Does COVID-19 Provide a Clue for Thrombosis in ITP?
One of the significant clinical manifestations of COVID-19 is thrombosis in the different circulatory beds, most commonly within pulmonary vasculature. Pathogenesis of this complication has not yet been elucidated, though some autopsy reports have shown high prevalence of microthrombi in various organs, including lungs, kidney, and heart.  One of these reports suggested the possibility of circulating megakaryocytes (MKs) as being contributory to this thrombotic feature. The concept of MKs as contributory to thrombosis and a related complication, fibrosis, was recently reviewed. Similarly, MKs may be hypothesized to play a role in the development of thrombosis in patients with immune thrombocytopenia (ITP).
Epidemiological studies were conducted in patients with ITP, and thrombosis was noted in those receiving thrombopoietin receptor agonists (TPO-RA). These revealed an increased risk of thrombosis even in the absence of any ITP-specific treatments. Possible reasons are still being investigated but include some well-known thrombotic risk factors like older age, splenectomy, and antiphospholipid syndrome. One of the culprits may be the circulating MKs similar to that found in COVID-19. This is especially true since there is increased MK activity in both ITP and its treatment with TPO-RA. 
Beside some forms of leukemias, the concept of circulating MKs in other nonneoplastic conditions is not new with the first observations made over six decades ago. Despite these early findings, the idea that the large platelet precursors being present in the circulation and even producing platelets in the pulmonary vascular bed has been a matter of debate. Even while some experts support a link between lung MKs and cardiorespiratory diseases, many opposing advocates argue that the finding of MKs in lung fields is a gravity phenomenon seen only in the postmortem period. Elegant work from Lefrançais et al has perhaps put an end to the debate and cemented the importance of lung MKs in platelet production, and it can confidently be said that at least a part of platelet pool can be generated within the lungs. In addition to the lungs, the placenta has also been shown to be a site of platelet production. The lungs being “nonfunctional” in the fetus, perfusion studies of placentae were undertaken by investigators who were able to isolate MKs with copious cytoplasm from this fetal respiratory organ. This study gives additional proof to the concept of circulating MKs and platelet production in sites other than the bone marrow, including the lungs. In this context, we have to wonder what may be the role of these circulating MKs.
Thrombocytosis is a common accompaniment of inflammatory states. It is also known to the platelet biologists that inflammatory cytokines like interleukins can stimulate MKs to produce platelets. This is indeed the case as has been demonstrated in patients with lung inflammation. Hansen and Pedersen collected blood from cubital veins and analyzed for MKs in 30 patients with bronchitis or bronchopneumonia and identified significantly higher circulating MKs in these patients. It is possible that the circulating MKs participate in the host-defense process by releasing chemokines and producing many young, active platelets at the inflammatory site (e.g., the lungs). Since platelets do not have the synthetic machinery to respond to the various infectious or inflammatory stimuli in a rapid manner (despite recent evidence of platelet mRNA), delivery of a large number of well-equipped platelets in the vicinity of infection or inflammation is far more advantageous than a distant release of platelets.
22 January 2021 (online)
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