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Developing guidelines for the reversal of anticoagulant and antithrombotic agents in the setting of intracranial hemorrhage.


Background: The use of anticoagulants and antithrombotic agents in the population is increasing as the population ages with a concomitant rise in chronic diseases such as atrial fibrillation. The incidence of intracranial hemorrhage (ICH) with these agents is small but clinically significant. The purpose of this article is to illustrate how a single institution developed anticoagulation-associated ICH treatment guidelines.

Methodology: A literature review of the topic was performed using the PubMed and Cochrane Evidence-Based Medicine review databases using keywords including antithrombotic agents, antiplatelet agents, traumatic brain injury, and intracranial hemorrhage. The results of the search were reviewed, and relevant English-language manuscripts were retained. The pharmacology of each agent was reviewed.

Results: Anticoagulants increase the risk and severity of ICH; the association is not as clear with the use of antithrombotic agents. Each agent's pharmacology and development is discussed, and reversal strategies are reviewed. Whereas some agents may be reversed medically, others are dialyzable, and a few agents have no effective reversal mechanism currently available. Conclusion: ICH, either primary or traumatic, that is complicated by these agents must be rapidly recognized and appropriately treated. Use of a common, simple clinical practice guideline will assist clinicians in intervening rapidly for this patient group.

Keywords: anticoagulant, antiplatelet, antithrombotic, intracranial hemorrhage, traumatic brain injury


A critical concern with the use of anticoagulants and antiplatelet agents is the small but significant risk of intracranial hemorrhage (ICH) and the potential for worsening hemorrhages in traumatic brain injury. The incidence of ICH associated with warfarin has been variously calculated to be 0.3%-2.0%. ICH mortality rates at 30 days are 30%-55%; in warfarin-related ICH, the number rises to 43%-60% (Le Roux, Pollack, Milan, & Schaefer, 2014). The incidence of patients experiencing a primary ICH is 7-10 fold higher in those on warfarin than those who are not on any anticoagulant. In addition, many of the patients who receive anticoagulant therapy are older adults and are at higher risk for falls and other traumatic injuries.

The overall mortality associated with anticoagulation-associated ICH is higher than average and is variously reported at 42%-67%, even with prothrombin complex concentrate (PCC) therapy (Le Roux et al., 2014). This subgroup of hemorrhages is linked with greater hemorrhagic expansion than those without concomitant use of anticoagulants. Mortality because of anticoagulant-associated ICHs has not changed in 20 years (Le Roux et al., 2014) suggesting that it may present room for process improvement and improved clinical practice guidelines.

Anticoagulant-associated ICHs and trauma complicated by these medications are no longer an infrequent clinical presentation in emergency departments and critical care units. Only recently have evidence-based guidelines for the reversal of these agents become available. The purpose of this article is to illustrate how a single institution, a trauma center, and a neuroscience institute developed such guidelines.

Materials and Methods

We conducted a literature review utilizing PubMed and Cochrane Evidence-Based Medicine Reviews databases. We then selected English-literature resources pertinent to our work. The articles we found were quite diverse, hence we were unable to conduct a formal meta-analysis. Rather, we found that most articles provided suggestions for reversal of anticoagulants and anti-platelet agents, which were comprehensively reviewed. We then reviewed the pharmacology literature to address the structure, pharmacology, and reversal (or lack of reversibility) of each agent as well as relevant outcome data.


Our review of the literature found that there were few randomized trials of reversal agents, but rather most were recommendations based on experiential and clinical practice. This precluded us from conducting a meta-analysis. However, the literature was sufficient to present consensus guidelines for reversal (see Supplemental Digital Content, available at Key elements within the guidelines are an understanding of the role of various anticoagulants, antithrombotics, and reversal agents.

Reversal Agents

Vitamin K (phytonadione) is actually a group of structurally similar, fat-soluble vitamins needed by the body for the process of coagulation. Vitamin K is an essential factor in the conversion processes unique to blood coagulation. Vitamin K in the setting of ICH is usually administered intravenously, with doses of 5-10 mg.

Desmopressin (DDAVP) is a synthetic replacement for vasopressin; it is a secretagogue of Von Willebrand factor. It induces a rise in intracellular cyclic adenosine monophosphate, which induces a release of Von Willebrand factor from secretory granules into the circulation. The exact mechanism of its role in the reversal of antiplatelet agents is not clear, but it does accelerate the activation of factor X as well as improve platelet adhesion on endothelial cells. Desmopressin is generally given subcutaneously at a dose of 0.3 mcg/kg.

Fresh frozen plasma (FFP) rapidly reverses coagulation factors (Cervera, Amaro, & Chamorro, 2012). However, it has several disadvantages. First, it must be thawed, a process that may take 20-30 minutes. Second, large volumes of FFP are generally needed to administer effective amounts of such factors, which may lead to fluid overload (Le Roux et al., 2014). Risk of fluid overload generally leads to slower infusion, thus delaying the reversal process.

Recombinant factor Vila (rVIIa) is administered off-label in doses of 10-90 mcg/kg as an intravenous bolus over 15 minutes for the treatment of ICH where Coumadin may be present. It is occasionally used in the setting of aspirin use or with the use of dabigatran. A concern in the use of rVIIa is overcorrection of international normalized ratio (INR) and thrombotic events (Le Roux et al., 2014). In this retrospective study of 101 patients taking Coumadin and having ICH, the embolic complication rate was 12.9% within 90 days of receiving rVIIa.

PCC complexes have been administered as either three- or four-factor agents, with the four-factor PCC (KCentra) becoming widely used at this time. These are virally inactivated, vitamin-K-dependent coagulation factors that are dissolved in saline before use (Dentali et al., 2011). It was approved for use in the United States in 2013 but has been used in Europe and Canada for a number of years. Several studies have suggested superior correction of coagulation with four-factor PCC than three-factor agents (Voils & Baird, 2012). In general, vitamin K is recommended with KCentra in warfarin-related bleeds to rapidly reverse INR (Le Roux et al., 2014).


Dabigatran (Pradaxa) was developed by Boehringer Ingelheim. It is a member of the class of direct thrombin inhibitors. It was approved for use in the United States in 2010 for the prevention of thrombotic events associated with nonvalvular atrial fibrillation. Follow-up studies have shown that dabigatran has a lower rate of ICH, ischemic stroke, and overall mortality when compared with warfarin, although gastrointestinal bleeding rates were slightly higher in the dabigatran group (Food and Drug Administration [FDA], 2011, 2012). Dabigatran is associated with a higher risk of thromboembolic events and major bleeding in the mechanical valve population (Pradaxa prescribing material, FDA; Eikelboom et al., 2013) and is thus not recommended for use in this group.

Before 2015, reversal of dabigatran was limited to the use of FFP, rVIIa, and PCC (marketed in the United States as KCentra [CSL Behring]). Laboratory studies of this reversal have been tested with various methods such as Sonoclot (Solbeck, Nilsson, Engstrom, Ostrowski, & Johansson, 2014) and thrombelastography (Solbeck et al., 2014). Dabigatran activity is difficult to quantify; however, a normal activated partial thromboplastin time is indicative of a lack of activity with the drug.

Newer reversal strategies for dabigatran have recently come to fruition. The U.S. FDA (2015) has now approved idarucizumab for emergent procedures and uncontrolled hemorrhage in the setting of known use of the anticoagulant. Administering two consecutive doses of 2.5 g intravenously, as bolus or injection, will immediately yield complete reversal of this new oral anticoagulant as measured by dilute thrombin time or ecarin clotting time. Previous methods of reversal would have suggested treatment with activated charcoal if the dabigatran dose was taken less than 2 hours earlier (Lauer, Pfeilschifter, Schaffer, Lo, & Foerch, 2013). In addition, given its low plasma protein binding (Chang, Dager, & Chin, 2013), dabigatran is also dialyzable. James, Palys, Lomboy, Lamm, and Simon (2013) recommend transfusion with FFP, rVIIa (10-90 mcg/kg), and the use of PCC (dosed by weight) to reverse dabigatran (Zhou et al., 2011).

Rivaroxaban (Xarelto) was the first available orally active direct factor Xa inhibitor, approved in the United States first in July 2011 for deep vein thrombosis prophylaxis in adults undergoing hip and knee replacement surgery and eventually in November 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation. Apixaban (Eliquis) is also a direct factor Xa inhibitor and was approved for treatment and secondary prophylaxis of deep vein thrombosis and pulmonary embolism (Connolly et al., 2011). It has a lower dependence on renal function than dabigatran and rivaroxaban (it has a higher plasma protein binding capacity). Both rivaroxaban and apixaban may prolong aPTT, but they react variably with different reagents. In addition, there is currently no standard for calibration of this assay (Fawole, Daw, & Crother, 2013), limiting the clinical utility of the test. James and colleagues (2013) have advocated the use of PCC, FFP, and rVIIa as reversal agents for rivaroxaban and apixaban, although current data are too weak to formulate a formal recommendation. Factor Xa activity assays may provide clinical data on the activity of the drugs.

Warfarin is a vitamin K antagonist and prevents the hepatic synthesis of vitamin-K-dependent clotting factors, such as II, VII, IX, and X. It began use in the 1950s as an anticoagulation agent; it was used as an antirodent agent. It is a highly effective agent in preventing embolic strokes associated with atrial fibrillation (Watanabe, Siddiqui, & Qureshi, 2012). Because diet and genetic variability can dramatically alter the activity of the drug, frequent serum testing of prothrombin time and INR is required. The newer agents were in fact developed to have similar or improved stroke protection, with no need for blood level monitoring and a more reliable dose-response relationship (James et al., 2013). Overall, the incidence of hemorrhage with dabigatran, apixaban, and rivaroxaban is lower than that with warfarin (Patel et al., 2011).

Antiplatelet Agents

The most common oral antiplatelet agents studied in the setting of ICH have been aspirin and clopidogrel (James et al., 2013). Naidech et al. (2012) found that aspirin and clopidogrel correlate with increased ICH volume, ICH growth, all-cause 14-day mortality, and poor outcome at 3 months. Aspirin has a long history of use after early studies at Oxford in the 1970s (Sutcliffe et al., 2013). The drug inhibits the production of thromboxane A2 in platelets, inhibiting platelet aggregation. Clopidogrel (Plavix, manufactured by Bristol-Myers Squibb and Sanofi) inhibits adenosine diphosphate receptors on platelet cells, preventing aggregation. It is one of the most commonly prescribed drugs in the world (Topol & Schork, 2011).

Platelet transfusions of 5-12.5 units have been considered for reversing aspirin and clopidogrel (James et al., 2013). A study of 45 patients on antiplatelet agents showed less hematoma growth and better overall outcomes when given a transfusion of platelets (Naidech et al., 2012). The recently published Cerebral Hemorrhagic and NXY-059 Treatment Trial found no relationship between prior antiplatelet use and the volume of ICH on baseline CT, ICH growth, or clinical outcome at 90 days.


The development and use of general guidelines in the setting of anticoagulant-/antiplatelet-associated ICH have not been well studied. In fact, practice patterns vary from institution to institution and often from provider to provider (Le Roux et al., 2014). In addition, a significant proportion of these uses are still considered "off-label" by the FDA. In the face of an increasing number of these hemorrhagic and traumatic events in our institution, we sought to develop a flexible guideline to address such situations. These were modeled from the work of Le Roux and colleagues (2014) as well as the Emergency Neurologic Life Support protocols available online from the Neurocritical Care Society (

We included reversal of antiplatelet agents at this time in the protocols, because this is the concern of a great deal of ongoing research. The field may stratify patients at greater risk receiving antiplatelet agents that may need consideration of reversal; otherwise, the trend is moving away from the use of platelets, desmopressin, and other agents.


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Questions or comments about this article may be directed to Michael A. Christensen, RN MSN ACNP-BC NVRN CNRN CCRN, at He is a Neurosurgery Nurse Practitioner, Sutter East Bay Neuroscience Institute, Castro Valley, CA.

Caleb M. Cooper, RN MSN ACACNP-BC, is Neurosurgery Nurse Practitioner, Sutter East Bay Neuroscience Institute, Castro Valley, CA.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

DOI: 10.1097/JNN.0000000000000210
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Author:Christensen, Michael A.; Cooper, Caleb M.
Publication:Journal of Neuroscience Nursing
Article Type:Report
Date:Oct 1, 2016
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