Single center evaluation on the use of conditionally ordered low molecular weight heparins in malignant hematology patients with venous thromboembolism.

BACKGROUND: Cancer and cancer-related treatments are significant independent risk factors for malignant hematology (MH) patients in developing venous thromboembolism (VTE). Treatment of VTE in MH patients at the Princess Margaret Cancer Centre is predominantly initiated with low molecular weight heparin (LMWH) in accordance with guidelines. While guidelines recommend against LMWH use in patients with thrombocytopenia, prescribers may order LMWH conditionally based on platelet values. Currently, there is a lack of consistent practice with variation in both the use of conditional orders as well as the threshold of platelet values for conditional orders. The objectives of the study were to (a) describe the use of conditionally ordered LMWH based on platelet values; (b) determine its safety by measuring administration concordance with conditional orders and bleeding event rates during inpatient admission; and (c) determine its efficacy by measuring the rate of worsening VTE or recurrence during inpatient admission. METHODS: Electronic records of MH inpatients admitted between January 2017 and December 2019 and who were administered at least one dose of an LMWH for the treatment of VTE were screened. RESULTS: One hundred and eight patients were screened to obtain 50 eligible patients with a median age of 59 years (SD = ±18.8 years). The most frequent MH diagnosis was acute lymphoblastic leukemia (30%). Sixty percent (n = 30) of patients received conditional orders. Out of 571 administrations, 543 (95%) were administered concordantly (Χ2(1) = 472, p < 0.0001). In this group of patients, 8 patients had either documented bleeding or experienced a drop in hemoglobin >10 g/L within a 72 h time frame. No patients experienced a recurrent VTE during inpatient treatment (for up to 40 days post-admission). CONCLUSIONS: It appears that conditionally ordered LMWH can be concordantly administered and is safe and effective in the treatment of VTE in MH patients experiencing thrombocytopenia. There were no reports of worsening or new VTE in our small sample.

Efficacy and cost analysis of eltrombopag in thrombocytopenia and poor graft function post allogeneic hematopoietic cell transplantation.

Eltrombopag has shown efficacy in the treatment of thrombocytopenia and poor graft function (PGF) after allogeneic hematopoietic cell transplantation (HCT) in retrospective observational studies, but is not approved for this indication. The cost of this drug is also a major concern in publicly funded health care systems. We collected data about patients who received eltrombopag for thrombocytopenia or PGF after HCT. Post-HCT thrombocytopenia, PGF, and eltrombopag response were defined as per previously published criteria. Primary outcome was treatment efficacy and secondary outcome was cost comparison between estimated treatment cost prior to and after initiation of eltrombopag. Seventeen patients (males 70.6%; median age = 58) received eltrombopag. Isolated thrombocytopenia was present in 11.8% (n = 2) patients while PGF was present in 88.2% (n = 15) of patients. After 8 weeks of treatment at the maximum dose of 150 mg orally daily, overall response rate (ORR) was seen in 76.5% (13/17) of patients: complete response (CR) in 10/13 patients and partial response (PR) in 3/13 patients. The use of eltrombopag was associated with an overall decrease in the total weekly care costs (5021 vs 2,524 CA$; P = 0.04). Thus, Eltrombopag is an efficacious and possibly cost-effective therapy for thrombocytopenia and PGF after allogeneic HCT.

A Christianson syndrome-linked deletion mutation (∆(287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death.

BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability. RESULTS: In the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death. CONCLUSIONS: These results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.