Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet factor 4

Abstract

Key Points• FcgRIIA activation is key for platelet aggregation in response to bacteria, and depends on IgG and aIIbb3 engagement.• PF4 binds to bacteria and reduces the lag time for platelet aggregation.Bacterial adhesion to platelets is mediated via a range of strain-specific bacterial surface proteins that bind to a variety of platelet receptors. It is unclear how these interactions lead to platelet activation. We demonstrate a critical role for the immune receptor FcgRIIA, aIIbb3, and Src and Syk tyrosine kinases in platelet activation by Staphylococcus aureus, Streptococcus sanguinis, Streptococcus gordonii, Streptococcus oralis, and Streptococcus pneumoniae. FcgRIIA activation is dependent on immunoglobulin G (IgG) and aIIbb3 engagement. Moreover, feedback agonists adenosine 59-diphosphate and thromboxane A 2 are mandatory for platelet aggregation. Additionally, platelet factor 4 (PF4) binds to bacteria and reduces the lag time for aggregation, and gray platelet syndrome a-granule-deficient platelets do not aggregate to 4 of 5 bacterial strains. We propose that FcgRIIA-mediated activation is a common response mechanism used against a wide range of bacteria, and that release of secondary mediators and PF4 serve as a positive feedback mechanism for activation through an IgG-dependent pathway. (Blood. 2014;123(20):3166-3174)

Platelet Interactions with Bacteria

“…The addition of plasma concentrations of fibrinogen to the gel filtered platelets failed to restore aggregation however addition of plasma concentrations of purified IgG fully restored platelet aggregation. More recently, Arman et al, demonstrated that S. sanguinis, S. gordonii but not S. pneumoniae require IgG's to induce platelet aggregation [69]. The site that IgG binds to was not identified in this study.…”

“…FcγRIIA is fast becoming the most important receptor in platelet bacterial interactions as it has been shown to inhibit all bacterial induced platelet activation including those triggered by S. aureus, S. epidermidis, S. sanguinis, S. gordonii, Streptococcus pneumonia, Streptococcus oralis, H. pylori and S. pyogenes [30,33,34,36,50,53,[66][67][68][69][70]. A key observation is that IgG is required for all of these bacteria to induce platelet aggregation, however antibody alone was not enough to trigger aggregation / activation of platelets.…”

“…In all cases engagement of another platelet receptor was required such as GPIIbIIIa, GPIbα, or Toll Like Receptors (TLR's). These observations suggest that FcγRIIa requires receptor clustering in order to trigger platelet activation [69]. Indeed FcγRIIa has been shown to be physically associated with GPIIbIIIa and GPIbα and therefore plays an important role in their respective signalling in an IgG-independent manner [71].…”

“…Translating animal studies to human disease is becoming increasingly difficult, especially with the identification that FcγRIIA is a key receptor involved in signal amplification in human platelets [69]. FcγRIIa is unique to higher primates and therefore calls into question the validity of using mouse, rat or rabbit animal models for studying plateletbacterial interactions [93], as they do not express FcγRIIa.…”

Bacteria exploit platelets

“…Arman and colleagues evaluated the effect of 5 bacterial strains belonging to the Staphylococcus and Streptococcus family on their ability to activate human platelets. 1 They show that the interaction of bacteria with platelets requires the platelet FcgRIIA receptor because the inhibition of FcgRIIA by monoclonal antibody IV.3 blocks platelet activation. They also show the requirement of plasma IgG and engagement of integrin by fibrinogen for the bacteria to induce platelet activation.…”