Coagulation profiles and thromboembolic events of bortezomib plus thalidomide and dexamethasone therapy in newly diagnosed multiple myeloma

Shen, Yongchun; Zhou, Xin; Wang, Zhi; Yang, Guohua; Jiang, Yuanqiang; Sun, Chao; Wang, Jing; Tong, Yi Tat; Guo, Hongwei

doi:10.1016/j.leukres.2010.08.007

Cited by 17 publications

(9 citation statements)

References 24 publications

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“…30 Additionally, bortezomib represses ADP-induced aggregation 27 and platelets isolated from patients receiving bortezomib are hyporesponsive to other stimuli. 6, 7 A second proteasome inhibitor, PSI, suppresses thrombosis in hypertensive animals. 44 …”

Section: Discussionmentioning

confidence: 99%

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Proteasome Proteolysis Supports Stimulated Platelet Function and Thrombosis

Gupta

Willard

et al. 2014

ATVB

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Objective Proteasome inhibitors are in use to treat hematologic cancers, but also reduce thrombosis. Whether the proteasome participates in platelet activation or function is opaque since little is known of the proteasome in these terminally differentiated cells. Approach and Results Platelets displayed all three primary proteasome protease activities, which MG132 and bortezomib (Velcade®) inhibited. Proteasome substrates are marked by ubiquitin, and platelets contained a functional ubiquitination system that modified the proteome by mono- and poly-ubiquitination. Systemic MG132 strongly suppressed formation of occlusive, platelet-rich thrombi in FeCl3-damaged carotid arteries. Transfusion of platelets treated ex vivo with MG132 and washed prior to transfusion into thrombocytopenic mice also reduced carotid artery thrombosis. Proteasome inhibition reduced platelet aggregation by low thrombin concentrations and ristocetin-stimulated agglutination through the GPIb-IX-V complex. This receptor was not appropriately internalized after proteasome inhibition in stimulated platelets, and spreading and clot retraction after MG132 exposure also were decreased. The effects of proteasome inhibitors were not confined to a single receptor as MG132 suppressed thrombin-, ADP-, and LPS-stimulated microparticle shedding. Proteasome inhibition increased ubiquitin decoration of cytoplasmic proteins, including the cytoskeletal proteins Filamin A and Talin-1. Mass spectrometry revealed a single MG132-sensitive tryptic cleavage after R1745 in an extended Filamin A loop, which would separate its actin-binding domain from its carboxy terminal GPIbα binding domain. Conclusions Platelets contain a ubiquitin/proteasome system that marks cytoskeletal proteins for proteolytic modification to promote productive platelet-platelet and platelet-wall interactions.

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Section: Discussionmentioning

confidence: 99%

“…5 Bortezomib therapy also associates with reduced thrombosis. 6, 7 Beyond this, there is little evidence of proteasome action on the platelet proteome, their activation, or on thrombosis.…”

Section: Introductionmentioning

confidence: 99%

Proteasome Proteolysis Supports Stimulated Platelet Function and Thrombosis

Gupta

Willard

et al. 2014

ATVB

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“…6 Although in vitro and ex vivo studies show that BZ inhibits platelet aggregation, the magnitude of this effect is not sufficient for explaining the profound decrease in VTEs noted with BZ. [7][8][9] Consequently, alternative mechanisms are likely operative and account for the antithrombotic effects of BZ.…”

Section: Introductionmentioning

confidence: 99%

The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2)

Nayak

Shi

Atkins

et al. 2014

Blood

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“…In a recently published Chinese series, the incidence of TEE was low in VTD therapy, with an overall rate of 3%, thus the authors did not recommend routine thromboprophylaxis for VTD [119]. Overall, the risk of TEE is quite low with bortezomib.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

2013

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Management of multiple myeloma (MM) has been drastically changed in the last 10 years thanks to the introduction of novel agents, which, combined with the backbone of classical chemotherapy, have led to a significant improvement in disease control. Bortezomib is the first reversible proteasome inhibitor approved for the treatment of MM, with wide synergism in vitro and in vivo with a plethora of drugs active for MM. In patients eligible for autologous stem cell transplantation (ASCT), the achievement of complete response or very good partial response before ASCT is associated with prolonged progression-free and overall survival. Thus, the goal of induction regimens should include, at least for younger patients, a continued improvement of the quality and depth of the achieved response. This article is focused on reviewing the major efforts in frontline therapy for MM, including bortezomib-containing induction regimens in patients either eligible or ineligible for ASCT.

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Coagulation profiles and thromboembolic events of bortezomib plus thalidomide and dexamethasone therapy in newly diagnosed multiple myeloma

Cited by 17 publications

References 24 publications

Proteasome Proteolysis Supports Stimulated Platelet Function and Thrombosis

Proteasome Proteolysis Supports Stimulated Platelet Function and Thrombosis

The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2)

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

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