A case-control study of bleeding risk in children with 22q11.2 deletion syndrome undergoing cardiac surgery.

Previous research suggests that individuals with 22q11.2 deletion syndrome (DS) have an increased risk of bleeding following cardiac surgery. However, current guidelines for management of patients with 22q11.2DS do not provide specific recommendations for perioperative management. This study sought to identify specific risk factors for bleeding in this patient population. Examine the factors determining bleeding and transfusion requirements in patients with 22q11.2DS undergoing cardiac surgery. This was a single center review of patients who underwent cardiac surgery at the Children's Hospital of Philadelphia from 2000 to 2016. Data was extracted from the medical record. Frequency of bleeding events, laboratory values, and transfusion requirements were compared. We included 226 patients with 22q11.2DS and 506 controls. Bleeding events were identified in 13 patients with 22q11.2DS (5.8%) and 27 controls (5.3%). Platelet counts were lower among patients with 22q11.2DS than in control patients, but not statistically different comparing bleeding to not bleeding. Patients with 22q11.2DS received more transfusions (regardless of bleeding status). However, multivariate analysis showed only procedure type was associated with increased risk of bleeding (p = .012). The overall risk of bleeding when undergoing cardiac surgery is not different in patients with 22q11.2DS compared to non-deleted patients. Though platelet counts were lower in patients with 22q11.2DS, only procedure type was significantly associated with an increased risk of bleeding.

Genetic variants in toll-like receptor 4 are associated with lack of steroid-responsiveness in pediatric ITP patients.

Although the most common front-line therapies for immune thrombocytopenia (ITP) have been in use for decades, it is still not possible to predict an individual patient's clinical course and response to therapy. Patients are managed with a trial-and-error approach and often suffer side effects of therapies which could have been avoided if response prediction were possible. Corticosteroids are the most frequently used upfront therapy for adults and children with ITP. Our group performed whole exome sequencing on a cohort of pediatric ITP patients, and identified two missense single nucleotide variants (SNV) in Toll-like receptor 4 (TLR4). These coding variants in TLR4 had an increased frequency in Caucasian patients with poor response to upfront steroid therapy. Both TLR4 (D299G; rs4986790) and TLR4 (T399I; rs4986791) had a minor allele frequency (MAF) of 20.7% in those patients unresponsive to steroids, but were present at lower allele frequencies of 2.3% and 3.4% in responders respectively (P < .001). These findings were consistent with the trend identified in an independent cohort of pediatric ITP patients treated with corticosteroids who underwent direct genotyping for both SNVs. This study identified two candidate genetic variants in two unique cohorts of ITP patients which may contribute to steroid response and have prognostic implications for treatment response in ITP.

Association of a positive direct antiglobulin test with chronic immune thrombocytopenia and use of second line therapies in children: A multi-institutional review.

Immune thrombocytopenia (ITP) is the most common autoimmune cytopenia in children. Approximately, 25% of patients develop chronic disease, which may be unpredictable and challenging to treat. It is not currently possible to predict at the time of presentation which patients will have chronic disease or will experience symptoms requiring second-line therapy defined as treatment beyond corticosteroids, intravenous immunoglobulin, or Rh immune globulin. A multi-institutional retrospective review of 311 pediatric patients with ITP was performed with the goal of identifying clinical characteristics associated with disease course. In a cohort of 216 patients tested and for whom disease status was known, a positive direct antiglobulin test (DAT) was associated with chronic ITP vs spontaneous resolution of disease (29.2% vs 8.1%, P < 0.001) as well as the need for treatment with second line agents (38.5% vs 11.4%, P < 0.001) in 241 patients. Controlling for the effect of Evans syndrome, defined as having two immune cytopenias, a positive DAT was independently associated with chronic ITP (OR = 2.7, 95% CI: 1.0-7.2, P = 0.041) and use of second-line agents (OR: 3.6, 95% CI: 1.7-7.7, P = 0.001) by multivariate logistic regression model. These findings demonstrate an association with positive DAT and chronic disease, as well as refractory disease requiring second-line agents.

2-O, 3-O desulfated heparin mitigates murine chemotherapy- and radiation-induced thrombocytopenia.

Thrombocytopenia is a significant complication of chemotherapy and radiation therapy. Platelet factor 4 (PF4; CXCL4) is a negative paracrine of megakaryopoiesis. We have shown that PF4 levels are inversely related to steady-state platelet counts, and to the duration and severity of chemotherapy- and radiation-induced thrombocytopenia (CIT and RIT, respectively). Murine studies suggest that blocking the effect of PF4 improves megakaryopoiesis, raising nadir platelet counts and shortening the time to platelet count recovery. We examined the ability of 2-O, 3-O desulfated heparin (ODSH), a heparin variant with little anticoagulant effects, to neutralize PF4's effects on megakaryopoiesis. Using megakaryocyte colony assays and liquid cultures, we show that ODSH restored megakaryocyte proliferation in PF4-treated Cxcl4-/- murine and human CD34+-derived megakaryocyte cultures (17.4% megakaryocyte colonies, P < .01 compared with PF4). In murine CIT and RIT models, ODSH, started 24 hours after injury, was examined for the effect on hematopoietic recovery demonstrating higher platelet count nadirs (9% ± 5% treated vs 4% ± 4% control) and significantly improved survival in treated animals (73% treated vs 36% control survival). Treatment with ODSH was able to reduce intramedullary free PF4 concentrations by immunohistochemical analysis. In summary, ODSH mitigated CIT and RIT in mice by neutralizing the intramedullary negative paracrine PF4. ODSH, already in clinical trials in humans as an adjuvant to chemotherapy, may be an important, clinically relevant therapeutic for CIT and RIT.

The 22q11.2 deletion syndrome: Cancer predisposition, platelet abnormalities and cytopenias.

The 22q11.2 deletion syndrome (DS) is associated with variable phenotypic expression as findings range from severely affected individuals with the classical triad of DiGeorge and velocardiofacial syndromes, including congenital heart disease, immunodeficiency, hypocalcemia, and palatal abnormalities, to subtly affected adults who only come to attention following the diagnosis of a more severely affected child. The multiple manifestations can affect all organ systems, including the hematologic system resulting in baseline lower platelet counts for individuals with 22q11.2DS and increased platelet size. In addition, there may be an associated increased risk of bleeding. Individuals with 22q11.2DS are also at increased risk of autoimmune cytopenias that can complicate the evaluation or management of other manifestations. Finally, there may be an increased risk of malignancy, although the mechanism for this risk is not fully understood. This review summarizes the currently available data on hematologic/oncologic manifestations of 22q11.2DS and reports on our findings within a large cohort of individuals with the deletion.