Platelet-Derived Inhibitors of Platelet Activation

When blood vessels are damaged, circulating platelets come into contact with activating stimuli that trigger aggregation and enable them to form a haemostatic plug. This process is subject to both positive and negative feedback to ensure that platelets respond appropriately to damage and do not form thrombi that totally occlude the vessel. Dysregulation of negative feedback mechanisms is believed to contribute to the increased risk of thrombosis associated with some diseases. Despite the association with thrombosis, platelet derived negative regulators of platelet activation are relatively poorly understood in comparison to mediators of platelet activation. However, it is increasingly apparent that the mechanisms by which platelets restrain activation are diverse and of equal complexity to those that mediate positive signalling. Some regulators, such as RASA3 and JAM-A, act as gatekeepers that must be deactivated for platelet activation to occur. In contrast, regulators that contain ITIMs, such as PECAM-1, are activated following stimulation and mediate negative regulation via phosphatases that restrain activation. Wnt3a and ESAM are thought to directly limit plateletplatelet adhesion by blocking activation of the fibrinogen receptor, integrin αIIbβ3. The various isoforms of PKC expressed by platelets provide a diverse and complex array of inhibitory effects including receptor desensitisation. Many platelet derived inhibitors have been identified but not fully characterised and so questions remain regarding the mechanisms that underlie their effects on platelet activity following their activation, inhibition or genetic disruption. In this chapter the current understanding and recent developments in the field of platelet-derived inhibitors of platelet activation will be discussed

Erratum: Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib (Blood Advances (2017) 1: 26 (2610-2623) DOI: 10.1182/bloodadvances.2017011999)

In "Acknowledgments" on page 2621 of the 12 December 2017 issue, funding from British Heart Foundation grant RG/15/2/31224 was not mentioned. The error has been corrected in the published article

Differential Proteoglycan Expression in Atherosclerosis Alters Platelet Adhesion and Activation

\ua9 2024 by the authors.Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In this study, the impact of differential plaque composition on platelet function and thrombus formation was investigated. Platelet adhesion, activation and thrombus formation under different shear stress conditions were assessed in response to individual proteoglycans and composites representing different plaque phenotypes. The results demonstrated that all the proteoglycans tested mediated platelet adhesion but not platelet activation, and the extent of adhesion observed was significantly lower than that observed with type I and type III collagens. Thrombus formation upon the rupture and erosion ECM composites was significantly reduced (p < 0.05) compared to relevant collagen alone, indicating that proteoglycans negatively regulate platelet collagen responses. This was supported by results demonstrating that the addition of soluble biglycan or decorin to whole blood markedly reduced thrombus formation on type I collagen (p < 0.05). Interestingly, thrombus formation upon the erosion composite displayed aspirin sensitivity, whereas the rupture composite was intensive to aspirin, having implications for current antiplatelet therapy regimes. In conclusion, differential platelet responses and antiplatelet efficacy are observed on ECM composites phenotypic of plaque rupture and erosion. Proteoglycans inhibit thrombus formation and may offer a novel plaque-specific approach to limit arterial thrombosis

Characterisation of urinary WFDC12 in small nocturnal basal primates, mouse lemurs (Microcebus spp.)

Mouse lemurs are basal primates that rely on chemo- and acoustic signalling for social interactions in their dispersed social systems. We examined the urinary protein content of two mouse lemurs species, within and outside the breeding season, to assess candidates used in species discrimination, reproductive or competitive communication. Urine from Microcebus murinus and Microcebus lehilahytsara contain a predominant 10 kDa protein, expressed in both species by some, but not all, males during the breeding season, but at very low levels by females. Mass spectrometry of the intact proteins confirmed the protein mass and revealed a 30 Da mass difference between proteins from the two species. Tandem mass spectrometry after digestion with three proteases and sequencing de novo defined the complete protein sequence and located an Ala/Thr difference between the two species that explained the 30 Da mass difference. The protein (mature form: 87 amino acids) is an atypical member of the whey acidic protein family (WFDC12). Seasonal excretion of this protein, species difference and male-specific expression during the breeding season suggest that it may have a function in intra- and/or intersexual chemical signalling in the context of reproduction, and could be a cue for sexual selection and species recognition

Protein kinase Cε and protein kinase Cθ double-deficient mice have a bleeding diathesis.

In comparison to the classical isoforms of protein kinase C (PKC), the novel isoforms are thought to play minor or inhibitory roles in the regulation of platelet activation and thrombosis.To measure the levels of PKCθ and PKCε and to investigate the phenotype of mice deficient in both novel PKC isoforms.Tail bleeding and platelet activation assays were monitored in mice and platelets from mice deficient in both PKCθ and PKCε.PKCε plays a minor role in supporting aggregation and secretion following stimulation of the collagen receptor GPVI in mouse platelets but has no apparent role in spreading on fibrinogen. PKCθ, in contrast, plays a minor role in supporting adhesion and filopodial generation on fibrinogen but has no apparent role in aggregation and secretion induced by GPVI despite being expressed at over 10 times the level of PKCε. Platelets deficient in both novel isoforms have a similar pattern of aggregation downstream of GPVI and spreading on fibrinogen as the single null mutants. Strikingly, a marked reduction in aggregation on collagen under arteriolar shear conditions is observed in blood from the double but not single-deficient mice along with a significant increase in tail bleeding.These results reveal a greater than additive role for PKCθ and PKCε in supporting platelet activation under shear conditions and demonstrate that, in combination, the two novel PKCs support platelet activation

Comparison of the solophenyl-red polarization method and the immunohistochemical analysis for collagen type III

In the present study, we have compared the staining pattern of the Solophenyl-Red 3 BL-method for the visualization of collagen type III with the immunohistochemical staining in serial sections from 7 skin wounds (wound age 3 days up to 4 weeks) to elucidate the specifity of the histochemical staining method. Large amounts of collagen type III were clearly detectable in the investigated wounds using the immunohistochemical technique. In the sections stained with Solophenyl-Red, however, only 3 out of 7 skin lesions showed a significant positive red staining at the wound margin or in the granulation tissue, while the adjacent normal connective tissue revealed a typical intensive staining. Using polarization microscopy no characteristic bright green fibrils, as reported for collagen type 111, could be seen in the wound areas without positive Solophenyl-Red staining. Since the localization of collagen type III detected by immunohistochemistry and the presumed distribution of this collagen type by the Solophenyl-Red method was not identical, the histochemical polarization method has to be regarded as non-specific for visualization of this collagen type

Recovery from Posttraumatic Stress Symptoms: A Qualitative Study of Attributions in Survivors of War

This study was funded by a grant from the European Commission, contract number INCO-CT-2004-50917

Characterisation of a small electrode HPGe detector

© 2019 Elsevier B.V. Small electrode HPGe detectors in an inverted coaxial geometry are increasingly in use in applications where both high efficiency and excellent energy resolution are required. The unusual electric field configuration of these detectors results in extremely long charge collection times compared to planar and coaxial devices. In this work we have characterised such a detector using gamma-ray coincidence measurements and optimised an electric field simulation to reproduce the positional variation of detector response. We show that, alongside accurate crystal geometry and applied electric potential, a temperature correction is crucial to correctly determining appropriate charge carrier mobility parameters. This work will help to guide the future development of HPGE detectors for applications including radioactive waste assay, radio-isotope dating, and fundamental nuclear physics

Primary care provider perceptions of intake transition records and shared care with outpatient cardiac rehabilitation programs

Abstract Background While it is recommended that records are kept between primary care providers (PCPs) and specialists during patient transitions from hospital to community care, this communication is not currently standardized. We aimed to assess the transmission of cardiac rehabilitation (CR) program intake transition records to PCPs and to explore PCPs' needs in communication with CR programs and for intake transition record content. Method 144 PCPs of consenting enrollees from 8 regional and urban Ontario CR programs participated in this cross-sectional study. Intake transition records were tracked from the CR program to the PCP's office. Sixty-six PCPs participated in structured telephone interviews. Results Sixty-eight (47.6%) PCPs received a CR intake transition record. Fifty-eight (87.9%) PCPs desired intake transition records, with most wanting it transmitted via fax (n = 52, 78.8%). On a 5-point Likert scale, PCPs strongly agreed that the CR transition record met their needs for providing patient care (4.32 ± 0.61), with 48 (76.2%) reporting that it improved their management of patients' cardiac risk. PCPs rated the following elements as most important to include in an intake transition record: clinical status (4.67 ± 0.64), exercise test results (4.61 ± 0.52), and the proposed patient care plan (4.59 ± 0.71). Conclusions Less than half of intake transition records are reaching PCPs, revealing a large gap in continuity of patient care. PCP responses should be used to develop an evidence-based intake transition record, and procedures should be implemented to ensure high-quality transitional care