Unconventional CD147‐dependent platelet activation elicited by SARS‐CoV‐2 in COVID‐19

Abstract

Background Platelet activation and thrombotic events characterizes COVID‐19. Objectives To characterize platelet activation and determine if SARS‐CoV‐2 induces platelet activation. Patients/Methods We investigated platelet activation in 119 COVID‐19 patients at admission in a university hospital in Milan, Italy, between March 18 and May 5, 2020. Sixty‐nine subjects (36 healthy donors, 26 patients with coronary artery disease, coronary artery disease, and seven patients with sepsis) served as controls. Results COVID‐19 patients had activated platelets, as assessed by the expression and distribution of HMGB1 and von Willebrand factor, and by the accumulation of platelet‐derived (plt) extracellular vesicles (EVs) and HMGB1 + plt‐EVs in the plasma. P‐selectin upregulation was not detectable on the platelet surface in a fraction of patients (55%) and the concentration of soluble P‐selectin in the plasma was conversely increased. The plasma concentration of HMGB1 + plt‐EVs of patients at hospital admission remained in a multivariate analysis an independent predictor of the clinical outcome, as assessed using a 6‐point ordinal scale (from 1 = discharged to 6 = death). Platelets interacting in vitro with SARS‐CoV‐2 underwent activation, which was replicated using SARS‐CoV‐2 pseudo‐viral particles and purified recombinant SARS‐CoV‐2 spike protein S1 subunits. Human platelets express CD147, a putative coreceptor for SARS‐CoV‐2, and Spike‐dependent platelet activation, aggregation and granule release, release of soluble P‐selectin and HMGB1 + plt‐EVs abated in the presence of anti‐CD147 antibodies. Conclusions Hence, an early and intense platelet activation, which is reproduced by stimulating platelets in vitro with SARS‐CoV‐2, characterizes COVID‐19 and could contribute to the inflammatory and hemostatic manifestations of the disease.

Chromogranin A plasma levels predict mortality in COVID-19

“…SARS-CoV-2 infection and consequent inflammation induce endothelial damage, platelet activation, thrombosis, microangiopathy and neo-angiogenesis in response to tissue injury [ 40 , 41 ]. Platelet derived microparticles [ 42 ] and high levels of angiopoietin-2, follistatin and PAI-1, markers of endothelial injury, increase the risk of mortality [ 43 ], and signs of intussusceptive angiogenesis, a proposed mechanism for vessel generation in late stages of chronic lung injury, have been found in lung biopsies of COVID-19 patients [ 44 ]. Thus, CgA accumulation in patients with severe COVID-19 might affect the microvascular response to the SARS-CoV-2 infection, possibly influencing the clinical outcome.…”

Platelets in Viral Infections – Brave Soldiers or Trojan Horses

“…However, while some reports demonstrate ACE2 expression on platelets ( 47 ), other studies did not find detectable level of ACE2 but suggest mechanisms independent of ACE2 ( 48 ), while others found no virus particles within platelets at all ( 49 ). Given the low expression of ACE2 on platelets, ACE2-independent platelet activation involving more abundantly expressed receptors such as extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) may be more important for direct platelet dysregulation by SARS-CoV-2 or its spike protein, respectively ( 50 ).…”

“…Both ACE2 and TMPRSS2 were found to be expressed on human and mouse platelets and on the megakaryocytic cell line MEG-01 ( 47 ), mediating virus binding and internalisation ( 47 , 158 ). Additionally, platelet EMMPRIN (CD147) is involved in spike protein-mediated platelet activation and SARS-CoV-2 may hitchhike on extracellular vesicles to enter platelets via membrane fusion, thereby circumventing the need for ACE2 ( 50 , 63 ). While platelets do not seem to support viral replication, MEG-01 cells can be infected at least temporarily, leading to rising intracellular and shed virions which suggests successful replication ( 158 ).…”

Platelet‐leukocyte interactions in COVID‐19: Contributions to hypercoagulability, inflammation, and disease severity

“…43 Of note, SARS-CoV-2 RNA has been detected in platelets from infected patients, 23,27,28 patients and from in vitro infection models. 21,27,28,42 However, even though the subgenomic viral RNA is detected in infected platelets, no viral progeny is produced, indicating an abortive replication cycle. 21…”

“…Increased platelet activation in COVID‐19 has been evidenced by alpha and dense granules release, integrin α IIb /β 3 activation, and platelet extracellular vesicle shedding 10,14,19‐21,23‐26 . Also, platelets from COVID‐19 patients were more adhesive to fibrinogen and collagen and more responsive to PAR‐1 and P2Y 12 agonists, leading to TXA 2 synthesis, aggregation, and cytokine secretion 10,14,20,23,27 .…”