Effects of ibrutinib treatment on murine platelet function during inflammation and in primary hemostasis

Lee, Robert H.; Piatt, Raymond; Conley, Pamela B.; Bergmeier, Wolfgang

doi:10.3324/haematol.2016.155978

Cited by 21 publications

(21 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The prolonged bleeding time was likely a reflection of the known effects of ibrutinib on platelet function. 13,18,20,21 Therefore, these results indicate that thrombocytopenia may occur in part because ibrutinib decreases the number of MKs by disrupting their differentiation from progenitor cells, even though ibrutinib also facilitates MK maturation (►Fig. 6K).…”

Section: Ibrutinib Induces Thrombocytopenia In Micementioning

confidence: 90%

“…[14][15][16] The bleeding tendency is thought to be mainly due to platelet dysfunction. [17][18][19] Recent studies have revealed that ibrutinib attenuates ITAM-mediated platelet activation 20 and causes off-target inhibition of integrin αIIbβ3 (glycoprotein GPIIb/IIIa, CD41/CD61) outside-in signaling, 13 glycoprotein VI (GPVI)-evoked signaling, 21 and Tec 19 ; these results partially explain the bleeding-related side effects of ibrutinib. Thrombocytopenia is a likely contributor to the increased risk of bleeding.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation

Huang

et al. 2020

Thromb Haemost

View full text Add to dashboard Cite

Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, has a favorable safety profile in patients with B cell-related malignancies. A primary adverse effect of ibrutinib is thrombocytopenia in the early stages of treatment, but platelet counts increase or recover as treatment continues. Currently, the effects of ibrutinib on megakaryopoiesis remain unclear. In this study, we investigated the mechanism by which ibrutinib induces thrombocytopenia using cord blood CD34+ hematopoietic stem cells (HSCs), a human megakaryoblastic cell line (SET-2), and C57BL/6 mice. We show that treatment with ibrutinib can suppress CD34+ HSC differentiation into megakaryocytes (MKs) and decrease the number of colony-forming unit-MKs (CFU-MKs). The ibrutinib-dependent inhibition of early megakaryopoiesis seems to mainly involve impaired proliferation of progenitor cells without induction of apoptosis. The effects of ibrutinib on late-stage megakaryopoiesis, in contrast to early-stage megakaryopoiesis, include enhanced MK differentiation, ploidy, and proplatelet formation in CD34+ HSC-derived MKs and SET-2 cells. We also demonstrated that MK adhesion and spreading, but not migration, were inhibited by ibrutinib. Furthermore, we revealed that integrin αIIbβ3 outside-in signaling in MKs was inhibited by ibrutinib. Consistent with previous clinical observations, in C57BL/6 mice treated with ibrutinib, platelet counts decreased by days 2 to 7 and recovered to normal levels by day 15. Together, these results reveal the pathogenesis of ibrutinib-induced transient thrombocytopenia. In conclusion, ibrutinib suppresses early megakaryopoiesis, as evidenced by inhibition of MK progenitor cell proliferation and CFU-MK formation. Ibrutinib enhances MK differentiation, ploidy, and proplatelet formation, while it impairs integrin αIIbβ3 outside-in signaling.

show abstract

Section: Ibrutinib Induces Thrombocytopenia In Micementioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation

Huang

et al. 2020

Thromb Haemost

View full text Add to dashboard Cite

show abstract

“…All flow cytometry experiments were performed using washed platelets or diluted whole blood collected into heparinised capillary tubes. Washed platelets were prepared as described previously [37]. In brief, centrifugation of diluted whole blood at 130 g for 4 minutes to obtain platelet rich plasma (PRP) followed by pelleting of platelets in the PRP in the presence of prostaglandin I2 (PGI 2 , Caymen Chemical, Michigan, USA).…”

Section: Methodsmentioning

confidence: 99%

STIM1 R304W causes muscle degeneration and impaired platelet activation in mice

et al. 2018

Self Cite

View full text Add to dashboard Cite

STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.

show abstract

“…In this respect, mice deficient for the adenosine diphosphate (ADP) receptor P2Y 12 , required for secondary platelet activation independent of Btk, 36,37 showed significantly increased bleeding time, platelet plug disruptions and re-bleeding as compared with WT mice in a saphenous vein laser injury model when treated with the Btk inhibitor ibrutinib. 38 To study redundancy of Btk and P2Y 12 signalling during Klebsiella infection, we treated PF4creBtk fl /Y mice and littermate controls with clopidogrel, a P2Y 12 receptor antagonist which inhibits secondary platelet aggregation and activation. 13,39 Clopidogrel did not impact on host defence and vascular integrity in littermate controls (►Fig.…”

Section: Btk and P2y 12 Signalling In Platelets Are Dispensable For Mmentioning

confidence: 99%

Platelet Btk is Required for Maintaining Lung Vascular Integrity during Murine Pneumococcal Pneumosepsis

et al. 2019

View full text Add to dashboard Cite

Platelet Bruton's tyrosine kinase (Btk) is an essential signalling protein for the collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type-lectin-like receptor-2, which are platelet receptors implicated in the maintenance of vascular integrity during inflammation. Moreover, platelets, platelet GPVI and Btk are important for host defence during murine bacterial pneumosepsis. The aim of this study was to determine the role of platelet Btk in vascular integrity and host defence during murine pneumosepsis caused by the common human pathogens Streptococcus pneumoniae and Klebsiella pneumoniae. Using the Cre-loxP system, male platelet-specific Btk-deficient mice (PF4creBtkfl/Y) were created. Similar to platelets from total Btk-deficient mice, platelets from PF4creBtkfl/Y mice showed abrogated aggregation and P-selectin expression when stimulated with the GPVI ligand cross-linked collagen-related peptide. Upon infection with S. pneumoniae, PF4creBtkfl/Y mice showed increased lung bleeding, but unimpaired anti-bacterial defence. During pneumosepsis evoked by K. pneumoniae, platelet Btk deficiency was not associated with lung bleeding and did not impact on host defence, even when platelet function was further compromised by blocking secondary platelet activation by the P2Y12 receptor antagonist clopidogrel. Together, these data indicate that, while platelet Btk is not important for anti-bacterial defence in pneumosepsis, its role in maintaining vascular integrity in the lung depends on the causative pathogen.

show abstract

Effects of ibrutinib treatment on murine platelet function during inflammation and in primary hemostasis

Cited by 21 publications

References 15 publications

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation

Ibrutinib Suppresses Early Megakaryopoiesis but Enhances Proplatelet Formation

STIM1 R304W causes muscle degeneration and impaired platelet activation in mice

Platelet Btk is Required for Maintaining Lung Vascular Integrity during Murine Pneumococcal Pneumosepsis

Contact Info

Product

Resources

About