Assessing Brain Capillaries in Coronavirus Disease 2019 | Neurology | JAMA Neurology | JAMA Network
[Skip to Navigation]
Figure.  Megakaryocytes in Cortical Capillaries of Patients With Coronavirus Disease 2019
Megakaryocytes in Cortical Capillaries of Patients With Coronavirus Disease 2019

A, Examples of megakaryocytes in cortical capillaries from affected cases (hematoxylin-eosin). B, CD61 antibody confirms megakaryocyte identity (cellmarque 161M-18; clone Ms/2f2). C, CD42b antibody further confirms megakaryocyte identity (abcam Ab183345; clone SP219). D, Platelet clusters also stained with CD61 antibody and are readily distinguished from megakaryocytes morphologically. The section thickness was 10 μm. Original magnification was ×1000 except for panel C (original magnification ×600).

Table.  Clinical Information for Affected Patientsa
Clinical Information for Affected Patientsa
1.
Helms  J, Kremer  S, Merdji  H,  et al.  Neurologic features in severe SARS-CoV-2 infection.   N Engl J Med. 2020;382(23):2268-2270. doi:10.1056/NEJMc2008597Google ScholarCrossref
2.
Couzin-Frankel  J. From ‘brain fog’ to heart damage, COVID-19’s lingering problems alarm scientists. Science. Published July 31, 2020. Accessed January 28, 2021. doi:10.1126/science.abe1147
3.
Mukerji  SS, Solomon  IH.  What can we learn from brain autopsies in COVID-19?   Neurosci Lett. 2021;742:135528. doi:10.1016/j.neulet.2020.135528PubMedGoogle Scholar
4.
Jensen  MP, Le Quesne  J, Officer-Jones  L,  et al.  Neuropathological findings in two patients with fatal COVID-19.   Neuropathol Appl Neurobiol. Published online September 8, 2020. doi:10.1111/nan.12662PubMedGoogle Scholar
5.
Duarte-Neto  AN, Monteiro  RAA, da Silva  LFF,  et al.  Pulmonary and systemic involvement in COVID-19 patients assessed with ultrasound-guided minimally invasive autopsy.   Histopathology. 2020;77(2):186-197. doi:10.1111/his.14160PubMedGoogle ScholarCrossref
6.
Rapkiewicz  AV, Mai  X, Carsons  SE,  et al.  Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series.   EClinicalMedicine. 2020;24:100434. doi:10.1016/j.eclinm.2020.100434PubMedGoogle Scholar
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Research Letter
    February 12, 2021

    Assessing Brain Capillaries in Coronavirus Disease 2019

    Author Affiliations
    • 1Department of Pathology, Johns Hopkins University, Baltimore, Maryland
    • 2Department of Otolaryngology, Johns Hopkins University, Baltimore, Maryland
    • 3Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
    JAMA Neurol. 2021;78(6):760-762. doi:10.1001/jamaneurol.2021.0225

    Evidence suggests brain involvement in coronavirus disease 2019 (COVID-19). Manifestations in acutely ill individuals often include confusion and alteration of consciousness. After this phase, many patients experience continued neurologic symptoms such as dysexecutive syndrome1 or “brain fog.”2 However, in autopsies from patients with COVID-19 who had neurologic abnormalities (reviewed in the study by Mukerji and Solomon3), investigations have largely not identified the chronic inflammation or marked neural changes typically associated with viral infection, and viral genetic material has been minimal or absent. It has been difficult to reconcile the experience of patients and clinicians that COVID-19 is altering cognition with tissue studies that show no evidence of encephalitis involving higher brain centers. We hypothesized that histopathology might provide insight. We report here a finding that may contribute in some cases, identified by analysis of brain tissue from patients who died of COVID-19.

    Methods

    The institutional review boards of Johns Hopkins University and Mass General Brigham approved this study, and the next of kin of each patient consented for use of tissues for research. We evaluated brain tissue from autopsies of patients with nucleic acid–proven severe acute respiratory syndrome coronavirus 2 infection and confirmed pulmonary pathology. We assessed the brains from the first 5 such cases at Johns Hopkins University; for 2 of these, only fragments of brain were available. Cases from Mass General Brigham were randomly selected from autopsies of individuals with COVID-19 performed between April 14 and May 15, 2020, and free of infarcts. Detailed information on these 15 patients as well as the 2 control patients without COVID-19 is provided in the eTable in the Supplement. COVID-19–negative cases were chosen because of comparable patient age and the presence of hypoxic-ischemic changes in brain. At autopsy, the cranium was opened with hand tools or a saw with a vacuum shroud to prevent aerosolization. Brains were fixed in neutral buffered formalin, 10%, for 2 weeks, then grossly examined and sectioned for microscopic assessment.

    Results

    In 5 cases (Table) in cortical capillaries, we identified large cell nuclei morphologically consistent with megakaryocytes (Figure, A). To further characterize these cells, we performed immunohistochemistry for CD61 and CD42b, markers of platelets and megakaryocytes. CD61 labels these cells (Figure, B), as does CD42b (Figure, C), confirming their megakaryocyte identity. The cells were distinct from platelet clusters, which were found in postmortem intravascular precipitates (Figure, D). Evaluation of the cortex of 2 patients who tested negative for COVID-19 who had hypoxic brain changes demonstrated no megakaryocytes on CD61.

    Discussion

    Prior to this pandemic, the study neuropathologists (D.W.N. and I.H.S.) had not seen megakaryocytes in brain vessels, and we find no reference to this in the literature. A recent report showed these cells in an infarcted brain in COVID-19,4 suggesting they could have been present in the brain circulation and entered the parenchyma during hemorrhage.

    Multiple lines of evidence indicate endothelial dysfunction may contribute to severe COVID-19 illness. Lung examination demonstrates megakaryocytes,5 and the cells have now been reported in other organs.6 One possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs. Although this initial study does not investigate mechanism, it is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable. By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment.

    Back to top
    Article Information

    Corresponding Author: David W. Nauen, MD, PhD, Department of Pathology, Johns Hopkins, 720 Rutland Ave, Ross Bldg 558, Baltimore, MD 21205 (dwnauen@jhmi.edu).

    Accepted for Publication: January 15, 2021.

    Published Online: February 12, 2021. doi:10.1001/jamaneurol.2021.0225

    Correction: This article was corrected on April 5, 2021, to fix an error in the Accepted for Publication date.

    Author Contributions: Dr Nauen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Nauen, Stewart.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Nauen, Stewart.

    Critical revision of the manuscript for important intellectual content: All authors.

    Administrative, technical, or material support: Stewart, Solomon.

    Conflict of Interest Disclosures: Dr Nauen reports grant support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke during the conduct of the study. Dr Hooper reports grants from the National Institutes of Health/National Cancer Institute during the conduct of the study. Dr Solomon reports grants from National Institutes of Health/National Institute of Neurological Disorders and Stroke during the conduct of the study and authorship payments and royalties from Elsevier outside the submitted work. No other disclosures were reported.

    References
    1.
    Helms  J, Kremer  S, Merdji  H,  et al.  Neurologic features in severe SARS-CoV-2 infection.   N Engl J Med. 2020;382(23):2268-2270. doi:10.1056/NEJMc2008597Google ScholarCrossref
    2.
    Couzin-Frankel  J. From ‘brain fog’ to heart damage, COVID-19’s lingering problems alarm scientists. Science. Published July 31, 2020. Accessed January 28, 2021. doi:10.1126/science.abe1147
    3.
    Mukerji  SS, Solomon  IH.  What can we learn from brain autopsies in COVID-19?   Neurosci Lett. 2021;742:135528. doi:10.1016/j.neulet.2020.135528PubMedGoogle Scholar
    4.
    Jensen  MP, Le Quesne  J, Officer-Jones  L,  et al.  Neuropathological findings in two patients with fatal COVID-19.   Neuropathol Appl Neurobiol. Published online September 8, 2020. doi:10.1111/nan.12662PubMedGoogle Scholar
    5.
    Duarte-Neto  AN, Monteiro  RAA, da Silva  LFF,  et al.  Pulmonary and systemic involvement in COVID-19 patients assessed with ultrasound-guided minimally invasive autopsy.   Histopathology. 2020;77(2):186-197. doi:10.1111/his.14160PubMedGoogle ScholarCrossref
    6.
    Rapkiewicz  AV, Mai  X, Carsons  SE,  et al.  Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series.   EClinicalMedicine. 2020;24:100434. doi:10.1016/j.eclinm.2020.100434PubMedGoogle Scholar
    ×