Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature

Abstract

Pulmonary megakaryocytes participate in the pathogenesis of lung damage, particularly in acute lung injury. Although megakaryocytes are not mentioned as a characteristic histologic finding associated to pulmonary injury, a few studies reveal that their number is increased in diffuse alveolar damage (DAD). In this autopsy study, we have observed a relevant number of pulmonary megakaryocytes in COVID-19 patients dying with acute lung injury (7.61 ± 5.59 megakaryocytes per 25 high-power fields vs. 1.14 ± 0.86 for the control group, p < 0.05). We analyzed samples of 18 patients, most of whom died after prolonged disease and use of mechanical ventilation. Most patients showed advanced DAD and abnormal coagulation parameters with high levels of fibrinogen, D-dimers, and variable thrombocytopenia. For comparison, pulmonary samples from a group of 14 non-COVID-19 patients dying with DAD were reviewed. They showed similar pulmonary histopathologic findings and an increase in the number of megakaryocytes (4 ± 4.17 vs. 1.14 ± 0.86 for the control group, p < 0.05). Megakaryocyte count in the COVID-19 group was greater but did not reach statistical significance (7.61 ± 5.59 vs. 4 ± 4.17, p = 0.063). Regardless of the cause, pulmonary megakaryocytes are increased in patients with DAD. Their high number seen in COVID-19 patients suggests a relation with the thrombotic events so often seen these patients. Since the lung is considered an active site of megakaryopoiesis, a prothrombotic status leading to platelet activation, aggregation and consumption may trigger a compensatory pulmonary response.

Implications of microscale lung damage for COVID-19 pulmonary ventilation dynamics: A narrative review

“…This was seen in the autopsy of a patient that died of pulmonary fibrosis after clearance of COVID-19 [ 98 ]. Some studies have looked at factors, other than DAD, that may contribute to the progression to fibrosis such as increased numbers of pulmonary megakaryocytes and endothelial to mesenchymal cell transition [ 99 , 100 ]. It is worth noting fibrosis is not specific to DAD, therefore it is important to account for health history of patients as it can be caused by other agents such as age, emphysema, and other previous exposures [ 45 , 55 , 70 ].…”

“…It is thought that neutrophils generate excess reactive oxygen species (ROS) leading to further lung damage, thrombosis, blood cell dysfunction, and systemic inflammatory response [ 47 ]. Other capillary components may contribute to pathogenesis and coagulopathy in COVID-19 such as pericyte damage, increased megakaryocytes, and damage to endothelial glycocalyx with increased hyaluronan [ 37 , 70 , 71 , 100 , 109 , 119 , 120 ].…”

COVID-19 Sepsis: Pathogenesis and Endothelial Molecular Mechanisms Based on “Two-Path Unifying Theory” of Hemostasis and Endotheliopathy-Associated Vascular Microthrombotic Disease, and Proposed Therapeutic Approach with Antimicrothrombotic Therapy

“…Could this have been due to overzealous vascular intervention for monitoring and more aggressive usage of controlled respiratory therapy in this hyped pandemic? The prevalent reports of coexisting PTE and relatively mild thrombocytopenia with evidence of active megakaryopoiesis in the lungs of COVID-19 35 , 65 , 66 may suggest locally produced platelets from reactive thrombocytosis could also have contributed to the formation of “multiple” small macrothrombi in the compromised vasculature of the lungs. Further, could it have been due to combined micro-macrothrombotic syndrome in the lungs similar to multiple peripheral digital gangrene?…”

“…Their interpretation is summarized based on endothelial pathogenesis. Mild to moderate thrombocytopenia → likely due to consumption during microthrombogenesis, but with partial compensation from extramedullary megakaryopoiesis in the lungs 35 , 65 , 66 Rare cases with schistocytes in blood film and hemolysis → likely due to: 1) uncommon hemolysis in ARDS of COVID-19 secondary to less production of C5b-9 than in viral sepsis; 15 and 2) less shear stress of blood flow at the pulmonary vasculature 35 Prolonged PT, if present → due to decreased FVII, FX, FV, FII and fibrinogen in hepatic coagulopathy Prolonged aPTT, if present → due to decreased FX, FV, FIX, FII and fibrinogen in hepatic coagulopathy Overexpression of ULVWF/VWF/VWF antigen and increased FVIII activity → due to endothelial exocytosis Decreased ADAMTS13 activity → due to: 1) heterozygous gene mutation or polymorphism; and/or 2) excessive release of ULVWF multimers creating an imbalance between the enzyme and substrate multimers Abnormal fibrinogen levels → increased likely due to early transient liver dysfunction and decreased due to advanced hepatic necrosis resulting from microthrombosis D-dimer → positive due to “fibrinolysis” in MODS and coexisting macrothrombosis with on-going EA-VMTD, but negative in “fibrinogenolysis” without MODS even with on-going EA-VMTD Soluble fibrin monomer (SFM) → positive due to increased “fibrinogenesis” FDP(s) → positive due to fibrinolysis and/or fibrinogenolysis …”

Platelets in COVID-19: “innocent by-standers” or active participants?

“…Для вируса SARS-CoV, во многом похожего на SARS-CoV-2 с точки зрения строения, показана способность ассоциироваться с тромбоцитарной N-аминопептидазой CD13, однако это взаимодействие не приводит к попаданию вируса внутрь тромбоцита [1]. С другой стороны, было показано, что SARS-CoV может попадать в мегакариоциты, оказывающиеся в легких [33,34]. Теоретически данный механизм может вносить вклад в патологию тромбоцитов и тромбоцитопению у пациентов.…”