-
Frontiers in Immunology 2022Chancre self-healing, a typical clinical phenomenon of primary syphilis, is essentially wound healing. The first response to a wound is constriction of the injured blood...
BACKGROUND
Chancre self-healing, a typical clinical phenomenon of primary syphilis, is essentially wound healing. The first response to a wound is constriction of the injured blood vessels and activation of platelets to form a fibrin clot. However, the role of in platelet activation and clot formation remains unclear.
OBJECTIVES
We aimed to elucidate the role of the outer membrane lipoprotein Tp0136 in human platelet activation and aggregation and explore the related mechanism.
METHODS
A series of experiments were performed to assess the effects of Tp0136 on human platelet activation and aggregation . The effect of Tp0136 on platelet receptors was studied by detecting PAR1 protein levels and studying related receptor sites. The involvement of the G/G signaling pathway downstream of PAR1 was explored.
RESULTS
Tp0136 significantly accelerated the formation of human platelet clots as well as platelet adhesion to and diffusion on fibrinogen to promote platelet aggregation. Tp0136 also potentiated P-selectin expression and PF4 release to promote platelet activation and downregulated PAR1 expression. The activation and aggregation induced by Tp0136 were reverted by the specific PAR1 antagonist RWJ56110 and the human PAR1 antibody. In addition, Tp0136 significantly enhanced G and G signaling activation, thereby triggering p38 phosphorylation and Akt-PI3K activation, increasing the release of intraplatelet Ca and attenuating the release of cytosolic cAMP. Furthermore, the specific PAR1 antagonist RWJ56110 significantly suppressed G and G signaling activation.
CONCLUSIONS
Our results showed that the Tp0136 protein stimulated human platelet activation and aggregation by downregulating PAR1 and triggered PAR1-dependent G and G pathway activation. These findings may contribute to our understanding of the self-healing of chancroid in early syphilis.
Topics: Humans; Lipoproteins; Platelet Activation; Platelet Aggregation; Receptor, PAR-1; Signal Transduction; Syphilis; Treponema pallidum
PubMed: 35296084
DOI: 10.3389/fimmu.2022.818151 -
European Heart Journal Jan 2010Clinical manifestations of atherothrombotic disease, such as acute coronary syndromes, cerebrovascular events, and peripheral arterial disease, are major causes of... (Review)
Review
Clinical manifestations of atherothrombotic disease, such as acute coronary syndromes, cerebrovascular events, and peripheral arterial disease, are major causes of mortality and morbidity worldwide. Platelet activation and aggregation are ultimately responsible for the progression and clinical presentations of atherothrombotic disease. The current standard of care, dual oral antiplatelet therapy with aspirin and the P2Y(12) adenosine diphosphate (ADP) receptor inhibitor clopidogrel, has been shown to improve outcomes in patients with atherothrombotic disease. However, aspirin and P2Y(12) inhibitors target the thromboxane A(2) and the ADP P2Y(12) platelet activation pathways and minimally affect other pathways, while agonists such as thrombin, considered to be the most potent platelet activator, continue to stimulate platelet activation and thrombosis. This may help explain why patients continue to experience recurrent ischaemic events despite receiving such therapy. Furthermore, aspirin and P2Y(12) receptor antagonists are associated with bleeding risk, as the pathways they inhibit are critical for haemostasis. The challenge remains to develop therapies that more effectively inhibit platelet activation without increasing bleeding complications. The inhibition of the protease-activated receptor-1 (PAR-1) for thrombin has been shown to inhibit thrombin-mediated platelet activation without increasing bleeding in pre-clinical models and small-scale clinical trials. PAR-1 inhibition in fact does not interfere with thrombin-dependent fibrin generation and coagulation, which are essential for haemostasis. Thus PAR-1 antagonism coupled with existing dual oral antiplatelet therapy may potentially offer more comprehensive platelet inhibition without the liability of increased bleeding.
Topics: Fibrinolytic Agents; Humans; Imines; Lactones; Platelet Activation; Platelet Aggregation Inhibitors; Pyridines; Receptor, PAR-1; Thrombosis
PubMed: 19948715
DOI: 10.1093/eurheartj/ehp504 -
Transfusion Medicine Reviews Oct 1998
Review
Topics: Blood Platelets; Humans; Platelet Activation; Platelet Function Tests; Platelet Transfusion
PubMed: 9798270
DOI: 10.1016/s0887-7963(98)80003-5 -
International Journal of Molecular... Apr 2024Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial... (Review)
Review
Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.
Topics: Humans; Thrombosis; Blood Platelets; Hemostasis; Platelet Activation; Animals; Platelet Adhesiveness; Platelet Aggregation
PubMed: 38732019
DOI: 10.3390/ijms25094800 -
International Journal of Molecular... Nov 2021Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic... (Review)
Review
Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic process regulated by different signaling networks. Therefore, there are now focused efforts to search for novel bioactive compounds which target receptors and pathways in the platelet activation process while preserving normal hemostatic function. The antiplatelet activity of numerous fruits and vegetables and their multiple mechanisms of action have recently been highlighted. In this review, we review the antiplatelet actions of bioactive compounds via key pathways (protein disulfide isomerase, mitogen-activated protein kinases, mitochondrial function, cyclic adenosine monophosphate, Akt, and shear stress-induced platelet aggregation) with no effects on bleeding time. Therefore, targeting these pathways might lead to the development of effective antiplatelet strategies that do not increase the risk of bleeding.
Topics: Animals; Blood Platelets; Hemorrhage; Hemostasis; Humans; Phytochemicals; Plaque, Atherosclerotic; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombosis
PubMed: 34830261
DOI: 10.3390/ijms222212380 -
American Journal of Physiology. Cell... Nov 2014Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the...
Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretion of platelets lacking functional sphingosine kinase 1 (sphk1(-/-)) and of wild-type platelets (sphk1(+/+)) were determined utilizing flow cytometry and chronolume luciferin assay. Cytosolic Ca(2+) activity ([Ca(2+)]i) and aggregation were measured using fura-2 fluorescence and aggregometry, respectively. In vitro platelet adhesion and thrombus formation were evaluated using a flow chamber with shear rates of 1,700 s(-1). Activation-dependent increase of [Ca(2+)]i, degranulation (release of alpha and dense granules), integrin αIIbβ3 activation, and aggregation were all significantly increased in sphk1(-/-) platelets compared with sphk1(+/+) platelets. Moreover, while platelet adhesion and thrombus formation under arterial shear rates were significantly augmented in Sphk1-deficient platelets, bleeding time and blood count were unaffected in sphk1(-/-) mice. In conclusion, sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation.
Topics: Animals; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Platelet Activation; Thrombosis
PubMed: 25231106
DOI: 10.1152/ajpcell.00029.2014 -
Anesthesiology Dec 2009
Topics: Humans; Milrinone; Perioperative Care; Phosphodiesterase Inhibitors; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors
PubMed: 19934858
DOI: 10.1097/ALN.0b013e3181c155ee -
Journal of Thrombosis and Haemostasis :... Feb 2011Traditionally viewed as major cellular components in hemostasis and thrombosis, the contribution of platelets to the progression of cancer is an emerging area of... (Review)
Review
Traditionally viewed as major cellular components in hemostasis and thrombosis, the contribution of platelets to the progression of cancer is an emerging area of research interest. Complex interactions between tumor cells and circulating platelets play an important role in cancer growth and dissemination, and a growing body of evidence supports a role for physiologic platelet receptors and platelet agonists in cancer metastases and angiogenesis. Platelets provide a procoagulant surface facilitating amplification of cancer-related coagulation, and can be recruited to shroud tumor cells, thereby shielding them from immune responses, and facilitate cancer growth and dissemination. Experimental blockade of key platelet receptors, such as GP1b/IX/V, GPIIbIIIa and GPVI, has been shown to attenuate metastases. Platelets are also recognized as dynamic reservoirs of proangiogenic and anti-angiogenic proteins that can be manipulated pharmacologically. A bidirectional relationship between platelets and tumors is also seen, with evidence of 'tumor conditioning' of platelets. The platelet as a reporter of malignancy and a targeted delivery system for anticancer therapy has also been proposed. The development of platelet inhibitors that influence malignancy progression and clinical testing of currently available antiplatelet drugs represents a promising area of targeted cancer therapy.
Topics: Blood Platelets; Disease Progression; Humans; Neoplasms; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors
PubMed: 21040448
DOI: 10.1111/j.1538-7836.2010.04131.x -
Middle East African Journal of... 2021The aim of the present study was to assess platelet activation by analyzing three platelet activation parameters in ocular Behçet's disease (BD): mean platelet volume...
PURPOSE
The aim of the present study was to assess platelet activation by analyzing three platelet activation parameters in ocular Behçet's disease (BD): mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT).
METHODS
Twenty-nine patients with active ocular BD (Group 1), 40 patients with inactive ocular BD (Group 2), and 40 healthy adult individuals serving as controls (Group 3) were evaluated. All of the individuals had been performed the complete ophthalmologic evaluation. The levels of MPV, PDW, and PCT were measured in each group.
RESULTS
The mean MPV level was 8.40 ± 0.97 in Group 1, 8.32 ± 1.04 in Group 2, and 7.77 ± 0.72 in Group 3. The mean PDW level was 15.12 ± 1.09 in Group 1, 14.97 ± 1.02 in Group 2, and 14.52 ± 0.82 in Group 3. The mean PCT level was 0.23 ± 0.07 in Group 1, 0.21 ± 0.04 in Group 2, and 0.18 ± 0.03 in Group 3. MPV, PDW, and PCT levels were significantly higher in ocular BD patients than controls ( < 0.05).
CONCLUSION
Platelet activation may affect vascular occlusion in ocular Behçet's patients with posterior segment involvement. This result may be important in evaluating ocular BD patients.
Topics: Adult; Behcet Syndrome; Humans; Mean Platelet Volume; Platelet Activation
PubMed: 35719287
DOI: 10.4103/meajo.MEAJO_324_19 -
The Biochemical Journal Mar 2015Rho GTPases are critical for platelet function. Although the roles of RhoA, Rac and Cdc42 are characterized, platelets express other Rho GTPases, whose activities are... (Review)
Review
Rho GTPases are critical for platelet function. Although the roles of RhoA, Rac and Cdc42 are characterized, platelets express other Rho GTPases, whose activities are less well understood. This review summarizes our understanding of the roles of platelet Rho GTPases and focuses particularly on the functions of Rif and RhoG. In human platelets, Rif interacts with cytoskeleton regulators including formins mDia1 and mDia3, whereas RhoG binds SNARE-complex proteins and cytoskeletal regulators ELMO and DOCK1. Knockout mouse studies suggest that Rif plays no critical functions in platelets, likely due to functional overlap with other Rho GTPases. In contrast, RhoG is essential for normal granule secretion downstream of the collagen receptor GPVI. The central defect in RhoG-/- platelets is reduced dense granule secretion, which impedes integrin activation and aggregation and limits platelet recruitment to growing thrombi under shear, translating into reduced thrombus formation in vivo. Potential avenues for future work on Rho GTPases in platelets are also highlighted, including identification of the key regulator for platelet filopodia formation and investigation of the role of the many Rho GTPase regulators in platelet function in both health and disease.
Topics: Animals; Blood Platelets; Humans; Platelet Activation; Platelet Aggregation; Signal Transduction; rho GTP-Binding Proteins
PubMed: 25748676
DOI: 10.1042/BJ20141404