The Proteasome Inhibitor Bortezomib Induces Apoptosis and Activation in Gel-Filtered Human Platelets

Abstract

Bortezomib (BTZ) has demonstrated its efficacy in several hematological disorders and has been associated with thrombocytopenia. There is controversy about the effect of BTZ on human platelets, so we set out to determine its effect on various types of platelet samples. Human platelets were investigated in platelet-rich plasma (PRP) and as gel-filtered platelets (GFPs). Mitochondrial inner membrane potential depolarization and phosphatidylserine (PS) and P-selectin expression levels were studied by flow cytometry, while thrombin generation was measured by a fluorescent method. In PRP, BTZ caused negligible PS expression after 60 min of treatment. However, in GFPs, PS expression was dose- and time-dependently increased in the BTZ-treated groups, as was P-selectin. The percentage of depolarized cells was also higher after BTZ pretreatment at both time points. Peak thrombin and velocity index increased significantly even with the lowest BTZ concentration (p = 0.0019; p = 0.0032) whereas time to peak and start tail parameters decreased (p = 0.0007; p = 0.0034). The difference between PRP and GFP results can be attributed to the presence of plasma proteins in PRP, as the PS-stimulating effect of BTZ could be attenuated by supplementing GFPs with purified human albumin. Overall, BTZ induces a procoagulant platelet phenotype in an experimental setting devoid of plasma proteins.

Prediction of venous thromboembolism in patients with multiple myeloma treated with lenalidomide, bortezomib, dexamethasone, and transplantation: Lessons from the substudy of IFM/DFCI 2009 cohort

“…Moreover, our incidence is lower than that observed in the Covut et al study (10.7% [95% CI: 8.2–13.2%]), but only 2.6% of their patients received heparin as prophylaxis 3 . Previous studies suggesting that bortezomib might have a protective effect are challenged by recent epidemiological literature as well as our results, 17–19 and by recent pathophysiological literature 20 . In the Ghansah et al study, bortezomib induced a procoagulant platelet phenotype even in an experimental setting devoid of plasma proteins 20 .…”

“…3 Previous studies suggesting that bortezomib might have a protective effect are challenged by recent epidemiological literature as well as our results, [17][18][19] and by recent pathophysiological literature. 20 In the Ghansah et al study, bortezomib induced a procoagulant platelet phenotype even in an experimental setting devoid of plasma proteins. 20 So, increased VTE risk could be an adverse event linked to bortezomib as well.…”

“…20 In the Ghansah et al study, bortezomib induced a procoagulant platelet phenotype even in an experimental setting devoid of plasma proteins. 20 So, increased VTE risk could be an adverse event linked to bortezomib as well.…”

Precision medicine: The use of tailored therapy in primary immunodeficiencies

“…Other monoclonal antibodies have been under evaluation and used as an alternative for auto-immune cytopenias including: belimumab a human recombinant IgG1λ monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), and indirectly inhibits B cell survival (autoreactive B-cell apoptosis) ( 180 ); bortezomib a dipeptide boronic acid derivative that inhibits the 26S proteasome, a protein complex that degrades ubiquitinated proteins in the ubiquitin-proteasome pathway, leading to cell cycle arrest and apoptosis ( 181 ); epratuzumab an anti-CD22 humanized monoclonal antibody derived from the murine IG2a monoclonal antibody that contributes to an alteration of the B cell receptor signaling complex, reducing signaling and activation of B cells ( 149 ) and ibrutinib is a small molecule that inhibits burton’s tyrosine kinase leading to perturbation of B-cell development due to the role of this target in the B-cell receptor signaling pathway ( 182 ). Daratumumab is a monoclonal antibody that targets CD38 receptors, and currently approved by EMA and FDA for multiple myeloma and light chain amyloidosis.…”