The issue of low-molecular-weight heparin (LMWH) use is commonly seen with patients and presents clinicians with a significant dilemma. It is common practice to stop all anticoagulation and antiplatelet agents once intracerebral hemorrhage (ICH) is detected. However, the diagnosis can sometimes be delayed, and the situation would be quite different if she had continued her LMWH. Reversal of anticoagulation, in the setting of continued, active bleeding, must be done on an emergent basis. The half-life of LMWH is 12 to 24 hours. There is no antidote that completely reverses the effect of LMWH, and such reversal reports are mostly anecdotal in the literature. Protamine sulfate is used intravenously to reverse unfractionated heparin and leads to full reversal. It is thought that protamine reverses approximately 60% of the effect of LMWH^1,2 based on in vitro studies.

It is unclear why protamine does not fully neutralize the anti-Xa activity of LMWH. One milligram of protamine is given for every 100 units of active unfractionated heparin, and per 1 mg of LMWH.³ The maximum dose of protamine is 50 mg, with a maximum infusion rate of 5 mg/min. Hypotension, severe anaphylaxis, and death have been reported with protamine use.⁴ These adverse reactions can often be minimized by premedication with antihistamines and steroids, as well as a slow rate of administration. If given in excess dose, protamine can have a paradoxical anticoagulant effect.

There are small studies describing recombinant activated factor VII (rFVIIa) for LMWH reversal, with some success. Doses in these studies ranged from 20 to 90 μg/kg.^5,6 The use of rFVIIa in the setting of spontaneous and warfarin-associated bleeding will be discussed later in this chapter.

A safe time to reinitiate full anticoagulation is determined on a case-by-case basis. If hematoma expansion does not occur and the patient does not receive decompressive surgery, in general, full anticoagulation may be resumed approximately 10 to 14 days after the bleeding episode. The decision as to when reinitiation of anticoagulation can occur in this setting must be decided with risk-benefit stratification.

The goal in this case would be rapid reversal of the underlying coagulopathy. For deep brain hemorrhages, neurosurgical intervention is usually not advocated. Warfarin functions as an anticoagulant by inhibiting the biosynthesis of vitamin K–dependent procoagulant factors II, VII, IX, and X.⁷ Higher risk of ICH is associated with the intensity of anticoagulation.⁸ However, often, as in this case, patients on warfarin present with ICH with an INR within therapeutic range.⁹ In oral anticoagulant–associated ICH, the risk of continued bleeding is very high. In patients with ICH, the use of warfarin increases the risk of progressive bleeding and decompensation and doubles the risk of death.^10,11 It is imperative that reversal of coagulopathy is initiated immediately. Treatment consists of vitamin K, fresh-frozen plasma (FFP), and prothrombin-complex concentrates (PCCs).

Vitamin K

The patient should immediately receive vitamin K 10 mg intravenously (IV) over 10 minutes to begin the reversal of warfarin, which can take 6 to 24 hours. Vitamin K administration is necessary for the sustained reversal of the INR. The American College of Chest Physicians guidelines recommend IV vitamin K in the face of life-threatening bleeding disorders.¹² Although anaphylaxis reactions have been reported with IV administration of vitamin K, the overall incidence is rare, 3 per 10,000 doses.^13,14 Anaphylaxis reactions have also been reported with non-IV routes of administration.¹⁵ In addition, the absorption of subcutaneous vitamin K can be unpredictable.¹⁶ Therefore, IV vitamin K is the preferred route of administration in this setting.

Fresh-Frozen Plasma

FFP may be used at a dose of 15 mL/kg to achieve prompt reversal of warfarin by providing factors II, VII, IX, and X. These are the factors that are vitamin K dependent and those that warfarin suppresses. However, obtaining FFP can take quite some time. After the request arrives at the blood bank, the FFP must be blood-type matched and thawed, which can lead to an unacceptable delay in the face of a life-threatening hemorrhage. Volume status is also a concern, as the amount of FFP needed to fully and continuously reverse the coagulopathy may not be possible without infusing an unacceptably high volume intravenously. The usual goal is to achieve an INR < 1.5, which reflects functioning of at least 40% of coagulation proteins, which is considered adequate for hemostasis.¹⁷ A typical unit of FFP contains 200 to 250 mL, and 1 unit typically lowers the INR by approximately 10%. One unit of plasma will raise coagulation factors by 2.5%. Patients usually require 6 to 12 units of FFP and frequently even more, which leads to increased risk of volume overload and pulmonary edema. Such volume may be enough to cause acute exacerbation of patients with known heart failure status. Severe allergic reactions, transfusion-associated circulatory overload, and transfusion-related acute lung injury (TRALI) can occur with FFP transfusion.¹⁸

Prothrombin-Complex Concentrate

PCCs are derived from large donor plasma pools and contain factors II, VII, IX, and X. They are highly concentrated coagulation factor replacement compounds that were originally developed for the treatment of hemophilia patients with inhibitors. They are rapid, in small volume, with no need for thawing, typing, and cross-matching. They have been found to normalize the INR more rapidly than vitamin K or FFP alone.^19,20 Three-factor PCCs were often used in an off-label setting with plasma in the setting of warfarin-associated CNS bleeding. In 2013, a 4-factor PCC was approved in the United States for vitamin K antagonist reversal in patients with bleeding or requiring emergency surgery or invasive procedure based on results of a phase IIIB clinical trial. Only 12% of those patients in that study had an ICH.²¹ In a nonrandomized prospective cohort study of 64 patients with warfarin-associated ICH, the use of 4-factor PCC corrected the INR without any increase in adverse events compared with FFP and was associated with less major hemorrhage and improved 3-month outcomes.²² For this reason, use of PCC is often preferred over multiple doses of FFP with excessive volume load.

Clinicians need to be cautious when using PCCs in patients in whom there is a suspicion of disseminated intravascular coagulation (DIC) as thromboembolic events have been reported. Although PCCs are generally considered safe to use, one should avoid the use in patients with DIC, hyperfibrinolysis, and a recent history of thromboembolism.

Recombinant Activated Factor VII

Factor VIIa is indicated for the treatment of hemophilia patients with inhibitors as well as patients with factor VII deficiency. Many studies have been published regarding the use of rFVIIa in the setting of spontaneous and warfarin-associated bleeding. Variable doses (10-90 μg/kg) have been used in studies attempting to reverse warfarin anticoagulation in the setting of ICH. These studies consist of case reports, case series, and retrospective cohort studies. Factor VIIa was found to lead to rapid reversal of the INR in these studies.^21-25 Because of the varied dosing, the end points assessed make it difficult to draw any other conclusion. However, in the phase III Factor VII for Acute Hemorrhagic Stroke Treatment (FAST) trial, which assessed the use of rFVIIa in spontaneous, noncoagulopathic hemorrhage, there was a reduced hematoma expansion rate with the drug despite no improvement in long-term clinical outcomes (refer to Chapter 2, Intracerebral Hemorrhage, for more detail). It is important to note that rFVIIa corrects the prothrombin time or INR, but this does not always correlate with cessation of bleeding.²⁶

Thromboembolic complications have occurred in this setting and rVIIa use. In the FAST trial, a 5% absolute increase in the number of arterial thrombotic events was found in the group treated with the highest dose (80 μg/kg) of rFVIIa. Thus, particular caution should be used in patients with underlying thrombotic risk.

This is an ideal scenario for considering the use of IV vitamin K 10 mg and PCC 50 units/kg (Table 52-1). PCC has been associated with thrombosis in recipients with hemophilia,²⁷ but in a review of PCC-treated patients, very few thrombotic episodes have been recorded.²⁸ In a 2008 publication,²⁹ Leissinger and colleagues reviewed the published evidence on the role of PCC in warfarin reversal. They identified 14 studies that included 460 patients, and 7 thrombotic complications were reported. There were no episodes of DIC. Overall, the thrombotic risk associated with the use of PCCs is reported to be low although not negligible.

The target-specific oral anticoagulants (TSOACs) are changing the landscape of care for patients who require antithrombotic therapy. Although warfarin is currently the most commonly used anticoagulant, this may change given the multiple food and drug interactions, as well as the need for monitoring. The targeted oral anticoagulants include dabigatran etexilate, apixaban, rivaroxaban, and endoxaban. Dabigitran is a direct thrombin inhibitor that was approved in the United States to reduce the risk of stroke in the setting of atrial fibrillation and for the prevention and treatment of thrombotic disease (ref). The other TSOACs are direct factor Xa inhibitors. Their half-lives and metabolism are listed in Table 52-2. Of note, dabigatran is mainly renally excreted.