EDH) are highly variable and include altered consciousness, headache, vomiting, drowsiness, confusion, aphasia, seizures, and hemiparesis. Some patients with acute EDH and transient loss of consciousness have a "lucid interval" with recovery of consciousness followed by deterioration due to hematoma enlargement. Symptoms of intracranial hemorrhage may include headache, nausea, vomiting, or neurologic deficit(s). It is important to distinguish between symptomatic hemorrhage and incidentally discovered hemorrhage on neuroimaging; both are potentially clinically serious, but the urgency and aggressiveness needed to manage symptomatic bleeding may be greater than that for an incidentally discovered subdural bleed that may already be stabilized or resolving. (See 'Neuroimaging' below.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 3/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Additional details of the presentation and diagnosis of intracranial hemorrhage are reviewed separately by etiology: Intracerebral hemorrhage (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation' and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis') Intraventricular hemorrhage (see "Intraventricular hemorrhage", section on 'Clinical presentation' and "Intraventricular hemorrhage", section on 'Diagnostic evaluation') Subarachnoid hemorrhage (see "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Clinical presentation' and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis') Subdural hematoma (see "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Clinical manifestations' and "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Diagnosis and evaluation') Epidural hematoma (see "Intracranial epidural hematoma in adults", section on 'Clinical manifestations' and "Intracranial epidural hematoma in adults", section on 'Diagnostic evaluation') Trauma We ask if there was direct trauma to the head. If the patient was injured in a motor vehicle accident or other trauma (eg, a fall), we determine how fast the vehicle was going and whether neurologic deterioration started before or after the accident. If the patient fell, we determine the distance fallen. Anticoagulant and other medications We ask the name of the anticoagulant and confirm that it is the same as that listed in the medical record. We also ask if the patient is taking other medication(s) that could affect hemostasis, such as an antiplatelet agent (eg, aspirin, clopidogrel) or a drug that may affect the metabolism of their anticoagulant. The tables provide examples of drug interactions for warfarin ( table 1) and the direct oral anticoagulants (DOACs) ( table 2). (See "Biology of warfarin and modulators of INR control", section on 'Drug interactions'.) Dose and timing The indication for the anticoagulant should be assessed as this helps in confirming the specific agent, the dose, and the risk of thrombosis if anticoagulation is stopped or reversed. We ask what anticoagulant dose the patient is using and when the last dose was taken. The strength and timing of the last dose taken may impact whether https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 4/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate reversal is necessary and, especially for andexanet alfa, the amount of reversal agent needed. We also assess whether it is possible that the patient may be anticoagulated to a greater degree than expected with routine dosing. This includes questioning about how they are taking the anticoagulant to ascertain possible overdose or incorrect dosing. For patients on warfarin, we ask about the timing and result of the most recent international normalized ratio (INR). Comorbidities We ask if the individual has renal or hepatic disease, which may affect clearance or metabolism of DOACs, as well as any intercurrent infection, which may affect the INR on warfarin. Disorders that alter gastrointestinal absorption of drugs may explain lack of anticoagulant effect in some cases. Concomitant uremia or thrombocytopenia may increase bleeding risk. The underlying condition necessitating anticoagulation may also be a factor in decision-making, especially for those at highest risk of thromboembolic complications (recent pulmonary embolism, mechanical heart valve). Patients with moderate-to-severe neurologic deficits due to acute stroke may be unable to provide a reliable history. In such cases, it is important to review the patient's medical record and ask family members, friends, and caregivers whether the patient is receiving an anticoagulant and if so, when it was last administered. In some cases, it may be reasonable to ask if there was a suspected suicide attempt. If no history is available, we base our assessment on the results of coagulation testing and imaging. Neuroimaging As noted above, neuroimaging is performed in individuals taking an anticoagulant who develop symptoms consistent with intracranial bleeding, including headache, nausea, vomiting, or neurologic defects. The need for intervention may be more urgent in those with symptomatic bleeding than for those with incidentally discovered bleeding. (See 'Rapid clinical assessment' above.) Acute intracranial hemorrhage must be confirmed by neuroimaging, typically with urgent noncontrast computed tomography (CT), or, less frequently, with magnetic resonance imaging (MRI), before undertaking interventions to reverse anticoagulation. It is not possible to distinguish bleeding from ischemia by history and physical examination alone. This is especially true for patients with atrial fibrillation, who are at increased risk for ischemic stroke, but it applies to all individuals. As an example, neurologic symptoms following a motor vehicle accident may be due to traumatic intracranial hemorrhage or due to an ischemic stroke leading to loss of control of the vehicle. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 5/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate In selected cases in which the time delay in obtaining intracranial imaging could be life threatening, the clinicians may decide to treat empirically; this is a challenging decision that weighs the risks and benefits of empiric treatment versus delaying therapy to confirm the diagnosis. As an example, anticoagulant reversal may be reasonable for an individual with head trauma who has papilledema and for whom brain imaging is not available. However, papilledema has causes aside from ICH and by itself (without brain imaging) is not enough evidence for reversal. Laboratory testing We perform the following testing as rapidly as possible: All patients PT with INR, activated partial thromboplastin time (aPTT), and complete blood count (CBC) with platelet count. Patients on dabigatran Thrombin time (TT); diluted thrombin time (dTT) or ecarin clotting time (ECT) may be performed but they are not widely available. Serum creatinine should also be measured, and creatinine clearance calculated, as dabigatran is primarily eliminated by renal clearance. Patients on an oral factor Xa inhibitor or low molecular weight (LMW) heparin Anti- factor Xa activity, creatinine, and calculated creatinine clearance. Selected patients Liver function tests, basic metabolic panel, and other testing to address suspected comorbidities or other causes of neurologic deterioration. TT and anti-factor Xa activity may not be routinely available at all institutions, although most hospitals can perform a TT. Obtaining a platelet count is important to ensure that the patient does not have concomitant thrombocytopenia, which might contribute to bleeding. The usefulness of these coagulation tests varies according to the anticoagulant agent: Warfarin A prolonged PT or INR (eg, INR 1.4) indicates that the patient is anticoagulated. The aPTT is also prolonged with warfarin. In some cases, an individual with a PT or INR at the high end of the normal range may be slightly anticoagulated, especially if the value is higher than his or her baseline before starting warfarin. The PT and INR are monitored daily to determine if the warfarin effect is persistent and additional vitamin K is needed. (See 'Warfarin' below.) Dabigatran High plasma levels of dabigatran may prolong the aPTT. However, the aPTT may be normal or near normal in patients with therapeutic levels of dabigatran. Therefore, https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 6/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate a prolonged aPTT indicates the need for reversal, but normal aPTT values cannot be used to establish the lack of dabigatran effect. The TT, dTT, and ECT are more sensitive to the anticoagulant effects of dabigatran than the aPTT. Therefore, we would not use a reversal agent if the TT, dTT, and/or ECT are normal. If the TT, dTT, or ECT are not available, anticoagulation status is determined from the history of dabigatran ingestion (eg, dose, time since last dose). (See 'Dabigatran' below.) Direct factor Xa inhibitors Direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are detected by anti-factor Xa activity calibrated to the specific agent. In some cases, anti- factor Xa activity calibrated to a different agent may show drug effect, although this is not optimal. The PT and aPTT may be helpful if prolonged but are not considered reliable indicators of anticoagulant effect. An anti-factor Xa activity that indicates a drug level of >30 ng/mL is evidence of anticoagulation. If anti-factor Xa activity is not available and the PT and aPTT are normal, anticoagulation status is determined from the history of anticoagulant ingestion. (See 'Apixaban, edoxaban, and rivaroxaban' below.) Unfractionated heparin Unfractionated heparin prolongs the aPTT and has anti-factor Xa activity. Heparin has a short half-life of approximately one hour after intravenous infusion. A normal aPTT indicates that the anticoagulant effect has resolved. (See 'Unfractionated heparin' below.) LMW heparin LMW heparin has anti-factor Xa activity. The assay should be calibrated to LMW heparin. A detectable LMW heparin level 0.3 international units/mL indicates LMW heparin effect. There is no anticoagulant effect if there is no detectable anti-factor Xa activity or if the anti-factor Xa activity indicates a LMW heparin level less than 0.3 international units/mL. (See 'LMW heparin' below.) The expected effect of anticoagulants on commonly used clotting tests is summarized in the table ( table 3). For warfarin, the extent of INR prolongation at the time of warfarin-associated ICH correlates with initial hematoma size, progressive hematoma enlargement after admission, functional outcome, and mortality [1-6]. Most episodes of warfarin-associated ICH occur in patients with a therapeutic level of anticoagulation (INR 2.0 to 3.5) [1,7-11]. However, even patients with a therapeutic INR can have an increased risk of bleeding, especially those older than 70 years of age. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) While similar data have not been obtained for all the other anticoagulants, it is likely that the intensity of the anticoagulant effect correlates with the severity of intracerebral bleeding, and https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 7/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate that any level of anticoagulation puts the patient at risk for adverse outcomes of intracranial bleeding compared with no anticoagulation. INDICATIONS FOR REVERSAL AND GOALS OF TREATMENT Acute intracranial hemorrhage Urgent anticoagulant reversal is indicated for patients with acute intracerebral (ICH), intraventricular, subarachnoid, or subdural hemorrhage associated with active anticoagulation. These types of hemorrhage are assumed to be life threating regardless of the extent of hemorrhage visible on initial brain imaging, since ongoing bleeding and hemorrhage enlargement can cause neurologic deterioration, elevation in intracranial pressure, and poor functional outcome or death [12]. An exception is that urgent reversal may not be necessary for a clinically stable patient with a small, chronic subdural hemorrhage and no evidence of elevated intracranial pressure; in such a case, the potential benefit of reversing anticoagulation (reduced risk of hematoma enlargement) must be weighed against the risk of thrombosis related to the underlying need for anticoagulation. As an example, anticoagulation with warfarin dose adjusted to achieve a therapeutic international normalized ratio (INR) may be continued in an individual with a mechanical heart valve and a small subdural hematoma with no signs of increased intracranial pressure, since the risk of valve thrombosis may be a greater concern than hematoma expansion. Another option in such an individual is to switch to heparin anticoagulation, which is easier to reverse quickly, while observing for clinical improvement. This subject is discussed in detail separately. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures" and "Antithrombotic therapy for mechanical heart valves".) As noted above, reversal is only appropriate after intracerebral bleeding has been documented on an imaging study. Empiric treatment for suspected intracranial hemorrhage in the absence of confirmation by one of these methods is not advised unless the patient is in extremis and imaging is not available. This is because reversal agents are potentially prothrombotic, and their use may cause harms without benefit if they are given to an individual who did not actually have a hemorrhage [12]. As noted above, some patients who are receiving an anticoagulant may not actually be anticoagulated, especially if they are on a short-acting agent and took their last dose several half-lives ago. The lack of anticoagulation was demonstrated in some of the trials evaluating reversal agents for the direct oral anticoagulants. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 8/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate The main goals of treatment are to rapidly reverse anticoagulation effects and to maintain reversal for a minimum of 72 hours, thereby limiting hemorrhage enlargement. This is important because hematoma growth, particularly within the first 24 hours after ICH, is an independent predictor of mortality and poor outcome. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Clinical risk factors'.) Reversal of anticoagulation, along with blood pressure control, is believed to improve outcomes in warfarin-associated ICH. In one observational study, reduced rates of hematoma enlargement were noted for patients who had reversal of INR <1.3 within four hours of admission (20 versus 42 percent) [13]. The combination of successful reversal of INR <1.3 and blood pressure control <160 mmHg within four hours was associated with lowered rates of hematoma enlargement (18 versus 44 percent) and in-hospital mortality (13 versus 21 percent). Lumbar puncture in suspected subarachnoid hemorrhage When there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT), lumbar puncture is generally required, except for selected patients with isolated headache, a normal neurologic examination, and high-quality brain imaging performed within six hours of headache onset that is negative for hemorrhage. The sensitivity of CT for detecting SAH decreases over the ensuing hours to days. The evaluation for SAH is discussed in detail separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Anticoagulation is considered a contraindication to lumbar puncture. Anticoagulation should be reversed for patients who require a lumbar puncture to rule out SAH while anticoagulated, as assessed by criteria described above (eg, INR 1.5 for warfarin; prolonged TT for dabigatran; anti-factor Xa activity assay that indicates a level of apixaban, rivaroxaban, or edoxaban over 30 ng/mL; history of ingestion in the preceding 24 to 48 hours if laboratory testing is inconclusive or unavailable). (See 'Laboratory testing' above.) GENERAL MEASURES FOR ALL ANTICOAGULANTS Discontinue all antithrombotic agents All anticoagulant and antiplatelet therapy should be discontinued. This includes discontinuation of the anticoagulant the patient is taking, and avoidance of other anticoagulants (eg, "routine" orders for heparin or low molecular weight (LMW) heparin administration for venous thromboembolism prophylaxis). These measures must be clearly stipulated in the medical record and ordering system. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 9/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate If an individual has another hemostatic defect such as moderate to severe thrombocytopenia (platelet count <50,000 to 100,000/microL) or use of dual antiplatelet therapy, consideration should be given to concomitant therapy for that defect as well. (See 'Other supportive care' below and 'Limited role of platelet transfusions' below.) Potential exceptions are noted above. (See 'Indications for reversal and goals of treatment' above.) Admit to intensive care Patients with acute anticoagulant-associated intracranial hemorrhage should be managed initially in an intensive care setting where frequent neurologic checks can detect neurologic deterioration, and hemodynamic monitoring can allow tighter blood pressure control and management. Control blood pressure Elevated blood pressure may predispose to hematoma expansion in patients with intracerebral hemorrhage (ICH), as already noted. (See 'Indications for reversal and goals of treatment' above.) We target a systolic blood pressure below 140 mmHg for ICH and below 160 mmHg for subarachnoid hemorrhage. Lower blood pressure targets in the acute setting increase the risk of hypoperfusion and infarction. We generally administer antihypertensive agents for those with a systolic blood pressure above 150 mmHg. Specific antihypertensive agents and the frequency of monitoring are discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) Other supportive care Other interventions include rapid and regular assessment of hemodynamic status and airway, along with optimization of body temperature, pH, and electrolyte balance. Rarely, transfusions may be needed, such as platelet transfusions for thrombocytopenia or red blood cell transfusions for anemia. (See 'Limited role of platelet transfusions' below.) Supportive measures are discussed in more detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of management'.) Supportive care related to the site of bleeding is presented elsewhere: Intracerebral hemorrhage (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 10/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Intraventricular hemorrhage (See "Intraventricular hemorrhage", section on 'Management'.) Subarachnoid hemorrhage (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Subdural hematoma (See "Subdural hematoma in adults: Management and prognosis".) Epidural hematoma (See "Intracranial epidural hematoma in adults", section on 'Management'.) Limited role of platelet transfusions Platelet transfusions generally are not indicated in the setting of intracranial bleeding, even for patients on concomitant antiplatelet therapy. Thrombocytopenia Platelet transfusion is appropriate for an individual with platelet counts <100,000/microL or with a known platelet function defect. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Actively bleeding patient' and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Platelet function disorders'.) Antiplatelet agents The available data from trials of patients with spontaneous ICH (eg, the PATCH trial) suggest that empiric platelet transfusions in those without thrombocytopenia may be hazardous and should generally be avoided. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Antiplatelet agents'.) Some clinicians use platelet transfusions for patients taking long-acting antiplatelet agents such as clopidogrel or prasugrel, but there is limited evidence to support this approach. Input from the neurologist and hematologist may be helpful in determining an individualized approach. Platelet transfusion is not considered useful for patients taking ticagrelor because ticagrelor is a reversible inhibitor of the adenosine diphosphate (ADP) receptor on the platelet surface and will bind to transfused platelets. REVERSAL STRATEGY FOR SPECIFIC ANTICOAGULANTS The reversal agent depends on which anticoagulant the patient is receiving. This should be confirmed from the history and in some cases, the results of coagulation testing. (See 'Rapid clinical assessment' above and 'Laboratory testing' above.) As noted above, reversal should be done as rapidly as possible but should only be done when intracerebral bleeding is documented (see 'Neuroimaging' above), in order to avoid giving https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 11/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate potentially prothrombotic drugs unnecessarily to a person with an increased thrombosis risk. Our approach for specific anticoagulants (outlined in the following sections) is largely consistent with general guidelines for reversing anticoagulation in the setting of severe bleeding as well as guidelines specific to hemorrhagic stroke [14-19]. A complete listing of society guidelines is presented separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults".) Warfarin Intracranial bleeding associated with warfarin anticoagulation should be treated with a rapid source of functional clotting factors as well as vitamin K to allow endogenous production of functional vitamin K-dependent factors. Warfarin works by interfering with carboxylation of the vitamin K-dependent clotting factors (factors II [prothrombin], VII, IX, and X). Carboxylation of these factors is essential for their function. The principal means of reversing warfarin rapidly is to replace these fully functional factors. The most rapidly acting source of functional factors is a 4-factor prothrombin complex concentrate (4-factor PCC). Convincing evidence of warfarin anticoagulation is based on a prolonged prothrombin time (PT) and an international normalized ratio (INR) outside the normal range ( 1.4 in most cases). (See 'Laboratory testing' above.) Reversal and monitoring strategy Our approach (described in the following sections) is similar to the 2022 guideline from the American Heart Association (AHA)/American Stroke Association (ASA), the 2018 guideline from the American Society of Hematology (ASH), and the 2012 guideline from the American College of Chest Physicians (ACCP), which recommend the following for serious or life-threatening bleeding associated with warfarin ( table 4) [16,18,19]: Hold warfarin. We also make sure that warfarin has been discontinued and that this is clearly stated in the medical record. Administer a 4-factor PCC; if a PCC is not available, a plasma product such as Fresh Frozen Plasma (FFP) or Thawed Plasma may be used. (See 'Reversal agent' below.) Administer intravenous vitamin K. (See 'Intravenous vitamin K' below.) The effects of these treatments is summarized in the table ( table 5) and an overview of warfarin-associated bleeding and reversal is presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR".) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 12/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate We recheck the PT/INR at approximately 30 minutes following PCC (or plasma) administration and periodically thereafter (eg, INR checked every four to six hours for the first 24 hours, and then checked daily for a few days) to ensure that the INR has become normal (<1.4 in most laboratories) and is maintained in the normal range [11,20]. If the INR remains elevated, additional doses of PCC or plasma may be given [21,22]. Details are presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Serious/life-threatening bleeding'.) Reversal agent For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma. Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII, such as recombinant activated factor VII (rFVIIa), or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. However, use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. We generally do not recommend the use of rFVIIa alone for treatment of warfarin-associated ICH because it does not replace factors II, IX, or X and may give a false sense of security by normalizing the INR without fully reversing warfarin effect. rFVIIa acts rapidly (eg, normalization of the INR within 10 minutes), but the half-life is only two to three hours, and repeated dosing or administration of another product would be required [23,24]. Although the INR is normalized rapidly with rFVIIa, the bleeding risk may persist due to dysfunction of other vitamin K- dependent factors. Thus, the normal INR may give a false sense of security and deprive the patient of other, more effective treatments. Additionally, 4-factor PCC is likely to carry a lower risk of thrombosis than products containing activated factors (rFVIIa or activated PCC, which contains activated factor VII). Prothrombin complex concentrate All four vitamin K-dependent factors are present in 4-factor PCC, which can be administered rapidly in a small volume ( table 6). Thus, 4-factor PCC is the preferred treatment ( table 4). Supporting evidence is summarized below. (See 'Efficacy of PCC versus plasma' below.) All institutions that treat patients with anticoagulant-associated hemorrhage should stock a 4- factor PCC. The available strategies for factor replacement are presented in order of preference; only one of these should be used, along with vitamin K: 4-factor PCC We generally give 4-factor PCC (Kcentra in the United States and Japan; Beriplex or Octaplex in Canada; Octaplex, Cofact, or Proplex in many European countries) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 13/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate as an initial fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). Fixed-dose PCC may be easier logistically to stock and deliver in emergencies, but supplemental PCC doses may be required for those with warfarin-associated ICH who have a higher INR (>3). Alternatively, the initial dose may be calculated by body weight and INR. If weight-based or INR-based dosing is used, institutional protocols should be followed. An example is 25 units/kg for INR 2 to 4; 35 units/kg for INR 4 to 6; and 50 units/kg for INR >6, with a maximum dose of 5000 units [25]. In a randomized trial involving 199 patients with warfarin-associated extracranial bleeding, the rate of effective hemostasis in those assigned to an initial fixed-dose PCC (1000 units) was similar to those assigned a calculated dose that incorporated body weight and INR (87 versus 90 percent) [26]. The median initial dose in the calculated dose group was 1750 units. An additional dose of PCC was given to four patients in the fixed-dose group compared with one in the weight-based group, but the door-to-needle time was shorter in the fixed-dose group (109 versus 142 minutes). The proportion of patients in each group reaching an INR 2.0 within 60 minutes was similar (91 versus 92 percent). 3-factor PCC plus a supplement If a 4-factor PCC is not available, a 3-factor PCC (Profilnine in the United States; Bebulin was discontinued in 2018) can be used. However, 3- factor PCC does not contain factor VII. Therefore, most experts recommend supplementing 3-factor PCC with rFVIIa at a dose of 20 mcg/kg or with plasma (eg, FFP, two units). If rFVIIa is used to supplement 3-factor PCC, we prefer a lower dose (20 mcg/kg) rather than higher doses. This is based on data from a randomized trial in 841 patients with spontaneous intracerebral hemorrhage (ICH; not warfarin-associated) that compared two doses of rFVIIa (80 and 20 mcg/kg) with placebo; PCC was not administered [27]. The primary outcome (severe disability or death) was similar among the three groups, despite less expansion of the hemorrhage in those receiving rFVIIa. Overall, thromboembolic events were similar in the three groups, but severe events (eg, cerebral infarction, myocardial infarction [MI]) were more common in those who received high-dose rFVIIa compared with placebo (8 versus 4 percent). Activated PCC Activated PCC (aPCC) contains factors II, VII, IX, and X; factor VII is mostly present in the activated form (VIIa). The only available aPCC is factor eight inhibitor bypassing activity (FEIBA). FEIBA generally is not used for reversing warfarin anticoagulation, because the activated factor VII is potentially more prothrombotic compared with the factor VII in 4-factor PCC (discussed above) that is not in the activated https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 14/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate state. However, retrospective data suggest that treatment with FEIBA does not increase the risk of thrombotic events compared with plasma products [28]. Plasma products if PCC is unavailable If prothrombin complex concentrate (PCC) is unavailable, a plasma product (eg, FFP, Thawed Plasma) can be used to provide clotting factors. However, plasma requires a much larger volume of administration, often delaying the time to normalization of the INR, during which time hemorrhage expansion can continue. This was illustrated in a series of 45 patients with ICH, in which the median time interval between admission to a neuro-intensive care unit and INR normalization with FFP was 30 hours (range: 14 to 50 hours) [29]. Thus, plasma is not a very effective intervention for reducing the expansion of the hemorrhage [12]. Plasma also carries risks of transfusion reactions. A reasonable approach is to give two units of plasma, recheck the INR, and give additional units if needed. The infusion rate for plasma depends on the patient's ability to tolerate the volume load. FFP and other plasma products such as Thawed Plasma are equally effective in reversing the effects of anticoagulation and are considered interchangeable. Thawed Plasma (FFP that has been stored by refrigeration at 1 to 6 degrees Celsius) has the advantage of being available for immediate use. Eight units (2 liters) of FFP or Thawed Plasma are often required to fully reverse anticoagulation in patients treated with warfarin or other vitamin K antagonists; the total number of units required depends on the extent of INR prolongation. (See "Clinical use of plasma components", section on 'Plasma products'.) Efficacy of PCC versus plasma Prothrombin complex concentrates (PCCs) normalize the INR more rapidly than infusion of plasma or vitamin K alone, often within 10 minutes of administration [11,21,30-33]. However, vitamin K should be administered concomitantly because the effect of PCC is transient (hours) [11]. (See "Plasma derivatives and recombinant DNA- produced coagulation factors", section on 'PCCs'.) Evidence supporting the use of 4-factor PCC in warfarin-associated intracranial bleeding mostly consists of small, randomized trials and observational studies in ICH. As examples: PCC versus plasma Two randomized trials comparing PCC with FFP in intracranial hemorrhage associated with vitamin K antagonists. One trial was stopped early due to safety concerns when the 4-factor PCC group appeared to have a lower rate of death (8 of