Prakrith Vijey

Brigham and Women's Hospital | BWH · Division of Hematology

Antisense oligonucleotides (ASOs) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2’MOE) ASOs have reported dose- and sequencespecific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. Th...

Background The mechanisms that regulate platelet biogenesis remain unclear; factors that trigger megakaryocytes (MKs) to initiate platelet production are poorly understood. Platelet formation begins with proplatelets which are cellular extensions originating from the MK cell body. Objectives Proplatelet formation is an asynchronous and dynamic pro...

Key Points Mouse megakaryocytes can differentially sort and package endocytosed fibrinogen and endostatin into distinct α-granules. Platelet progenitors contain subpopulations of α-granules.

Introduction Antisense oligonucleotides (ASOs) are a new class of single-stranded DNA based drugs that hold great therapeutic promise for their disease modifying potential in a wide range of genetic diseases. Preclinical toxicology studies in monkeys, as well as late stage clinical trials in humans, have upon repeated dosing, reported events of ASO...

Megakaryocytes (MKs) are specialized precursor cells committed to producing and proliferating platelets. In a cytoskeletal-driven process, mature MKs generate platelets by releasing thin cytoplasmic extensions, named proplatelets, into the sinusoids. Due to knowledge gaps in this process and mounting clinical demand for non-donor-based platelet sou...

Key Points XPO1 blockade causes thrombocytopenia by inhibiting TPO signaling and blocking the differentiation of stem cells into megakaryocytes. Selinexor-induced thrombocytopenia is reversible when TPO agonists are administered in the absence of selinexor (drug holiday).

Background: Proteasome inhibitors such as bortezomib, a chemotherapeutic used to treat multiple myeloma, induce thrombocytopenia within days of initiation. The mechanism for this thrombocytopenia has been tied to data revealing that proteasome activity is essential for platelet formation. The major pathway of selective protein degradation uses ubiq...