1. Introduction
Over the last few years our understanding of the role of platelets has evolved. While originally considered to be solely involved in thrombus formation recent studies suggest that they play an important role in the innate immune system. As the most numerous particles in the blood platelets are the first responders to any breaches in the vasculature where they bind to the damaged vessel and aggregate to seal the leak. They also become activated and secrete the contents of their granules, which contain anti-microbial peptides, which acts to sterilise the wound and to recruit other immune cells. As a result thrombocytopenia is a common response to infection by many different organisms [1, 2].
As part of the innate immune system platelets express many different pathogen recognition molecules that are involved in immune function rather than thrombosis. Thus platelets express Toll-Like Receptors (TLRs), which are pathogen recognition receptors [3] and in particular platelet TLR2 [4], TLR4 [5] and TLR7 [6] have been shown to be functional. Another important immune receptor is FcγRIIa, a receptor for the Fc-portion of IgG, which is typically expressed on phagocytic cells [7]. While platelets express functional FcγRIIa there is evidence of limited phagocytic ability for platelets [8-11]. DC-SIGN is another important pattern recognition molecule [12] that has been identified on platelets and found to be functional [13]. While both immune-mediated and haemostasis-mediated platelet activation result in activated platelets the platelet response is quite different in both cases [14].
The best-studied example of a role of platelets in infection is that with bacterial infection. While most effort has focused on Gram-positive bacteria many bacteria have been shown to activate platelets and these studies show a number of common features. The interaction of bacteria with platelets typically occurs due to direct binding to platelets, binding of a platelet-binding plasma protein to the bacteria or the secretion of a substance that activates platelets [1, 15, 16]. Typically streptococcal species such as
2. Platelets in viral infection
While thrombocytopenia and in severe cases disseminated intravascular coagulation (DIC) are associated with bacterial infection this is also true for viral infection. Viral Haemorrhagic Fever (VHF) is similar to sepsis and both can be considered as forms of Systemic Inflammatory Response Syndrome (SIRS) [19, 20]. Equally thrombocytopenia is a common response to viral infections. However, it is worth noting that in some case the use of anti-viral agents may mediate the thrombocytopenia such as where neuraminidase inhibitors are associated with an immune thrombocytopenia [21] and abacavir enhances platelet activity by inhibiting guanylate cyclase [22].
2.1. Viral Haemorrhagic fever
Unlike with bacteria where virtually any species can lead to sepsis the viral equivalent (VHF) only occurs with members of 4 families of viruses known collectively as VHF viruses [20, 23].
Dengue haemorrhagic fever is unusual as it typically occurs in response to a secondary infection with the primary infection producing relatively minor ‘flu-like symptoms. In fact there are 4 serotypes of DENV and it is infection with a second serotype that leads to dengue haemorrhagic fever. This suggests that the presence of anti-DENV antibodies is necessary for DHF to occur and this process is known as antibody-dependent enhancement (ADE) [31, 32]. These antibodies have been shown to enhance virus uptake and replication through an interaction with Fc receptors [32-35]. However, just as antibody binding to bacteria can trigger platelet activation it is likely that antibody binding to DENV will also activate platelets in an FcγRIIa-dependent manner. This platelet activation has been shown to lead to enhanced permeability [36]. Bone marrow infection occurs in animal models of Dengue [37], which could lead to thrombocytopenia due to impaired platelet production.
2.2. Other viral infections
Although there is a paucity of data on the mechanisms involved thrombocytopenia is a common response to many viral infection and not just VHF. However, in general, viral-induced thrombocytopenia is either due to platelet activation leading to consumption or infection of the megakaryocytes leading to impaired platelet production.
While the strategy of an anti-viral sponge is effective it is not without its problems. Excessive platelet activation can lead to disseminated intravascular coagulation such as occurs in an extreme form in VHF. Correcting this DIC is critical for survival of the patient. Equally the prolonged hyper-activity of platelets in HIV-positive patients is a risk factor for cardiovascular disease in these patients. There is some evidence that anti-platelet agents can play a role here but as they inhibit platelet activity they may not be the ideal solution especially in DIC. A better strategy is to identify the mechanisms involved in the thrombocytopenia and to develop an inhibitor of the virus-platelet interaction without compromising platelet function (Figure 1). Interestingly FcγRIIa has been found to be an important drug target in bacteria-platelet interactions [1, 16] and there is evidence that with some viruses it may also be an important drug target as well [55].
3. Parasites
As platelets are part of the innate immune system and interact with bacteria and viruses they also interact with parasites. In this context they bind to parasites and in some cases will kill them. As a result there can be a thrombocytopenia as well as evidence of micro-thrombi formation. The most studied parasites that interacts with platelets are the malaria parasites [88] although there has been some work on other parasites as well.
3.1. Malaria
Malaria is a mosquito borne parasite infection (
Platelets have been shown to be involved in clumping of parasitized red cells [108] and they have been found to accumulate in the brains of patients with cerebral malaria [108, 109].
3.2. Role of the endothelium
The endothelium plays an important role in the pathogenesis of malaria. The clumped RBC’s bind to the endothelium and can ultimately occlude smaller blood vessels, especially in the brain. Activated endothelium is a key component of cerebral malaria and has been shown to occur in children [122]. Overproduction of cytokines plays a major role in the activation of the endothelium [123, 124]. One of the key cytokines involved is TNF, which is produced by macrophages in response to malaria antigens [125], possibly acting on TNFR2 [126]. Platelets play a significant role in the destruction of TNF-activated endothelial cells [127-129] while TGFβ1 released from activated platelets can kill TNF-activated endothelial cells [130].
A recent model has been proposed that draws together many of these observations in malaria (Figure 2). Activated endothelial cells secrete high molecular weight vWf, which form strings under high shear. Platelets bind to these strings, which also bind to the activated endothelial cells. Infected RBCs can then in turn bind to the immobilised platelets ultimately occluding the blood vessel which if in the cerebral micro-circulation leads to cerebral malaria [131].
3.3. Other parasites
Schistosomes are trematodes and a major pathogen that causes over 200 million cases of schistosomiasis per year. Thrombocytopenia is a common symptom of infection with
Trypanosomatids are unicellular parasites with a single flagellum and there are two clinically relevant genera. Genus
4. Conclusions
It is clear that platelets are a key component of the innate immune system where they are the initial responders to infection. They appear to respond to the full range of pathogens including bacteria, parasites and viruses. Thus, thrombocytopenia is a characteristic symptom of infection by any organism. The response to bacteria infection is the best studied and a key role of the platelets is the secretion of anti-microbial peptides that as their name implies kill bacteria. While there is evidence that this also occurs with parasites it may not be true of viruses as they are not cells. There are what appear to be conflicting data on the role of platelets in infection. On one hand severe thrombocytopenia is associated with poor outcome suggesting that platelet activation is important in pathogenesis. On the other hand thrombocytopenic animals are more likely to have a poor outcome suggesting that platelets prevent the disease.
These conflicting data can be resolved in a model where platelets have a dual role. Upon initial exposure to a pathogen there is a decline in platelet number due to the initial immune response. Platelets are activated and bind the pathogen. This then results in pathogen killing or at least clearance of the platelet-pathogen complex from the circulation. If that works then it is the end of the story. The pathogen is ultimately cleared and the disease resolves. However, sometimes platelets fail to clear the pathogen or pathogen replication exceeds the clearance. As a result there is excessive platelet activation that can progress to disseminated intravascular coagulation. Thus, in the early stage of infection platelets are good as they help clear the pathogen, however, in the later stages of infection platelets are bad as they are contributing to the problem.
This then leads to the question of whether platelets are a good target for treating infection. It has been proposed that anti-platelet agents may not be wise in patients with malaria since they are protective [152]. However, it is important to appreciate the stage of the disease. During the early stages of an infection an anti-platelet agent would be undesirable, as it would inhibit the immune functions of the platelets. However, as the disease progresses towards DIC an anti-platelet agent would be desirable as at this point platelets are now part of the problem and their excessive activation must be contained. While conventional anti-platelet agents may be useful in a patient with VHF or DIC this may not be advisable. The result may be that platelet number is preserved but the price paid would be platelet function, which in VHF would exacerbate the bleeding problems. Thus, a better approach may be targeting the platelet receptors that mediate the interactions with the pathogen. This would prevent platelet activation while maintaining platelet function. While some of these targets are likely to be pathogen specific a good target may be FcγRIIa. It has been shown to be critical in bacteria-induced platelet activation but also appears to play a role in some viral infections.
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