piperidines and Purpura--Thrombocytopenic--Idiopathic

Topics: Adenine; Antineoplastic Agents; Biomarkers; Humans; Immunoglobulins, Intravenous; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Platelet Count; Protein Kinase Inhibitors; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Pyrimidines; Treatment Outcome

Topics: Blood Platelets; Humans; Piperidines; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia

Topics: Adenine; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Female; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Pyrimidines

The aim of the present study was to investigate the therapeutic effect of halofuginone (HF) in the treatment of idiopathic thrombocytopenic purpura (ITP) and explore the underlying mechanism. Sixty ITP mice were divided into four groups including control group, low dose group (25 mg/kg HF), medium dose group (50 mg/kg HF), and high dose group (100 mg/kg HF). Corresponding dose of HF was administrated by gavage daily in HF groups for 7 days, and the same volume of saline was given in control group. Platelet counts were 28.87 ± 3.91 × 10(9)/L, 57.13 ± 2.75 × 10(9)/L, 86.73 ± 3.06 × 10(9)/L and 89.73 ± 2.84 × 10(9)/L in control group, low dose group, medium dose group, and high dose group respectively, on day 7 after intragastrically administration of HF or saline. Compared with control group, three HF groups showed significantly increased levels of INF-γ and IL-2 (all P < 0.05), and significantly decreased concentrations of IL-4 and IL-10(all P < 0.05). The expression of T-bet mRNA increased and the expression of GATA-3 mRNA decreased (all P < 0.05) in ITP mice after intragastric administration with different dose of HF. HF significantly recovered peripheral platelet counts in ITP mice through promoting Th1 cell differentiation and attenuating Th2 differentiation in ITP mice.

Topics: Animals; CD3 Complex; Cell Differentiation; Cytokines; Female; GATA3 Transcription Factor; Male; Mice; Mice, Inbred BALB C; Piperidines; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Quinazolinones; RNA, Messenger; T-Box Domain Proteins; Th1 Cells; Th2 Cells

Migration of megakaryocytes (MKs) from the proliferative osteoblastic niche to the capillary-rich vascular niche is essential for proplatelet formation and platelet release. In this study, we explore the role of surface glycoprotein receptors and signaling proteins in regulating MK migration and platelet recovery after immune-induced thrombocytopenia. We show that spreading and migration of mouse primary bone marrow-derived MKs on a fibronectin matrix are abolished by the Src family kinases inhibitor PP1, the Syk kinase inhibitor R406 and the integrin alphaIIbbeta3 antagonist lotrafiban. We also demonstrate that these responses are inhibited in primary phospholipase C gamma2 (PLCgamma2)-deficient MKs. Conversely, MK spreading and migration were unaltered in the absence of the collagen receptor, the glycoprotein VI-FcRgamma-chain complex. We previously reported a correlation between a defect in MK migration and platelet recovery in the absence of platelet endothelial cell adhesion molecule-1 and the tyrosine phosphatase CD148. This correlation also holds for mice deficient in PLCgamma2. This study identifies a model in which integrin signaling via Src family kinases and Syk kinase to PLCgamma2 is required for MK spreading, migration, and platelet formation.

Topics: Animals; Benzodiazepines; Blood Platelets; Cell Movement; Cell Shape; Cells, Cultured; Intracellular Signaling Peptides and Proteins; Megakaryocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxazines; Phospholipase C gamma; Phosphorylation; Piperidines; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Proto-Oncogene Proteins pp60(c-src); Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Pyridines; Pyrimidines; Signal Transduction; Syk Kinase; Thrombopoiesis

We describe the perioperative management of a pregnant woman at 19 weeks' gestation with idiopathic thrombocytopenic purpura requiring laparoscopic splenectomy. The preoperative platelet count ranged between 1 and 5 x 10(9)/L and did not respond to conventional medical therapy. To reduce the risk of intracerebral hemorrhage, platelets were transfused before induction of anesthesia to maintain platelet count closer to 20 x 10(9)/L. The blood pressure was monitored continuously via an arterial line and remifentanil was infused to prevent a hypertensive response to induction/intubation, carbon dioxide insufflation, and surgery. After the splenic artery was clamped, additional platelet units were transfused to assure surgical hemostasis.

Topics: Adult; Analgesics, Opioid; Blood Pressure; Female; Heart Rate, Fetal; Hemorrhage; Humans; Infant, Newborn; Laparoscopy; Male; Piperidines; Platelet Count; Platelet Transfusion; Pregnancy; Purpura, Thrombocytopenic, Idiopathic; Remifentanil; Splenectomy