key: cord-1048057-h16u2byz authors: Kincaid, Keith J.; Simpkins, Alexis N. title: Failure of Anticoagulation to Prevent Stroke in Context of Lupus-Associated Anti-Phospholipid Syndrome and Mild COVID-19 date: 2021-04-12 journal: J Stroke Cerebrovasc Dis DOI: 10.1016/j.jstrokecerebrovasdis.2021.105817 sha: bd3d9cb9dd1ebf94a0a7da616cea1b074faf847c doc_id: 1048057 cord_uid: h16u2byz Hypercoagulability and virally-mediated vascular inflammation have become well-recognized features of the SARS-CoV-2 virus infection, COVID-19. Of growing concern is the apparent ineffectiveness of therapeutic anticoagulation in preventing thromboembolic events among at-risk patient subtypes with COVID-19. We present a 43-year-old female with a history of seropositive-antiphospholipid syndrome and systemic lupus erythematosus who developed an acute ischemic stroke in the setting of mild COVID-19 infection despite adherence to chronic systemic anticoagulation. The clinical significance of SARS-CoV-2-mediated endothelial cell dysfunction and its propensity for producing macrovascular events in the absence of coagulopathy warrants further investigation and likely represents the disease-defining pathology of COVID-19. Two weeks later, the patient returned to a hospital after a seizure. Her exam was notable for fluent aphasia and right upper and lower extremity weakness. She was not a candidate for acute intervention as the lastknown-well time was unknown, and the patient's INR was 2.49 at the time of presentation. She was normotensive, afebrile, and tachycardic with normal sinus rhythm. Cerebral imaging revealed an area of cortical and subcortical diffusion restriction of the left parietal and superior temporal lobes on diffusionweighted magnetic resonance imaging (MRI) consistent with acute ischemic infarction (Figure 1a & 1b) and left middle cerebral artery occlusion (Figure 1c ). An echocardiographic evaluation, stroke labs, and telemetry were unremarkable. After an uneventful hospitalization, the patient was discharged home with outpatient rehabilitative services and transitioned to apixaban for anticoagulation by her hematologist. Of note, prior to this stroke, the patient had not had any recent thrombotic events related to her lupus and anti-phospholipid syndrome since being initiated on immunosuppressants and coumadin greater than 10 years prior. Acute thrombotic events have become a primary feature of COVID-19, attributable to both a proinflammatory hypercoagulable state and virally-mediated vascular inflammation. 2, 3 Numerous studies have substantiated that COVID-19-associated coagulopathy (characterized by mild thrombocytopenia, elevated D-dimer, elevated serum cytokines, elevated serum inflammatory markers, and prolonged prothrombin time) 4 appears to worsen with increasing disease severity, evidenced by associations between mortality rate and D-dimer level. As such, prophylactic anticoagulation has become a guideline recommendation for all patients hospitalized with COVID-19, regardless of severity. [4] [5] [6] For patients with pre-existing hypercoagulable states, such as APS, recommendations speculate that a higher target of anticoagulation may be necessary to attenuate the risk of thrombotic events. 7 However, reports of acute thrombotic events among individuals with COVID-19 despite anticoagulation are concerning, in particular among those with severe disease are at increased risk. 8 Acute thromboses have also been reported among those with only mild disease (without viral pneumonia or hypoxia) and in whom the features of COVID-19-associated coagulopathy are absent. 2, 9, 10 Animal models have demonstrated that SARS-CoV-2 can invade the brain through axonal transport via infection of olfactory neurons, but data demonstrating direct causality of stroke by neuroinvasion of SARS-CoV-2 in humans remains lacking. 11 Altogether, these findings suggest that SARS-CoV-2 endotheliitis may play a more significant role than expected in the formation of thromboses in COVID-19. Endothelial cell dysfunction is emerging as the disease-defining pathology underlying COVID-19. 12, 13 It is now well established that SARS-CoV-2 infects the endothelial cells of multiple organ systems via the angiotensin converting enzyme 2 (ACE2) receptor, ultimately resulting in apoptosis and necrosis of endothelial cells 14 . As inflammation builds, further organ systems deteriorate and serve as inflammatory furnaces of cytokine production through well understood physiological positive-feedback loops. 12 Quickly, the elements of Virchow's Triad (vascular inflammation, hemostasis, and hypercoagulability) develop with a widespread capacity to precipitate formation of micro-and macro-vascular thromboses. To substantiate this, pathological studies have overwhelmingly demonstrated evidence of multimodal microvascular injury consistent with both vascular inflammation and endothelial cell dysfunction. 15 This may explain why thrombosis occurs despite activation of the ACE2/angiotensin-(1-7)/Mas receptor axis, a pathway shown to attenuate thrombosis formation in mouse models. 16 In conclusion, SARS-CoV-2 endotheliitis may represent an unfamiliar mechanism of stroke which both meets clinical significance and warrants further investigation. Of great concern is the possibility that risk of major thrombotic phenomena may not be reassuringly attenuated by means of anticoagulation. Studies of mild COVID-19 examining the association between disease symptoms and incidence of cerebrovascular sequelae are likely to be worthwhile. Additionally, clinical trials addressing alternative goals of anticoagulation would be informative, as are trials examining anti-inflammatory agents and their effect on the incidence of cerebrovascular events in patients with COVID-19. None of the authors have any conflicts of interest to disclose. National Institutes of Health COVID-19 Treatment Guidelines Panel. 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