Article, Neurology

Secondary hematoma expansion in intracerebral hemorrhage during rivaroxaban therapy

Unlabelled imageHematoma expansion in intracer”>American Journal of Emergency Medicine 32 (2014) 947.e3-947.e5

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American Journal of Emergency Medicine

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Case Report

Secondary hematoma expansion in intracerebral hemorrhage during rivaroxaban therapy?

Abstract

Hematoma size is a key prognostic parameter in intracerebral hemorrhage (ICH); hence, secondary hematoma enlargement is an important event. Hematoma enlargement occurs more frequently and over a prolonged period in ICH patients on vitamin K antagonists compared with nonAnticoagulated patients. So far, little is known about the natural history of ICH associated with new oral anticoag- ulants. Here, we present a 76-year-old woman anticoagulated with rivaroxaban who presented with a computed tomography showing a right basal ganglia ICH with ventricular extension. Although pro- thrombin concentrate was administered to reverse anticoagulation, follow-up cranial computed tomography demonstrated secondary hematoma enlargement. The patient deteriorated and died 10 days after from further rebleeding and consequently withdrawal of life- prolonging therapy. Postmortem examination revealed no specific cause of bleeding.

A 76-year-old woman with a previous history of ischemic stroke and Arterial hypertension and on secondary Stroke prevention for atrial fibrillation with rivaroxaban (Xarelto(R); 20 mg 1-0-0) experi- enced a sudden onset of headache and rapidly developed left-sided hemiplegia. Upon arrival of the emergency medical services, she presented awake and orientated with dysarthria and left-sided hemiplegia, with a Glasgow Coma Scale (GCS) of 15. Because her systolic blood pressure exceeded 200 mm Hg, urapidil was injected. After admission to the nearest regional hospital, cranial computed tomography showed a right-sided intracerebral hemorrhage (ICH) with ventricular extension (Fig.). Platelet count, international normalized ratio (1.05) and partial thromboplastin time (28.7 seconds) were within the reference range. Glomerular filtration rate was slightly decreased to 70 mL/min. Immediately after CCT (approximately 1.5 hours after onset), 3500 U of prothrombin complex concentrate was given. At that time, the patient was drowsy (GCS 11), but rapid further deterioration of the clinical status was noted subsequently (GCS 5). The patient was intubated and transferred via helicopter to our neurologic intensive care unit. A first follow-up CCT performed directly after arrival showed secondary hematoma enlargement and hydrocephalus. computed tomographic angiography did not show any signs of underlying cerebrovascular pathology. Calibrated rivaroxaban-specific factor Xa activity mea- sured 6 hours after onset (4 to 5 hours after prothrombin complex

? Disclosures: RV, consulting and lecture fees from Boehringer Ingelheim, Bayer, BMS-Pfizer, St Jude Medical, Apoplex Technologies, and Sanofi and research support from Boehringer, Bayer, Apoplex Technologies, and Daichyi Sankyo; and JP, travel support from Pfizer.

concentrate administration) yielded a plasma concentration of

17.9 ng/mL. The international normalized ratio, activated partial thromboplastin time, thrombin time, and antithrombin 3 were within the reference range. An External ventricular drain (EVD) was placed. Additional follow-up CCTs performed on days 2 and 3 showed no further hematoma enlargement. Intraventricular lysis therapy with recombinant tissue plasminogen activator (1 mg every 8 hours) was performed on days 3 and 4 resulting in successful clot resolution in the fourth ventricle. Because CCT on day 5 showed a new bleeding next to the EVD and intracranial pressure was elevated, a second EVD was inserted from the other side. No further intraventricular lysis therapy was administered. Follow-up computed tomography on day 6 showed further hematoma enlargement. With drainage of both EVDs, intracranial pressure remained stable. Cranial computed tomography on day 9 showed constant blood distribution. Because of the unfavorable prognosis, palliative care was started, and the patient died on day 10. Postmortem brain autopsy revealed no specific cause of the bleeding other than hypertensive microangio- pathy. Particularly no vascular malformation, no signs of cerebral amyloid angiopathy, and no underlying tumor were found.

This is the first report of secondary hematoma expansion in an ICH patient treated with the novel oral anticoagulant rivaroxaban [1- 3]. Prevention of secondary hematoma expansion has been recog- nized as a major target of ICH therapy in the last decade. Treatment with recombinant factor VIIa or with intensive blood pressure lowering can prevent hematoma enlargement in nonanticoagulated patients, although the effect on clinical outcome of these in- terventions is controversial [4-7]. There is limited evidence from case series that secondary hematoma enlargement is more frequent and occurs over prolonged periods in patients anticoagulated with vitamin K antagonists [1,8]. Based on plausibility, expert guidelines recommend antagonizing the effect of vitamin K antagonists using coagulation factors [1,2]. In contrast, there are no data on the natural history of ICH associated with new oral anticoagulant (NOAC). Recently, secondary hematoma expansion was reported in a case of dabigatran-related ICH [9]. In particular, it is unknown whether secondary hematoma enlargement is more frequent in ICH associ- ated with NOAC as compared with nonanticoagulated patients. Such knowledge would be relevant to determine whether attempts to antagonize the anticoagulatory effect of NOAC are justified. Because specific antagonists for the NOACs are not yet available in the clinical setting [10], prothrombin concentrate or factor VIIa has been recommended based on preclinical and phase I studies, but these agents carry the risk of thromboembolic complications [11-13].

Our case shows that hematoma enlargement occurs in ICH patients

on NOAC. However, we cannot determine whether similar secondary hematoma enlargement would have happened in this patient

0735-6757/(C) 2014

947.e4 J.C. Purrucker et al. / American Journal of Emergency Medicine 32 (2014) 947.e3947.e5

Fig. Cranial Computed tomographic scans showing intracerebral hemorrhage with ventricular extension before (A, 08:38 PM; Graeb IVH score 5) and after (B, 02:06 AM; Graeb IVH score 10) prothrombin concentrate administration. C, Representative coronary brain slices after fixation in formalin showing the extensive ICH in the right basal ganglia and thalamus with ventricular extension. Lateral and third ventricle are filled with blood and extended.

independent of rivaroxaban anyway. Approximately 35% of nonati- coagulated patients presenting within 4 hours after ICH onset experience relevant hematoma enlargement during the subsequent 24 hours [14]. Subsequent clinical course with repetitive Bleeding complications as well as the hypertensive microangiopathy found upon postmortem examination of the brain suggests an intracerebral hemorrhagic diathesis in this patient. Although our case cannot resolve this question, it illustrates the dilemma that stroke physicians are currently facing in the emergency care of these patients.

An important unresolved issue is how anticoagulation with an NOAC is detected and quantified in the emergency setting. Standard coagulation testing (PT and PTT) in our patient showed normal values already at the initial presentation. Specific coagulation testing for the NOACs is not yet widely available [10]. Our calibrated factor Xa test approximately 18 hours after the last intake of rivaroxaban showed a rather low plasma concentration. There are currently no coagulation tests allowing to monitor the response to administration of unspecific hemostatic agents such as prothrombin complex concentrate [13].

Initial CCT was performed at Stadtklinik Baden-Baden, Baden- Baden, Germany (departments of neurology and anesthesiology).

Jan C. Purrucker, MD Department of Neurology Heidelberg University Hospital

Heidelberg, Germany E-mail address: [email protected]

David Capper, MD Department of Neuropathology Ruprecht-Karls-Universitat Heidelberg

Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ)

Heidelberg, Germany

Lars Behrens, MD Department of Neuroradiology Heidelberg University Hospital

Heidelberg, Germany

Roland Veltkamp, MD, PhD Department of Neurology Heidelberg University Hospital

Heidelberg, Germany

http://dx.doi.org/10.1016/j.ajem.2014.01.042

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