Faculty Bibliography

SUMMARY/CONCLUSIONS:This review discusses the current evidence regarding perioperative hormone therapy for transgender individuals, with an emphasis on strategies to reduce the risk of perioperative venous thromboembolism. Historically, surgeons routinely discontinued estrogen therapy in the perioperative period with the goal of reducing the risk of venous thromboembolism. However, abrupt estrogen cessation may also lead to adverse emotional and physiologic effects, including an exacerbation of one's gender dysphoria. The data on the relationship of feminizing hormones and venous thromboembolism in the perioperative setting are largely based on extrapolation of hormone regimens that are no longer in use and may not accurately reflect the actual risk of venous thromboembolism. Future studies will allow surgeons to engage in evidence-based, patient-centered, informed consent while also minimizing the risk of complications, such as venous thromboembolism.

Patients with autoimmune multi-lineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N=12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response, including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1-3 months of starting sirolimus. Double negative T (DNT) cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multi-lineage cytopenias secondary to common variable immune deficiency (CVID), Evans syndrome (ES) or systemic lupus erythematosus (SLE), and most achieved a CR (N= 8), although the time to CR was often slower than was seen in ALPS. Six children with single lineage autoimmune cytopenias were treated and only two responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over one year (median 2 years, range 1-4.5 years). In summary, sirolimus led to complete and durable responses in a majority of children with refractory multi-lineage autoimmune cytopenias. The responses seen in ALPS patients were profound suggesting that sirolimus should be considered as a first-line, steroid-sparing treatment for patients needing chronic therapy. The results in other multi-lineage autoimmune cytopenia cohorts were encouraging and sirolimus should be considered in children with SLE, ES, and CVID.

Intracranial haemorrhage (ICH) is the most serious type of bleeding for patients with haemophilia. Prior published reports regarding ICH predate the widespread provision of prophylaxis. Our study objectives were to determine risk factors for ICH and whether prophylaxis reduces ICH occurrence. We performed a nested case-control study of persons with haemophilia, >/=2 years of age enrolled in the Centers for Disease Control and Prevention Universal Data Collection project. Of 10 262 patients 199 (1.9%) experienced an ICH for an incidence rate of 390/10 patient years. Head trauma was reported in 44% (88/199). ICH mortality was 19.6% (39/199). Significant risk factors for ICH included a high titre inhibitor [odds ratio (OR) = 4.01, 95% confidence interval (2.40-6.71)], prior ICH [OR = 3.62 (2.66-4.92)] and severe haemophilia [OR = 3.25 (2.01-5.25)]. Prophylaxis was associated with a significant risk reduction for ICH occurrence in patients with severe haemophilia who were negative for human immunodeficiency virus or an inhibitor, with an OR of 0.52 (0.34-0.81) and 0.50 (0.32-0.77) respectively. The most significant risk factors for ICH included the presence of an inhibitor, prior ICH, severity of haemophilia and reported head trauma. This is the first study to demonstrate that prescribed prophylaxis conferred a protective effect against ICH in patients with uncomplicated severe disease

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (> or = 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs

BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)