RESUMEN
Increasing awareness and availability of tests for anti-PF4/heparin complex antibodies has raised concerns about indiscriminate testing and inappropriate diagnosis of heparin-induced thrombocytopenia. A retrospective review of HITS testing at a large tertiary centre was performed to determine test patterns and incidence of HITS. Records of anti-PF4 tests over 4 years were reviewed. Positive results were matched against patient medical records and records of heparin utilisation for the diagnosis of HITS. Total of 33,308 patients (9.89 % of admissions) were exposed to at least 1 day of unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Of 346 anti-PF4 antibody assays performed, 52 (15 %) were positive. Seventeen patients (4.9 % of total) were determined to have HITS. Of these, 13 cases (76 %) were patients who were initiated on haemodialysis via central venous catheters. Five patients (29 %) subsequently experienced thrombosis. The rate of HITS in patients given UFH was 0.33 %. HITS occurred in only one patient given LMWH. Of 1337 patients with chronic renal failure initiated on long term haemodialysis, the incidence of HITS was 0.97 %. Despite increased awareness of HITS, testing frequency remains conservative. An overwhelming majority of HITS cases were diagnosed among patients initiated on haemodialysis.
Asunto(s)
Heparina/efectos adversos , Trombocitopenia/etiología , Anticuerpos/análisis , Heparina de Bajo-Peso-Molecular/efectos adversos , Humanos , Incidencia , Registros Médicos , Factor Plaquetario 4/inmunología , Diálisis Renal/efectos adversos , Estudios Retrospectivos , Centros de Atención Terciaria , Trombocitopenia/inducido químicamente , Trombocitopenia/diagnósticoRESUMEN
Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.