br Conflict of interest br Introduction Platelets

Conflict of interest
Introduction Platelets are anucleate blood cells essential for hemostasis and wound healing; tight regulation of platelet numbers is crucial for human health. Platelets are synthesized and released from bone marrow megakaryocytes into the circulation where they remain for 7–10 days [1]. In humans, the normal circulating platelet count ranges from 150,000–450,000 platelets/μl of whole blood. A reduction in platelet count below 150,000 platelets/μl is termed thrombocytopenia, a condition that increases the risk of potentially life-threatening hemorrhage [2]. Drug-induced thrombocytopenia (DIT) can occur following administration of a wide range of medications, including antibiotics, cardiac drugs and anti-neoplastic agents [3]. DIT-inducing agents can perturb platelet counts in one of 2 ways: centrally, by exerting cytotoxic effects on bone marrow megakaryocytes, thus reducing platelet synthesis (Fig. 1A); or peripherally, by enhancing clearance of platelets already in circulation (Fig. 1B). Drugs can accelerate the destruction of circulating platelets through both immune- and nonimmune-mediated mechanisms.
Immune-mediated platelet destruction In immune-mediated platelet destruction, drug-dependent Triacetyl Resveratrol bind to platelets, either directly or alongside accessory proteins [4]. Platelets are then phagocytosed by macrophages that recognize the drug-dependent antibody on the platelet surface. The subject of immune-mediated DIT is covered in-depth by several excellent review articles [3,[5], [6], [7]] and as such is only briefly mentioned here. There are 6 subtypes of immune-mediated DIT that reflect different spatial configurations of the drug and antibody molecules interacting at the platelet surface. These subtypes of immune-mediated platelet destruction are summarized in Table 1.
Nonimmune-mediated platelet destruction In contrast to immune-mediated DIT, nonimmune-mediated platelet destruction is described as a direct cytotoxic effect of the drug molecules on the platelets. For example, thrombocytopenia was previously reported to result from the chemotherapeutic administration of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). The purported mechanism was attributed to altered platelet-endothelial cell interactions, and therefore, antibody-independent [8,9]. However, over the past 7 years, considerable evidence has emerged in support of another form of nonimmune-mediated platelet destruction: platelet apoptosis, or programmed cell death. Published evidence from multiple groups clearly indicate that thrombocytopenia-inducing drugs attenuate platelet numbers by triggering pro-apoptotic signaling.
Pro-apoptotic signaling in platelets Apoptosis is a programmed form of cell death that results in a controlled clearance of cells by macrophages, without eliciting an inflammatory response. Apoptosis is essential for the removal of damaged cells from the body and maintaining appropriate cell populations in developing tissues [10]. This form of cell death contrasts with necrosis, which is characterized by the uncontrolled rupture and release of cellular contents [11], resulting in tissue damage. The recognition that platelets undergo apoptosis is a relatively new concept that has been increasingly documented over the past 10–15 years [[12], [13], [14]]. As is observed in nucleated cells, apoptotic platelets typically exhibit cytoplasmic shrinkage, membrane protrusions known as “blebs” and increased cell surface exposure of phosphatidylserine (PS) [10,15] which denotes a cell's slated clearance by phagocytes [16]. Pro-apoptotic signaling pathways are classified as extrinsic or intrinsic (Fig. 2). Extrinsic apoptosis is specifically mediated by extracellular ligand binding to “death” receptors, however, both pathways culminate in the activation of caspases 3 and 7, cysteine proteases that orchestrate cell death by degrading cellular proteins. Therefore, the de-regulation of normal apoptotic signaling mechanisms would plausibly explain amplified platelet destruction observed in drug-induced thrombocytopenia.