The involvement of platelets in non-thrombotic processes

doi:10.1016/0165-6147(88)90120-4

Trends in Pharmacological Sciences

Volume 9, Issue 2, February 1988, Pages 66-71

https://doi.org/10.1016/0165-6147(88)90120-4 Get rights and content

Abstract

The platelet, the smallest blood element, has tended to be considered only in the context of physiological homeostatic mechanisms and pathological conditions such as thrombosis and related cardiovascular diseases. However, it now seems that this view is too limited. Clive Page reviews the increasing evidence that the platelet has fundamental physiological roles in natural defence mechanisms and as a source of growth factors. These other roles may have pathological counterparts when platelets are activated inappropriately, namely allergic inflammation and asthma.

References (34)

A. Capron et al.
Immunol. Today
(1986)
S.I. Wasserman et al.
J. Allergy Clin. Immunol.
(1984)
S.R. Durham et al.
Lancet
(1985)
F.M. Cuss et al.
Lancet
(1986)
E. Frigas et al.
J. Allergy Clin. Immunol.
(1986)
N.R. Spinks et al.
Lancet
(1987)
C. O'Neill et al.
Fertil. Steril.
(1987)
R.L. Nachman et al.
A.L. Copley
Folia Haematol.
(1979)
P. Hilgard

M. Joseph et al.

Eur. J. Immunol.

(1986)

J.C. Ameisen et al.

Int. Archs Allergy Appl. Immunol.

(1985)

M. Joseph et al.

Eur. J. Respir. Dis.

(1986)

A.J. Lewis et al.

Agents Actions

(1984)

J.Y. Cesbron et al.

Nature

(1987)

C.P. Page et al.

P. Gresele et al.

N. Engl. J. Med.

(1982)

Cited by (66)

Procoagulant State of Sleep Apnea Depends on Systemic Inflammation and Endothelial Damage
2022, Archivos de Bronconeumologia
Growing evidence shows a hypercoagulable state in obstructive sleep apnea (OSA) that could be a risk factor for thromboembolic disease.
We aimed to elucidate mechanisms involved in the procoagulant profile observed in patients with OSA and to investigate the potential utility of global tests in its characterization.
Thirty-eight patients with severe OSA without previous history of thrombosis and nineteen healthy age- and sex-matched controls were included.
Kinetic of clot formation was determined using rotational thromboelastometry.
Haemostatic capacity of plasma and microparticles was determined by Calibrated Automated Thrombinography.
Platelet surface receptors, activation markers and formation of platelet/leukocytes aggregates were analyzed by flow cytometry.
Thromboelastometry showed a procoagulant state in patients with OSA that did not seem to be related to a basal activation of platelets but by the increased existence of platelet/leukocyte aggregates.
Patients with OSA presented many signs of endothelial damage such as increased plasma levels of E-selectin and cfDNA and enhanced thrombin generation due to the presence of microparticles rich in tissue-factor, which is related to OSA severity.
OSA induces an enhancement in the dynamics of clot formation which appears to be caused by at least two pathological mechanisms. First, a greater formation of platelet-leukocyte aggregates; secondly, endothelial damage which provokes a greater procoagulant potential due to the increase in tissue factor-rich microparticles. Moreover, this study has identified thromboelastometry and thrombin generation assay as useful tools to evaluate the prothrombotic state in these patients.
Existen pruebas crecientes que muestran un estado de hipercoagulabilidad en la apnea obstructiva del sueño (AOS) que podría ser un factor de riesgo de desarrollar enfermedad tromboembólica.
Nuestro objetivo fue dilucidar los mecanismos involucrados en el perfil procoagulante que se ha observado en los pacientes con AOS e investigar la posible utilidad de las pruebas globales en su caracterización.
Se incluyeron 38 pacientes con AOS grave sin antecedentes de trombosis y 19 controles sanos emparejados por edad y sexo.
La cinética de la formación del coágulo se determinó mediante tromboelastometría rotacional.
La capacidad hemostática del plasma y las micropartículas se determinó mediante trombinografía automatizada calibrada.
Los receptores de la membrana plaquetaria, los marcadores de activación plaquetaria y la formación de agregados de plaquetas-leucocitos se analizaron mediante citometría de flujo.
La tromboelastometría mostró un estado procoagulante en pacientes con AOS que no parecía estar relacionado con una activación basal de las plaquetas, sino por el aumento de agregados de plaquetas-leucocitos.
Los pacientes con AOS presentaban muchos signos de daño endotelial, como un aumento de los niveles plasmáticos de E-selectina y ADNcf y una mayor generación de trombina debido a la presencia de micropartículas ricas en factor tisular, que se relaciona con la gravedad de la AOS.
La AOS induce un aumento de la dinámica de la formación de coágulos que parece estar causada por al menos 2 mecanismos patológicos. Primero, una mayor formación de agregados plaquetas-leucocitos; segundo, el daño endotelial que provoca un mayor potencial procoagulante debido al aumento de micropartículas ricas en factor tisular. Además, este estudio ha identificado la tromboelastometría y el ensayo de generación de trombina como herramientas útiles para evaluar el estado protrombótico en estos pacientes.
A novel murine model of pulmonary fibrosis: the role of platelets in chronic changes induced by bleomycin
2021, Journal of Pharmacological and Toxicological Methods
Citation Excerpt :
Indeed, platelets are a major source of TGF-β (Momi et al., 2017; Pitchford et al., 2019; Wilson & Wynn, 2009) and the observation of platelet accumulation into lung tissue and the correlation between platelet numbers in the BAL and fibrotic markers in this model would suggest a direct contribution of platelets to the pathological response. Platelet recruitment into lungs has also been observed in models of asthma, sterile inflammation, and bacterial infection, and it has recently been reported that platelet recruitment into the lung can be independent of the recruitment of other inflammatory cells (Eisinger et al., 2018; Lefrancais et al., 2017; Momi et al., 2017; Page, 1988; Petito et al., 2018; Pitchford et al., 2019; Zaid et al., 2020). Furthermore, we have previously reported that platelet depletion in a murine model of chronic allergic lung inflammation was able to reduce remodelling events in the airway wall, processes that could not be inhibited by the chronic administration of dexamethasone that was otherwise effective at suppressing airways inflammation (Cleary et al., 2019).
Idiopathic pulmonary fibrosis (IPF) is a disease that causes scarring and destruction of lung tissue that is ultimately fatal. There is a need to develop improved treatments for IPF. One problem with identifying novel treatments of IPF is the poor predictability of current preclinical models. Few model investigate lung function changes, rather relying on histological changes which doesn't adequately reflect the complete clinical situation. The aim of this study was to establish a novel model of pulmonary fibrosis where we could investigate changes in lung function, and histology. We have also utilised this model to investigate the role of platelets in pulmonary fibrosis as platelets have been recognised as having a broader role than just facilitating haemostasis.
Lung fibrosis was induced in male C57BL6/J mice by intranasal bleomycin on Days 0, 1, 2, 5, 6 and 7. Platelets were depleted by twice-weekly administration of anti-platelet antibodies. On Day 35 mice were assessed by examining lung function, platelet infiltration into lung tissues and bronchoalveolar lavage fluid (BAL), levels of BAL Tissue growth factor (TGF)-β levels, and the degree of fibrosis evaluated histologically.
Repeated bleomycin administration caused loss of lung function associated with fibrosis assessed histologically. Platelet depletion resulted in a reduction in fibrosis and modest inhibition of lung function changes.
We have established a novel model of pulmonary fibrosis that is associated with a decline in lung function similar to the clinical setting. Furthermore, platelet depletion resulted in a less severe fibrosis suggesting that targeting platelets maybe worth further investigation.
Platelets
2021, Encyclopedia of Respiratory Medicine, Second Edition
Clinical evidence exists demonstrating changes in platelet behavior and function in inflammatory diseases and infections of the respiratory tract, in particular in asthma, rhinitis, acute lung injury arising from Adult Respiratory Distress Syndrome (ARDS), COVID-19 and chronic obstructive pulmonary disease (COPD). Despite being anucleate, platelets participate in the pathogenesis of these disorders in a manner distinct from their effects in thrombosis and hemostasis. These include the expression of adhesion molecules, the release of proinflammatory mediators, tissue-degrading enzymes, cationic proteins, and the ability to undergo chemotaxis. Platelets can themselves be activated by mediators released by other inflammatory cells. There is now substantial experimental evidence that supports a role for platelets in the development of immunity, leukocyte recruitment to inflamed tissue, airways hyperresponsiveness, lung remodeling and repair, and pulmonary hypertension.
Pharmacological strategies for targeting platelet activation in asthma
2019, Current Opinion in Pharmacology
Citation Excerpt :
This contradiction would suggest that the nature of participation of platelets in inflammatory events of host defence is fundamentally different to the essential platelet activation during haemostasis [19]. A concept for a dichotomy in platelet activation was proposed by Page in 1988 [20], and an implication is that drugs developed to target platelet activation in inflammatory diseases will need to be different to current anti-platelet drugs used for secondary prevention of thrombosis. Platelets are an attractive target as a solution for novel anti-inflammatory therapies for a number of reasons: 1) the involvement of platelets in inflammation can occur at various levels of the immune response, and have substantial roles in critical processes (for example platelet-dependent leukocyte recruitment), therefore, to target platelet activation would reduce the likelihood of operational redundancy; 2) rapid anti-inflammatory effects are induced experimentally by targeting platelet activation via GPCR antagonism; 3) the short platelet lifespan (8–10 days) offers an opportunity to manipulate windows of anti-inflammatory therapy when host-defence to an opportunistic infection cannot be compromised.
The activation of platelets during host defence and inflammatory disorders has become increasingly documented. Clinical studies of patients with asthma reveal heightened platelet activation and accumulation into lung tissue. Accompanying studies in animal models of allergic lung inflammation, using protocols of experimentally induced thrombocytopenia proclaim an important role for platelets during the leukocyte recruitment cascade, tissue integrity, and lung function. The functions of platelets during these inflammatory events are clearly distinct to platelet functions during haemostasis and clot formation, and have led to the concept that a dichotomy (or polytomy, depending on what else platelets do) in platelet activation exists. The platelet, therefore, presents us with novel opportunities for modulating these inflammatory responses. This review discusses the rationale and effectiveness of current anti-platelet drugs in their use to supress inflammation with regard to asthma, and the need to consider novel possibilities for pharmacological modulation of platelet function associated with inflammation that are pharmacologically distinct to current anti-platelet therapies.
A dichotomy in platelet activation: Evidence of different functional platelet responses to inflammatory versus haemostatic stimuli
2018, Thrombosis Research
Citation Excerpt :
In vivo studies have also supported the hypothesis that the pro-inflammatory role of platelets is distinct from the role of platelets in haemostasis, as platelet-dependent inflammatory cell recruitment may be inhibited by drugs not influencing platelet aggregation [9,10]. These observations, describing a divergence in platelet functions, support the hypothesis of the existence of a 'dichotomy in platelet activation' originally proposed by one of us nearly two decades ago [24], with the triggering of different platelet functions depending on the inflammatory versus haemostatic nature of the stimulus. The aim of the present study was therefore to systematically evaluate in vitro the effect of a panel of either agonists classically associated with haemostatic processes (ADP, collagen [Coll], convulxin [CVX], epinephrine [Epi], TRAP-6 and the TxA2 analogue U46619) or inflammatory stimuli (fMLP, histamine [Hist], interleukin-1β [IL-1β], lipopolysaccharide [LPS], macrophage-derived chemokine-[MDC/CCL22], stromal cell-derived factor-1α-[SDF-1α/CXCL12] and serotonin [5-HT]) on a series of primarily haemostatic or inflammatory functions of platelets.
Platelets participate in inflammatory disorders through a variety of different functional responses, including chemotaxis, platelet-leukocyte complex formation and facilitation of leukocyte recruitment that are thought to be distinct from platelet aggregation. This may account for why classical anti-platelet drugs have failed to ameliorate inflammatory disorders where platelets are known to participate, suggesting that distinct pathways may control inflammatory and haemostatic functions of platelets. In the present study, we have therefore investigated the effect of different stimuli on several different functions of platelets preferentially involved either in haemostasis or in inflammation.
Human platelets were stimulated with either inflammatory (fMLP, histamine, IL-1β, LPS, MDC/CCL22, SDF-1α/CXCL12 and 5-HT) or haemostatic (ADP, collagen, convulxin, epinephrine, TRAP-6 and U46619) stimuli. Aggregation, platelet-leukocyte complex formation, platelet migration and platelet protein phosphorylation were assessed.
Haemostatic stimuli induced platelet aggregation, whilst inflammatory agonists induced platelet migration. The haemostatic stimuli, with the exception of epinephrine, and some of the inflammatory stimuli induced platelet-leukocyte complex formation, even if to a different extent. Furthermore, inflammatory stimuli induced a shorter lasting profile of platelet protein phosphorylation compared with haemostatic stimuli.
Stimulation of platelets with inflammatory stimuli triggers the activation of non haemostatic functions different from those induced by haemostatic stimuli, supporting the existence of alternative platelet responses depending on the stimulus (haemostatic or inflammatory). A deeper understanding of the biochemical pathways behind these functional differences may lead to the development of novel therapeutic options targeting the inflammatory actions of platelets, without affecting their critical role in haemostasis.
Diverse signalling of the platelet P2Y<inf>1</inf> receptor leads to a dichotomy in platelet function
2018, European Journal of Pharmacology
Citation Excerpt :
We were the first to identify a divergent, or ‘biased’, signalling event centred on the platelet purinergic P2Y1 receptor that controls leukocyte recruitment during inflammation, but that does not affect haemostasis (Amison et al., 2015, 2017b). This divergence in platelet function supports the hypothesis: ‘Dichotomy in platelet activation’, whereby platelet activation is considered distinct following activation with inflammatory stimuli versus aggregatory stimuli (Page, 1988). The role of purinergic receptor activation in the regulation of leukocyte activation, adhesion molecule expression and motility has received considerable attention (Chen et al., 2006; Ferrari et al., 2016).
Platelet P2Y₁ receptor signalling via RhoGTPases is necessary for platelet-dependent leukocyte recruitment, where no platelet aggregation is observed. We investigated signalling cascades involved in distinct P2Y₁-dependent platelet activities in vitro, using specific inhibitors for phospholipase C (PLC) (U73122, to inhibit the canonical pathway), and RhoGTPases: Rac1 (NSC23766) and RhoA (ROCK inhibitor GSK429286). Human platelet rich plasma (for platelet aggregation) or isolated washed platelets (for chemotaxis assays) was treated with U73122, GSK429286 or NSC23766 prior to stimulation with adenosine diphosphate (ADP) or the P2Y₁ specific agonist MRS2365. Aggregation, chemotaxis (towards f-MLP), or platelet-induced human neutrophil chemotaxis (PINC) towards macrophage derived chemokine (MDC) was assessed. Molecular docking of ADP and MRS2365 to P2Y₁ was analysed using AutoDock Smina followed by GOLD molecular docking in the Accelrys Discovery Studio software.
Inhibition of PLC, but not Rac1 or RhoA, suppressed platelet aggregation induced by ADP and MRS2365. In contrast, platelet chemotaxis and PINC, were significantly attenuated by inhibition of platelet Rac1 or RhoA, but not PLC. MRS2365, compared to ADP had a less pronounced effect on P2Y₁-induced aggregation, but a similar efficacy to stimulate platelet chemotaxis and PINC, which might be explained by differences in molecular interaction of ADP compared to MRS2365 with the P2Y₁ receptor. Platelet P2Y₁ receptor activation during inflammation signals through alternate pathways involving Rho GTPases in contrast to canonical P2Y₁ receptor induced PLC signalling. This might be explained by selective molecular interactions of ligands within the orthosteric site of the P2Y₁ receptor.

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Trends in Pharmacological Sciences

The involvement of platelets in non-thrombotic processes

Abstract

Immunol. Today

J. Allergy Clin. Immunol.

Lancet

Lancet

J. Allergy Clin. Immunol.

Lancet

Fertil. Steril.

Folia Haematol.

Eur. J. Immunol.

Int. Archs Allergy Appl. Immunol.

Eur. J. Respir. Dis.

Agents Actions

Nature

N. Engl. J. Med.