A proof of evidence supporting abnormal immunothrombosis in severe COVID-19: naked megakaryocyte nuclei increase in the bone marrow and lungs of critically ill patients

Abstract

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.

Abnormal immunothrombosis and lupus anticoagulant in a catastrophic COVID-19 recalling Asherson’s syndrome

“…The numerous NK-MK found on post-mortem lung specimens are maybe related to high interleukin-6 (IL-6) serum levels (> 2.300 ρg/mL) from cytokine storm stimulating pulmonary megakaryocytopoiesis, being IL-6 endowed of megakaryocytopoietic activity [5]. NK-MK in fact mean megakaryocytes cytoplasm has been consumed to produce neo-platelets, then released when still alive in the lung microcirculation with prothrombotic effects, which can be dramatically amplified by LAC.…”

“…On minimally invasive post-mortem examination as per US Centers for Disease Control and Prevention's guidelines, we have disclosed one-order-of-magnitude increase of nakedmegakaryocyte-nuclei (NK-MK), i.e. 100-140 cm 2 versus 14-15 cm 2 in normal conditions [5], inside the damaged lungs of a 44-year-old Philippine male COVID-19 patient, discovered LAC-positive shortly before death [silica clotting time (SCT) screen & confirm: 1,68 & 1,79; diluted Russell's viper venom test (DRVVT) screen & confirm: 2,07 & 1,15; normal ratios: ≤ 1,20], and died 8 days after hospitalization in a clinical scenario refractory to standard high acuity care recalling Asherson's syndrome, also named «catastrophic antiphospholipid syndrome» (Fig. 1).…”

“…In case of imbalance, immunothrombosis can rapidly become abnormal and to evolve into disseminated intravascular coagulation (DIC) [2]. Coronavirus disease 2019 (COVID-19) is a complex disease with many clinicopathological issues, including respiratory, immune, and coagulative ones [3][4][5]. Lupus anticoagulant (LAC) is an antiphospholipid (aPL) autoantibody, which in vivo works as procoagulant, despite the misnomer due to its in vitro properties, by interacting with platelet and endothelial membrane phospholipids, so rising adhesion and aggregation of platelets [6].…”

Does COVID-19 Provide a Clue for Thrombosis in ITP?

“…Autopsy reports of patients who succumbed to COVID-19 provide proof to this possibility, along with the demonstration of several naked MK nuclei in the lung tissue. 13 An Italian study reported on the autopsy data from nearly 40 patients and identified an increased number of CD61 antibody-positive MKs in the lung capillaries of almost all patients. 14 They however did not correlate the MK load with the microthrombi which were omnipresent in these lung samples.…”

COVID-19 Disease and Cardiac Surgery: Reciprocal Interrelations

“…They demonstrate also a greater power of aggregation and adhesion to fibrin filaments, and favor production of microcomplexes with neutrophils, monocytes and T lymphocytes. 5 This pathology affects not only the pulmonary microvessels, but also, in the COVID-19 hypercoagulative milieu, causes thromboembolic complications in medium/large sized vessels, differently expressing, according to their hemodynamics, from mural thrombi, occasionally discovered, to a complete thrombosis. In surgery, all this increases the risk of thrombo-embolic events, and after a cardiopulmonary bypass specifically affects the pulmonary vessels and further deranges the hemostatic system.…”