Cultural and co-designed principles for developing a Maori kaumatua housing village to address health and social wellbeing.

BACKGROUND: The current study is a case study of a Maori (Indigenous people of New Zealand) organisation and their developmental processes in creating a kaumatua (older people) housing village for health and social wellbeing. This study identifies how a set of established co-design and culturally-centred principles were enacted when creating and developing the village. METHOD: A mixed-method concurrent design was used in creating the case with interviews (n = 4), focus groups (N = 4 with 16 total participants) and survey questionnaires (n = 56) involving kaumatua and organisation members. RESULTS: Survey results illustrate that suitable and affordable housing are associated with self-rated health, loneliness, and life satisfaction. The primary purpose of the housing village was to enable kaumatua to be connected to the marae (community meeting house) as part of a larger vision of developing intergenerational housing around the marae to enhance wellbeing. Further, key themes around visioning, collaborative team and funding, leadership, fit-for-purpose design, and tenancy management were grounded in cultural elements using te ao Maori (Maori worldview). CONCLUSION: This case study illustrates several co-design and culturally-centred principles from a previously developed toolkit that supported the project. This case study demonstrates how one community enacted these principles to provide the ground for developing a housing project that meets the health and social wellbeing of kaumatua.

Tuakana-teina peer education programme to help Maori elders enhance wellbeing and social connectedness.

BACKGROUND: There are significant inequities between Maori (Indigenous people) and non-Maori in ageing outcomes. This study used a strengths-based approach based on the key cultural concept of mana motuhake (autonomy and self-actualisation) to develop a tuakana-teina (literally older sibling-younger sibling) peer education programme to assist kaumatua (elders) in addressing health and social needs. The purpose of this study was to test the impact on those receiving the programme. Three aims identify the impact on outcomes, resources received and the cost effectiveness of the programme. METHODS: Five Kaupapa Maori (research and services guided by Maori worldviews) iwi (tribe) and community providers implemented the project using a partnership approach. Tuakana (peer educators) had up to six conversations each with up to six teina (peer learners) and shared information related to social and health services. A pre- and post-test, clustered staggered design was the research design. Participants completed a baseline and post-programme assessment of health and mana motuhake measures consistent with Maori worldviews. Open-ended questions on the assessments, five focus groups, and four individual interviews were used for qualitative evaluation. FINDINGS: A total of 113 kaumatua were recruited, and 86 completed the programme. The analysis revealed improvements in health-related quality of life, needing more help with daily tasks, life satisfaction, paying bills and housing problems. Qualitative results supported impacts of the programme on mana motuhake and hauora (holistic health) through providing intangible and tangible resources. Cost-effectiveness analysis showed that the intervention is cost effective, with a cost per QALY of less than the conventional threshold of three times GDP per capita. CONCLUSIONS: A culturally-resonant, strengths-based programme developed through a participatory approach can significantly improve health and social outcomes in a cost-effective way. TRIAL REGISTRY: Clinical trial registry: Trial registration: (ACTRN12620000316909). Prospectively registered 06/03/2020, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379302&isClinicalTrial=False .

Enhancing health outcomes for Maori elders through an intergenerational cultural exchange and physical activity programme: a cross-sectional baseline study.

Background: The study offers baseline data for a strengths-based approach emphasizing intergenerational cultural knowledge exchange and physical activity developed through a partnership with kaumatua (Maori elders) and kaumatua service providers. The study aims to identify the baseline characteristics, along with correlates of five key outcomes. Methods: The study design is a cross-sectional survey. A total of 75 kaumatua from six providers completed two physical functioning tests and a survey that included dependent variables based in a holistic model of health: health-related quality of life (HRQOL), self-rated health, spirituality, life satisfaction, and loneliness. Results: The findings indicate that there was good reliability and moderate scores on most variables. Specific correlates included the following: (a) HRQOL: emotional support (ß = 0.31), and frequent interaction with a co-participant (ß = 0.25); (b) self-rated health: frequency of moderate exercise (ß = 0.32) and sense of purpose (ß = 0.27); (c) spirituality: sense of purpose (ß = 0.46), not needing additional help with daily tasks (ß = 0.28), and level of confidence with cultural practices (ß = 0.20); (d) life satisfaction: sense of purpose (ß = 0.57), frequency of interaction with a co-participant (ß = -0.30), emotional support (ß = 0.25), and quality of relationship with a co-participant (ß = 0.16); and (e) lower loneliness: emotional support (ß = 0.27), enjoyment interacting with a co-participant (ß = 0.25), sense of purpose (ß = 0.24), not needing additional help with daily tasks (ß = 0.28), and frequency of moderate exercise (ß = 0.18). Conclusion: This study provides the baseline scores and correlates of important social and health outcomes for the He Huarahi Tautoko (Avenue of Support) programme, a strengths-based approach for enhancing cultural connection and physical activity.

Pim Kinases: Important Regulators of Cardiovascular Disease.

Pim Kinases; Pim-1, Pim-2, and Pim-3, are a family of constitutively active serine/threonine kinases, widely associated with cell survival, proliferation, and migration. Historically considered to be functionally redundant, independent roles for the individual isoforms have been described. Whilst most established for their role in cancer progression, there is increasing evidence for wider pathological roles of Pim kinases within the context of cardiovascular disease, including inflammation, thrombosis, and cardiac injury. The Pim kinase isoforms have widespread expression in cardiovascular tissues, including the heart, coronary artery, aorta, and blood, and have been demonstrated to be upregulated in several co-morbidities/risk factors for cardiovascular disease. Pim kinase inhibition may thus be a desirable therapeutic for a multi-targeted approach to treat cardiovascular disease and some of the associated risk factors. In this review, we discuss what is known about Pim kinase expression and activity in cells of the cardiovascular system, identify areas where the role of Pim kinase has yet to be fully explored and characterised and review the suitability of targeting Pim kinase for the prevention and treatment of cardiovascular events in high-risk individuals.

Adaptation and implementation processes of a culture-centred community-based peer-education programme for older Maori.

BACKGROUND: Health inequities experienced by kaumatua (older Maori) in Aotearoa, New Zealand, are well documented. Examples of translating and adapting research into practice that identifies ways to help address such inequities are less evident. The study used the He Pikinga Waiora (HPW) implementation framework and the Consolidated Framework for Implementation Research (CFIR) to explore promising co-design and implementation practices in translating an evidence-based peer-education programme for older Maori to new communities. METHODS: The study was grounded in an Indigenous methodology (Kaupapa Maori) and a participatory research approach. Data were collected from research documentation, community meeting and briefing notes, and interviews with community researchers. RESULTS: The data analysis resulted in several key promising practices: Kaumatua mana motuhake (kaumatua independence and autonomy) where community researchers centred the needs of kaumatua in co-designing the programme with researchers; Whanaungatanga (relationships and connectedness) which illustrated how community researchers' existing and emerging relationships with kaumatua, research partners, and each other facilitated the implementation process; and Whakaoti Rapanga (problem-solving) which centred on the joint problem-solving undertaken by the community and university researchers, particularly around safety issues. These results illustrate content, process, and relationship issues associated with implementation effectiveness. CONCLUSIONS: This study showed that relational factors are central to the co-design process and also offers an example of a braided river, or He Awa Whiria, approach to implementation. The study offers a valuable case study in how to translate, adapt, and implement a research-based health programme to Indigenous community settings through co-design processes. TRIAL REGISTRATION: The project was registered on 6 March 2020 with the Australia New Zealand Clinical Trial Registry: ACTRN12620000316909 . Prospectively registered.

Codesigning a Culture-Centered Age-Friendly Community for Maori Kaumatua: Cultural Principles and Practices.

OBJECTIVES: This study examined a Maori (Indigenous people of Aotearoa New Zealand) age-friendly housing development. Two Maori community groups worked with multiple stakeholders to codesign a culture-centered, kaumatua (older adults) urban housing community. The purpose was to identify codesign and culture-centered principles in the development. METHODS: Kaupapa Maori (Maori-centered) and participatory research methodologies guided the culture-centered research design. Data collection included 27 interviews with 19 residents and 12 organizational stakeholders; three focus groups with residents' families, service providers, and nonresident kaumatua (n = 16); and project documents. Data analysis used the framework method. RESULTS: Three codesign process themes emerged: (a) Kaumatua-centered vision; (b) realizing the vision; and (c) living the shared vision. DISCUSSION: Accounting for cultural practices in codesigning age-friendly and culture-centered housing for and with Indigenous older adults helps meet their cultural, social, health, and economic needs. The research offers a practical pathway to developing age-friendly housing environments for Maori kaumatua, their communities, wider society, and other Indigenous people.

Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function.

Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as signal transducer and activator of transcription, STAT, inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by platelet agonists. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.

Identifying the Facilitators and Barriers in Disseminating and Adopting a Health Intervention Developed by a Community-Academic Partnership.

The literature regarding implementation science of evidence-based health interventions in Maori communities is limited, and there is a push for new and innovative delivery methods of health interventions in New Zealand. The purpose of the study was to identify the facilitators and barriers in implementing a health intervention designed by others and was framed by the Consolidated Framework for Implementation Research (CFIR). This study explored general perceptions of the implementation process and also included a case study, the Kaumatua Mana Motuhake (older people's autonomy and self-actualization) project; a codesigned peer education intervention for older Maori. Semistructured interviews (N = 17) were conducted via face-to-face, phone, or Zoom with health and social service professionals with experience working with Maori communities. Thematic analysis was used to analyze the data. The facilitators included community engagement, program structure, program adaptability and creators' experience. The barriers consisted of funding access, funding constraints and organizational constraints. The findings support key elements within the CFIR, highlighting the importance of community engagement and adaptability. Additionally, this study identified nuanced aspects of funding and resources that constrain organisations in employing health interventions designed by others.

Enhancing Well-Being and Social Connectedness for Maori Elders Through a Peer Education (Tuakana-Teina) Programme: A Cross-Sectional Baseline Study.

Background: Maori kaumatua (elders) face stark health and social inequities compared to non-Maori New Zealanders. The tuakana-teina (older sibling-younger sibling) peer education programme is a strengths-based approach to enhance well-being and social connectedness. The purpose of this study is to present the baseline data from this programme and identify correlates of well-being outcomes. Method: Participants included 128 kaumatua who completed a self-report survey about health-related quality of life, spirituality, social connection and loneliness, life satisfaction, cultural identity and connection, elder abuse, health service utilisation and demographics. Findings: Multiple regression models illustrated the following correlates of outcomes: (a) self-rated health: needing more help with daily tasks (ß = -0.36) and housing problems (ß = -0.17); (b) health-related quality of life: needing more help with daily tasks (ß = -0.31), housing problems (ß = -0.21), and perceived autonomy (ß = 0.19); (c) spiritual well-being: understanding of tikanga (cultural protocols) (ß = 0.32) and perceived autonomy (ß = 0.23); (d) life satisfaction: social support (ß = 0.23), sense of purpose (ß = 0.23), cultural identity (ß = 0.24), trouble paying bills (ß = -0.16), and housing problems (ß = -0.16); (e) loneliness: elder abuse (ß = 0.27), social support (ß = -0.21), and missing pleasure of being with whanau (extended family) (ß = 0.19). Conclusions: Key correlates for outcomes centred on social support, housing problems, cultural connection and perceived autonomy. These correlates are largely addressed through the programme where tuakana/peer educators provide support and links to social and health services to teina/peer recipients in need. This study illustrates needs and challenges for kaumatua, whilst the larger programme represents a strengths-based and culturally-centred approach to address health issues related to ageing in an Indigenous population.

Low-dose Btk inhibitors selectively block platelet activation by CLEC-2.

Inhibitors of the tyrosine kinase Btk have been proposed as novel antiplatelet agents. In this study we show that low concentrations of the Btk inhibitor ibrutinib block CLEC-2-mediated activation and tyrosine phosphorylation including Syk and PLCγ2 in human platelets. Activation is also blocked in patients with X-linked agammaglobulinemia (XLA) caused by a deficiency or absence of Btk. In contrast, the response to GPVI is delayed in the presence of low concentrations of ibrutinib or in patients with XLA, and tyrosine phosphorylation of Syk is preserved. A similar set of results is seen with the second-generation inhibitor, acalabrutinib. The differential effect of Btk inhibition in CLEC-2 relative to GPVI signalling is explained by the positive feedback role involving Btk itself, as well as ADP and thromboxane A2 mediated activation of P2Y12 and TP receptors, respectively. This feedback role is not seen in mouse platelets and, consistent with this, CLEC-2-mediated activation is blocked by high but not by low concentrations of ibrutinib. Nevertheless, thrombosis was absent in 8 out of 13 mice treated with ibrutinib. These results show that Btk inhibitors selectively block activation of human platelets by CLEC-2 relative to GPVI suggesting that they can be used at 'low dose' in patients to target CLEC-2 in thrombo-inflammatory disease.

Zafirlukast is a broad-spectrum thiol isomerase inhibitor that inhibits thrombosis without altering bleeding times.

BACKGROUND AND PURPOSE: Multiple members of the thiol isomerase (TI) family of enzymes are present in and released by platelets. Inhibition of these enzymes results in diminished platelet responses, aggregation, adhesion and thrombus formation. Recently, the therapeutic potential of TI inhibition has been recognised and drug-development technologies were used to identify selective small molecule inhibitors. To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin, is known to be nephrotoxic, which prohibits its systemic therapeutic usage. EXPERIMENTAL APPROACH: We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. A total of 3,641 compounds were screened for inhibitory effects on the redox activity of ERp5, protein disulphide isomerase (PDI), ERp57, ERp72 and thioredoxin in an insulin turbidity assay. Of the lead compounds identified, zafirlukast was selected for further investigation. KEY RESULTS: When applied to platelets, zafirlukast diminished platelet responses in vitro. Zafirlukast was antithrombotic in murine models of thrombosis but did not impair responses in a model of haemostasis. Since TIs are known to modulate adhesion receptor function, we explored the effects of zafirlukast on cell migration. This was inhibited independently of cysteinyl LT receptor expression and was associated with modulation of cell-surface free thiol levels consistent with alterations in redox activity on the cell surface. CONCLUSION AND IMPLICATIONS: We identify zafirlukast to be a novel, potent, broad-spectrum TI inhibitor, with wide-ranging effects on platelet function, thrombosis and integrin-mediated cell migration. Zafirlukast is antithrombotic but does not cause bleeding.

Maori Becoming Peer Educators in Later Life: Impacts on Identity, Well-being, and Social Connectedness.

OBJECTIVE: The aim of this study was to examine ways that older Maori (New Zealand's Indigenous people) enhanced their ability to be peer educators and how this role impacted on their sense of purpose and well-being in later life. METHOD: Kaupapa Maori and community-based participatory research principles guided the peer intervention involving 26 Maori kaumatua (older people 55 years and older) as peer educators (tuakana) for 121 other kaumatua (teina) facing transitions in later life. Each pair held up to 3 conversations; independent coders rated tuakana communication skills. We used mixed methods in a pre- and post-test, clustered staggered design. Participants completed baseline and post-intervention assessments of health and well-being consistent with Maori worldviews. 5 focus groups involving 22 teina and 1 with 5 tuakana were held. RESULTS: Tuakana communication skills were rated as high by teina and independent coders. Qualitative analysis supported the importance of Maori communication processes for the role. Further, three measures increased significantly from the baseline to the final period for tuakana accounting for about 15% of the variance in these variables: sense of purpose (p = .07), self-rated health (p = .05), and health-related quality of life (p = .04). The qualitative analysis supported the benefits of the peer educator role for older Maori including enhanced sense of identity, well-being, and social connectedness. DISCUSSION: The results demonstrated that kaumatua had strong communication in the peer educator role and that the intervention has positive impacts for them. The study contributes to peer intervention research that may help to improve experiences ofIndigenous and other older people.

Kaumatua Mana Motuhake Poi: a study protocol for enhancing wellbeing, social connectedness and cultural identity for Maori elders.

BACKGROUND: The Aotearoa New Zealand population is ageing accompanied by health and social challenges including significant inequities that exist between Maori and non-Maori around poor ageing and health. Although historically kaumatua (elder Maori) faced a dominant society that failed to realise their full potential as they age, Maori culture has remained steadfast in upholding elders as cultural/community anchors. Yet, many of today's kaumatua have experienced 'cultural dissonance' as the result of a hegemonic dominant culture subjugating an Indigenous culture, leading to generations of Indigenous peoples compelled or forced to dissociate with their culture. The present research project, Kaumatua Mana Motuhake Poi (KMMP) comprises two interrelated projects that foreground dimensions of wellbeing within a holistic Te Ao Maori (Maori epistemology) view of wellbeing. Project 1 involves a tuakana-teina/peer educator model approach focused on increasing service access and utilisation to support kaumatua with the greatest health and social needs. Project 2 focuses on physical activity and cultural knowledge exchange (including te reo Maori--Maori language) through intergenerational models of learning. METHODS: Both projects have a consistent research design and common set of methods that coalesce around the emphasis on kaupapa kaumatua; research projects led by kaumatua and kaumatua providers that advance better life outcomes for kaumatua and their communities. The research design for each project is a mixed-methods, pre-test and two post-test, staggered design with 2-3 providers receiving the approach first and then 2-3 receiving it on a delayed basis. A pre-test (baseline) of all participants will be completed. The approach will then be implemented with the first providers. There will then be a follow-up data collection for all participants (post-test 1). The second providers will then implement the approach, which will be followed by a final data collection for all participants (post-test 2). DISCUSSION: Two specific outcomes are anticipated from this research; firstly, it is hoped that the research methodology provides a framework for how government agencies, researchers and relevant sector stakeholders can work with Maori communities. Secondly, the two individual projects will each produce a tangible approach that, it is anticipated, will be cost effective in enhancing kaumatua hauora and mana motuhake. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ( ACTRN12620000316909 ). Registered 6 March 2020.

Kaumatua Mana Motuhake: peer education intervention to help Maori elders during later-stage life transitions.

BACKGROUND: Aotearoa/New Zealand has a population that is ageing and there are challenges to health and social outcomes related to related to key life transitions (e.g., retirement, change in health conditions, loss of spouse). Further, there are significant inequities between Maori (Indigenous people) and non-Maori in ageing outcomes. The purpose of this study was to test the impacts and cost effectiveness of a tuakana/teina (peer education) intervention on kaumatua (elders) receiving the intervention. This study was framed by a strengths-based approach based on the key cultural concept of mana motuhake (autonomy and self-actualisation). METHODS: This study was grounded in principles of Kaupapa Maori and community-based participatory research to bring together a diverse group of stakeholders to co-develop and co-evaluate the intervention. The intervention had tuakana (peer educators) having conversations with up to six teina (recipients) and providing information related to health and social services. The research design was a pre- and post-test, clustered staggered design. Participants completed a baseline assessment of health and mana motuhake measures consistent with Maori worldviews along with two follow-up assessments (one after the first intervention group completed its activities and a second after the second intervention group completed its activities). Additionally, five focus groups and open-ended questions on the assessments were used to provide qualitative evaluation. FINDINGS: A total of 180 kaumatua were recruited to the intervention with 121 completing it. The analysis revealed improvements over time in the expected direction on most of the variables. However, only three of the variables had statistically significant intervention effects: received support, tribal identity, and trouble paying bills. Qualitative results supported impacts of the intervention on mana motuhake, social connectedness, and tangible/information support related to services. Cost-effectiveness analysis showed that the intervention is cost effective, with a cost per QALY of less than the conventional threshold of three times gross domestic product per capita. CONCLUSIONS: The findings support the relevancy and importance of kaumatua knowledge to create a strengths-based approach to improve health and social outcomes. This study demonstrates that a contextually based and culturally safe age-friendly environments can facilitate engagement and participation by kaumatua for kaumatua. TRIAL REGISTRY: Australia New Zealand Clinical Trial Registry (ACTRN12617001396314); Date Registered: 3 October 2017 (retrospectively registered); https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373733&isClinicalTrial=False.

Correlates of Health-Related Quality of Life for Maori Elders Involved in a Peer Education Intervention.

The purpose of this study was to identify social determinant and communication correlates of health-related quality of life for kaumatua (Maori elders) in New Zealand. A total of 209 kaumatua completed a self-report survey of self-rated health, physical/mental quality of life, spirituality, and a series of questions about social determinants (e.g., factors related to income) and communication variables (e.g., loneliness, social support, cultural identity, and perceived burden/benefit). The survey was baseline data for a peer education intervention to help kaumatua work through life transitions in older age. The main findings of this study were that social determinants, particularly difficulty paying bills, accounted for a small amount of variance in physical/mental quality of life and self-rated health. Further, the communication correlates of loneliness, perceived burden, and desired support accounted for about three times as much variance in these two outcomes all with negative associations. Strength of tribal identity, importance of whanau (extended family), and knowledge of tikanga (customs and protocols) accounted for a moderate amount variance in spirituality with positive associations. These findings have important theoretical and practical implications for positive aging.

Kaumatua Mana Motuhake: A study protocol for a peer education intervention to help Maori elders work through later-stage life transitions.

BACKGROUND: The Aotearoa/New Zealand population is ageing and numerous studies demonstrate with this phenomenon comes increases in non-communicable diseases, injuries and healthcare costs among other issues. Further, significant inequities exist between Maori (Indigenous peoples of Aotearoa/New Zealand) and non-Maori around poor ageing and health. Most research addressing these issues is deficit oriented; however, the current research project takes a strengths-based approach that highlights the potential of kaumatua (elders) by asserting mana motuhake (autonomy, identity and self-actualisation). We believe that the esteem of elders in Maori culture signals transformative potential. Specifically, this project utilises a 'tuakana-teina' (older sibling/younger sibling) peer-educator model, where kaumatua work with other kaumatua in relation to health and wellbeing. The objectives of the project are (a) to develop the capacity of kaumatua as peer educators, whilst having positive impacts on their sense of purpose, health and wellbeing; and (b) to enhance the social and health outcomes for kaumatua receiving the intervention. METHODS: The research is grounded in principles of Kaupapa Maori and community-based participatory research, and brings together an Indigenous community of kaumatua, community health researchers, and academic researchers working with two advisory boards. The project intervention involves an orientation programme for tuakana peer educators for other kaumatua (teina). The research design is a pre- and post-test, clustered staggered design. All participants will complete a baseline assessment of health and wellbeing consistent with Maori worldviews (i.e., holistic model). The tuakana and teina participants will be divided into two groups with the first group completing the intervention during the first half of the project and the second group during the second half of the project. All participants will complete post-test assessments following both interventions allowing comparison of the two groups along with repeated measures over time. DISCUSSION: The findings will provide an evidence base for the importance and relevancy of kaumatua knowledge to create contextually based and culturally safe age-friendly environments that facilitate engagement and participation by kaumatua for kaumatua. If the model is effective, we will seek to facilitate the dissemination and scalability of the intervention. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ( ACTRN12617001396314 ); Date Registered: 3 October 2017 (retrospectively registered).

Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation mediated by glycoprotein VI.

Ibrutinib and acalabrutinib are irreversible inhibitors of Bruton tyrosine kinase used in the treatment of B-cell malignancies. They bind irreversibly to cysteine 481 of Bruton tyrosine kinase, blocking autophosphorylation on tyrosine 223 and phosphorylation of downstream substrates including phospholipase C-γ2. In the present study, we demonstrate that concentrations of ibrutinib and acalabrutinib that block Bruton tyrosine kinase activity, as shown by loss of phosphorylation at tyrosine 223 and phospholipase C-γ2, delay but do not block aggregation in response to a maximally-effective concentration of collagen-related peptide or collagen. In contrast, 10- to 20-fold higher concentrations of ibrutinib or acalabrutinib block platelet aggregation in response to glycoprotein VI agonists. Ex vivo studies on patients treated with ibrutinib, but not acalabrutinib, showed a reduction of platelet aggregation in response to collagen-related peptide indicating that the clinical dose of ibrutinib but not acalabrutinib is supramaximal for Bruton tyrosine kinase blockade. Unexpectedly, low concentrations of ibrutinib inhibited aggregation in response to collagen-related peptide in patients deficient in Bruton tyrosine kinase. The increased bleeding seen with ibrutinib over acalabrutinib is due to off-target actions of ibrutinib that occur because of unfavorable pharmacodynamics.

Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib.

The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII.