Platelet size as a mirror for the immune response after SARS-CoV-2 vaccination.

Platelets provide cellular hemostasis but also adopt several immune functions. They directly interact with viruses and bacteria, cross‐talk with other immune cells, and participate in inflammation and wound repair.

Platelets are known effector cells in adverse immune response to vaccines. A prominent example is the adverse reaction of vaccine‐induced immune thrombotic thrombocytopenia (VITT). , , VITT is a rare side effect occurring 4–30 days after application of adenoviral vector based COVID‐19 vaccines and caused by immunoglobulin G class platelet‐activating antibodies directed against the platelet chemokine platelet factor 4. , , , These antibodies form immune complexes with platelet factor 4 that are recognized by platelet Fc gamma IIa receptors, inducing strong activation of platelets and procoagulant platelet formation. Although VITT is a dramatic pathologic process, platelets likely contribute to the intended immunization process after vaccination against SARS‐CoV‐2. In this context, it is an interesting question how platelets physiologically respond to vaccination against SARS‐CoV‐2.

In this issue of Journal of Thrombosis and Haemostasis, Flego and Cesaroni et al. investigated features of the platelet‐immune crosstalk in healthy recipients of two doses of the mRNA‐based SARS‐CoV‐2 vaccine BNT162b2. They found a rapid cytokine response including increased levels of several interleukins, interferons, and tumor necrosis factor‐α. They further detected signs of an elevated platelet turnover after vaccination. Platelet counts were only slightly altered but the mean platelet volume (MPV), platelet large cell ratio, and platelet distribution width showed a progressive increase during 20 days after the first vaccination. This increase correlated well with the antibody response against the SARS‐CoV‐2 spike protein.

The increase of the platelet size indices is indicative of an inflammatory process in response to vaccination following the sequence: I. vaccination → II. cytokine release → III. altered platelet generation → IV. change of platelet size and function (Figure 1). Normal platelet turnover is characterized by an equilibrium between platelet generation and clearance and a reciprocal relationship between platelet size and platelet counts in the circulation. , This is tightly controlled by thrombopoietin levels. Platelet size decreases when healthy subjects receive thrombopoietin. In systemic inflammation, several cytokines influence megakaryopoiesis and platelet generation. For example, interleukin‐1α (IL‐1α) levels increase upon inflammation and promote platelet release by the rupture of megakaryocytes in the absence of elevated thrombopoietin, which is accompanied by an increased platelet size. This was shown in mice, where IL‐1α mediated platelet release led to the generation of larger platelets than thrombopoietin‐stimulated megakaryocytes. Likewise, Flego, Cesaroni, and colleagues found a strong positive association between elevated MPV and IL‐1β levels after vaccination in their study.

FIGURE 1

Hypothesis how SARS‐CoV‐2 vaccination affects platelet turnover and function (drawings: https://www.somersault1824.com)

The increase of platelet size was associated with phenotypical changes of platelets, including increased levels of the integrins αIIb and Ibα, the inhibitory receptor PECAM‐1 and glycoprotein (GP) VI. Larger platelets carry more platelet surface receptors under steady‐state platelet turnover and are more responsive to platelet agonists. , In the study of Flego and Cesaroni et al., however, platelets respond significantly stronger to convulxin (an agonist of GPVI) especially after the second vaccination at day 21. At that time point, the MPV and platelet receptor levels were already decreased compared with earlier time points. This could mean that an increased responsiveness is also adopted by smaller platelets on the long run, when platelet turnover has been temporarily increased after vaccination. Consequently, platelet size indices such as the MPV may not be good surrogates for platelet function, when platelet turnover changes. However, the authors reasonably argue, that changes of the MPV, platelet large cell ratio, and platelet distribution width may serve as parameters to judge on the immune response after vaccination. These items are easy to measure by routine cell counters. The authors show that individuals with a fast immune response with regard to anti‐spike antibody production experienced a cytokine response shortly after vaccination, which was paralleled by an early increase of the MPV. In contrast, slow responders had a delayed cytokine response accompanied by a delayed increase of platelet size after vaccination.

The observations made by Flego, Cesaroni, and colleagues are useful to generate new hypotheses and highlight that vaccination results in a physiologic inflammatory response involving platelets and their size by affecting platelet turnover. It would be interesting to target these responses also after application of other vaccines and to dissect physiologic from pathologic immune reactions. This will increase our understanding of platelets as contributor and effector cell in rare adverse vaccination reactions. In this regard, the ongoing worldwide vaccination campaign is not only the most sufficient strategy to fight the SARS‐CoV‐2 pandemic, it may also provide an extraordinary opportunity to study immune functions of platelets.

CONFLICT OF INTEREST

Dr. Thiele reports personal fees from Bristol Myers Squibb, Bayer, Daichii Sankyo, Pfizer, Novo Nordisk, Chugai Pharma, and Novartis, all of which are outside of the submitted manuscript. The other authors have no conflicts of interest to declare.

AUTHOR CONTRIBUTIONS

Thomas Thiele, Silas L. Schwarz, and Stefan Handtke wrote the manuscript. Stefan Handtke and Thomas Thiele prepared the figure. All authors approved the final version.