Pediatric Multisystem Inflammatory Syndrome of COVID19 is also a "platelet hyperactivation syndrome", just like Kawasaki's Disease is.

The underlying pathophysiology is:

Half of circulating platelet biogenesis occurs in lungs from megakaryocytes.

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This biogenesis occurs in pulmonary circulation endothelium.

Pulmonary circulation endothelium is injured due to SARS-CoV-2 by apoptosis of pericytes that hold together the endothelium.

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Pulmonary circulation endothelium is then exposed due viral insult with pro-thrombotic antigens, thereby resulting in platelet activation to “wall off” the pathogen. This is protective and necessary to reduce viremia but can go haywire in some with

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... baseline high platelet reactivity (old, male, non-O blood group) and endothelial dysfunction (metabolic syndrome, CKD, etc).

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Platelet activation when exposed to this "injured" pulmonary endothelium leads to release, from platelet granules, of vasoactive and pro-thrombotic mediators. The goal is to attract more platelets and neutrophils to the site of "injury" in the alveolar capillaries.

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This process in any other organ has a brake as once the injured endothelium is “walled off,” the immunothrombosis ceases and platelet-derived vasoactive mediators are then circulated in the lymphovascular system and “cleared” by the body.

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Part of that clearing of platelet-derived mediators of thrombosis occurs precisely in the lung, in the pulmonary endothelium. Pulmonary circulation is also where platelets have been shown to "sequester" and undergo recalibration and replenishment with vasoactive mediators.

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Among the most important platelet-derived mediators is serotonin. Serotonin is cleared 95% by the pulmonary endothelium, the very organ that is injured and dysfunctional in COVID19.

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In COVID19 lung, the initial immunothrombosis leads to platelet-derived serotonin release, but this serotonin will not be processed by the pulmonary endothelium, which itself is subject of viral injury and reflex immunothrombosis and serotonin-mediated vasoconstriction.

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This coincidence leads to a feed-forward cycle of progressive serotonin buildup in the pulmonary circulation, in turn causing progressive platelet aggregation, further serotonin release, and a vicious cycle of immunothrombosis in the affected pulmonary circulation.

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This leads to back pressure buildup against an occluded capillary bed, eventually leading to intrapulmonary right to left shunt development. This shunt dumps the platelet-derived serotonin into the systemic circulation, exposing systemic circulation to ...

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... transiently high level of extracellular serotonin (agitation, hyperpnea, diarrhea). This eventually returns via right heart back to the pulmonary circulation, where uninjured healthy pulmonary endothelium processes and reuptakes serotonin as it normally does.

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In the old, male, and non-O blood group with metabolic syndrome, platelets at baseline are hyperactive and have a higher content of serotonin and other vasoactive mediators in their granules, which leads to a high degranulation of platelets upon activation ...

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... as platelets comes across viral-induced pulmonary endothelial injury. This leads to a larger serotonin release, and a larger and more rapid feed-forward vicious cycle of immunothrombosis, as described above in the injured pulmonary circulation ...

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... only to be held in its tracks with proper and “early” anticoagulation and anti-thrombotics. If not prevented early, this can easily end up in heparin-resistance as is seen in HIT with hyperactive platelets, which in that case is due to anti-PF4 immune complexes.

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In children, platelets are not as hyperactive and endothelium does not harbor yet as much dysfunction at baseline, and this feed-forward cycle of immunothrombosis after COVID19 insult resolves spontaneously.

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However, pulmonary endothelium nevertheless is injured at least in a few areas due to viral insult, without causing any discernible symptoms in children, and the pulmonary endothelium remains activated with exposed pro-thrombotic antigens and a hyper-activating behavior.

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This leads to a subset of platelets released in a "hyperactive" state from the injured pulmonary endothelium. This subset of hyperactive platelets reach systemic capillaries and cause “vasculitic” and "microthrombotic" phenomena, including Kawasaki disease ...

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Hyperactive platelets and excess serotonin are implicated in primary pathophysiology of Kawasaki disease, as hypothesized here as well for COVID19, with ASA and IVIg in Kawasaki established as therapy to target and reduce platelet (and immune complex mediated) hyperactivity.

Studies showing hyperactive platelets in COVID19 already attest to this theory:
1) https://www.medrxiv.org/content/10.1101/2020.06.23.20137596v1
2) https://ashpublications.org/blood/article/doi/10.1182/blood.2020007214/461106/Platelet-Gene-Expression-and-Function-in-COVID-19
3) https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2020007008/461219/Neutrophil-Extracellular-Traps-NETs-Contribute-to?redirectedFrom=fullte

@boilard_eric @ZaidYounes9 @FrederikDenorme @cameronks @andrewchernaik @srrezaie @VectorSting @__ice9 Future research should perhaps evaluate platelet hyperactivity in (1) Pediatric Multisystem Inflammatory Syndrome of COVID19 and (2) "long-hauler" COVID19 patients.