The nuts and bolts of the platelet release reaction

Joshi, Smita; Whiteheart, Sidney W.

doi:10.1080/09537104.2016.1240768

Cited by 57 publications

(53 citation statements)

References 112 publications

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“…They initiate inflammation by releasing a heterogeneous mix of protein molecules that include, transforming growth factor beta (TGF-β), P-selectin, CD40L and RANTES[171–173,121]. These molecules are an assortment of cytokines and adhesion molecules that directly bind or activate or elicit homing responses for monocytes, neutrophils and even T-lymphocytes as chemoattractants to the endothelium, inhibit apoptotic signals and promotes extravasation into affected sites [169,121,142,144].…”

Section: Platelet Mediated Thrombogenesis Inflammatory and Resolutimentioning

confidence: 99%

Platelet “first responders” in wound response, cancer, and metastasis

Menter

Kopetz

Hawk

et al. 2017

Cancer Metastasis Rev

145

115

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Platelets serve as “First Responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation and wound biology that leads to sterilization, tissue repair and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation and metastasis. This process, along with the hypercoagulable states associated with malignancy is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “First Responder” role of platelets during diverse physiologic stresses provides a useful therapeutic target that deserves further exploration.

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Section: Platelet Mediated Thrombogenesis Inflammatory and Resolutimentioning

confidence: 99%

Platelet “first responders” in wound response, cancer, and metastasis

Menter

Kopetz

Hawk

et al. 2017

Cancer Metastasis Rev

145

115

View full text Add to dashboard Cite

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“…Platelets contain Soluble N -ethylmaleimide Sensitive Fusion Protein Attachment Protein Receptor (SNARE) proteins, which drive membrane fusion and cargo exocytosis [6]. They are known to mediate inter-compartmental trafficking in most cells [67], but no such role has been established in platelets.…”

Section: Endocytic Routes In Plateletsmentioning

confidence: 99%

“…Dense granules contain small molecules important for recruiting platelets and augmenting coagulation. α-Granules contain polypeptides that modulate everything from adhesion to angiogenesis and inflammation [6]. Despite our knowledge of granules, the functions of these other “organelles” are relatively ill-defined in platelets.…”

Section: Introductionmentioning

confidence: 99%

The ins and outs of endocytic trafficking in platelet functions

Banerjee

Whiteheart

2017

Current Opinion in Hematology

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Purpose of review While platelet endocytosis has been recognized in granule cargo loading and the trafficking of several platelet surface receptors, its acute physiological relevance is poorly understood as is its mechanism. This review discusses the current understanding of platelet endocytosis and its implications for platelet function. Recent findings Recent studies are beginning to identify and define the proteins that mediate platelet endocytosis. These studies have shown that platelets contain different endosomal compartments and may use multiple endocytic routes to take in circulating molecules and surface proteins. The studies have also shown that platelet endocytosis is involved in several aspects of platelet function such as signaling, spreading, as well as granule cargo loading. Summary Mechanistic studies of platelet endocytosis have shown it to be not only involved in granule cargo loading but also in various other platelet functions important for hemostasis and beyond.

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“…Platelet secretion is an important and early event in platelet activation,48 and is known to be triggered by TXA 2 . Thus, we next determined whether the TPR vaccine would exert inhibitory effects on platelet secretion.…”

Section: Resultsmentioning

confidence: 99%

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Alshbool

Karim

Espinosa

et al. 2018

JAHA

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BackgroundDespite the well‐established role for the thromboxane A2 receptor (TPR) in the development of thrombotic disorders, none of the antagonists developed to date has been approved for clinical use. To this end, we have previously shown that an antibody targeted against TPR's ligand‐binding domain inhibits platelet activation and thrombus formation, without exerting any effects on hemostasis. Thus, the goal of the present studies is to design a novel TPR‐based vaccine, demonstrate its ability to trigger an immune response, and characterize its antiplatelet and antithrombotic activity.Methods and ResultsWe used a mouse keyhole limpet hemocyanin/peptide‐based vaccination approach rationalized over the TPR ligand‐binding domain (ie, the C‐terminus of the second extracellular loop). The biological activity of this vaccine was assessed in the context of platelets and thrombotic diseases, and using a host of in vitro and in vivo platelet function experiments. Our results revealed that the TPR C‐terminus of the second extracellular loop vaccine, in mice: (1) triggered an immune response, which resulted in the development of a C‐terminus of the second extracellular loop antibody; (2) did not affect expression of major platelet integrins (eg, glycoprotein IIb‐IIIa); (3) selectively inhibited TPR‐mediated platelet aggregation, platelet‐leukocyte aggregation, integrin glycoprotein IIb‐IIIa activation, as well as dense and α granule release; (4) significantly prolonged thrombus formation; and (5) did so without impairing physiological hemostasis.ConclusionsCollectively, our findings shed light on TPR's structural biological features, and demonstrate that the C‐terminus of the second extracellular loop domain may define a new therapeutic target and a TPR vaccine‐based approach that should have therapeutic applications.

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The nuts and bolts of the platelet release reaction

Cited by 57 publications

References 112 publications

Platelet “first responders” in wound response, cancer, and metastasis

Platelet “first responders” in wound response, cancer, and metastasis

The ins and outs of endocytic trafficking in platelet functions

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

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The nuts and bolts of the platelet release reaction

Cited by 57 publications

References 112 publications

Platelet “first responders” in wound response, cancer, and metastasis

Platelet “first responders” in wound response, cancer, and metastasis

The ins and outs of endocytic trafficking in platelet functions

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

Contact Info

Product

Resources

About

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis