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SARS-Cov-2 Vaccination Induced Cerebral Venous Sinus Thrombosis: Do Megakaryocytes, Platelets and Lipid Mediators Make up the Orchestra?

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SARS-Cov-2 Vaccination Induced Cerebral Venous Sinus Thrombosis: Do Megakaryocytes, Platelets and Lipid Mediators Make up the Orchestra? Free Neuropathology 2:18 (2021) Chiang et al doi: https://doi.org/10.17879/freeneuropathology-2021-3395 page 1 of 8 Opinion Piece SARS-CoV-2 vaccination induced cerebral venous sinus thrombosis: Do megakaryocytes, platelets and lipid mediators make up the orchestra? Kate Chander Chiang1, Ravi Raghavan2, Ajay Gupta1,3 1 KARE Biosciences, Orange, CA 92869, USA 2 Department of Pathology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA 3 Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, CA 92868, USA Corresponding author: Ajay Gupta · Division of Nephrology, Hypertension and Kidney Transplantation · University of California Irvine (UCI) School of Medicine · Orange, CA 92868 · USA [email protected] Submitted: 6 June 2021 · Accepted: 1 July 2021 · Copyedited by: Biswarathan Ramani · Published: 7 July 2021 Abstract The COVID-19 vaccines comprised of adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2 are highly effective but associated with rare thrombotic complications. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein expressed locally stimulates neutralizing antibody and cellular immune responses. These vaccines have been associated with thromboem- bolic events including cerebral venous sinus thrombosis (CVST). S glycoprotein stimulates the expression of cy- clooxygenase-2 (COX-2) and leads to massive generation of thromboxane A2 in COVID-19. Megakaryocytes ex- press CAR and we postulate that S glycoprotein stimulated generation of thromboxane A2 leads to megakaryo- cyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinuses express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses could be further activated by thromboxane A2-dependent podoplanin-CLEC2 signaling, leading to CVST. A prothrombotic hormonal milieu, and increased generation of thromboxane A2 and platelet activation in healthy females compared to males is consistent with increased risk for CVST observed in women. We propose that antiplatelet agents targeting thromboxane A2 receptor signaling such as low-dose aspirin merit considera- tion for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to young adults at risk of thrombosis provided there are no contraindications. Keywords: SARS-CoV-2, COVID-19, Vaccine, Thrombosis, Cerebral venous sinus thrombosis, Aspirin, Thromboxane, COX-2, Adenoviral vector, Megakaryocyte Copyright: © 2021 The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited, a link to the Creative Commons license is provided, and any changes are indicated. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Free Neuropathology 2:18 (2021) Chiang et al doi: https://doi.org/10.17879/freeneuropathology-2021-3395 page 2 of 8 Abbreviations may be about 10 per million vaccinated. Antibodies to platelet factor 4 (PF4)/heparin complexes have 7 TxA2 - thromboxane A2, DIC - disseminated in- been recently reported in a few patients. However, travascular coagulopathy, COX - cyclooxygenase, the significance of this finding remains to be estab- TTP - thrombotic thrombocytopenic purpura, CVST - lished. As of April 12, 2021, about 6.8 million doses cerebral venous sinus thrombosis, CLEC - C-type lec- of the Janssen vaccine have been administered in tin-like receptor - TLR, toll-like receptor, CAR - cox- the U.S.8 CDC and FDA are reviewing data involving sackievirus and adenovirus receptor, COVID-19 - six reported U.S. cases of CVST in combination with coronavirus disease 2019, SARS-CoV-2 - severe thrombocytopenia.8 All six cases occurred among acute respiratory syndrome coronavirus 2, PF4 - women between the ages of 18 and 48, and symp- platelet factor 4 toms occurred 6 to 13 days after vaccination.8 SARS-CoV-2 is known to cause thromboinflam- Introduction mation leading to thrombotic microangiopathy, pul- monary thrombosis, pedal acro-ischemia (“COVID- COVID-19 disease is caused by a novel positive- toes”), arterial clots, strokes, cardiomyopathy, coro- strand RNA coronavirus (SARS-CoV-2), which be- nary and systemic vasculitis, deep venous throm- longs to the Coronaviridae family, along with the se- bosis, pulmonary embolism, and microvascular vere acute respiratory syndrome (SARS) and the thrombosis in renal, cardiac and brain vascular- Middle East respiratory syndrome (MERS) corona- ture.9-14 Cerebral venous sinus thrombosis (CVST) 1 viruses. The genome of these viruses encodes sev- has also been reported in COVID-19 patients.15 eral non-structural and structural proteins, including Amongst 34,331 hospitalized COVID-19 patients, spike, envelope, membrane, and nucleocapsid pro- CVST was diagnosed in 28.16 In a multicenter, multi- 2 teins. The majority of the vaccines for COVID-19 national, cross sectional, retrospective study of 8 pa- that employ administration of viral antigens or viral tients diagnosed with CVST and COVID-19, seven gene sequences aim to induce neutralizing antibod- were women with an average age of 63 years.17 In a ies against the viral spike protein (S), preventing up- combined series of 41 patients with COVID-19 and take through the ACE2 receptor, and thereby block- CVST, the average age was about 50 years (SD, 16.5 3 ing infection. years).17 The pathobiology of thrombotic events as- The Janssen COVID-19 vaccine (Johnson & sociated with the AstraZeneca vaccine should be Johnson) is comprised of a recombinant, replication- viewed in the context of mechanisms underlying incompetent Ad26 vector, encoding a stabilized var- thromboinflammation that complicates SARS-CoV-2 iant of the SARS-CoV-2 spike protein. The ChAdOx1 infection and COVID-19 disease. nCoV-19 vaccine (AZD1222, Vaxzevria®) was devel- oped at Oxford University and consists of a replica- A. Role of COX-2 and thromboxane A2 tion-deficient chimpanzee adenoviral vector ChA- in thromboinflammation complicating 4 dOx1, encoding the S protein. In US Phase III trials, adenovirus-based COVID-19 vaccine Vaxzevria has been demonstrated to have 79% effi- cacy at preventing symptomatic COVID-19, and encoding the Spike protein of SARS- 100% efficacy against severe or critical disease and CoV-2 hospitalization, with comparable efficacy across eth- nicity, gender and age.5 However, Vaxzevria has Thromboinflammation in COVID-19 seems to been associated with thrombotic and embolic be primarily caused by endothelial, platelet and neu- events including disseminated intravascular coagu- trophil activation, platelet-neutrophil aggregates lation (DIC) and cerebral venous sinus thrombosis and release of neutrophil extracellular traps (CVST), occurring within 14 days after vaccination, (NETs).13,18 Platelet activation in COVID-19 is fueled mostly in people under 55 years of age, the majority by a lipid storm characterized by massive increases 6 of whom have been women. Data from Europe sug- in thromboxane A2 (TxA2) levels in the blood and gests that the event rate for thromboembolic events Free Neuropathology 2:18 (2021) Chiang et al doi: https://doi.org/10.17879/freeneuropathology-2021-3395 page 3 of 8 bronchoalveolar lavage fluid.19,20 Cyclooxygenase the splanchnic circulation could activate platelets lo- (COX) enzymes catalyze the first step in the biosyn- cally, leading to splanchnic vein thrombosis associ- 30 thesis of thromboxane A2 from arachidonic acid, and ated with adenovirus vaccines. COX-2 expression is induced by the spike protein of coronaviruses.21 We postulate that an aberrant in- Spike protein of coronaviruses is known to in- duce COX-2 gene expression.21,31 COX-2 expression is crease in thromboxane A2 generation induced by the induced during normal human megakaryopoiesis spike protein expression from adenovirus vaccines 32 leads to thromboinflammation and CVST. and characterizes newly formed platelets. While in healthy controls <10% of circulating platelets ex- The support for the above proposed mecha- press COX-2, in patients with high platelet genera- nism comes from the following observations. First, tion, up to 60% of platelets express COX-2.32 Gener- when mice of different age groups were infected ation of TxA2 by platelets is markedly suppressed by with SARS-CoV virus, the generation of TxA2 was COX-2 inhibition in patients with increased megakar- markedly increased in younger mice compared to yopoiesis versus healthy subjects.32 Therefore, we middle aged mice.22 Furthermore, in children with postulate that expression of spike protein induces asymptomatic or mildly symptomatic SARS-CoV-2 COX-2 expression and generation of thromboxane infection, microvascular thrombosis and thrombotic A2 by megakaryocytes. TxA2 promotes biogenesis of 19 microangiopathy occur early in infection. These activated platelets expressing COX-2. Platelet TxA2 observations are consistent with the higher risk for generation leads to platelet activation and aggrega- thrombosis in adults under 60 years of age, com- tion, and thereby thromboinflammation (Figure 1). pared with the older age group.6,7 Second, platelets from female mice are much
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