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- Novel manifestations of immune dysregulation and granule defects in gray platelet syndromePublication . Sims, Matthew C; Mayer, Louisa; Collins, Janine H; Bariana, Tadbir K; Megy, Karyn; Lavenu-Bombled, Cecile; Seyres, Denis; Kollipara, Laxmikanth; Burden, Frances S; Greene, Daniel; Lee, Dave; Rodriguez-Romera, Antonio; Alessi, Marie-Christine; Astle, William J; Bahou, Wadie F; Bury, Loredana; Chalmers, Elizabeth; Da Silva, Rachael; De Candia, Erica; Deevi, Sri V V; Farrow, Samantha; Gomez, Keith; Grassi, Luigi; Greinacher, Andreas; Gresele, Paolo; Hart, Dan; Hurtaud, Marie-Françoise; Kelly, Anne M; Kerr, Ron; Le Quellec, Sandra; Leblanc, Thierry; Leinøe, Eva B; Mapeta, Rutendo; McKinney, Harriet; Michelson, Alan D; Morais, Sara; Nugent, Diane; Papadia, Sofia; Park, Soo J; Pasi, John; Podda, Gian Marco; Poon, Man-Chiu; Reed, Rachel; Sekhar, Mallika; Shalev, Hanna; Sivapalaratnam, Suthesh; Steinberg-Shemer, Orna; Stephens, Jonathan C; Tait, Robert C; Turro, Ernest; Wu, John K M; Zieger, Barbara; Kuijpers, Taco W; Whetton, Anthony D; Sickmann, Albert; Freson, Kathleen; Downes, Kate; Erber, Wendy N; Frontini, Mattia; Nurden, Paquita; Ouwehand, Willem H; Favier, Remi; Guerrero, Jose AGray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.
- Guidelines on COVID-19 Vaccine Induced Thrombosis, Bleeding, and ThrombocytopeniaPublication . Morais, Sara; Cruz, EugéniaAfter widespread vaccination with COVID-19 vaccines, there have been worldwide reports on thrombosis, bleeding, and thrombocytopenia. Recently, a rare syndrome with a high mortality rate consisting of an unusual combination of thrombocytopenia and thrombosis, in particular cerebral venous sinus thrombosis, which clinically resembles heparin-induced thrombocytopenia, was reported following vaccination. Different statements and recommendations were developed regarding the definition, diagnosis, and treatment of these rare complications. We present here a protocol with recommendations, based on current evidence.
- Aggressive Neuroblastoma in a Pediatric Patient with Severe Hemophilia APublication . Costa, Lídia; Couto, Maria Eduarda; Moutinho, Juliana; Ferreira, Ana Maia; Costa, Emilia; Roncon, Susana; Santos, Luisa Lopes; Cruz, Eugénia; Morais, SaraDespite the extensive information regarding hemophilia's hemorrhagic complications, the literature on cancer in hemophilia is scarce, especially in pediatric patients. Many uncertainties remain concerning diagnosis and workup. We report a rare case of two severe diseases (neuroblastoma and hemophilia A (HA)) concomitantly present in the same pediatric patient. We highlight that the diagnosis of severe HA did not have a negative impact on the patient's oncologic course. This case also illustrates the significance of the cooperation among different specialties and hospitals when caring for the same patient.
- αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrumPublication . Morais, Sara; Oliveira, Jorge; Lau, Catarina; Pereira, Mónica; Gonçalves, Marta; Monteiro, Catarina; Gonçalves, Ana; Matos, Rui; Sampaio, Marco; Cruz, Eugénia; Freitas, Inês; Santos, Rosário; Lima, MargaridaBackground: Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives: To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods: We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results: Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions: Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.