Ibrutinib, but not zanubrutinib, induces platelet receptor shedding of GPIb-IX-V complex and integrin αIIbβ3 in mice and humans

Dobie, Gasim; Kuriri, Fahd A.; Omar, Musab M A; Alanazi, Fehaid; Gazwani, Ali M; Tang, Chloe Pek Sang; Sze, Daniel Man-Yuen; Handunnetti, Sasanka; Tam, Constantine S.; Jackson, Denise E.

doi:10.1182/bloodadvances.2019000640

Cited by 50 publications

(42 citation statements)

References 32 publications

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“…In contrast, another study comparing ibrutinib and zanubrutinib found large differences of their effects on platelets [ 87 ]. By using the same doses of ibrutinib and zanubrutinib to incubate PRP and washed platelets and to treat mice, the authors found that ibrutinib but not zanubrutinib induced platelet receptor shedding of GPIb and integrin αIIbβ3 in mice and humans.…”

Section: Btk Inhibitors (Btki)mentioning

confidence: 99%

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Hundelshausen

Siess

2021

Cancers

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Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi.

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Section: Btk Inhibitors (Btki)mentioning

confidence: 99%

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Hundelshausen

Siess

2021

Cancers

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“…A further set of signaling processes that can trigger receptor shedding includes activation of protein kinase C ( 97 , 110 ), p38 mitogen-activated protein kinase ( 108 ), and apoptosis ( 110 , 111 ). Recently, it was shown that the Bruton's tyrosine kinase (Btk) inhibitor ibrutinib induced a time- and dose-dependent shedding of the GPIb-IX complex by increasing ADAM17 activation ( 112 ). Platelets from leukemia patients treated with ibrutinib showed reduced expression of the GPIb-IX complex, and also in mice, ibrutinib treatment resulted in elevated levels of soluble GPIbα ( 112 ).…”

Section: Adam and Adamts Proteasesmentioning

confidence: 99%

“…Recently, it was shown that the Bruton's tyrosine kinase (Btk) inhibitor ibrutinib induced a time- and dose-dependent shedding of the GPIb-IX complex by increasing ADAM17 activation ( 112 ). Platelets from leukemia patients treated with ibrutinib showed reduced expression of the GPIb-IX complex, and also in mice, ibrutinib treatment resulted in elevated levels of soluble GPIbα ( 112 ).…”

Section: Adam and Adamts Proteasesmentioning

confidence: 99%

Platelet Membrane Receptor Proteolysis: Implications for Platelet Function

Heemskerk

Baaten

2021

Front. Cardiovasc. Med.

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The activities of adhesion and signaling receptors in platelets are controlled by several mechanisms. An important way of regulation is provided by proteolytic cleavage of several of these receptors, leading to either a gain or a loss of platelet function. The proteases involved are of different origins and types: (i) present as precursor in plasma, (ii) secreted into the plasma by activated platelets or other blood cells, or (iii) intracellularly activated and cleaving cytosolic receptor domains. We provide a comprehensive overview of the proteases acting on the platelet membrane. We describe how these are activated, which are their target proteins, and how their proteolytic activity modulates platelet functions. The review focuses on coagulation-related proteases, plasmin, matrix metalloproteinases, ADAM(TS) isoforms, cathepsins, caspases, and calpains. We also describe how the proteolytic activities are determined by different platelet populations in a thrombus and conversely how proteolysis contributes to the formation of such populations.

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“…Treatment with ibrutinib, but not zanubrutinib, leads to time and dose-dependent shedding of GP1b α and GPIX from the platelet surface by an ADAM17-dependent mechanism, reduced GP1b-IX complex formation and integrin α IIb β 3 surface expression, and decreased thrombus formation under arterial flow. 47 These effects may explain differences in bleeding mechanism between the two drugs, although major bleeding remains a concern with zanubrutinib. In distinction from acalabrutinib, zanubrutinib absorbance is not affected by co-administration with gastric acid-reducing agents, including proton-pump inhibitors.…”

Section: How Does Zanubrutinib Fit Into the Treatment Landscape Of CLmentioning

confidence: 99%

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia

Rhodes¹,

Mato²

2021

DDDT

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Ibrutinib, but not zanubrutinib, induces platelet receptor shedding of GPIb-IX-V complex and integrin αIIbβ3 in mice and humans

Abstract: Key Points Ibrutinib but not zanubrutinib induces shedding of GPIb-IX complex in an ADAM17-dependent manner; GPIX has not been shown previously. Ibrutinib, but not zanubrutinib, induces shedding of integrin αIIbβ3 by an unknown sheddase.

Cited by 50 publications

References 32 publications

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Platelet Membrane Receptor Proteolysis: Implications for Platelet Function

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia

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