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Panteleev, M.A.; Sveshnikova, A.N.; Shakhidzhanov, S.S.; Zamaraev, A.V.; Ataullakhanov, F.I.; Rumyantsev, A.G. Platelets and Red Blood Cells with SARS-CoV-2. Encyclopedia. Available online: (accessed on 20 June 2024).
Panteleev MA, Sveshnikova AN, Shakhidzhanov SS, Zamaraev AV, Ataullakhanov FI, Rumyantsev AG. Platelets and Red Blood Cells with SARS-CoV-2. Encyclopedia. Available at: Accessed June 20, 2024.
Panteleev, Mikhail A., Anastasia N. Sveshnikova, Soslan S. Shakhidzhanov, Alexey V. Zamaraev, Fazoil I. Ataullakhanov, Aleksandr G. Rumyantsev. "Platelets and Red Blood Cells with SARS-CoV-2" Encyclopedia, (accessed June 20, 2024).
Panteleev, M.A., Sveshnikova, A.N., Shakhidzhanov, S.S., Zamaraev, A.V., Ataullakhanov, F.I., & Rumyantsev, A.G. (2023, December 15). Platelets and Red Blood Cells with SARS-CoV-2. In Encyclopedia.
Panteleev, Mikhail A., et al. "Platelets and Red Blood Cells with SARS-CoV-2." Encyclopedia. Web. 15 December, 2023.
Platelets and Red Blood Cells with SARS-CoV-2

Interaction of platelets and red blood cells with SARS-CoV-2, their mechanisms, consequences, and pathological significance.

SARS-CoV-2 platelet erythrocyte integrin ACE-2 procoagulant platelets

1. Introduction

The first impressions of COVID-19 were associated with obvious severe pulmonary manifestations, which gave the name to the virus responsible for them. However, over a short period of several months, it became clear that the disease significantly affects not only the lungs but also many other systems in the patient’s body [1]. Among them, changes in the blood system and immune system dysregulation played a key role in the pathophysiology of disease and mortality [2]. In particular, impaired oxygen transport and the high risk of thrombotic complications attract special attention to what happens to RBCs (red blood cells) and platelets. The mechanisms of these changes are still far from being completely clear, and their understanding might be important for the development of novel diagnostic and treatment options [3].
The direct role of pathogens in hematological changes during infectious diseases is not frequently observed. Indeed, the most common acute infections prefer various mucous membranes or other tissues that are more accessible and less protected than blood, and only in extreme cases may they progress into viremia or bacteremia. When these occur, sepsis usually causes a severe and multifaceted reaction mediated by an overreaction of the immune system rather than the pathogens themselves. Though there is a category of pathogens that might even seek to get into the blood cells or deep tissues, they have special strategies to hide their presence in the blood as much as possible, and such diseases are more likely to be chronic.
It is now believed that viremia in COVID-19 is consistent with this picture; it is not obligatory in this disease, but it is not uncommon and is clearly associated with disease severity [4][5][6]. SARS-CoV-2 may use membrane-attached ACE2 (angiotensin-converting enzyme 2) to invade host cells, although a dual role of ACE2 in the disease has been proposed [7]. The most life-threatening and health-threatening features of COVID-19, such as the disseminated intravascular activation of blood coagulation, show many parallels with other types of sepsis [8]. It may not be an exaggeration to say that one of the main peculiarities of COVID-19 is that this respiratory virus is unusually active in the blood and causes viremia too often. In light of this, it is especially important to understand how SARS-CoV-2 interacts with blood and vascular cells.
Over the years, platelets and RBCs have been found to engage in numerous two-way interactions with various pathogens, including some viruses, which may have important pathophysiological consequences. Prominent examples include the binding and replication of dengue virus by platelets [9] and their progenitor cells, megakaryocytes [10], and the internalization and transport of influenza virus by platelets [11]. RBC surface proteins are capable of binding a variety of pathogens, and the role of RBCs in inhibiting bacterial phagocytosis [11] and in the transport and replication of bacteria [12] and malaria parasites is well documented. However, there is much less information about RBC interactions with viruses [13].
Pathogens can significantly impact cellular physiology, positively or negatively influencing the virus. Their direct or indirect effects play a crucial role in disease progression. Despite the fact that disturbances in the hemostasis and oxygen transport systems were early identified as striking pathophysiological features and leading causes of mortality in COVID-19 [14], the role of interactions between the virus and blood cells in the development of these disorders remains unclear [15][16].

2. Two-Way Interactions of SARS-CoV-2 with RBCs and Their Precursors

There is currently little evidence that SARS-CoV-2 actively interacts with or invades mature erythrocytes, although the binding of the virus to erythrocyte proteins has been suggested [17]. One interesting possible receptor for this interaction is the Band3 anion transport protein [18], while another is the blood group system determinator basigin, also known as CD147 [19][20]. A recent study, which remains in preprint form at the moment, found an extensive association of SARS-CoV-2 with RBCs in a murine model [21]. The study also suggested an interaction with heme itself and the possible contribution of this interaction to the multi-organ spread of the virus.
On the contrary, there are quite a few indications that the virus significantly interacts with the ACE2-bearing immature erythrocyte precursors [20][22]. The COVID-19 infection of these cells dysregulates iron and hemoglobin metabolism and stimulates their reproduction [20][22]. Indeed, circulating erythroid progenitors are a characteristic feature of patients’ blood, and their concentrations are negatively correlated with hemoglobin and leukocyte levels [20][23]. This drop in hemoglobin levels, coupled with increased erythropoiesis, is considered to be one of the important mechanisms of hypoxia and respiratory problems in patients with COVID-19 [24]. Interestingly, these features are most pronounced in the original Wuhan virus and appear less in the Delta and Omicron clades [25].
Patients’ RBCs are furthermore characterized by anisocytosis, a variability in sizes [26]. The ability of RBCs to penetrate small capillaries (filterability) negatively correlates with the severity of the patient’s condition and is a predictor of a negative prognosis [27]. It also correlates with C-reactive protein levels, suggesting an inflammatory nature of the problem. In view of the recent finding that red blood cell distribution width is associated with increased interactions of blood cells with the vascular wall [28], it is tempting to suggest linking anistocytosis with the poorly understood aspect of RBCs and their role in thrombosis and hemostasis. It is considered fairly well-established that RBCs determine blood mechanics and facilitate platelet transport, and this mechanism is vital to both hemostasis and thrombosis [29][30][31]. The altered size of RBCs in COVID-19 could therefore alter the dynamic behavior of the bulk flow and thus contribute to the platelet margination effect [32]. The ability of erythrocytes to support membrane-dependent blood coagulation reactions on their surface or to activate blood coagulation with their microvesicles has been much more controversial, but it seems noticeable, at least in pathological situations [33][34][35]. Indeed, it was found that RBCs exhibited significantly elevated apoptotic markers in the COVID-19 patients, which even correlated with D-dimer, suggesting a contribution of RBCs in the thrombotic complications of the disease [36]. Other functions of erythrocytes in thrombosis also cannot be excluded [37][38]. Although the field in general remains only marginally explored, the already available evidence and the considerations discussed make it likely that RBC changes contribute to thrombotic risks in COVID-19.

3. Interaction of SARS-CoV-2 with Platelets and Its Significance for the Virus

The first report of the detection of SARS-CoV-2-related RNA in platelets of patients with COVID-19 appeared in mid-2020 [39]: viral RNA was detected in platelets in approximately 20% of patients, regardless of disease severity. Around the same time, another study reported that platelets were positive for viral RNA in 6% of patients [40]. The same study reported that platelets express the major receptor for the coronavirus’s entry into different cell types, angiotensin-converting enzyme 2 (ACE2), as well as the serine protease TMPRSS2, which is important for spike protein priming. The presence of ACE2 and TMPRSS2 in platelets was confirmed by another report, which has remained a preprint [41]. Over the next three years, several additional potential receptors facilitating the binding and entry of SARS-CoV-2, apart from ACE2, were identified. These included Band3, which is expressed on both platelets and the surface of RBCs [42]. Although the presence of ACE2 in platelets and the mechanism of entry of the original coronavirus variant are not yet clear, there is already evidence that different variants of SARS-CoV-2 likely use different receptors [42], as discussed below. One interesting possibility could be CD147 [19][42].
The simpler question of the presence of SARS-CoV-2 and ACE2 in platelets has indeed been raised again and again [43]. Immunofluorescence methods are known to have low reliability and specificity when detecting low levels of antigens, and the majority of proteomic and transcriptomic studies in 2020–2021 could not identify ACE2 in platelets [44]. For example, an in-depth study of platelet gene expression and function in COVID-19 failed to detect ACE2 in platelets, either RNA or protein [45]; viral RNA was detected only in two out of 25 patients. However, a comparison of methodologies showed that the result was highly dependent on the method: while PCR detected viral RNA in a minority or none of the patients, RNA-sequencing showed the presence of fragments of the viral genome in all patients [46]. Finally, transmission electron microscopy does detect viral particles in the patient’s platelets [47].
Given these data, it can be tentatively concluded that platelets from patients with COVID-19 are, after all, likely to contain SARS-CoV-2, although the mechanism of entry is not certain. What could be the consequences of the virus infection? The possibilities discussed in the context of a pathogen in blood cells are defense against the immune system, exposure or presentation to the immune system attack, transport and transmission to other tissues, and replication (which is difficult for a virus in platelets and RBCs). The in vitro incubation of platelets and MEG01 megakaryocyte-like cells with SARS-CoV-2 confirmed the ability of both cell types to slowly engulf the virus without replicating it [48]. This study did not detect ACE2 or TMPRSS2 in platelets. Increased autophagy markers in platelets from COVID-19 patients and their co-localization with coronavirus proteins suggest that platelets digest the virus through the xenophagy process [47]. On the other hand, changes in the differentiation and expression of antiviral proteins in circulating megakaryocytes from patients with COVID-19 and evidence that megakaryocytes can become infected with the virus through infected platelets [49] suggest that platelets may contribute to the spread of the virus and the development of negative changes in systemic circulation. Considering that the lungs are among the potential sites of thrombocytopoiesis, the presence of infected megakaryocytes in this area could potentially lead to direct respiratory invasion.

4. Platelets and Endothelium: Ways of Interaction

It is now believed that platelets play not one but two vital roles in maintaining the integrity of the vascular wall. First, they are involved in repairing damage caused by traumatic injuries. This process occurs under conditions of high flow rates and requires the formation of a hemostatic plug [50]. Second, they support the homeostasis of the endothelium and the tightness of intercellular contacts, which is achieved by single platelets without the formation of a hemostatic plug [51]. This function may be especially relevant during coronavirus infection.
Although the traditional view focuses on platelet adhesion and activation related to the proteins of the intercellular matrix, primarily collagens, it has long been known that platelets are capable of direct adhesion to endothelial cells [52]. In healthy vessels, platelet–endothelial interaction is prevented both by the presence of endogenous platelet inhibitors (NO and prostacyclin) and by the absence of platelet adhesion sites on the endothelial surface. This picture changes radically with micro-damage, inflammation, or the presence of other cells on the vessel wall, e.g., immune or cancer cells. In these cases, the main adhesion bridges are pairs P-selectin (active platelets)-PSGL-1 (inactive/active endothelium), GP1b (platelets)—vVW (active endothelium), integrins (active platelets)—fibrinogen—integrins (active endothelium), and CLEC-2 (platelets)—podoplanin (active endothelium) [53]. A separate case is the interaction of platelets with fibrin when the activated endothelium exposes tissue factor [52]. As seen from the list above, platelet adhesion requires either their activation or the activation of the endothelium. In the case of micro-damage, platelet activation can occur due to a certain amount of ADP from damaged cells. In the case of inflammation, it could be caused by interactions between glycoprotein Ib and von Willebrand factor or cytokines secreted by immune cells [54].
It should be further noted that, with the exception of platelet adhesion to vVW, all other cases of the adhesion and activation of platelets at the site of adhesion are likely to result in the secretion of the contents of their granules. It is unknown what role this process plays in endothelial physiology; however, platelet-derived growth factors are well known to promote the development of vascular tumors, vascular growth, and vascular cell proliferation [55]. There is evidence that platelets normally reduce the permeability of the endothelium to albumin [56], while, during inflammation, activated platelets increase the permeability of the vascular endothelium [57]. Thanks to this, the virus from the blood can enter the endothelium and sub-endothelial layer.
Although platelets have long been considered important for maintaining the health of the vascular wall, the first experimental and molecular evidence of the protective role of platelets appeared in 2008, when it was shown how inflammation causes bleeding in thrombocytopenia [58]. It is now quite reliably established that this function of platelets does not require the formation of an aggregate. How exactly bleeding (which platelets protect against) occurs depends on the specific location and associated factors. For example, in most cases, hemorrhage is associated with the transmigration of leukocytes. This further complicates an understanding of the role of platelets, since leukocyte recruitment also requires platelets.
Unlike hemostasis and thrombosis, which require approximately the same set of platelet functions, preventing endothelial damage requires different sets of functions in different organs [51]. For example, hemostasis and thrombosis always fundamentally require GPIb (for primary platelet attachment) and GPIIb-IIIa (for the stabilization of aggregates). This is not the case for vascular wall integrity: GPIb is important for the maintenance of pulmonary and cerebral vascular endothelium in ischemic stroke (but not in the ischemia-reperfusion model). GPIIb-IIIa is important for brain and lung endothelium in most models but not cutaneous hemorrhage. In contrast, GPVI and CLEC-2 appear to be less important in hemostasis but consistently appear to be involved in both endothelial protection and inflammatory bleeding.
Moreover, three years ago, it was shown that platelets can be targeted at endothelial junctions due to the fibrin gradient [59]. Platelets can then release numerous molecules that drive the local endothelial reprogramming and healing of micro-damage. This pathway is crucial for maintaining vascular homeostasis. It may be involved in both the protective functions of platelets during COVID-19 and potentially aiding virus spread. However, it is unlikely to easily lead to the entry of the virus from the cytoplasm, especially if the hypothesis of its association with mitochondria, as described below, is correct.
To what extent can viruses enter the endothelium through the direct uptake of material from platelets? The topic of platelet absorption by endothelial cells is quite controversial, although there is evidence in favor of some mechanisms of this kind [60]. The endocytosis of platelet microvesicles by endotheliocytes is much better documented [61]. This leads to the entry of platelet contents into endothelial cells, including both endothelium-reprogramming miRNA [62] and entire mitochondria [63]. In this regard, the possibility of the endocytosis of platelet microvesicles with SARS-CoV-2 by endothelial cells seems promising because this is a direct route of infection of the endothelium without the participation of receptors discussed when considering the problems of hemostasis. Given the recently demonstrated ability of platelet microvesicles to penetrate bone marrow and influence megakaryocytes [64], which is definitely an attractive opportunity for a virus, this mechanism cannot be ruled out.


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