Although their central role is to control bleeding and to induce thrombosis, platelets are important inflammatory and immune cells as well as modulators of angiogenesis. This review focuses on the ...different roles of platelets in hemostasis, thrombosis, inflammation, arteriosclerosis, angiogenesis, antimicrobial host defense and hematogenous tumor metastasis. Platelets are the central regulators of hemostasis. On their surface the important thrombin burst takes place. Platelets cause atherothrombotic vascular occlusions. However, they are probably involved in early stages of arteriosclerosis, e.g. extravasation of leukocytes at sites of vascular injury, formation of foam cells and proliferation of smooth muscle cells. These processes are triggered by secretion of proinflammatory substances and growth factors as well as by platelet-cell interactions via specific adhesive axes. During infections platelets kill pathogens through secretion of antimicrobial substances and extracellular traps or nets. Platelets facilitate the revascularisation of ischemic tissue and therefore even promote tumor growth.
The vasodilator‐stimulated phosphoprotein (VASP) is associated with actin filaments and focal adhesions, which form the interface between the cytoskeleton and the extracellular matrix. VASP is ...phosphorylated by both the cAMP‐ and cGMP‐dependent protein kinases in a variety of cells, including platelets and smooth muscle cells. Since both the cAMP and cGMP signalling cascades relax smooth muscle and inhibit platelet activation, it was speculated that VASP mediates these effects by modulating actin filament dynamics and integrin activation. To study the physiological relevance of VASP in these processes, we inactivated the VASP gene in mice. Adult VASP‐deficient mice had normal agonist‐induced contraction, and normal cAMP‐ and cGMP‐dependent relaxation of intestinal and vascular smooth muscle. In contrast, cAMP‐ and cGMP‐mediated inhibition of platelet aggregation was significantly reduced in the absence of VASP. Other cAMP‐ and cGMP‐dependent effects in platelets, such as inhibition of agonist‐induced increases in cytosolic calcium concentrations and granule secretion, were not dependent on the presence of VASP. Our data show that two different cyclic, nucleotide‐dependent mechanisms are operating during platelet activation: a VASP‐independent mechanism for inhibition of calcium mobilization and granule release and a VASP‐dependent mechanism for inhibition of platelet aggregation which may involve regulation of integrin function.
The role of the platelet glycoprotein (GP) Ib-V-IX receptor in thrombin activation of platelets has remained controversial although good evidence suggests that blocking this receptor affects platelet ...responses to this agonist. The mechanism of expression of procoagulant activity in response to platelet agonists is also still obscure. Here, the binding site for thrombin on GPIb is shown to have a key role in the exposure of negatively charged phospholipids on the platelet surface and thrombin generation, in response to thrombin, which also requires protease-activated receptor-1, GPIIb-IIIa, and platelet-platelet contact. Von Willebrand factor binding to GPIb is not essential to initiate development of platelet procoagulant activity. Inhibition of fibrinogen binding to GPIIb-IIIa also failed to block platelet procoagulant activity. Both heparin and low molecular weight heparin block thrombin-induced platelet procoagulant activity, which may account for part of their clinical efficacy. This study demonstrates a new, critical role for platelet GPIb in hemostasis, showing that platelet activation and coagulation are tightly interwoven, which may have implications for alternative therapies for thrombotic diseases.
Alpha defensins, key players in the innate immune system, accumulate in airway secretions of patients with various chronic inflammatory lung disorders. Activated platelets secret a wide range of ...biologically active substances capable of inducing or augmenting airway inflammatory responses. The interaction between alpha-defensins and platelets was examined.
Activation of platelets by NHP-1 or NHP-2 was assessed by flowcytometry. We analyzed among other things, CD62 expression as a marker of alpha-granule secretion, CD63 expression as a marker of dense body secretion, and binding of fibrinogen, thrombospondin-1 and several coagulation factors to the platelet surface. In addition platelet surface expression of CD40L, a protein belonging to the TNF family, that stimulates dendritic cells, B cells and endothelium cells, was measured and soluble CD40L was quantified by Elisa.
The used alpha defensins induced strong platelet activation in a dose and time dependent manner. 10μM of NHP-1 or NHP-2 induced platelet stimulation comparable to 1U/ml of the strong agonist thrombin. Platelets bound fibrinogen and thrombospondin-1, secreted the contents of their granules, bound coagulation factors and even built microparticles. NHP-1 and NHP-2 induced CD40L expression on the platelet surface and soluble CD40L was found in the platelet supernatant when platelets were activated.
Platelets are underappreciated for their contributions to host defense and inflammatory processes. This is the first description that peptides of the innate immune system activate platelets. This new discovered mechanism might be at least in part, responsible for the formation of thrombi in connection with inflammatory processes.
Zusammenfassung
Neben ihrer Funktion als Steuerzellen von Hämostase bzw. Thrombose sind Thrombozyten wichtige Entzündungszellen, Abwehrzellen und Modulatoren der Angiogenese. Dieser Übersichtsartikel ...fasst die verschiedenen Rollen der Thrombozyten bei Blutstillung, Thrombose, Entzündung, Arterioklerose, Angiogenese, Infektabwehr und hämatogener Tumormetastasierung zusammen. Thrombozyten sind die Steuerzellen der Hämostase. Auf ihrer Oberfläche findet die Vermehrung von Thrombin statt. Thrombozyten verursachen atherothrombotische Gefäßverschlüsse, sind aber auch schon in der frühen Phase der Arteriosklerose an der Auswanderung von Leukozyten in das entzündete Gewebe, an der Schaumzellbildung und Proliferation glatter Muskelzellen beteiligt, indem sie proinflammatorische Substanzen und Wachstumsfaktoren sezernieren und über spezifische Adhäsionsachsen interagieren. Bei Infekten wehren Thrombozyten Pathogene durch die Sekretion antimikrobieller Substanzen und durch Bildung von Fangnetzen ab. Thrombozyten fördern die Revaskularisierung von ischämischem Gewebe, aber unterstützen damit auch das Tumorwachstum.
Aggretin, a potent platelet activator, was isolated from Calloselasma rhodostoma venom, and 30-amino acid N-terminal sequences of both subunits were determined. Aggretin belongs to the heterodimeric ...snake C-type lectin family and is thought to activate platelets by binding to platelet glycoprotein alpha(2)beta(1). We now show that binding to glycoprotein (GP) Ib is also required. Aggretin-induced platelet activation was inhibited by a monoclonal antibody to GPIb as well as by antibodies to alpha(2)beta(1). Binding of both of these platelet receptors to aggretin was confirmed by affinity chromatography. No binding of other major platelet membrane glycoproteins, in particular GPVI, to aggretin was detected. Aggretin also activates platelets from Fc receptor gamma chain (Fcgamma)-deficient mice to a greater extent than those from normal control mice, showing that it does not use the GPVI/Fcgamma pathway. Platelets from Fcgamma-deficient mice expressed fibrinogen receptors normally in response to collagen, although they did not aggregate, indicating that these platelets may partly compensate via other receptors including alpha(2)beta(1) or GPIb for the lack of the Fcgamma pathway. Signaling by aggretin involves a dose-dependent lag phase followed by rapid tyrosine phosphorylation of a number of proteins. Among these are p72(SYK), p125(FAK), and PLCgamma2, whereas, in comparison with collagen and convulxin, the Fcgamma subunit neither is phosphorylated nor coprecipitates with p72(SYK). This supports an independent, GPIb- and integrin-based pathway for activation of p72(SYK) not involving the Fcgamma receptor.
Aggretin, a potent platelet activator, was isolated from Calloselasma rhodostoma venom, and 30-amino acid N-terminal sequences of both subunits were determined. Aggretin belongs to the heterodimeric ...snake C-type lectin family and is thought to activate platelets by binding to platelet glycoprotein alpha sub(2) beta sub(1). We now show that binding to glycoprotein (GP) Ib is also required. Aggretin-induced platelet activation was inhibited by a monoclonal antibody to GPIb as well as by antibodies to alpha sub(2) beta sub(1). Binding of both of these platelet receptors to aggretin was confirmed by affinity chromatography. No binding of other major platelet membrane glycoproteins, in particular GPVI, to aggretin was detected. Aggretin also activates platelets from Fc receptor gamma chain (Fc gamma )-deficient mice to a greater extent than those from normal control mice, showing that it does not use the GPVI/Fc gamma pathway. Platelets from Fc gamma -deficient mice expressed fibrinogen receptors normally in response to collagen, although they did not aggregate, indicating that these platelets may partly compensate via other receptors including alpha sub(2) beta sub(1) or GPIb for the lack of the Fc gamma pathway. Signaling by aggretin involves a dose-dependent lag phase followed by rapid tyrosine phosphorylation of a number of proteins. Among these are p72 super(SYK), p125 super(FAK), and PLC gamma 2, whereas, in comparison with collagen and convulxin, the Fc gamma subunit neither is phosphorylated nor coprecipitates with p72 super(SYK). This supports an independent, GPIb- and integrin-based pathway for activation of p72 super(SYK) not involving the Fc gamma receptor.
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