498 Bruton’s tyrosine kinase (BTK) inhibitors impede platelet aggregation but not adhesion to collagen. Article Swipe

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Thomas Kartika , Lorena Buitrago , Jihong Li , Barry S. Coller ·

YOU? · · 2024 · Open Access · · DOI: https://doi.org/10.1017/cts.2024.422

OBJECTIVES/GOALS: The research objectives of this project are to elucidate the effects of Bruton’s tyrosine kinase inhibitors (BTKi) of varying target specificity on platelet function with regard to platelet aggregation, adhesion, spreading, and intracellular signaling as measured by kinase phosphorylation. METHODS/STUDY POPULATION: Blood from healthy volunteers was obtained and processed to obtain both washed platelets and platelet-rich plasma. The samples were then treated with one of the BTKi drugs or with vehicle (DMSO) at concentrations matching patient blood concentrations derived from clinical trials and pharmacokinetic studies. The incubated samples were then analyzed in an aggregometer using one of several agonists. Aggregation was stopped after five minutes with a perchloric acid-based lysis buffer. The samples were then analyzed by SDS-PAGE and immunoblotting to quantify BTK protein and BTK phosphorylation. Adhesion was assessed by incubating washed platelets treated with BTKi on microtiter wells coated with fibrinogen or collagen and quantifying adherent platelets by their endogenous acid phosphatase activity. RESULTS/ANTICIPATED RESULTS: We found that ibrutinib, zanubrutinib, and pirtobrutinib all completely inhibited collagen-induced platelet aggregation, whereas they did not inhibit aggregation induced by thrombin, ristocetin, arachidonic acid, or the PAR1 activator peptide SFLLRN (T6). Acalabrutinib inhibited collagen-induced platelet aggregation only at high concentrations (1-2 micromolar). At the lower concentration of 200 nanomolar, comparable to the concentration required for the other BTK inhibitors to completely inhibit platelet aggregation, acalabrutinib failed to inhibit aggregation but did inhibit auto-phosphorylation, indicating an impact on signaling. None of the BTKi drugs inhibited adhesion of platelets to collagen-coated surfaces. DISCUSSION/SIGNIFICANCE: Our data show the inhibitory effect of BTKi on collagen-induced platelet aggregation and signaling. However, it remains unclear whether the inhibition is due to an effect on BTK itself or other related kinases. Better insight into the mechanisms of platelet inhibition by BTKi may help guide the development of BTKi with a lower risk of hemorrhage.

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Bruton's tyrosine kinase Tyrosine kinase Platelet aggregation Platelet Platelet adhesion Platelet adhesiveness Adhesion Chemistry Tyrosine Cell biology Medicine Immunology Biochemistry Biology Signal transduction Organic chemistry

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Type: article
Language: en
Landing Page: https://doi.org/10.1017/cts.2024.422
PDF: https://www.cambridge.org/core/services/aop-cambridge-core/content/view/FF87457004379DF3913AF19E0BCD6EB2/S2059866124004229a.pdf/div-class-title-498-bruton-s-tyrosine-kinase-btk-inhibitors-impede-platelet-aggregation-but-not-adhesion-to-collagen-div.pdf
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DOI: https://doi.org/10.1017/cts.2024.422

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Title: 498 Bruton’s tyrosine kinase (BTK) inhibitors impede platelet aggregation but not adhesion to collagen.

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Language: en

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Publication year: 2024

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Publication date: 2024-04-01

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Authors: Thomas Kartika, Lorena Buitrago, Jihong Li, Barry S. Coller

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Landing page: https://doi.org/10.1017/cts.2024.422

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PDF URL: https://www.cambridge.org/core/services/aop-cambridge-core/content/view/FF87457004379DF3913AF19E0BCD6EB2/S2059866124004229a.pdf/div-class-title-498-bruton-s-tyrosine-kinase-btk-inhibitors-impede-platelet-aggregation-but-not-adhesion-to-collagen-div.pdf

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Concepts: Bruton's tyrosine kinase, Tyrosine kinase, Platelet aggregation, Platelet, Platelet adhesion, Platelet adhesiveness, Adhesion, Chemistry, Tyrosine, Cell biology, Medicine, Immunology, Biochemistry, Biology, Signal transduction, Organic chemistry

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abstract_inverted_index.into	285
abstract_inverted_index.only	195
abstract_inverted_index.risk	303
abstract_inverted_index.show	252
abstract_inverted_index.that	160
abstract_inverted_index.then	61, 90, 115
abstract_inverted_index.they	172
abstract_inverted_index.this	5
abstract_inverted_index.were	60, 89, 114
abstract_inverted_index.with	25, 63, 70, 106, 136, 142, 300
abstract_inverted_index.(T6).	189
abstract_inverted_index.Blood	42
abstract_inverted_index.acid,	182
abstract_inverted_index.after	103
abstract_inverted_index.blood	77
abstract_inverted_index.drugs	68, 241
abstract_inverted_index.found	159
abstract_inverted_index.guide	295
abstract_inverted_index.lower	203, 302
abstract_inverted_index.lysis	110
abstract_inverted_index.other	215, 280
abstract_inverted_index.their	151
abstract_inverted_index.using	95
abstract_inverted_index.wells	140
abstract_inverted_index.(BTKi)	17
abstract_inverted_index.(DMSO)	72
abstract_inverted_index.Better	283
abstract_inverted_index.SFLLRN	188
abstract_inverted_index.coated	141
abstract_inverted_index.effect	255, 275
abstract_inverted_index.failed	224
abstract_inverted_index.impact	234
abstract_inverted_index.itself	278
abstract_inverted_index.kinase	15, 38
abstract_inverted_index.obtain	51
abstract_inverted_index.regard	26
abstract_inverted_index.target	20
abstract_inverted_index.trials	82
abstract_inverted_index.washed	53, 133
abstract_inverted_index.buffer.	111
abstract_inverted_index.derived	79
abstract_inverted_index.effects	11
abstract_inverted_index.healthy	44
abstract_inverted_index.induced	177
abstract_inverted_index.inhibit	175, 220, 226, 230
abstract_inverted_index.insight	284
abstract_inverted_index.minutes	105
abstract_inverted_index.patient	76
abstract_inverted_index.peptide	187
abstract_inverted_index.plasma.	57
abstract_inverted_index.project	6
abstract_inverted_index.protein	124
abstract_inverted_index.related	281
abstract_inverted_index.remains	266
abstract_inverted_index.samples	59, 88, 113
abstract_inverted_index.several	98
abstract_inverted_index.stopped	102
abstract_inverted_index.treated	62, 135
abstract_inverted_index.unclear	267
abstract_inverted_index.varying	19
abstract_inverted_index.vehicle	71
abstract_inverted_index.whereas	171
abstract_inverted_index.whether	268
abstract_inverted_index.Adhesion	128
abstract_inverted_index.However,	264
abstract_inverted_index.RESULTS:	157
abstract_inverted_index.SDS-PAGE	118
abstract_inverted_index.adherent	148
abstract_inverted_index.adhesion	243
abstract_inverted_index.analyzed	91, 116
abstract_inverted_index.assessed	130
abstract_inverted_index.clinical	81
abstract_inverted_index.collagen	145
abstract_inverted_index.function	24
abstract_inverted_index.kinases.	282
abstract_inverted_index.matching	75
abstract_inverted_index.measured	36
abstract_inverted_index.obtained	47
abstract_inverted_index.platelet	23, 28, 169, 193, 221, 260, 289
abstract_inverted_index.quantify	122
abstract_inverted_index.required	212
abstract_inverted_index.research	2
abstract_inverted_index.studies.	85
abstract_inverted_index.tyrosine	14
abstract_inverted_index.activator	186
abstract_inverted_index.activity.	155
abstract_inverted_index.adhesion,	30
abstract_inverted_index.agonists.	99
abstract_inverted_index.elucidate	9
abstract_inverted_index.incubated	87
abstract_inverted_index.inhibited	167, 191, 242
abstract_inverted_index.platelets	54, 134, 149, 245
abstract_inverted_index.processed	49
abstract_inverted_index.signaling	34
abstract_inverted_index.surfaces.	248
abstract_inverted_index.thrombin,	179
abstract_inverted_index.Bruton’s	13
abstract_inverted_index.acid-based	109
abstract_inverted_index.comparable	208
abstract_inverted_index.completely	166, 219
abstract_inverted_index.endogenous	152
abstract_inverted_index.fibrinogen	143
abstract_inverted_index.ibrutinib,	161
abstract_inverted_index.incubating	132
abstract_inverted_index.indicating	232
abstract_inverted_index.inhibition	270, 290
abstract_inverted_index.inhibitors	16, 217
abstract_inverted_index.inhibitory	254
abstract_inverted_index.mechanisms	287
abstract_inverted_index.microtiter	139
abstract_inverted_index.nanomolar,	207
abstract_inverted_index.objectives	3
abstract_inverted_index.perchloric	108
abstract_inverted_index.signaling.	236, 263
abstract_inverted_index.spreading,	31
abstract_inverted_index.volunteers	45
abstract_inverted_index.Aggregation	100
abstract_inverted_index.POPULATION:	41
abstract_inverted_index.aggregation	176, 194, 227, 261
abstract_inverted_index.arachidonic	181
abstract_inverted_index.development	297
abstract_inverted_index.hemorrhage.	305
abstract_inverted_index.phosphatase	154
abstract_inverted_index.quantifying	147
abstract_inverted_index.ristocetin,	180
abstract_inverted_index.specificity	21
abstract_inverted_index.aggregation,	29, 170, 222
abstract_inverted_index.aggregometer	94
abstract_inverted_index.micromolar).	200
abstract_inverted_index.Acalabrutinib	190
abstract_inverted_index.METHODS/STUDY	40
abstract_inverted_index.acalabrutinib	223
abstract_inverted_index.concentration	204, 211
abstract_inverted_index.intracellular	33
abstract_inverted_index.pirtobrutinib	164
abstract_inverted_index.platelet-rich	56
abstract_inverted_index.zanubrutinib,	162
abstract_inverted_index.concentrations	74, 78, 198
abstract_inverted_index.immunoblotting	120
abstract_inverted_index.collagen-coated	247
abstract_inverted_index.pharmacokinetic	84
abstract_inverted_index.collagen-induced	168, 192, 259
abstract_inverted_index.phosphorylation.	39, 127
abstract_inverted_index.OBJECTIVES/GOALS:	0
abstract_inverted_index.RESULTS/ANTICIPATED	156
abstract_inverted_index.auto-phosphorylation,	231
abstract_inverted_index.DISCUSSION/SIGNIFICANCE:	249
cited_by_percentile_year
countries_distinct_count	0
institutions_distinct_count	4
citation_normalized_percentile.value	0.08207582
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False