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Nature Reviews. Immunology Aug 2023Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ... (Review)
Review
Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ damage, morbidity and death. Platelets have long been known for their role in primary haemostasis, but they are now also considered to be components of the immune system and to have a central role in the pathogenesis of IMIDs. In patients with IMIDs, platelets are activated by disease-specific factors, and their activation often reflects disease activity. Here we summarize the evidence showing that activated platelets have an active role in the pathogenesis and the progression of IMIDs. Activated platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis. Targeting platelet activation and targeting the interaction of platelets with the immune system are novel and promising therapeutic strategies in IMIDs.
Topics: Humans; Blood Platelets; Immunomodulating Agents; Platelet Activation; Inflammation; Thrombosis
PubMed: 36707719
DOI: 10.1038/s41577-023-00834-4 -
Nature Communications Aug 2023Aberrant coagulation and thrombosis are associated with severe COVID-19 post-SARS-CoV-2 infection, yet the underlying mechanism remains obscure. Here we show that serum...
Aberrant coagulation and thrombosis are associated with severe COVID-19 post-SARS-CoV-2 infection, yet the underlying mechanism remains obscure. Here we show that serum levels of SARS-CoV-2 envelope (E) protein are associated with coagulation disorders of COVID-19 patients, and intravenous administration of the E protein is able to potentiate thrombosis in mice. Through protein pull-down and mass spectrometry, we find that CD36, a transmembrane glycoprotein, directly binds with E protein and mediates hyperactivation of human and mouse platelets through the p38 MAPK-NF-κB signaling pathway. Conversely, the pharmacological blockade of CD36 or p38 notably attenuates human platelet activation induced by the E protein. Similarly, the genetic deficiency of CD36, as well as the pharmacological inhibition of p38 in mice, significantly diminishes E protein-induced platelet activation and thrombotic events. Together, our study reveals a critical role for the CD36-p38 axis in E protein-induced platelet hyperactivity, which could serve as an actionable target for developing therapies against aberrant thrombotic events related to the severity and mortality of COVID-19.
Topics: Humans; Animals; Mice; SARS-CoV-2; COVID-19; Platelet Activation; Thrombosis; Blood Coagulation; Transcription Factors; CD36 Antigens
PubMed: 37604832
DOI: 10.1038/s41467-023-40824-7 -
Redox Biology Sep 2023Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate....
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate. Thrombocytopenia is a major clinical manifestation observed in SFTS patients, but the underlying mechanism remains largely unclear. Here, we explored the effects of SFTSV infection on platelet function in vivo in severely infected SFTSV IFNar mice and on mouse and human platelet function in vitro. Results showed that SFTSV-induced platelet clearance acceleration may be the main reason for thrombocytopenia. SFTSV-potentiated platelet activation and apoptosis were also observed in infected mice. Further investigation showed that SFTSV infection induced platelet reactive oxygen species (ROS) production and mitochondrial dysfunction. In vitro experiments revealed that administration of SFTSV or SFTSV glycoprotein (Gn) increased activation, apoptosis, ROS production, and mitochondrial dysfunction in separated mouse platelets, which could be effectively ameliorated by the application of antioxidants (NAC (N-acetyl-l-cysteine), SKQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) and resveratrol). In vivo experiments showed that the antioxidants partially rescued SFTSV infection-induced thrombocytopenia by improving excessive ROS production and mitochondrial dysfunction and down-regulating platelet apoptosis and activation. Furthermore, while SFTSV and Gn directly potentiated human platelet activation, it was completely abolished by antioxidants. This study revealed that SFTSV and Gn can directly trigger platelet activation and apoptosis in an ROS-MAPK-dependent manner, which may contribute to thrombocytopenia and hemorrhage during infection, but can be abolished by antioxidants.
Topics: Humans; Animals; Mice; Severe Fever with Thrombocytopenia Syndrome; Reactive Oxygen Species; Bunyaviridae Infections; Antioxidants; Glycoproteins; Thrombocytopenia; Platelet Activation
PubMed: 37544244
DOI: 10.1016/j.redox.2023.102837 -
The Veterinary Clinics of North... Dec 2023Platelet-rich plasma (PRP) is an orthobiologic therapy composed of platelets, leukocytes, red blood cells, and plasma proteins. PRP has been used for 20 years, but... (Review)
Review
Platelet-rich plasma (PRP) is an orthobiologic therapy composed of platelets, leukocytes, red blood cells, and plasma proteins. PRP has been used for 20 years, but progress determining efficacy has been slow. The definitions and classification of PRP are reviewed, and the use of PRP for tendon, ligament, and joint disease is discussed with a focus on findings of basic science and clinical studies, platelet activation, concurrent administration of nonsteroidal anti-inflammatory drugs, and treatment complications. Finally, the advantages of platelet lysates and freeze-dried platelets are discussed. The promising results of a PRP lysate optimized for antibiofilm and antimicrobial properties are introduced.
Topics: Animals; Horses; Horse Diseases; Blood Platelets; Platelet-Rich Plasma
PubMed: 37550126
DOI: 10.1016/j.cveq.2023.06.007 -
Journal of Crohn's & Colitis Nov 2023Our aims were to better understand the interplay of diet and gut microbiota in Crohn's disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus...
Gut Microbiome-Generated Phenylacetylglutamine from Dietary Protein is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Model Possibly via Platelet Activation.
OBJECTIVES
Our aims were to better understand the interplay of diet and gut microbiota in Crohn's disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus on phenylacetylglutamine [PAGln], a diet-derived meta-organismal prothrombotic metabolite.
DESIGN
We collected faecal and serum samples from a CD cohort [n = 136] and healthy controls [n = 126] prior to treatment, and quantified serum PAGln using LC-MS/MS. Diet was assessed using food-frequency questionnaires. Mice [C57BL/6] were fed high/low-protein diets and administered dextran sodium sulphate [DSS] to examine plasma PAGly, thrombosis potential, and colitis severity. PAGly or saline was administered to DSS-induced colitis mice, and colitis severity and colonic tissue gene expression were examined. P-selectin and CD40L expression were determined in human platelet-rich plasma [n = 5-6] after exposure to platelet agonists following PAGln priming. Bioinformatic analysis and bacterial culturing identified the main contributor of PAGln in CD.
RESULTS
PAGln, a meta-organismal prothrombotic metabolite, is associated with CD. Administration of PAGly exacerbated colitis in a mouse model and upregulated coagulation-related biological processes. Antiplatelet medicine, dipyridamole, attenuated PAGly-enhanced colitis susceptibility. PAGln enhanced platelet activation and CD40L expression in platelet-rich plasma ex vivo. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid [PAA]-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients.
CONCLUSION
Taken together, ppdc-carrying Proteobacteria-generated PAGln from dietary protein is associated with CD and exacerbates colitis possibly via platelet-induced coagulation and inflammation These results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD.
Topics: Humans; Animals; Mice; Crohn Disease; Gastrointestinal Microbiome; Dietary Proteins; CD40 Ligand; Chromatography, Liquid; Mice, Inbred C57BL; Tandem Mass Spectrometry; Colitis; Platelet Activation; Dextran Sulfate; Disease Models, Animal
PubMed: 37350766
DOI: 10.1093/ecco-jcc/jjad098 -
Pharmaceuticals (Basel, Switzerland) Aug 2023Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is... (Review)
Review
Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is established by solid evidence. PCSK9 inhibitors have proven to be a valuable and practical resource for lowering the LDL cholesterol of many patients in recent years. Their inhibitory effect on atherosclerosis progression seems to be driven not just by lipid metabolism modification but also by LDL-independent mechanisms. We review the effect of PCSK9 inhibitors on various mechanisms involving platelet activation, inflammation, endothelial dysfunction, and the resultant clot formation. The main effectors of PCSK9 activation of platelets are CD36 receptors, lipoprotein(a), oxidised LDL particles, tissue factor, and factor VIII. Many more molecules are under investigation, and this area of research is growing rapidly.
PubMed: 37765005
DOI: 10.3390/ph16091197 -
Frontiers in Immunology 2023Psoriasis is a chronic inflammatory skin disease with a prevalence of 0.14% to 1.99%. The underlying pathology is mainly driven by the abnormal immune responses... (Review)
Review
Psoriasis is a chronic inflammatory skin disease with a prevalence of 0.14% to 1.99%. The underlying pathology is mainly driven by the abnormal immune responses including activation of Th1, Th17, Th22 cells and secretion of cytokines. Patients with psoriasis are more likely to develop cardiovascular disease (CVD) which has been well recognized as a comorbidity of psoriasis. As mediators of hemostasis and thromboinflammation, platelets play an important part in CVD. However, less is known about their pathophysiological contribution to psoriasis and psoriasis-associated CVD. A comprehensive understanding of the role of platelet activation in psoriasis might pave the path for more accurate prediction of cardiovascular (CV) risk and provide new strategies for psoriasis management, which alleviates the increased CV burden associated with psoriasis. Here we review the available evidence about the biomarkers and mechanisms of platelet activation in psoriasis and the role of platelet activation in intriguing the common comorbidity, CVD. We further discussed the implications and efficacy of antiplatelet therapies in the treatment of psoriasis and prevention of psoriasis-associated CVD.
Topics: Humans; Cardiovascular Diseases; Inflammation; Thrombosis; Psoriasis; Comorbidity; Platelet Activation
PubMed: 37654493
DOI: 10.3389/fimmu.2023.1238647 -
European Heart Journal. Cardiovascular... Nov 2023Platelet activation and endothelial dysfunction contribute to adverse outcomes in patients with acute coronary syndromes (ACS). The goals of this study were to assess... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Platelet activation and endothelial dysfunction contribute to adverse outcomes in patients with acute coronary syndromes (ACS). The goals of this study were to assess the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on markers of platelet activation and endothelial dysfunction in ACS patients and the interaction among PCSK9, platelets, and endothelial cells (ECs) on left internal mammary artery (LIMA) vascular endothelium using specimens obtained during coronary artery bypass surgery (CABG).
METHODS AND RESULTS
Acute coronary syndromes patients enrolled in the Evolocumab in ACS trials were randomized to placebo or a single dose of 420 mg evolocumab within 24 h of hospitalization. Serum samples for analysis of platelet factor 4 (PF4) and P-selectin, markers of platelet activation, and von Willebrand factor (vWF), a marker of endothelial dysfunction, were obtained at baseline and 30 days. Additionally, LIMA segments obtained during CABG from patients who were and were not receiving evolocumab were immunostained with PCSK9; CD61, a platelet-specific marker; and CD31, an endothelial cell-specific marker. Forty-six participants were randomized to placebo or to evolocumab. Controlling for baseline levels, PF4 and vWF were significantly lower in the evolocumab, than in the placebo, group at 30 days. Immunostaining of LIMA specimens from twelve participants undergoing CABG revealed colocalization of PCSK9, CD61, and CD31 at the vascular endothelium. Administration of evolocumab was associated with decreased overlap of PCSK9, CD61, and CD31.
CONCLUSIONS
Proprotein Convertase Subtilisin/Kexin 9 inhibition decreases markers of platelet activation and endothelial dysfunction in ACS patients. PCSK9 is associated with platelets and vascular ECs in LIMA segments and PCSK9 inhibition decreases that interaction.
Topics: Humans; Proprotein Convertase 9; Acute Coronary Syndrome; Endothelial Cells; von Willebrand Factor; Cholesterol, LDL; Platelet Activation; Proprotein Convertases; Biomarkers; Subtilisins
PubMed: 37468450
DOI: 10.1093/ehjcvp/pvad051 -
Blood Nov 2023Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the...
Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12(S)-hydroxy-eicosatrienoic acid (12-HETrE), which is produced in platelets, was shown to limit platelet reactivity by activating the prostacyclin receptor. Here, we demonstrated the synthesis of a novel analog of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk of bleeding. Human platelet activation was assessed using aggregometry, flow cytometry, western blot analysis, total thrombus formation analysis system, microfluidic perfusion chamber, and thromboelastography. Hemostasis, thrombosis, and bleeding assays were performed in mice. CS585 was shown to potently target the prostacyclin receptor on the human platelet, resulting in a highly selective and effective mechanism for the prevention of platelet activation. Furthermore, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk of bleeding in the mouse model. Hence, CS585 represents a new validated target for the treatment of thrombotic diseases without the risk of bleeding or off-target activation observed with other prostaglandin receptor agonists.
Topics: Animals; Humans; Mice; Receptors, Epoprostenol; Oxylipins; Platelet Activation; Blood Platelets; Hemostasis; Thrombosis; Hemorrhage; Platelet Aggregation
PubMed: 37624927
DOI: 10.1182/blood.2023020622