Targeting platelet receptor function in thrombus formation: The risk of bleeding

Swieringa, Frauke; Kuijpers, Marijke J. E.; Heemskerk, Johan W. M.; Meijden, Paola E. J. van der

doi:10.1016/j.blre.2013.12.001

Cited by 44 publications

(51 citation statements)

References 167 publications

(203 reference statements)

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“…They have a plethora of membrane receptors, including receptors for thrombin, thromboxane, ADP, ATP, prostaglandins, von Willebrand factor, collagen, CLEC-2 ligand, fibrinogen, and laminin. Platelets rapidly adhere via receptor-ligand interactions, become activated involving intracellular signaling, secrete contents from the dense and α-granules, and aggregate to form thrombi (Berndt et al, 2014;Swieringa et al, 2014b). Activated platelets also express surface phospholipids that promote localized coagulation (Versteeg et al, 2013) leading to thrombin generation and fibrin formation.…”

Section: Plateletsmentioning

confidence: 99%

Erythrocyte–Platelet Interaction in Uncomplicated Pregnancy

Swanepoel

Pretorius

2014

Microsc Microanal

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Maternal and fetal requirements during uncomplicated pregnancy are associated with changes in the hematopoietic system. Platelets and erythrocytes [red blood cells (RBCs)], and especially their membranes, are involved in coagulation, and their interactions may provide reasons for the changed hematopoietic system during uncomplicated pregnancy. We review literature regarding RBC and platelet membrane structure and interactions during hypercoagulability and hormonal changes. We then study interactions between RBCs and platelets in uncomplicated pregnancy, as their interactions may be one of the reasons for increased hypercoagulability during uncomplicated pregnancy. Scanning electron microscopy was used to study whole blood smears from 90 pregnant females in different phases of pregnancy. Pregnancy-specific interaction was seen between RBCs and platelets. Typically, one or more platelets interacted through platelet spreading and pseudopodia formation with a single RBC. However, multiple interactions with RBCs were also shown for a single platelet. Specific RBC-platelet interaction seen during uncomplicated pregnancy may be caused by increased estrogen and/or increased fibrinogen concentrations. This interaction may contribute to the hypercoagulable state associated with healthy and uncomplicated pregnancy and may also play a fundamental role in gestational thrombocytopenia.

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Section: Plateletsmentioning

confidence: 99%

Erythrocyte–Platelet Interaction in Uncomplicated Pregnancy

Swanepoel

Pretorius

2014

Microsc Microanal

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“…They all use a direct or indirect tyrosine kinase pathway for downstream signaling [9]. The contribution of each of receptor and its signal in thrombus formation or its bleeding risk, when absent, is under active study [10].…”

Section: Platelet Tyrosine Kinase Signalingmentioning

confidence: 99%

Receptor Tyrosine Kinases in Human Platelets: A Review of Expression, Function and Inhibition in Relation to the Risk of Bleeding or Thrombocytopenia from Phase I through Phase III Trials

Sater¹,

G²,

et al. 2017

JCPCR

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Tyrosine kinases (TKs) are divided into two main categories: receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases (NRTK). RTKs include approximately 21 families. Examples of RTKs are epidermal growth factor receptor (EGFR), plateletderived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Tyrosine Kinase Inhibitors (TKIs) are used to treat both hematologic and solid malignancies. They have variable side effects, one of which is a platelet type bleeding diathesis.

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“…The TxA2 receptor (TP-receptor) is a G-protein coupled receptor with seven transmembrane regions. Similar to ADP the platelet response is transient, but the TxA2 stimulation amplifies the response of other platelet agonists (38). The TxA2 molecule has a short half-life, approximately 30s, thereby limiting the impact that the molecule might have down-stream of the thrombus.…”

Section: Tp-receptormentioning

confidence: 99%

“…Thrombin cleaves both receptors at their N-terminal extracellular domains, thereby creating a new N-terminus, a tethered ligand, which activates the receptor, presumably by binding to the extracellular loop II, and thereby inducing a conformation shift (40,41). The receptors are coupled to the G-proteins G12/13a and Gqa which through downstream signalling via ROCK activation and via PLC, respectively, leads to shape change, granule secretion and integrin activation (38).…”

Section: Par1 and Par4mentioning

confidence: 99%

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Counting and Tracking: Development and Use of New Methods for Detailed Analysis of Thrombus Formation

Tunströmer¹

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Blood platelets are a part of the complex system called haemostasis aimed at ensuring our blood's continuous transport of oxygen and nutrients throughout the body. The transport is ensured by limiting blood loss due to vessel injury and in this process, the platelets form a plug in the damaged area, reinforced by the formation of fibrin. Similar mechanisms may cause thrombus formation, often triggered by atherosclerotic plaque rupture, causing vessel occlusion, embolism or ischemia, which may cause irreversible damage to the heart or the brain.Platelet research is crucial for improved prevention and treatment of thrombotic disorders. For such research, flow chambers are an interesting tool for studies of platelet adhesion, aggregation and thrombus formation under similar flow conditions as in the blood vessels, which is important, as the flow affects the mechanisms involved in both haemostasis and thrombosis. Flow chambers can be designed for specific purposes, such as for the study of haemostasis at specific flow conditions or to evaluate drugs or biomaterials. In this thesis, our aim has been to improve the usefulness of in-vitro flow chambers and develop a more robust and informative image analysis of such experiments.Initially, we introduced an internal control within each flow chamber experiment, thereby reducing the experimental variance caused by unknown factors. Furthermore, control and sample were thus exposed to identical experimental settings. By using platelet count as quantification of thrombus formation we introduce a method of analysis with increased or similar sensitivity to today's standards. The platelet count method facilitated comparison of results obtained in different types of flow chambers by an absolute scale of measurement, independent of user settings. The platelet count method was further developed so that additional parameters could be analysed, providing more information about each individual platelet and the overall thrombus. The parameters analysed included platelet stability, height, movement and contraction. The method was used to evaluate how the pharmacokinetics of a reversible (ticagrelor) and irreversible (prasugrel) platelet ADP-receptor inhibitor affected the overall thrombus formation. Especially, how a non-inhibited platelet fraction, formed between drug administrations of irreversible inhibitors, affected thrombus formation. In addition, we sought to understand the regulation of the thrombin receptor, PAR1, expression in cancer cells. We found the microRNA miR20b to be antioncogenic through its downregulation of PAR1 expression.This thesis contains numerous flow chamber experiments. However, for further use and full potential of the method increased standardisation is important. Our work regarding the quantification and analysis of flow chamber experiments will contribute to a more robust analysis and maybe even more important, provide new and detailed information on thrombus formation. Populärvetenskaplig sammanfattningVåra celler är i konstant behov av syre och...

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Targeting platelet receptor function in thrombus formation: The risk of bleeding

Cited by 44 publications

References 167 publications

Erythrocyte–Platelet Interaction in Uncomplicated Pregnancy

Erythrocyte–Platelet Interaction in Uncomplicated Pregnancy

Receptor Tyrosine Kinases in Human Platelets: A Review of Expression, Function and Inhibition in Relation to the Risk of Bleeding or Thrombocytopenia from Phase I through Phase III Trials

Counting and Tracking: Development and Use of New Methods for Detailed Analysis of Thrombus Formation

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