Drug-induced thrombocytopenia: MIBS trumps LIBS

Chong, Beng H.

doi:10.1182/blood-2012-04-423939

Cited by 7 publications

(8 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pretreatment of FcγRIIa mAb (i.e., CD32), an ITAM-bearing transmembrane receptor responsible for α IIb β 3 outside-in signaling [16], completely inhibited platelet aggregation caused by TFV-3/AP2 ( Figure 4C), suggesting that FcγRIIa is essential for activation. 7 of 20 and elicited FcRIIa-mediated platelet aggregation [29] and platelet consumption [11]. The recent report also indicated that eptifibatide-induced thrombocytopenia is associated with an increase in circulating procoagulant platelet-derived microparticles [14].…”

Section: Combination Of Tfv-1 With Ap2 Does Not Induce Fcγriia-mediatmentioning

confidence: 98%

“…Immune thrombocytopenia occurs on first exposure to RGD-mimetic agents. That is, platelet count usually declines sharply within hours of the commencement of drug administration, demonstrating the presence of a naturally occurring antiplatelet antibody in patients who took these kinds of drugs [11]. Previous reports have revealed that upon binding of RGD-mimetic drugs to integrin IIb3, the ligand-binding capacity increased in the activated integrin and intrinsic antibodies recognized conformational changes in IIb3 induced by drugs [12].…”

Section: Tfv-1 Binding To Integrin Iib3 Does Not Prime the Resting mentioning

confidence: 99%

“…Toxins 2020, 12,11 3 of 20 3 of 20 flavoviridis; and the partial sequence of TFV-3 had 80% sequence identity with trimestatin [21] ( Figure 1F), another disintegrin from the same venom. (A) Purification of TFV1 and TFV3.…”

Section: Purification and Characterization Of Tfv1 And Tfv3mentioning

confidence: 99%

“…We previously reported that upon drug-induced LIBS exposure, the mimetic drug-dependent antibody (DDAb) mAb, AP2, which was raised against the epitopes of α IIb β 3 , recruited FcγRIIa [19] and elicited FcγRIIa-mediated platelet aggregation [29] and platelet consumption [11]. The recent report also indicated that eptifibatide-induced thrombocytopenia is associated with an increase in circulating procoagulant platelet-derived microparticles [14].…”

Section: Combination Of Tfv-1 With Ap2 Does Not Induce Fcγriia-mediatmentioning

confidence: 99%

“…Life-threatening thrombocytopenia and bleeding, common severe side effects of these RDG-mimetic drugs and α IIb β 3 antagonists [9,10], are associated with induction of drug-induced integrin conformational changes and ligand-induced binding site (LIBSs) exposure of integrin α IIb β 3 [11,12]. Various reports indicate that thrombocytopenia after exposure to α IIb β 3 antagonists is linked to drug-dependent antibody binding (DDAb) to platelets [10].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

A Novel αIIbβ3 Antagonist from Snake Venom Prevents Thrombosis without Causing Bleeding

Kuo

Chung

Pan

et al. 2019

Toxins

View full text Add to dashboard Cite

Life-threatening thrombocytopenia and bleeding, common side effects of clinically available α IIb β 3 antagonists, are associated with the induction of ligand-induced integrin conformational changes and exposure of ligand-induced binding sites (LIBSs). To address this issue, we examined intrinsic mechanisms and structure-activity relationships of purified disintegrins, from Protobothrops flavoviridis venom (i.e., Trimeresurus flavoviridis), TFV-1 and TFV-3 with distinctly different pro-hemorrhagic tendencies. TFV-1 with a different α IIb β 3 binding epitope from that of TFV-3 and chimeric 7E3 Fab, i.e., Abciximab, decelerates α IIb β 3 ligation without causing a conformational change in α IIb β 3 , as determined with the LIBS antibody, AP5, and the mimetic, drug-dependent antibody (DDAb), AP2, an inhibitory monoclonal antibody raised against α IIb β 3 . Consistent with their different binding epitopes, a combination of TFV-1 and AP2 did not induce FcγRIIa-mediated activation of the ITAM-Syk-PLCγ2 pathway and platelet aggregation, in contrast to the clinical antithrombotics, abciximab, eptifibatide, and disintegrin TFV-3. Furthermore, TFV-1 selectively inhibits Gα 13 -mediated platelet aggregation without affecting talin-driven clot firmness, which is responsible for physiological hemostatic processes. At equally efficacious antithrombotic dosages, TFV-1 caused neither severe thrombocytopenia nor bleeding in FcγRIIa-transgenic mice. Likewise, it did not induce hypocoagulation in human whole blood in the rotational thromboelastometry (ROTEM) assay used in perioperative situations. In contrast, TFV-3 and eptifibatide exhibited all of these hemostatic effects. Thus, the α IIb β 3 antagonist, TFV-1, efficaciously prevents arterial thrombosis without adversely affecting hemostasis. Keywords: arterial thrombosis; antiplatelet agent; integrin α IIb β 3 ; bleeding side effect; snake venom proteins; disintegrins Key Contribution: Current α IIb β 3 antagonists are efficacious anti-thrombotics, but have significant adverse bleeding effects. This study clarifies a pathologically intrinsic mechanism in drug-induced thrombocytopenia and identifies a new candidate that may lead to development of safer anti-thrombotics with significantly reduced bleeding risk.

show abstract