Drug-Induced Immune Thrombocytopenia

Bemt, Patricia M. L. A. van den; Meyboom, R.H.B.; Egberts, Toine C. G.

doi:10.2165/00002018-200427150-00007

Cited by 124 publications

(82 citation statements)

References 98 publications

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“…This disorder primarily occurs via two distinct mechanisms: (i) decreased platelet production via cytotoxic effects on MKs and their precursors as observed with some cytotoxic chemotherapeutic agents (23) and (ii) accelerated platelet destruction in peripheral blood via immune-mediated thrombocytopenia (24) and as observed with a number of drug classes including nonsteroidal anti-inflammatories, and sulfonamides (24).…”

Section: Discussionmentioning

confidence: 99%

Potential Mechanisms for Thrombocytopenia Development with Trastuzumab Emtansine (T-DM1)

Uppal¹,

Doudement²,

Mahapatra³

et al. 2015

Clinical Cancer Research

154

109

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Purpose: Trastuzumab-emtansine (T-DM1) is an antibodydrug conjugate (ADC) comprising the cytotoxic agent DM1 conjugated to trastuzumab with a stable linker. Thrombocytopenia was the dose-limiting toxicity in the phase I study, and grade !3 thrombocytopenia occurred in up to 13% of patients receiving T-DM1 in phase III studies. We investigated the mechanism of T-DM1-induced thrombocytopenia.Experimental Design: The effect of T-DM1 on platelet function was measured by aggregometry, and by flow cytometry to detect the markers of activation. The effect of T-DM1 on differentiation and maturation of megakaryocytes (MK) from human hematopoietic stem cells was assessed by flow cytometry and microscopy. Binding, uptake, and catabolism of T-DM1 in MKs, were assessed by various techniques including fluorescence microscopy, scintigraphy to detect T- [H 3 ]-DM1 and 125 I-T-DM1, and mass spectrometry. The role of FcgRIIa was assessed using blocking antibodies and mutant constructs of trastuzumab that do not bind FcgR.Results: T-DM1 had no direct effect on platelet activation and aggregation, but it did markedly inhibit MK differentiation via a cytotoxic effect. Inhibition occurred with DM1-containing ADCs but not with trastuzumab demonstrating a role for DM1. MKs internalized these ADCs in a HER2-independent, FcgRIIa-dependent manner, resulting in intracellular release of DM1. Binding and internalization of T-DM1 diminished as MKs matured; however, prolonged exposure of mature MKs to T-DM1 resulted in a disrupted cytoskeletal structure.Conclusions: These data support the hypothesis that T-DM1-induced thrombocytopenia is mediated in large part by DM1-induced impairment of MK differentiation, with a less pronounced effect on mature MKs.

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Section: Discussionmentioning

confidence: 99%

Potential Mechanisms for Thrombocytopenia Development with Trastuzumab Emtansine (T-DM1)

Uppal¹,

Doudement²,

Mahapatra³

et al. 2015

Clinical Cancer Research

154

109

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“…52,53 Furthermore, thrombocytopenia has been reported in more than 30% of patients with sepsis. In these patients, thrombocytopenia is usually associated with disseminated intravascular coagulation (DIC), with increased platelet destruction.…”

mentioning

confidence: 99%

Cytopenias among ART-naive patients with advanced HIV disease on enrolment to care and treatment services at a tertiary hospital in Tanzania: A crosssectional study

et al. 2017

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“…Based on several reports from the United States and Europe, the estimated incidence is around 10 cases per million population per year, but the number could be higher in hospitalized or elderly patients. 5 Drug-induced thrombocytopenia typically results from either non-immune or immune mediated mechanisms. Non-immune thrombocytopenia is common and results from the suppression of platelet production by general myelotoxicity (e.g., chemotherapy agents), dose-dependent myelosuppression (e.g., linezolid), or interference with specific megakaryocyte function (e.g., bortezomib).…”

Section: Discussionmentioning

confidence: 99%

Vancomycin-induced severe asymptomatic immune thrombocytopenia: a rare cause

2015

SWRCCC

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Drug-Induced Immune Thrombocytopenia

Cited by 124 publications

References 98 publications

Potential Mechanisms for Thrombocytopenia Development with Trastuzumab Emtansine (T-DM1)

Potential Mechanisms for Thrombocytopenia Development with Trastuzumab Emtansine (T-DM1)

Cytopenias among ART-naive patients with advanced HIV disease on enrolment to care and treatment services at a tertiary hospital in Tanzania: A crosssectional study

Vancomycin-induced severe asymptomatic immune thrombocytopenia: a rare cause

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