The relative importance of platelet integrins in hemostasis, thrombosis and beyond

Integrins are heterodimeric transmembrane receptors composed of α and β chains, with an N-terminal extracellular domain forming a globular head corresponding to the ligand binding site. Integrins regulate various cellular functions including adhesion, migration, proliferation, spreading and apoptosis. On platelets, integrins play a central role in adhesion and aggregation on subendothelial matrix proteins of the vascular wall, thereby ensuring hemostasis. Platelet integrins belong either to the β1 family (α2β1, α5β1 and α6β1) or to the β3 family (αIIbβ3 and αvβ3). On resting platelets, integrins can engage their ligands when the latter are immobilized but not in their soluble form. The effects of various agonists promote an inside-out signal in platelets, increasing the affinity of integrins for their ligands and conveying a modest signal reinforcing platelet activation, called outside-in signaling. This outside-in signal ensures platelet adhesion, shape change, granule secretion and aggregation. In this review, we examine the role of each platelet integrin in hemostatic plug formation, hemostasis and arterial thrombosis and also beyond these classical functions, notably in tumor metastasis and sepsis

Immobilized fibrinogen activates human platelets through GPVI

GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinogen activates platelets through GPVI. While mouse platelets fail to spread on fibrinogen, human-GPVI-transgenic mouse platelets show full spreading and increased Ca2+ signalling through the tyrosine kinase Syk. Direct binding of fibrinogen to human GPVI was shown by surface plasmon resonance and by increased adhesion of human GPVI-transfected Rbl-2H3 cells to fibrinogen relative to mock-transfected cells. Blockade of human GPVI with the Fab of the monoclonal antibody 9O12 impairs platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human GPVI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow

Imaging thrombosis with 99mTc-labeled RAM.1-antibody in vivo.

Platelets play a major role in thrombo-embolic diseases, notably by forming a thrombus that can ultimately occlude a vessel. This may provoke ischemic pathologies such as myocardial infarction, stroke or peripheral artery diseases, which represent the major causes of death worldwide. The aim of this study was to evaluate the specificity of radiolabeled Rat-Anti-Mouse antibody (RAM.1).We describe a method to detect platelets by using a RAM.1 coupled with the chelating agent hydrazinonicotinic acid (HYNIC) conjugated toWe demonstrated a quick and strong affinity of the radiolabeled RAM.1 for the platelet thrombus. Results clearly demonstrated the ability of this radioimmunoconjugate for detecting thrombi from 10 min post injection with an exceptional thrombi uptake. Using FeClThanks to the high sensitivity of SPECT, we provided evidence that [journal articleresearch support, non-u.s. gov't2018 062018 03 17importe

Number and mode of inheritance of QTL influencing backfat thickness on SSC2p in Sino-European pig pedigrees

<p>Abstract</p> <p>Background</p> <p>In the pig, multiple QTL associated with growth and fatness traits have been mapped to chromosome 2 (SSC2) and among these, at least one shows paternal expression due to the IGF2-intron3-G3072A substitution. Previously published results on the position and imprinting status of this QTL disagree between analyses from French and Dutch F2 crossbred pig populations obtained with the same breeds (Meishan crossed with Large White or Landrace).</p> <p>Methods</p> <p>To study the role of paternal and maternal alleles at the IGF2 locus and to test the hypothesis of a second QTL affecting backfat thickness on the short arm of SSC2 (SSC2p), a QTL mapping analysis was carried out on a combined pedigree including both the French and Dutch F2 populations, on the progeny of F1 males that were heterozygous (A/G) and homozygous (G/G) at the IGF2 locus. Simulations were performed to clarify the relations between the two QTL and to understand to what extent they can explain the discrepancies previously reported.</p> <p>Results</p> <p>The QTL analyses showed the segregation of at least two QTL on chromosome 2 in both pedigrees, i.e. the IGF2 locus and a second QTL segregating at least in the G/G F1 males and located between positions 30 and 51 cM. Statistical analyses highlighted that the maternally inherited allele at the IGF2 locus had a significant effect but simulation studies showed that this is probably a spurious effect due to the segregation of the second QTL.</p> <p>Conclusions</p> <p>Our results show that two QTL on SSC2p affect backfat thickness. Differences in the pedigree structures and in the number of heterozygous females at the IGF2 locus result in different imprinting statuses in the two pedigrees studied. The spurious effect observed when a maternally allele is present at the IGF2 locus, is in fact due to the presence of a second closely located QTL. This work confirms that pig chromosome 2 is a major region associated with fattening traits.</p

A double‐edged sword: The complex interplay between engineered nanoparticles and platelets

Abstract Nanoparticles (NP) play a crucial role in nanomedicine, serving as carriers for localized therapeutics to allow for precise drug delivery to specific disease sites and conditions. When injected systemically, NP can directly interact with various blood cell types, most critically with circulating platelets. Hence, the potential activation/inhibition of platelets following NP exposure must be evaluated a priori due to possible debilitating outcomes. In recent years, various studies have helped resolve the physicochemical parameters that influence platelet‐NP interactions, and either emphasize nanoparticles' therapeutic role such as to augment hemostasis or to inhibit thrombus formation, or conversely map their potential undesired side effects upon injection. In the present review, we discuss some of the main effects of several key NP types including polymeric, ceramic, silica, dendrimers and metallic NPs on platelets, with a focus on the physicochemical parameters that can dictate these effects and modulate the therapeutic potential of the NP. Despite the scientific and clinical significance of understanding Platelet‐NP interactions, there is a significant knowledge gap in the field and a critical need for further investigation. Moreover, improved guidelines and research methodologies need to be developed and implemented. Our outlook includes the use of biomimetic in vitro models to investigate these complex interactions under both healthy physiological and disease conditions

Platelet Integrins in Tumor Metastasis: Do They Represent a Therapeutic Target?

Platelets are small anucleated cell fragments that ensure the arrest of bleeding after a vessel wall injury. They are also involved in non-hemostatic function such as development, immunity, inflammation, and in the hematogeneous phase of metastasis. While the role of platelets in tumor metastasis has been recognized for 60 years, the molecular mechanism underlying this process remains largely unclear. Platelets physically and functionally interact with various tumor cells through surface receptors including integrins. Platelets express five integrins at their surface, namely α2β1, α5β1, α6β1, αvβ3, and αIIbβ3, which bind preferentially to collagen, fibronectin, laminin, vitronectin, and fibrinogen, respectively. The main role of platelet integrins is to ensure platelet adhesion and aggregation at sites of vascular injury. Two of these, α6β1 and αIIbβ3, were proposed to participate in platelet–tumor cell interaction and in tumor metastasis. It has also been reported that pharmacological agents targeting both integrins efficiently reduce experimental metastasis, suggesting that platelet integrins may represent new anti-metastatic targets. This review focuses on the role of platelet integrins in tumor metastasis and discusses whether these receptors may represent new potential targets for novel anti-metastatic approaches

Ultrasonic testing of the biomechanical properties of donation blood

Abstract Background. Donated blood is routinely preserved for about six weeks. After that, a considerable amount of unused blood is discarded for safety. We carried out sequential measurements of the ultrasonic parameters (Velocity of propagation of ultrasound, its attenuation, and relative nonlinearity coefficient B/A) for red blood cells (RBCs) bags in their physiological preserving conditions in the blood bank, in a given experimental setup, to investigate the gradual deteriorations in the biomechanical properties of RBCs. Materials and Methods. We discuss our primary findings, which indicate the applicability of ultrasound techniques as a quantitative quick, non-invasive routine check for the validity of sealed blood bags. The technique can be applied during and beyond the regular preservation period, thus enabling deciding for each bag to either further preserve or withdraw. Results and Discussion. Considerable increases in the velocity of propagation (ΔV = 966 m s−1) and ultrasound attenuation (Δα = 0.81 dB C−1m−1) were detected to take place during the preservation time. Likewise, the relative nonlinearity coefficient showed a generally rising trend during the preservation period (Δ(B/A) = 0.0129). At the same time, a distinctive feature characteristic of a specific blood group type is realized in all cases. Due to the complex stress-strain relations and their reflection on the hydrodynamics and flow rate of non-Newtonian fluids, the increased viscosity of long-preserved blood may justify the known post-transfusion flow complications.</jats:p

A macrofluidic model to investigate the intrinsic thrombogenicity of clinically used stents and develop less thrombogenic stents

Microfluidic blood flow models have been instrumental to study the functions of blood platelets in hemostasis and arterial thrombosis. However, they are not suited to investigate the interactions of platelets with the foreign surfaces of medical devices such as stents, mainly because of the dimensions and geometry of the microfluidic channels. Indeed, the channels of microfluidic chips are usually rectangular and rarely exceed 50 to 100 μm in height, impairing the insertion of clinically used stents. To fill this gap, we have developed an original macrofluidic flow system, which precisely reproduces the size and geometry of human vessels and therefore represents a biomimetic perfectly suited to insert a clinical stent and study its interplay with blood cells. The system is a circular closed loop incorporating a macrofluidic flow chamber made of silicone elastomer, which can mimic the exact dimensions of any human vessel, including the coronary, carotid or femoral artery. These flow chambers allow the perfect insertion of stents as they are implanted in patients. Perfusion of whole blood anticoagulated with hirudin through the device at relevant flow rates allows one to observe the specific accumulation of fluorescently labeled platelets on the stent surface using video-microscopy. Scanning electron microscopy revealed the formation of very large thrombi composed of tightly packed activated platelets on the stents