As abundant, circulating, vascular guards, platelets are uniquely positioned to detect and respond to vascular damage to stop bleeding and maintain vascular homeostasis. These same qualities make platelets valuable sensors of circulating pathogens. The platelets’ abilities to bind and potentially endocytose pathogens (depending on size), become activated, and secrete a host of bioactive molecules suggest that they can be a pivotal part of the response to an infection. Interactions between platelets and viruses or bacteria have long been known, but their significance to immune responses has only recently become the focus of research.

Bacteria are well-known pathogens that can cause diseases with thrombotic complications, e.g., infective endocarditis, pneumonia, sepsis, and hemolytic uremic syndrome (HUS). They exhibit diverse abilities to interact with platelets and can induce platelet activation, adhesion, aggregation, and secretion. Some species appear to interact with platelets via multiple pathways. Previous reviews have focused on the many platelet surface receptors and how they bind pathogens. Here, we take a bacteria-centric view examining how eight different bacterial pathogens affect platelets through direct and indirect binding, secretion of bacterial proteins, and internalization. We specifically address how each species uses different mechanisms to affect platelet function and cause cardiovascular complications.

The interactions between bacteria and platelets are complicated, dynamic, and evolving. Some interactions are part of the host defense system, while others affect bacterial evasion of this response. Certain bacteria directly or indirectly interact with platelets to trigger their activation or manipulate their functions, dysregulate their immune responses, or exacerbate thrombosis. While not the only mechanism by which bacteria form thrombi, bacteria can adhere to endothelial cells, disturb their permeability, and expose the procoagulant sub-endothelium, which is a normal platelet activation for hemostasis. Platelets express an array of receptors and secretory granules that enable them to recognize and respond to different bacterial species (31). Upon encountering bacteria, platelets can rapidly adhere, activate intracellular signaling pathways, and release antimicrobial substances stored within their granules to destroy the invading pathogens. The released molecules can recruit other immune cells, e.g., neutrophils and monocytes, thereby contributing to the overall host defense against bacterial infections. However, bacteria-platelet complexes can shield the bacteria from antibiotics. S. aureus generates biofilms, which shield it from immune responses and render it more resistant to antimicrobial therapies (39). These biofilms contain proteins, polysaccharides, and extracellular DNA, which ensnare and trigger platelets, promoting their aggregation (40). This platelet activation promotes the recruitment of immune cells that secrete cytokines and tissue factors, potentially leading to organ damage if the biofilm is adjacent (39, 41). Infective endocarditis (IE) is a well-known example of a biofilm-associated disease. Its pathogenesis primarily involves the development of septic vegetations—bacterial colonies embedded within fibrin and platelet aggregates that form on heart valves (42). The presence of platelets is essential for in vitro biofilm formation (40). Despite these clear interactions, the significance of platelet-bacterial interaction is unclear and challenging to modulate therapeutically. Platelet responses appear essential for the immune response; however, extensive platelet activation leads to thrombotic events that exacerbate bacterial infection, enhance bacterial survival, and ultimately are detrimental to patients.

The study of platelet-bacteria interactions has a long history. In 1901, Levaditi first reported how rabbit platelets interact with Vibrio cholera, demonstrating that platelets aggregate when incubated with the bacteria (43). However, not until the 1970’s did Clawson and White conduct specific studies of the interactions between platelets and bacteria (44–47). More recently, platelets have been shown to endocytose bacteria such as S. aureus in vivo and in vitro, and the process is enhanced by platelet activation, but the fate of bound/endocytosed bacteria was unclear (48, 49). While this remains an active area of research, some insights were clarified with recent reports showing that platelets can kill some bacterial species (e.g., S. aureus and E. coli), but not others (e.g., S. pneumoniae) (50, 51). Platelets kill E. coli in a manner enhanced by platelet factor 4 (PF4) and anti-PF4/Heparin antibodies (51), while efficient killing of S. aureus requires neither (50). Interestingly, platelets cannot kill S. pneumoniae (50). S. pneumoniae make platelets unresponsive to TRAP-6 stimulation and induce phosphatidylserine (PS) exposure on the platelet surface (50). The latter effect might indicate the conversion of platelets into a procoagulant form or the induction of platelet apoptosis. Such data emphasize the complexity of the interactions between platelets and bacteria, as such interactions depend on the bacterial species and strain. In addition to the pathophysiological complexity of platelets’ interaction with bacteria, experimental variations in the literature often result in contradictory data regarding the reactivity of specific bacterial strains with platelets. Some of the experimental variations are caused by the form of platelets used in experiments [i.e., washed platelets or platelet-rich plasma (PRP)], platelet-to-bacteria ratio, and the platelet activation assay metric (i.e., aggregation or P-selectin exposure). Hence, depending on the bacterial strain, platelets can have a positive or negative impact on bacterial spreading and survival.

S. aureus is a spherical gram-positive bacterium, commensal on the skin and mucous surfaces. Once in the bloodstream, it is a hazardous pathogen capable of inducing necrotizing infections marked by extensive inflammation and tissue damage. This is due to its ability to secrete proteins and enzymes such as proteases, lipases, nucleases, and hyaluronidase, which degrade surrounding tissues (62). S. aureus is equipped with elements that protect it from the immune response generated against tissue damage and is capable of escaping the immune system in several ways, such as the release of chemotaxis inhibitors, leukocyte toxins, complement inactivators, and other antimicrobial peptides (62).

Severe S. aureus infections have been linked to a higher risk of thrombosis, especially deep vein thrombosis (DVT) and disseminated intravascular coagulation (DIC), as the bacteria can have effects on the pro-coagulant and inflammatory pathways and on the anticoagulation factors (63, 64). S. aureus was the first bacterium shown to be endocytosed by platelets, but ADP was required (5, 44, 49). Platelets bind and extend their pseudopods to encapsulate S. aureus, thus limiting bacterial dissemination into the bloodstream (65). Platelets are involved in the eradication of systemic infections (65). Under normal conditions, platelets patrol Kupffer cells (KCs) through a “touch and go” mechanism that involves GPIb and vWF at the KC surface (66). This process is intensified during infection, where platelets are the first cells to arrive in an infected liver, even before neutrophils (66). KCs capture S. aureus and platelets switch from “touch and go” mechanism to “sustained GPIIb/IIIa-dependent adhesion”, which traps the bacteria and limits their spread (66). This process limits liver dysfunction and is essential for S. aureus eradication and host survival (66). Platelets are also involved in the generation of a more specific immune response in a process that depends on GPIb and C3. This directs some bacteria to the spleen to activate CD8α⁺ dendritic cells (67). S. aureus can also induce platelet aggregation and apoptosis. The aggregation response is unique compared to other bacterial species. S. aureus induces aggregation with a shorter lag time (2–5 min) than other species, such as S. sanguinis or S. gordonii (15–20 min) (68, 69). Apoptosis induction is mediated through the degradation of Bcl-xL protein (anti-apoptosis protein), which increases the exposure of PS, which supports the coagulation system (36).

S. aureus modulates thrombosis through a diverse array of surface elements, which in most cases fall into two categories: Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs) and Secretable Expanded Repertoire Adhesive Molecules (SERAMs). MSCRAMMs are connected to the peptidoglycan through a sortase-anchoring motif, while SERAMs are affixed to the bacterial cell surface through non-covalent means (70). Using these proteins, S. aureus modulates thrombosis (induction or resolution) through the mechanisms discussed below (see Figure 1 ).

S. pneumoniae is a lancet-shaped, gram-positive bacterium that is a leading cause of life-threatening, community-acquired pneumonia (CAP) (5). The severity of CAP correlates with the development of thrombocytopenia (113). Besides CAP, S. pneumoniae can cause sepsis and, on rare occasions, IE (114–116). Recent studies have shown that a significant portion of CAP-associated fatalities may be linked to cardiovascular incidents occurring during infection (117, 118). Such events have various causes, including S. pneumoniae itself and its virulence factors, but there is a growing recognition that platelet activation contributes (119).

In the 1970s, the interaction between platelets and S. pneumoniae was first suggested, but this has not been without controversy (46, 120). Some reports showed platelet activation and aggregation upon the addition of S. pneumoniae, and other reports did not (46, 120). The interaction between platelets and S. pneumoniae is serotype-specific, as some serotypes induced platelet activation, while others did not (46, 120). In contrast to S. aureus, which is killed by platelets and their releasate, S. pneumoniae is not killed by platelets nor their releasates, but it affects the viability of platelets as they become unresponsive to TRAP-6 stimulation and expose PS on their surfaces (50). The latter effect might indicate the conversion into procoagulant platelets or that S. pneumoniae induces platelet apoptosis.

Schrottmaier et al. recently showed that the phosphatidylinositol 3-kinase catalytic subunit (p110β) in platelets is essential for the innate immune responses against S. pneumoniae (121). The presence of p110β in platelets is essential for neutrophil activation and to prevent S. pneumoniae propagation (121). They also found that the inhibition or genetic deletion of p110β impairs the recruitment and phagocytosis of neutrophils and monocytes, hinders their infiltration, and enhances bacterial dissemination (121). Verschoor et al. showed that platelets can bind nonencapsulated S. pneumoniae in a GPIb- and C3-dependent process (67). However, platelets did not bind or direct capsulated S. pneumoniae to the spleen to activate CD8α⁺ T-cells (67). The presence of the capsule prevents the deposition of complement proteins on S. pneumoniae (67). How S. pneumoniae induces platelet activation is elusive, though several mechanisms are suggested. Figure 2A summarizes how S. pneumoniae interacts/activates platelets and induces prothrombotic/pro-inflammatory conditions through one or a combination of the following mechanisms.

The interactions between gram-negative bacteria and platelets are less studied (59). E. coli is a rod-shaped, gram-negative bacterium first identified by Theodor Escherich in 1885 (149). Most strains are human or animal commensals localized in the gastrointestinal tract (149). However, some have acquired virulent factors, which associate them with several human diseases such as sepsis and HUS (149, 150). HUS presents as a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure (137). E. coli can be divided into two main categories: intestinal and extraintestinal pathogenic E. coli (59). Each group has several strains, with enterohemorrhagic E. coli (EHEC) being the most studied strain (59). Consistent with the controversial results when studying bacteria and platelets, the interaction between E. coli and platelets has been extensively debated, specifically on the involvement of platelet TLR4 and FcγRIIA receptors and the effects of LPS on platelets (150–153). The effects are strain-dependent, which was confirmed as platelets or their relesates promote or inhibit the growth of different E. coli strains (154, 155).

Platelets can endocytose E. coli, pre-opsonized with IgG, through the FcγRII receptor to kill them (5). E. coli activates platelets through GPIIb/IIIa (150, 152) and that activation is enhanced in the presence of complement, thromboxane A₂, and ADP (150, 152). The released PF4 by activated platelets binds to polyanions on E. coli to form a complex (51), which helps opsonize PF4-coated E. coli and mediate their killing in a GPIIb/IIIa- and FcγRIIa-dependent process (51). These interactions are more complicated, as the interactions between platelets and E. coli vary between individuals (150). The most common molecules that E. coli uses to affect platelet functions are LPS and Shiga toxin ( Figure 2B ).

S. sanguinis is an opportunistic bacterium that inhabits the human mouth (69). S. sanguinis is the most frequent causative microorganism of IE (185). Upon bloodstream entrance, S. sanguinis can cause several complications, such as adhering to host extracellular matrix protein and/or platelets, colonizing the heart valves and ultimately leading to IE (185, 186). S. sanguinis strains are divided into three categories based on their ability to induce platelet activation ex vivo (187, 188). Type 1: adhere and activate platelets with a short delay time, type 2: do not adhere but activate platelets with a longer delay time; and type 3: do not adhere or activate platelets (187).

The first streptococcal surface protein to bind and activate platelets to be identified was the platelet-associated aggregation protein (PAAP) (61, 189, 190). PAAP has a collagen-like epitope that can activate platelets through an uncharacterized receptor, but it is suggested to be GPIIb/IIIa or GPIb and not GPVI (61, 189–191). The interaction between platelets and S. sanguinis is shear-dependent and seems to be mediated through GPIb (60). Platelets isolated from Bernard Soulier syndrome patients (lacking GPIb on their platelets) failed to respond to S. sanguinis, and blocking antibodies against GPIb inhibited both aggregation and adhesion induced by S. sanguinis (187).

In addition to GPIb, platelet aggregation in response to S. sanguinis relies on GPIIb/IIIa and thromboxane A₂. However, aggregation does not occur through direct binding to GPIIb/IIIa, as blocking this receptor with antagonists had no effect (187). Aggregation induced by S. sanguinis is mediated through both GPIIb/IIIa and GPIb, which can occur through either a vWF-independent mechanism or via glycosylated adhesions containing SRRs, such as serine-rich protein A (SrpA) and hemagglutinin salivary antigen (Hsa). Both bind to GPIb in a sialic acid-dependent manner (52, 192). The interaction with GPIb is through SrpA, which is not the only mechanism to activate platelets, as its deletion did not inhibit platelet activation but prolonged the lag time for platelet aggregation (61). In addition to GPIb, S. sanguinis can activate platelets in a complement-dependent process and through FcγRllA as well (193–195). However, certain strains of S. sanguinis stimulate the release of RANTES, PF4, sCD40L, sCD62p, and PDGF-AB from platelets, and other strains do not (196). Thus, it appears that different strains of S. sanguinis can induce platelet activation via different mechanisms, and they further differ in their requirements for thromboxane A₂ or ADP for platelet activation (196). Figure 2C summarizes the main S. sanguinis proteins that can activate platelets.

S. gordonii is a commensal, oral bacterium that causes several complications (i.e., IE) (197). As with other bacteria, the platelet-S. gordonii interaction is strain-specific (61). Some strains have a long lag time in aggregometry experiments, while others have shorter ones or fail to activate platelets altogether (61). S. gordonii possesses SRR adhesin proteins (e.g., gordonii surface proteins glycosylated streptococcal protein B (GspB), Hsa, and SrpA), which bind to a variety of sialylated glycoproteins or the extracellular sialoglycans on GPIbα (198, 199). These SRR adhesins trigger platelet activation by interacting with platelet GPIb in a shear-dependent process (60, 198). While Hsa binds to N-linked sialic acids on GPIb and GPIIb/IIIa, GspB binds to O-linked sialic acids on GPIb on the membrane-proximal mucin-like core of GPIb (200). S. gordonii also induces platelet activation through the platelet adherence protein A (PadA), which specifically interacts with GPIIb/IIIa to induce platelet aggregation and adhesion (201). There are multiple sites of PadA binding to GPIIb/IIIa, resulting in platelet adhesion, dense granule secretion, and spreading on immobilized S. gordonii (201). However, PadA is dispensable for S. gordonii -platelet aggregation but is essential for adhesion of bacteria to platelets (202).

PadA and Hsa are needed for S. gordonii binding to cellular fibronectin and vitronectin, and to promote the formation of biofilms (203). Platelets can bind to immobilized S. gordonii through GPIIb/IIIa and GPIbα through PadA and Hsa, respectively (204). S. gordonii expresses two cell wall-associated polypeptides, streptococcal surface protein A and B (SspA and SspB, belonging to the antigen 1/antigen 2 family) (205). Both of these proteins induce GPIIb/IIIa-dependent aggregation and their deletion extends the lag time for platelet aggregation but does not affect adhesion to platelets (61, 205).

S. gordonii-mediated platelet aggregation also involves FcγRllA (206). The activation of FcγRIIA is dependent on IgG binding and GPIIb/IIIa involvement (77). Platelet releasate is essential, with released ADP and thromboxane A₂ being needed for platelet aggregation by S. gordonii (77). Conversely, released PF4 binds to bacteria and reduces the lag time for platelet aggregation by S. gordonii (77). Figure 2D summarizes the main S. gordonii proteins that can activate platelets.

P. gingivalis is a gram-negative, anaerobic bacterium that is the major cause of periodontitis (207). P. gingivalis infection can increase thrombosis risks in patients with atherosclerosis, ischemic stroke, aneurysm, and atrial fibrillation (208–211). P. gingivalis has multiple effects on platelets. Platelets can endocytose P. gingivalis without the need for other agonists (i.e., ADP) (212). P. gingivalis secretes cysteine proteinases called gingipains, which have trypsin-like activity (213) and are essential for P. gingivalis virulence (214). Through gingipains, P. gingivalis enhances pneumococcal adhesion to alveoli by inducing PAFR expression (133). There are two types of gingipains; lysine-specific protease (Kgp) and three variants of the arginine-specific protease (Rgp): RgpA_cat, RgpB, and high-molecular-weight arginine-specific gingipain A (HRgpA) (215). RgpB and HRgpA induce platelet activation and aggregation by activating PAR1 and PAR4 (213). The incubation of P. gingivalis with human whole blood increased the potential of thrombosis (216). P. gingivalis induces platelet aggregation, P-selectin expression, platelet neutrophil aggregation, and NET formation (217). This effect can or cannot be modified by the addition of ADP (217). In addition, P. gingivalis increases the free calcium concentration in platelets and induces the release of RANTES from platelets, but at the same time, it can degrade it (218). Rgp and Kgp express a gingipain-derived hemagglutinin domain (Hgp44) at the C-termini, which undergoes autoproteolytic cleavage (219). Hgp44 was shown to be essential for platelet aggregation and activation (219). Also, LPS isolated from P. gingivalis enhances platelet spreading and filopodial extensions (220). The increase of filopodial extensions is mediated by the activation of Cdc42, which is a small GTPase that is essential for filopodial formation (220). Thus, RgpB, HRgpA, Hgp44, and LPS, produced by P. gingivalis can induce platelet aggregation and activation. Figure 2E summarizes the main P. gingivalis proteins that can activate platelets.

H. pylori is a gram-negative bacterium known for its role in peptic ulcers, but it also contributes to cardiovascular diseases (CVDs; e.g., myocardial infarction (MI), atherosclerosis, and immune thrombocytopenic purpura (ITP)) (221). H. pylori-infected patients develop chronic ITP, which is a result of platelet destruction by autoantibodies (221). H. pylori can cause thrombocytopenia without preceding bacteremia through a mechanism mediated by autoantibodies that destroy platelets (5). Consistently, patients treated with H. pylori eradication therapy have increased platelet counts (222). The development of thrombocytopenia involves the H. pylori low-molecular-weight antigen (Lpp20), which binds to platelets and can specifically react with sera from patients with H. pylori to induce chronic ITP ( Figure 2F ) (223). H. pylori requires the presence of plasma proteins, such as vWF and specific IgGs, to induce platelet aggregation and activation (61, 224). Function-blocking antibodies against vWF or GPIba inhibited H. pylori-induced platelet aggregation (224). This was confirmed in Bernard Soulier Syndrome patients who failed to respond to H. pylori (61). However, as with any bacteria, some strains of H. pylori activate platelets, and some do not (221).

S. epidermidis, is a coagulase-negative strain present on skin that can cause endocarditis and infections of medical-implemented devices (82). S. epidermidis can cause fibrin clot rupture, which leads to infected clot embolization and cause systemic infection (225). In general, coagulase-negative staphylococci are less virulent than positive bacteria such as S. aureus (226). S. epidermidis can, directly and indirectly, interact with platelets through the serine aspartate dipeptide repeat G (SdrG), which is an MSCRAMM (82). The direct interaction involves GPIIb/IIIa and indirect interaction involves fibrinogen, IgG, and FcγRII (82). S. epidermidis can crosslink GPIIb/IIIa and FcγRIIA to activate platelets (82). Figure 2G summarizes the main P. gingivalis proteins that can activate platelets.

While platelet activation plays a key role in helping the body eliminate viral and bacterial infections, excessive platelet stimulation can worsen disease outcomes, particularly in conditions like IE and sepsis. In preclinical studies for IE and sepsis, antiplatelet therapy such as aspirin has shown promising results when used as prophylactic or adjunct therapy (227–231). In both sepsis and IE, platelets are essential in the first line to remove pathogens. However, once the infection is established, platelet activation can worsen the condition. Extensive activation leads to thrombotic events that exacerbate the infection, promote bacterial survival, and ultimately harm the patient. Therefore, in theory, inhibiting platelet activity should be beneficial. As a result, several prospective and retrospective clinical studies have investigated whether antiplatelet therapies can reduce infection-related complications. However, no clear conclusions have yet been reached regarding their effectiveness in preventing or slowing the progression of infection (232–241). The main limitations of these studies include small sample sizes, which make it challenging to achieve statistical significance, as well as significant variability in patient age, underlying health conditions, the duration and dosage of antiplatelet therapy before or after the onset of infection, and the bacterial strains responsible for the disease (242). Despite the complexity of platelet–bacteria interactions, current research provides a solid foundation for future clinical applications. For example, platelet activation markers could be used as early diagnostic or prognostic tools in sepsis or IE, while targeted modulation of platelet responses could help reduce pathological thrombosis without compromising immune defense. An ideal target would be FcγRIIA receptor on the platelet surface since it is needed for pathogen-induced platelet activation (53). Furthermore, understanding specific bacterial virulence factors that alter platelet function opens new opportunities for precision medicine, where therapies are tailored based on the infecting pathogen’s profile. Ultimately, integrating platelet-related findings into clinical practice holds promise for improving the management and outcomes of severe bacterial infections.

Our understanding of platelet functions as immune cells has dramatically expanded, suggesting that they are crucial to responses to microbial infections. The interactions between platelets and pathogens are dynamic, multifaceted, and complicated processes that involve host defense mechanisms and microbial evasion strategies. Bacteria have also evolved mechanisms to exploit platelet functions for their benefit. While some bacteria have surface molecules that facilitate their adhesion and activation of platelets, others do not. Instead, some bacteria use plasma proteins as adapters to connect them with platelets. The most frequently exploited plasma proteins are fibrinogen, IgG, and vWF. These bind to GPIb and GPIIb/IIIa, which are frequently involved in the direct interaction between platelets and bacteria ( Figure 3 ). However, these interactions alone are generally not sufficient to trigger platelet activation. For most bacterial species, platelet activation relies on FcγRIIa signaling. Inhibiting FcγRIIa—either through antibody blockade or depletion of specific IgG—effectively prevents platelet activation. This demonstrates that the interaction between IgG and FcγRIIa is crucial for initiating platelet activation. This is a unique feature of the immune response of platelets. For hemostasis, one type of receptor activation is sufficient to activate platelets.

Throughout this review, we have highlighted how most of these interactions lead to platelet consumption, dysregulated immune responses, or exacerbation of thrombotic events ( Table 1 ). However, platelets are also involved in immune responses against bacteria and in their eradication. The presence of platelets is essential for TNF- α release following LPS injection in mice. Platelets are important in preventing liver injury during S. aureus infection. Platelets are key to neutrophil activation and preventing S. pneumoniae propagation. Platelets are capable of endocytosing and killing certain bacteria such as S. aureus and E. coli. Despite these insights, the importance of the platelet immune response against bacterial infection is still understudied. A major challenge in the field is the absence of FcγRIIa on mouse platelets. In mice, bacteria-driven platelet activation does not rely on FcγRIIa and is likely to follow mechanisms that might be distinct from humans. Other challenges also include contradictory findings, perhaps more reflective of the assays used or other technical issues such as the form of platelets used (washed platelets or PRP), platelets to bacteria ratio, bacterial strains, incubation times and temperature, incubation condition (static or stirring), platelet isolation methods, and platelet activation assay read out (aggregation or P-selectin exposure). It is hoped that our summary of the strategies bacteria use to affect platelets will help guide the needed research into the mechanisms underlying these effects.