Introduction:A recent randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET), confirmed that exposure to recombinant FVIII (rFVIII) products doubled the risk of inhibitor development compared to plasma-derived FVIII (pdFVIII) in previously untreated (or minimally treated) patients (PUPs) with severe haemophilia A. SIPPET post hoc analyses showed that early exposure to rFVIII was more immunogenic and that rFVIII could harm low-risk PUPs with non-null mutations. Clinical implications of SIPPET findings for the haemophilia community were unclear. Aim: Study the impact of the SIPPET study and its post hoc analyses on clinical practice for PUPs with severe haemophilia A in the United States. Methods: Members of the North American Hemophilia and Thrombosis Research Society (HTRS) completed two online questionnaires related to SIPPET publications and PUP management (study period: 12/2016-8/2018). Results: Over 50% participated the study. Sixty per cent expressed methodological concerns about the SIPPET study, yet 55% shared the study with new families. During the study period, rFVIII selection fell from 43/61 (70%) to 15/54 (28%) while use of pdFVIII and shared decision-making increased from 5/61 (8%) to 9/54 (17%) and from 4/61 (7%) to 10/54 (19%), respectively. Based on post hoc analyses, 44/54 (82%) would change their clinical practice with 31/44 (70%) using pdFVIII for PUPs. Barriers to translation of SIPPET analyses included study design concerns, non-inclusion of novel therapies, inability to perform genetic testing at diagnosis and risk of plasma-derived infections. Conclusion: Despite the methodological concerns about the SIPPET study, this Grade I evidence appears to have influenced the clinical practice of haemophilia providers in the United States. | 765 SANDE Et Al.

We have identified two locations with novel multiplasmic length variants in the mitochondrial DNA of a family with diabetes and deafness. At nt568 in the D-loop, the 6-bp polycytidine tract was found to be variable in length up to a total of 12 residues. A second region with length variants was found at nt8281 in the intergenic COII-tRNA(Lys) region, which consists of two copies of the 9-bp repeat CCCCCTCTA. Only the second repeat occurs in a heteroplasmic C(9-14)A form with both T residues largely deleted. In addition, the mtDNA contained a number of new homoplasmic point mutations. Both length variants are stably inherited in a maternal way with no major changes in their length distribution. In contrast, during culture of fibroblasts from the proband the average length of the polycytidine tracts is increased at both locations indicating a fibroblast-specific genetic instability. Cybrid cells containing mtDNA from the proband proliferate less efficient than cybrids with wild-type mtDNA in co-culture experiments, suggesting functional consequences of the mtDNA length variants or the additional homoplasmic point mutations. Since oxygen consumption was not severely affected, these mutation seem less detrimental for mitochondrial function than the A3243G diabetogenic mutation and most other pathogenic mtDNA mutations. The contribution of mtDNA length variants to the phenotype of members of this family is discussed.

Introduction: Splenectomy is performed for several conditions, some of which include trauma, immune thrombocytopenia (ITP), clonal myeloid neoplasms, and malignancy. Removal of the spleen can lead to reactive thrombocytosis, with an incidence of approximately 75% to 82%. While it is known that platelet counts frequently increase post-splenectomy, the exact timing of the increase, as well as how much of an increase is expected based on the diagnosis at splenectomy has not been systematically studied. To address this knowledge gap, a retrospective analysis of platelet counts in patients who underwent splenectomy has been performed, subdividing patients by the surgical indication. Methods: The University of Iowa Hospitals and Clinics electronic medical record was queried for all patients treated in years 2012-2016 with a noted history of splenectomy utilizing corresponding ICD-9 and ICD-10 codes. Indication for and date of splenectomy as well as all platelet counts were extracted. In cases without an exact date of splenectomy, the date was set as the mid-point of the reported month or year (e.g. 1997 set as June 30, 1997). Patients were sorted by splenectomy indication into ITP, clonal myeloid neoplasm, non-myeloid malignancy, and trauma/other categories. ITP patients were divided further into responders, partial responders, and non-responders. Patients were included if they had platelet count data available within the first 5 years post-splenectomy. The 180-day time course of the platelet counts was graphed for patients who had at least 5 platelet counts performed 1-180 days after splenectomy. A curve of best fit was identified for each graph. From that curve of best fit, peak platelet count, days to peak platelet count, platelet count at stable state, and days to stable state were calculated. Additionally, average platelet counts for time intervals extending from prior to splenectomy to 5 years post-splenectomy were calculated for each group, including all counts available from any patient in that group. Results: We identified 129 patients with a history of splenectomy. Median age at splenectomy was 36 years (range 2-94 years) with 59 females and 70 males. Eighty patients underwent splenectomy for trauma/other, 21 for non-myeloid malignancy, 6 for clonal myeloid neoplasm, and 22 for ITP. Among the ITP patients, 16 experienced complete response (2 with subsequent relapse), 3 were partial responders, and 3 were non-responders. Overall, the trauma/other group showed the greatest degree of post-splenectomy thrombocytosis, rising from a preoperative platelet count of 154k/µL to a maximum of 835k/µL at postoperative day 15.7. In comparison, the non-myeloid malignancy group rose from 95k/µL in the week pre-splenectomy to a maximum of 345k/µL at day 23.7. The trauma/other group also reached stable state more quickly (day 22.2 vs. 38.0) and at a higher platelet count (581k/µL vs. 240 k/uL) than the non-myeloid neoplasm group. By 1-5 years post-splenectomy, 95% of patients in our analysis had platelet counts within the standard normal range of 150-450 k/µL, albeit trauma/other and ITP responder patients had platelet counts toward the upper end of the normal range. Comparing ITP responders to partial responders, both groups showed a relative increase from baseline platelet count by days 22-29. Both groups also reached a stable platelet count by 1-5 years post-splenectomy with responders averaging 335k/µL vs. partial responders at 88k/µL. ITP responders also had a higher platelet count at 1-5 years post-op than the non-myeloid malignancy group (224k/µL). Conclusions: Our results support the well-known phenomenon of post-splenectomy thrombocytosis and illustrate the difference in platelet count response by surgical indication. Furthermore, our results suggest that post-splenectomy patients should be considered to have a different "normal range" for platelet count than non-splenectomized patients. A prospective analysis with standardized platelet count intervals would be valuable in verifying the results of this study and better addressing the meaning of "abnormal" platelet counts in asplenic patients. Disclosures No relevant conflicts of interest to declare.

We report a mediastinal neuroblastoma in an octogenarian with paraneoplastic syndrome of inappropriate antidiuretic hormone secretion (SIADH). Neuroblastomas are very rare tumors in adults, with thoracic or mediastinal locations being especially uncommon. These neoplasms have been occasionally associated with the SIADH. Given the rarity of incidence and paucity of diagnostic and outcomes data, the significance of standard neuroblastoma prognostic characteristics is unclear, and no treatment paradigms exist for these patients. Further studies are needed to inform future clinical guidelines.

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