key: cord-0827898-0gb68g8i authors: Shinohara, Yoshimi; Miyaoka, Ryo; Hirosawa, Makoto; Yamamoto, Junkoh title: Predictors of intracerebral hemorrhage in COVID-19 date: 2021-01-28 journal: J Clin Neurosci DOI: 10.1016/j.jocn.2021.01.031 sha: 098a168c70f2dbe7fd75119323df2cde8a317777 doc_id: 827898 cord_uid: 0gb68g8i • In COVID-19, intracerebral hemorrhage is a rare complication, but it seems the patients may have something in common. • It is presumed renal dysfunction, long-term clinical course in critically ill patients, antiplatelet therapy, anticoagulation as the predictors of ICH. • From previous reports, it was postulated that the affecting factors of ICH were endotheliopathy and unstable coagulation function. • To prevent the onset of ICH, it is recommended to consider early termination of anticoagulation. We read with interest the case series regarding intracranial hemorrhage in COVID-19 by Fayed I, et al. [1] . Except for hemorrhagic infarction, the other two cases have backgrounds of underlying diseases with antiplatelet therapy, developed intracranial hemorrhage in the context of anticoagulation. They have undergone a severe clinical course for more than a week before the identification of bleeding. From their situation of respiratory failure and high D-dimer, it is presumed that they have been in a COVID-19associated coagulopathy (CAC) state that could causes pulmonary embolism and pulmonary epithelial thrombosis [2] . CAC is being used to describe the coagulation changes in COVID-19 and characterized by the early coagulation dysfunction as a risk factor for thromboembolism. The prognosis improved by anticoagulation therapy during the early phase of COVID-19. Therefore, it has been recommended to begin the anticoagulation therapy based on the coagulation test screening [3] . We experienced a case of COVID-19 that followed a similar clinical course. A 79-year-old male with a history of myelodysplastic syndromes (MDS) on immunosuppressant and coronary artery stenosis status on aspirin was transferred to the emergency department with severe respiratory failure. Blood tests showed high inflammatory states and acute renal dysfunction. After testing positive for SARS-CoV-2, he was diagnosed co-infection with bacterial pneumonia and SARS-CoV-2. Since his high D-dimer and Sepsis-induced coagulopathy (SIC) score was 4, he was diagnosed CAC and started a heparin drip based Letter to the editor: Predictors of ICH in COVID-19 3 on the current medical consensus [3, 4] . The heparin level remained within the control range, in addition to his home dose of aspirin. On the seventh day of hospitalization, he suddenly presented with right hemiparesis and sensory disturbance, and left intracerebral hemorrhage (ICH) was revealed by an urgent computed tomography (CT) (Fig.1A) . Diagnostic workup was completed with magnetic resonance imaging (MRI) later, but did not show any underlying pathology for the origin (Fig.1B) . Two hypotheses were proposed as the pathogenesis of ICH in COVID-19 patients. As the author advocate, one is the direct invasion of SARS-CoV-2 into the central nervous system (CNS), which is assumed due to retrograde transfer via peripheral nerve [5, 6] . The other is the endotheliopathy, which has been proposed various hypothesis about the mechanism. One is that viral replication inducing inflammatory cell infiltration and apoptosis of endothelial cells [7] . Another hypothesis is the consequence of massive inflammatory effects under the cytokine storm as observed in patients with sepsis resultant prothrombotic properties [3] . Because we and the authors did not detect any focal deficit or imaging findings in the cases, it is suggested that endotheliopathy is more suspicious as the mechanism of bleeding than CNS viral infiltration. Interestingly, our case had a background of immunosuppressive therapy for MDS and coinfection with bacterial pneumonia. Since the immunosuppressive state that could suppress cytokine storms but induce hyper viremia, the mechanism of endotheliopathy due to intracellular proliferation of SARS-CoV2 could be presumed. Letter to the editor: Predictors of ICH in COVID- 19 4 To the best of our knowledge, there were 15 cases (including our case) of COVID-19 associated with ICH, those with the particulars of the clinical course (Supplementary table 1) [1, 5, 8 -13] . The average time between onset of initial symptoms and ICH identification was 20.4 days. 13 of 15 (87%) patients were on anticoagulant therapy, and concomitant antiplatelet therapy was observed in 31%. Along with respiratory dysfunction, 92% presented renal dysfunction (defined as creatinine > 1.2 mg/dl or description suggesting the condition) and 40% were undergoing hemodialysis. It is capable of being anticipated that anticoagulation affects the onset of ICH. Our case was identified with irregular shaped hematoma, the characteristic finding of the ICH containing fluid-blood level, which has a high specificity for patients with anticoagulation [14] . In terms of monitoring proper anticoagulant therapy, it is suggested that following anti-FXa activity with aPTT measurements should be considered, because CAC-induced hyperfibrinogenemia may cause both hypercoagulability and heparin resistance [3] . 87% were not measured anti-FXa activity at time of ICH. In these reports, possibly including cases of iatrogenic bleedings due to unstable control of coagulation function because of concurrent renal dysfunction. An important point to emphasize is that ICH, an uncommon complication in patients of COVID-19, can be induced by long-term anticoagulation. Therefore, we should pay attention to maintain the proper therapeutic range and consider early termination of anticoagulation, especially in cases with renal Letter to the editor: Predictors of ICH in COVID-19 5 dysfunction. In addition, it may be necessary to accumulate cases of concomitant use with antiplatelet drugs and consider reviewing the current medical consensus. 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