Acquired platelet antagonism: off-target antiplatelet effects of malignancy treatment with tyrosine kinase inhibitors

Platelets can contribute to tumor progression and metastasis. Cancer patients are at increased risk of thrombosis, and advanced stages of cancer are associated with thrombocytosis or increased platelet reactivity. Tyrosine kinase inhibitors (TKIs) are widely used as a targeted strategy for cancer treatment, with the aim of prolonging progression-free survival of the patients. Because of their broad kinase target spectrum, most TKIs inevitably have off-target effects. Platelets rely on tyrosine kinase activity for their activation. Frequently observed side effects are lowering of platelet count and inhibition of platelet functions, whether or not accompanied by an increased bleeding risk. In this review, we aim to give insights into: (i) 38 TKIs that are currently used for the treatment of different types of cancer, either on the market or in clinical trials; (ii) how distinct TKIs can inhibit activation mechanisms in platelets; and (iii) the clinical consequences of the antiplatelet effects of TKI treatment. For several TKIs, the knowledge on affinity for their targets does not align with the published effects on platelets and reported bleeding events. This review should raise awareness of the potential antiplatelet effects of several TKIs, which will be enhanced in the presence of antithrombotic drugs

Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques

Background: In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y(12) receptors. However, such models do not predict involvement of P2Y(12) in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y(12) in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. Methodology: Plaques in the carotid arteries from Apoe(-/-) mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y(12) blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. Principal Findings: Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y(12) blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y(12) reduced the thrombi and increased embolization events. These P2Y(12) effects were present at shear rates >500 s(-1), and they persisted in the presence of coagulation. P2Y(12)-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. Conclusions/Significance: Platelet P2Y(12) receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y(12) function is restricted to high shear flow conditions, and is preserved in the presence of coagulation

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

In this review, we presume that the process of thrombus formation, as assessed in whole blood flow studies and in experimental (murine) thrombosis studies, reflects the platelet responses in human haemostasis and thrombosis. Following this concept, we give an up-to-date overview of the main platelet receptors and signalling pathways that contribute to thrombus formation and are used as targets in (pre)clinical intervention studies to prevent cardiovascular disease. Discussed are receptors for thrombin, thromboxane, ADP, ATP, prostaglandins, von Willebrand factor, collagen, CLEC-2 ligand, fibrinogen and laminin. Sketched are the consequences of receptor deficiency or blockage for haemostasis and thrombosis in mouse and man. Recording of bleeding due to (congenital) platelet dysfunction or (acquired) antiplatelet treatment occurs according to different protocols, while common laboratory methods are used to determine platelet function

Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow

The importance of factor Xa generation in thrombus formation has not been studied extensively so far. Here, we used mice deficient in either factor VIII or factor IX to determine the role of platelet-stimulated tenase activity in the formation of platelet-fibrin thrombi on collagen. With tissue factor present, deficiency in factor VIII or IX markedly suppressed thrombus growth, fibrin formation and platelet procoagulant activity (phosphatidylserine exposure). In either case, residual fibrin formation was eliminated in the absence of tissue factor. Effects of factor deficiencies were antagonized by supplementation of the missing coagulation factor. In wild-type thrombi generated under flow, phosphatidylserine-exposing platelets bound (activated) factor IX and factor X, whereas factor VIII preferentially co-localized at sites of von Willebrand factor binding. Furthermore, proteolytic activity of the generated activated factor X and thrombin was confined to the sites of phosphatidylserine exposure. With blood from a hemophilia A or B patient, the formation of platelet-fibrin thrombi was greatly delayed and reduced, even in the presence of high concentrations of tissue factor. A direct activated factor X inhibitor, rivaroxaban, added to human blood, suppressed both thrombin and fibrin formation. Together, these data point to a potent enforcement loop in thrombus formation due to factor X activation, subsequent thrombin and fibrin generation, causing activated factor X-mediated stimulation of platelet phosphatidylserine exposure. This implies that the factor VIII/factor IX-dependent stimulation of platelet procoagulant activity is a limiting factor for fibrin formation under flow conditions, even at high tissue factor concentrations

Diabetes quality management in Dutch care groups and outpatient clinics:A cross-sectional study

BACKGROUND: In recent years, most Dutch general practitioners started working under the umbrella of diabetes care groups, responsible for the organisation and coordination of diabetes care. The quality management of these new organisations receives growing interest, although its association with quality of diabetes care is yet unclear. The best way to measure quality management is unknown and it has not yet been studied at the level of outpatient clinics or care groups. We aimed to assess quality management of type 2 diabetes care in care groups and outpatient clinics. RESULTS: Quality management was measured with online questionnaires, containing six domains (see below). They were divided into 28 subdomains, with 59 (care groups) and 57 (outpatient clinics) questions respectively. The mean score of the domains reflects the overall score (0-100%) of an organisation. Two quality managers of all Dutch care groups and outpatient clinics were invited to fill out the questionnaire. Sixty care groups (response rate 61.9%) showed a mean score of 59.6% (CI 57.1-62.1%). The average score in 52 outpatient clinics (response rate 50.0%) was 61.9% (CI 57.5-66.8%). Mean scores on the six domains for care groups and outpatient clinics respectively were: ‘organisation of care’ 71.9% (CI 68.8-74.9%), 76.8% (CI 72.8-80.7%); ‘multidisciplinary teamwork’ 67.1% (CI 62.4-71.9%), 71.5% (CI 65.3-77.8%); ‘patient centeredness’ 46.7% (CI 42.6-50.7%), 62.5% (CI 57.7-67.2%); ‘performance management’ 63.3% (CI 61.2-65.3%), 50.9% (CI 44.2-57.5%); ‘quality improvement policy’ 52.6% (CI 49.2-56.1%), 50.9% (CI 44.6-57.3%); and ‘management strategies’ 56.0% (CI 51.4-60.7%), 59.0% (CI 52.8-65.2%). On subdomains, care groups scored highest on ‘care program’ (83.3%) and ‘measured outcomes’ (98.3%) and lowest on ‘patient safety’ (15.1%) and ‘patient involvement’ (17.7%). Outpatient clinics scored high on the presence of a ‘diabetic foot team’ (81.6%) and the support in ‘self-management’ (81.0%) and low on ‘patient involvement’ (26.8%) and ‘inspection of medical file’ (28.0%). CONCLUSIONS: This nationwide assessment reveals that the level of quality management in diabetes care varies between several subdomains in both diabetes care groups and outpatient clinics

Actively coping with violation:Exploring upward dissent patterns in functional, dysfunctional, and deserted psychological contract end states

Recently, scholars have emphasized the importance of examining how employees cope with psychological contract violation and how the coping process contributes to psychological contract violation resolution and post-violation psychological contracts. Recent work points to the important role of problem-focused coping. Yet, to date, problem-focused coping strategies have not been conceptualized on a continuum from constructive to destructive strategies. Consequently, potential differences in the use of specific types of problem-focused coping strategies and the role these different strategies play in the violation resolution process has not been explored. In this study, we stress the importance of focusing on different types of problem-focused coping strategies. We explore how employee upward dissent strategies, conceptualized as different forms of problem-focused coping, contribute to violation resolution and post-violation psychological contracts. Two sources of data were used. In-depth interviews with supervisors of a Dutch car lease company provided 23 case descriptions of employee-supervisor interactions after a psychological contract violation. Moreover, a database with descriptions of Dutch court sentences provided eight case descriptions of employee-organization interactions following a perceived violation. Based on these data sources, we explored the pattern of upward dissent strategies employees used over time following a perceived violation. We distinguished between functional (thriving and reactivation), dysfunctional (impairment and dissolution) and deserted psychological contract end states and explored whether different dissent patterns over time differentially contributed to the dissent outcome (i.e., psychological contract end state). The results of our study showed that the use of problem-focused coping is not as straightforward as suggested by the post-violation model. While the post-violation model suggests that problem-focused coping will most likely contribute positively to violation resolution, we found that this also depends on the type of problem-focused coping strategy used. That is, more threatening forms of problem-focused coping (i.e., threatening resignation as a way to trigger one's manager/organization to resolve the violation) mainly contributed to dysfunctional and deserted PC end states. Yet, in some instances the use of these types of active coping strategies also contributed to functional violation resolution. These findings have important implications for the literature on upward dissent strategies and psychological contract violation repair

Reduced masticatory function is related to lower satellite cell numbers in masseter muscle

The physiology of masseter muscles is known to change in response to functional demands, but the effect on the satellite cell (SC) population is not known. In this study, the hypothesis is tested that a decreased functional demand of the masseter muscle causes a reduction of SCs. To this end, twelve 5-week-old male Sprague-Dawley rats were put on a soft diet (SD, n = 6) or a hard diet (HD, n = 6) and sacrificed after 14 days. Paraffin sections of the superficial masseter and the m. digastricus (control muscle) were stained with haematoxylin and eosin for tissue survey and with anti-myosin heavy chain (MHC) for slow and fast fibres. Frozen sections of both muscles were double-stained for collagen type IV and Pax7. Slow MHC fibres were equally distributed in the m. digastricus but only localized in a small area of the m. masseter. No differences between HD or SD for the m. digastricus were found. The m. masseter had more SCs per fibre in HD than in SD (0.093 ± 0.007 and 0.081 ± 0.008, respectively; P = 0.027). The m. masseter had more fibres per surface area than the m. digastricus in rats with an SD group (758.1 ± 101.6 and 568.4±85.6, P = 0.047) and a HD group (737.7 ± 32.6 and 592.2 ± 82.2; P = 0.007). The m. digastricus had more SCs per fibre than the m. masseter in the SD group (0.094 ± 0.01 and 0.081 ± 0.008; P = 0.039). These results suggest that reduced masseter muscle function is related to a lower number of SCs. Reduced muscle function might decrease microdamage and hence the requirement of SCs in the muscle fibre

Characterization of the fundamental properties of wireless CSMA multi-hop networks

A wireless multi-hop network consists of a group of decentralized and self-organized wireless devices that collaborate to complete their tasks in a distributed way. Data packets are forwarded collaboratively hop-by-hop from source nodes to their respective destination nodes with other nodes acting as intermediate relays. Existing and future applications in wireless multi-hop networks will greatly benefit from better understanding of the fundamental properties of such networks. In this thesis we explore two fundamental properties of distributed wireless CSMA multi-hop networks, connectivity and capacity. A network is connected if and only if there is at least one (multi-hop) path between any pair of nodes. We investigate the critical transmission power for asymptotic connectivity in large wireless CSMA multi-hop networks under the SINR model. The critical transmission power is the minimum transmission power each node needs to transmit to guarantee that the resulting network is connected aas. Both upper bound and lower bound of the critical transmission power are obtained analytically. The two bounds are tight and differ by a constant factor only. Next we shift focus to the capacity property. First, we develop a distributed routing algorithm where each node makes routing decisions based on local information only. This is compatible with the distributed nature of large wireless CSMA multi-hop networks. Second, we show that by carefully choosing controllable parameters of the CSMA protocols, together with the routing algorithm, a distributed CSMA network can achieve the order-optimal throughput scaling law. Scaling laws are only up to order and most network design choices have a significant effect on the constants preceding the order while not affecting the scaling law. Therefore we further to analyze the pre-constant by giving an upper and a lower bound of throughput. The tightness of the bounds is validated using simulations

GALEX, Optical and IR Light Curves of MQ Dra: UV Excesses at Low Accretion Rates

Ultraviolet light curves constructed from NUV and FUV detectors on GALEX reveal large amplitude variations during the orbital period of the Low Accretion Rate Polar MQ Dra (SDSSJ1553+55). This unexpected variation from a UV source is similar to that seen and discussed in the Polar EF Eri during its low state of accretion, even though the accretion rate in MQ Dra is an order of magnitude lower than even the low state of EF Eri. The similarity in phasing of the UV and optical light curves in MQ Dra imply a similar location for the source of light. We explore the possibilities of hot spots and cyclotron emission with simple models fit to the UV, optical and IR light curves of MQ Dra. To match the GALEX light curves with a single temperature circular hot spot requires different sizes of spots for the NUV and FUV, while a cyclotron model that can produce the optical harmonics with a magnetic field near 60 MG requires multipoles with fields > 200 MG to match the UV fluxes.Comment: accepted for ApJ; 15 pages, 7 tables, 8 fig

Nutritional Assessment in Inflammatory Bowel Disease (IBD)-Development of the Groningen IBD Nutritional Questionnaires (GINQ)

Diet plays a key role in the complex etiology and treatment of inflammatory bowel disease (IBD). Most existing nutritional assessment tools neglect intake of important foods consumed or omitted specifically by IBD patients or incorporate non-Western dietary habits, making the development of appropriate dietary guidelines for (Western) IBD patients difficult. Hence, we developed a food frequency questionnaire (FFQ), the Groningen IBD Nutritional Questionnaires (GINQ-FFQ); suitable to assess dietary intake in IBD patients. To develop the GINQ-FFQ, multiple steps were taken, including: identification of IBD specific foods, a literature search, and evaluation of current dietary assessment methods. Expert views were collected and in collaboration with Wageningen University, division of Human Nutrition and Health, this semi-quantitative FFQ was developed using standard methods to obtain a valid questionnaire. Next, the GINQ-FFQ was digitized into a secure web-based environment which also embeds additional nutritional and IBD related questions. The GINQ-FFQ is an online self-administered FFQ evaluating dietary intake, taking the previous month as a reference period. It consists of 121 questions on 218 food items. This paper describes the design process of the GINQ-FFQ which assesses dietary intake especially (but not exclusively) in IBD patients. Validation of the GINQ-FFQ is needed and planned in the near future.</p