Dear Editor,
We read with great interest the recent review of thrombocytopenia mechanisms in COVID-19 [1]. The authors meticulously analyze mechanisms raising questions on potential therapeutic targets. Taking into account the rapidly accumulating knowledge in COVID-19, our correspondence aims to highlight an important pathophysiological aspect of thrombocytopenia that simultaneously acts as a therapeutic target: complement activation.
Indeed, recent evidence suggests that severe COVID-19 resembles the pathophysiology and phenotype of complement-mediated thrombotic microangiopathies (TMAs) [2]. Thrombocytopenia is one of the major characteristics of TMAs, along with microangiopathic hemolytic anemia, and organ damage, such as neurological, renal, and cardiac dysfunction. Recent studies have suggested cells with high expression of angiotensin-converting enzyme 2 (ACE2) are target cells of COVID-19. Such cells include cardiac pericytes. Patients with heart failure have increased ACE2 expression and are therefore expected to be of high risk of cardiac injury due to COVID-19 [3]. In a similar manner, ACE2 is highly expressed on podocytes and tubule epithelial cells of the kidney, as well as in the vasculature of neurons [4]. A recent study also suggested SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) tropism for the kidney [5]. Taken together, these data suggest that COVID-19 causes organ damage, similar to that of TMA.
Complement activation plays a central role in the pathophysiology of TMAs that have been categorized into the wider group of complement-mediated TMAs [5]. Studies of previous coronaviruses have established activation of complement component C3 in the pathophysiology of ARDS (acute respiratory distress syndrome) [6]. In severe COVID-19, complement activation products, including C5b-9, C4d, and MAPS-2 (mannose-binding protein-associated serine protease 2), have been detected in the microvasculature of lung and skin biopsies [7]. Complement activation products (C3b, iC3b, C3dg, and C4d) have been also found increased on circulating erythrocytes from COVID-19 patients using flow cytometry [8]. Furthermore, two recent preprint studies have shown additional evidence of complement activation. Gao et al. detected excessive proximal and terminal complement activation that was alleviated by anti-C5a treatment [9]. Skendros et al reported evidence of terminal complement activation and NET (neutrophil extracellular trap) formation in COVID-19 immunothrombosis. Interestingly, complement inhibition at the level of C3 disrupted TF expression in neutrophils [10].
Since effective treatment is available for complement-mediated TMA [11], recognition of complement activation in COVID-19 simultaneously renders a complement therapeutic target. The first-in-class terminal complement inhibitor, eculizumab, has been administered in four patients with severe COVID-19, leading to successful disease outcomes [12]. Furthermore, the compstatin-based inhibitor AMY-101 has also shown safety and efficacy of C3 inhibition in severe COVID-19 [13]. Ongoing clinical trials with ravulizumab (a long-acting C5 inhibitor) will prove safety and efficacy in this setting. Although cost-effectiveness analyses are not expected to be performed, it should be noted that the cost of FDA-approved complement inhibitors (eculizumab and ravulizumab) cannot be overlooked. However, the next-generation complement therapeutics are expected to overcome this challenge [14].
These data suggest that thrombocytopenia in severe COVID-19 could be considered through the prism of a complement-mediated TMA. In such cases, complement inhibition is expected to be safe and effective. Since the duration of the pandemic still remains unknown, ongoing studies are eagerly expected to confirm the role of complement activation and inhibition in this setting.
References
Xu P, Zhou Q, Xu J (2020) Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol 99(6):1205–1208. https://doi.org/10.1007/s00277-020-04019-0
Gavriilaki E, Brodsky RA (2020) Severe COVID-19 infection and thrombotic microangiopathy: success doesn't come easily. Br J Haematol 189:e227–e230. https://doi.org/10.1111/bjh.16783
Chen L, Li X, Chen M, Feng Y, Xiong C (2020) The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 116(6):1097–1100. https://doi.org/10.1093/cvr/cvaa078
Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 82(15):7264–7275. https://doi.org/10.1128/JVI.00737-08
Gavriilaki E, Anagnostopoulos A, Mastellos DC (2019) Complement in thrombotic microangiopathies: unraveling Ariadne’s thread Into the labyrinth of complement therapeutics. Front Immunol 10:337. https://doi.org/10.3389/fimmu.2019.00337
Risitano AM, Mastellos DC, Huber-Lang M, Yancopoulou D, Garlanda C, Ciceri F, Lambris JD (2020) Complement as a target in COVID-19? Nat Rev Immunol 20:343–344. https://doi.org/10.1038/s41577-020-0320-7
Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, Laurence J (2020) Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 220:1–13. https://doi.org/10.1016/j.trsl.2020.04.007
Lam LM, Murphy SJ, Kuri-Cervantes L, Weisman AR, Ittner CAG, Reilly JP et al (2020) Erythrocytes reveal complement activation in patients with COVID-19. medRxiv. https://doi.org/10.1101/2020.05.20.20104398.
Gao T, Hu M, Zhang X, Li H, Zhu L, Liu H et al. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation. medRxiv. 2020:2020.03.29.20041962. https://doi.org/10.1101/2020.03.29.20041962
Skendros P, Mitsios A, Chrysanthopoulou A, Mastellos DC, Metallidis S, Rafailidis P et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. medRxiv. 2020:2020.06.15.20131029. https://doi.org/10.1101/2020.06.15.20131029
Gavriilaki E, Brodsky RA (2020) Complementopathies and precision medicine. J Clin Invest 130(5):2152–2163. https://doi.org/10.1172/JCI136094
Diurno F, Numis FG, Porta G, Cirillo F, Maddaluno S, Ragozzino A et al (2020) Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci 24(7):4040–4047. https://doi.org/10.26355/eurrev_202004_20875
Mastaglio S, Ruggeri A, Risitano AM, Angelillo P, Yancopoulou D, Mastellos DC, Huber-Lang M, Piemontese S, Assanelli A, Garlanda C, Lambris JD, Ciceri FThe first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin Immunol 2020:108450. https://doi.org/10.1016/j.clim.2020.108450
Mastellos DC, Ricklin D, Lambris JD (2019) Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18(9):707–729. https://doi.org/10.1038/s41573-019-0031-6
Acknowledgments
Given the limited number of references allowed in this perspective, the authors thank the colleagues who are not specifically cited for their contribution and their understanding.
Author information
Authors and Affiliations
Contributions
E.G. and E.G. drafted and edited the manuscript. I.S and A.A edited and approved the final manuscript.
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethical approval
Not applicable.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gavriilaki, E., Sakellari, I., Gavriilaki, M. et al. Thrombocytopenia in COVID-19: pathophysiology matters. Ann Hematol 100, 2139–2140 (2021). https://doi.org/10.1007/s00277-020-04183-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-020-04183-3