Abstract

Background: Anticoagulants prevent thrombosis in patients with atrial fibrillation (AF) and venous thromboembolism but increase the risk of hemorrhagic complications. If severe bleeding occurs with anticoagulant use, discontinuation and rapid reversal are essential. However, the optimal timing for resuming anticoagulants after using reversal agents remains unclear. Here, we report early cerebral infarction following the use of andexanet alfa (AA), a specific reversal agent for factor Xa inhibitors, in a patient with traumatic acute subdural hematoma (ASDH). The possible causes of thromboembolic complication and the optimal timing for anticoagulant resumption are discussed.

Case Description: An 84-year-old woman receiving rivaroxaban for AF presented with impaired consciousness after a head injury. Computed tomography (CT) revealed right ASDH. The patient was administered AA and underwent craniotomy. Although the hematoma was entirely removed, she developed multiple cerebral infarctions 10 h after the surgery. These infarctions were considered cardiogenic cerebral embolisms and rivaroxaban was therefore resumed on the same day. This case indicates the possibility of early cerebral infarction after using a specific reversal agent for factor Xa inhibitors.

Conclusion: Most studies suggest that the safest time for resuming anticoagulants after using reversal agents is between 7 and 12 days. The present case showed that embolic complications may develop much earlier than expected. Early readministration of anticoagulant may allow for adequate prevention of the acute thrombotic syndromes.

Keywords: Acute subdural hematoma, Andexanet alfa, Anticoagulant, Cerebral infarction

INTRODUCTION

Direct oral anticoagulants (DOAC), including factor Xa inhibitors, reduce the incidence of thromboembolic events in patients with atrial fibrillation (AF) or venous thromboembolism.[ 25 , 30 , 32 , 34 , 45 ] Intracranial hemorrhage (ICH) is one of the most significant complications of DOAC.[ 3 ] DOAC-induced coagulopathy often enlarges ICH, resulting in poor outcome.[ 21 ] Adequate supportive care and discontinuation of DOAC are essential for bleeding management. In addition, rapid reversal of anticoagulation provides hemostasis, which improves clinical outcomes. Andexanet alfa (AA) is a modified recombinant inactive form of human factor Xa that specifically reduces anti-factor Xa activity.[ 1 , 5 , 6 , 24 , 38 ] When reversal of factor Xa inhibitors is needed due to life-threatening or uncontrolled bleeding, the administration of AA is considered.

While the efficacy of such reversal agents is being established, the timing of anticoagulant therapy resumption remains controversial. After reversal of anticoagulant therapy, the risk of thromboembolic events increases with delays in anticoagulant resumption. Clinicians must make the difficult decision regarding when to resume anticoagulants.

Anticoagulant-associated traumatic acute subdural hematoma (ASDH) is a devastating injury with high morbidity and mortality.[ 2 , 3 , 8 , 20 , 35 ] In the acute phase of traumatic ASDH, coagulation and fibrinolytic activity changes dynamically and may adversely affect complicated injuries. The risk of thrombotic events is high in the 1^st week because of a prothrombotic state induced by trauma.[ 27 , 31 , 40 ] The risk remains high until anticoagulant therapy is resumed. The pathophysiology of traumatic ASDH may not be the same as that of spontaneous ICH in terms of coagulation and fibrinolytic disorders.

In this report, we present a case of traumatic ASDH during anticoagulation therapy that resulted in early cerebral infarction after AA administration. We also discuss the timing of anticoagulant resumption in patients with traumatic ASDH who received anticoagulant reversal agents. The study participant provided informed consent and the study design was approved by the appropriate Ethics Review Board.

CASE REPORT

An 84-year-old woman with a medical history of AF, hypertension, diabetes mellitus, and cerebral infarction and who was receiving rivaroxaban (15 mg/day) experienced frequent falls in her residential facility due to delirium. She then developed a consciousness disorder on awakening. She was transferred to our hospital with a diagnosis of the right ASDH [ Figure 1a ]. The Glasgow Coma Scale score was 6. Her pupils were equal and round, and reactive to light and movement. Plasma fibrinogen concentration at admission (332 mg/dL) was within the normal range; however, D-dimer concentration was elevated (6.78 µg/mL). The Prothrombin Time-International Normalized Ration (1.16) was not prolonged. AA (400 mg) was intravenously administered 16 h after the last rivaroxaban oral administration, followed by a continuous infusion of 4 mg/min for 120 min. The patient subsequently underwent surgery. Stable hemostasis was achieved during the surgery, resulting in blood loss of 100 mL. Although AF persisted during surgery, no hypotensive events occurred, and mean blood pressure was always above 65 mmHg. An immediate postoperative computed tomography (CT) scan revealed complete ASDH removal [ Figure 1b ]; however, the patient had poor postoperative arousal. Brain magnetic resonance imaging showed multiple fresh cerebral infarctions day after the surgery [ Figures 1c and d ]. Magnetic resonance angiography showed no injury or stenosis of carotid and vertebral arteries [ Figures 1e and f ]. Postoperative blood tests showed that D-dimer concentration peaked at 4.78 µg/mL and there was no evidence of disseminated intravascular coagulation. On the day of the onset of cerebral infarction, transthoracic echocardiography was performed, which revealed no intracardiac thrombus and no evidence of the right-to-left shunt. Lower limb venous ultrasound demonstrated no venous thrombus in her both legs. These infarctions were considered cardiogenic cerebral embolisms and rivaroxaban was resumed on the same day. Two months later, she was transferred to a long-term care hospital with a modified Rankin Scale of 5.

Figure 1:

Neuroradiological findings of the case. (a) Plain computed tomography (CT) taken at admission showing a right-sided acute subdural hematoma with low-density areas in some places. (b) CT immediately after surgery showing total subdural hematoma removal and effective intracranial decompression. (c and d) Magnetic resonance imaging taken the day after surgery showing multiple acute cerebral infarctions in the bilateral cerebellar hemispheres, corpus callosum, and cerebral cortex. (e and f) Magnetic resonance angiography showed no vascular abnormalities such as cerebral vascular stenosis, occlusion, or vasospasm.

DISCUSSION

Anticoagulant therapy is effective in preventing ischemic disease in patients with AF, mechanical cardiac valve replacement, or deep venous thrombosis. In contrast, it increases the risk of poor outcomes in patients with traumatic ASDH, mainly resulting from the size or delayed enlargement of the hematoma.[ 11 , 18 , 23 , 29 , 42 , 46 ] Pretraumatic conditioning with anticoagulants is closely associated with “talk and deteriorate” in patients with ASDH.[ 19 , 44 ] Thus, anticoagulant reversal should be considered in cases of life-threatening bleeding or when surgery is required. AA, recently approved as a specific reversal agent for factor Xa inhibitors, can effectively normalize coagulopathy in such situations. Stable hemostasis was obtained both intra and postoperatively in the present case.

On the other hand, discontinuation and/or reversal of anticoagulants may increase the risk of thromboembolic complications. In the present case, cardiogenic embolic infarctions occurred within a day after reversal of anticoagulation with AA. The mechanism of thromboembolic complications may be related to the following factors: (1) characteristics of the reversal agent itself, (2) underlying personal health condition, and (3) pathogenesis of the hemorrhage.

Thromboembolic risk related to characteristics of the reversal agent

It is believed that AA does not exert procoagulant effects. It is unable to cleave prothrombin into thrombin because the serine in the active site is replaced by alanine.[ 1 ] However, the 30-day thromboembolic rate was 9.7% in the ANNEXA-4 study.[ 6 ] A meta-analysis suggested that the incidence of thrombotic complications was 10.7%, which is more frequent than in other DOAC reversal agents.[ 12 ] Recently, it has been demonstrated that the independent procoagulant effect of AA is mediated by the inhibition of the tissue factor pathway inhibitor (TFPI).[ 24 ] Since TFPI is a major inhibitor of the factor VIIa complex, a decrease in its activity may lead to increased thrombogenesis. AA also affects endogenous modulators that regulate hemostasis, including antithrombin and glycosaminoglycan.[ 38 ] It may promote a procoagulant environment by disrupting anticoagulation at multiple sites in addition to reducing anti-factor Xa activity.

Thromboembolic risk related to underlying disease

The risk of thromboembolic complications may be different in each patient depending on the underlying disease for which anticoagulation is introduced. It is suggested that anticoagulants should be resumed earlier than previously thought, approximately 3 days after medical presentation.[ 17 ] The case reported here had underlying chronic AF, with a CHADS₂ score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke [double weight]) score of 6. Thus, the risk of embolism with the withdrawal of anticoagulants was high.[ 40 ]

Thromboembolic risk related to the pathogenesis of the hemorrhage

The patient had sustained traumatic ASDH. The coagulation/ fibrinolytic system may be abnormal in traumatic hemorrhage compared with nontraumatic hemorrhage, resulting in postoperative hypercoagulability.[ 9 , 16 ] Trauma-induced release of tissue factors into the systemic circulation instigates the extrinsic pathway. It may invoke diffuse intravascular activation of coagulation, leading to fibrin deposition and thromboembolic ischemia.[ 9 , 13 , 47 ] The incidence of posttraumatic cerebral infarction (PTCI) is approximately 10%.[ 43 , 49 ] The mechanisms of PTCI include embolism, hypercoagulable state, vascular compression, vasospasm, and blunt cerebrovascular injury.[ 14 , 49 , 50 ]

PTCI of the occipital lobe is well described and often results from compression of the posterior cerebral artery against the tentorium by the herniating medial temporal lobe. Middle cerebral artery territory infarcts may occur as a result of displacement from mass lesions and herniation as well. Cerebral infarction in this case did not depend on the area of vascular control; the multiple small infarcts suggest a cause other than cerebral herniation. Other mechanisms may include vasospasm or thromboembolic events from injured carotid and vertebral arteries. However, magnetic resonance angiography demonstrated no concomitant vascular injury in this patient. Based on the above, the discontinuation of anticoagulants and use of the reversal agent were likely involved in the embolism in this case.

Appropriate time to resume anticoagulants

It appears safe to discontinue anticoagulation for brief periods in nontraumatic anticoagulant-related cerebral hemorrhage.[ 30 , 34 ] In principle, anticoagulation should be resumed as soon as the bleeding risk is reduced.[ 6 , 12 , 22 , 32 , 37 , 48 ] However, there are no consensus guidelines for resuming anticoagulation therapy after traumatic ASDH. Traumatic ASDH is a different entity compared with spontaneous ICH, as injured patients are more hypercoagulable than the general population. Table 1 summarizes previous reports on the initiation of anticoagulants after traumatic brain injury (TBI). All reports concluded that anticoagulation resumption decreased the incidence of ischemic stroke and all-cause mortality, whereas the incidence of hemorrhagic complications remained the same or increased. The resumption time was approximately 7–12 days after the injury.

Table 1:

Summary of reports on resuming anticoagulant after traumatic brain injury.

Three of the reports summarized in Table 1 used a specific reversal agent for anticoagulants in the acute phase. According to a report from a Level I trauma center in the United States, 7–9.5 days after injury was the appropriate resumption time,[ 36 ] whereas the Japan Head Trauma Data Bank reported the median time for resuming anticoagulants as 9 days after injury.[ 41 ] Furthermore, Haji et al. reported anticoagulant resumption in 2–16 days in patients with TBI aged >65 years.[ 15 ] In particular, patients with mechanical valves and those at high risk of embolism should resume anticoagulants as early as possible, that is within 2–3 days after injury.

There have been some reports of heparin initiation in the hyperacute phase within 24 h after injury for deep vein thrombosis prevention.[ 4 , 7 , 26 , 33 ] Shahan et al. reviewed 93 patients with blunt cerebrovascular injury who were immediately infused with low-dose heparin during hospitalization.[ 39 ] There was no increase in the likelihood of worsening hemorrhage compared to patients without heparin administration. Thus, it may be acceptable to start anticoagulants in the hyperacute phase in patients with traumatic ASDH, if hemostasis has been restored. A multicenter randomized trial (Restart Traumatic Intracranial Hemorrhage) is currently underway to determine when to restart DOAC in patients with TBI, and the results are awaited.[ 28 ]

As observed in the present case, cerebral infarction sometimes occurs early after reversal agent use. A meta-analysis of taking anticoagulants showed all thromboembolic complication occurred within a few days (1–4 days) of reversal agent administration.[ 10 ] Therefore, early resumption of anticoagulants should be considered for embolism prevention. In fact, no thromboembolic events were observed after resumption of oral anticoagulation in the ANNEXA-4 study.[ 6 ] As AA has only been approved for a short time, analysis of real-world data on embolic complications after use in patients with traumatic ASDH is warranted. At present, the resumption of anticoagulants must be determined after considering the risk of bleeding and thromboembolic complications in each patient. It is desirable to establish the criteria for anticoagulant resumption in patients with traumatic ASDH through accumulation of cases.

CONCLUSION

AA was used as an effective reversal agent to achieve hemostasis in a patient with traumatic ASDH. The patient had thromboembolic events, and it cannot be ruled out that AA may have been a contributing factor to their occurrence. In patients with traumatic ASDH treated with AA, early anticoagulant resumption may need to be considered because of the higher embolization risk. More real-world studies on AA use, including the timing of anticoagulant resumption, will greatly add to our knowledge and comfort in using this important drug.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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