Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell–cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell–related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease

Thoracic lymphangiomatosis in a child

An 8-year-old boy who presented with a mediastinal mass, pulmonary infiltrates, and disseminated intravascular coagulation was diagnosed with lymphangiomatosis. Despite medical management, he developed multiple organ failure and died. The authors discuss the diagnostic findings, medical management, and pathology and review 52 additional cases of thoracic lymphangiomatosis from the literature. Patients presented with chylothorax (49%), a mass (47%), pulmonary infiltrates (45%), bone lesions (39%), splenic lesions (19%), cervical involvement (15%), disseminated intravascular coagulation (9%), and skin involvement (7%). Children (<16 years) had a worse prognosis than older patients (39% vs. 0% mortality). All patients who died had either parenchymal lung involvement or pleural effusion. Thoracic lymphangiomatosis should be included in the differential diagnosis of a mediastinal mass with pulmonary findings

Inhibition of Collagenolytic Activity and Metastasis of Tumor Cells by a Recombinant Human Tissue Inhibitor of Metalloproteinases

Metalloproteinases secreted by tumor cells play an important role in metastasis. In the present study, we determined whether an inhibitor of these proteinases could inhibit the ability of tumor cells to degrade collagen and to metastasize. Metalloproteinases with degradative activities for type I collagen, type IV collagen, gelatin, and casein were secreted by a highly metastatic rat embryo cell line (4R) transfected by c-Ha-rasl (also known as HRAS1). These metalloproteinases were identified by sodium dodecyl sulfate substrate-poly-acrylamide gel electrophoresis as 92-kilodalton and 68-kilodalton gelatinolytic enzymes and 48-kilodalton and 45-kilodalton caseinolytic proteinases. A recombinant human tissue inhibitor of metalloproteinases (rTIMP) completely inhibited the proteolytic activities of these enzymes and was also a potent inhibitor of the proteolytic degradation of collagen by intact c-Ha-rasl-transfected cells. The ability of these cells to colonize the lungs after intravenous injection into nude mice was inhibited by 83% when rTIMP was repeatedly injected intraperitoneally into the animals. These data demonstrate that rTIMP is a potent inhibitor of the metalloproteinase activities of these cells and can also inhibit their metastatic potential. [J Natl Cancer Inst 82: 589–595, 1990

Does Vitamin D Deficiency Play a Role in Sickle Cell Nephropathy?

Abstract Abstract 4755 Background: Although improvements in the management of sickle cell disease (SCD) have increased patient survival into adulthood, morbidity and mortality from end-organ damage remain major concerns. One of the most serious complications of SCD is renal failure, affecting about 20% of patients. Secondary prevention of the progression of SCD nephropathy is hindered by a lack of easily modifiable risk factors. Based on animal and observational human studies, vitamin D deficiency is potentially a novel, modifiable risk factor that may interrupt or delay the progression of kidney disease by suppressing renin gene expression and inflammation. Studies have reported varying prevalence rates of vitamin D deficiency in patients with SCD patients but their clinical significance is uncertain. The purpose of this exploratory study was to determine the association of vitamin D insufficiency with albuminuria among a cohort of patients with SCD. Methods: This cross-sectional study was performed using a cohort of patients with SCD. Serum creatinine, serum cystatin C, spot urine for albumin/creatinine ratio, 25-hydroxyvitamin D [25(OH) D] levels, measures of hemolysis, inflammation and other laboratory studies were obtained. Vitamin D insufficiency was defined as 25(OH) D levels ?30 ng/ml. Results: 27 patients with SS disease were evaluated. The mean age was 18 +/− 4.9 years; 40% were males and 60 % females. Mean GFR by serum creatinine was 167 +/− 40 ml/min/1.73 m2 and by cystatin C was 150 +/− 29.4 ml/min/1.73 m2. Increased protein/creatinine ratio (ratio ? 0.2) occurred in 29 % of patients (n= 9). Increased albumin/creatinine ratio (ACR ?30 mg/g of creatinine, mean 216 mg/g of creatinine) occurred in 37% of patients (n= 10). 88% of subjects showed vitamin D insufficiency [n=24, mean 17+/− 7 ng/ml]. Mean 25 OH vitamin D level was 14.8 +/− 8.9 ng/ml (5–28) and 18.2 +/− 5 ng/ml (12–30) in subjects with and without albuminuria, respectively. Urinary ACR inversely correlated with 25(OH) D levels (r=-.4, P=.02). No correlations were observed between urinary ACR and other clinical or laboratory parameters (age, hemoglobin levels, percentage of reticulocytes and lactate dehydrogenase levels). Proteinuria correlated with age (r=-.4, P=.02) and reticulocyte counts (r=-.4, P=.02) in SS disease but not with other parameters. Conclusion: In conclusion, vitamin D insufficiency was common and significantly associated with albuminuria among patients with SCD. Additional studies are needed to clarify the causal relationship of vitamin D insufficiency with albuminuria and to determine the role of vitamin D supplementation to attenuate the development of SCD nephropathy. Disclosures: No relevant conflicts of interest to declare

Serum Cystatin C Is a Better Marker for Renal Function Than Serum Creatinine in Children with Sickle Cell Disease

Abstract High serum creatinine is a late manifestation for patients (pts) with sickle cell disease (SCD) who develop severe renal dysfunction, because creatinine is secreted by the renal tubules. Serum cystatin C is a cysteine proteinase inhibitor, that is produced by all nucleated cells in the body, does not undergo tubular secretion, and reflects glomerular filtration rate (GFR)accurately. Normal levels for serum cystatin C are 0.5–1.3 mg/L for children 1–17 years, and 0.5–1 mg/L for adults. The purpose of this study was to compare serum cystatin C and serum creatinine as markers of GFR in children with SCD with different levels of albuminuria. Twenty pts (mean age 16.4, range 9–21 years) had serum creatinine, serum cystatin, and 24-hour urine for creatinine clearance. Pts with normoalbuminuria (N=11) had mean serum creatinine of 0.55±0.14 mg/L, creatinine clearance of 168±36 ml/min/1.73m2, normal serum cystatin C 0.78±0.16 mg/L, and normal estimated GFR derived from cystatin of 106±27 ml/min/1.73m2. In contrast, pts with proteinuria (N=4) had higher or abnormal serum cystatin C (mean 1.25 ±0.34, range 0.9–1.7 mg/L) and reduced estimated GFR (mean 59±21, range 35–85) consistent with poor kidney function; nevertheless, the serum creatinine (0.7±0.2) and creatinine clearance remained normal (125±27). Pts with only microalbuminuria (N=5) maintained normal levels of cystatin C and estimated GFR by cystatin. We conclude that serum cystatin C discriminated better for kidney dysfunction than serum creatinine and creatinine clearance with significantly different values between patients with normoalbuminuria and macroalbuminuria (p=0.038). More studies are warranted in order to investigate further the value of serum cystatin C in the monitoring of patients with SCD and albuminuria

Development of a Low-Cost Electrical Impedance-Based Microflow Cytometer

Sickle Cell Disease (SCD) is a genetic condition caused by a mutated hemoglobin molecule (HbS) found in red blood cells (RBCs). HbS polymerizes in low oxygen environments and contribute to painful vaso-occlusion in patients. Laboratory diagnosis of SCD is typically made by detection of the presence of sickle cells by peripheral blood smear, and presence of HbS by electrophoresis and high-performance liquid chromatography. Recently, flow cytometry technique in companion with sickling assays has demonstrated the capability in quantitative measurements of sickle cells at single-cell level, using software algorithm for cell-imaging analysis (Van Beers et. al. American Journal of Hematology 2014), and electrical impedance (Liu et. al. Sensors and Actuators B: Chemical 2018). Here, we show a portable, cost-efficient electrical impedance-based sensor and its capability to be used in conjunction with microfluidics-based sickling assay for microflow cytometry of sickle cells. The impedance microflow cytometer is based on a commercially available integrated circuit (IC), the AD5933. Using a microcontroller and additional circuitry on a custom designed printed circuit board, we are able to produce sinusoidal signals of up to 100kHz in frequency and sample up to 200 data points per second, at a cost under $60 in materials to create. The impedance measurement range is optimized to work in companion with microfluidic chips in general. In order to measure sickle cells, the impedance microflow cytometer is used in companion with our unique Polydimethylsiloxane (PDMS) microfluidic cell sickling assay (Du et. al. PNAS 2014). Cells are suspended in phosphate buffered saline (PBS) medium and move in the microchannel using a pressure driven flow. Impedance measurement is achieved using two Ti/Au electrodes embedded in the microchannel as cells flow past the electrodes. Data is captured and made available for post processing using a customized MATLAB script. RBCs from healthy donors and SCD patients were used to demonstrate the capability of the developed system. The results showed that our system can separate between normal RBCs and sickle cells, as well as between sickled and unsickled cells. The performance in detection of sickle cells is comparable to a commercial impedance analyzer. This proof-of-concept design aims to minimize the physical space needed for cytometry as well as bring affordable and reliable cytometry results within its given limitations. Figure Disclosures Alvarez: Forma Therapeutics: Consultancy; Novartis: Consultancy

Hemophilic Pseudotumor: An Important Differential Diagnosis of an Intracranial Mass

Hemophilic pseudotumor is a rare complication of hemophilia. We present the case of a male toddler with moderate hemophilia A and cranial hemophilic pseudotumor managed with factor VIII infusions. We also provide a review of the literature. Recognition of this rare manifestation of this complication of hemophilia is important to provide correct treatment and avoid unnecessary investigations, particularly biopsy, which is contraindicated in this condition

Optimal Hemoglobin Level for Pediatric Sickle Cell Patients Who Undergo Adenotonsillectomy

Abstract Background:The prevalence of obstructive sleep apnea syndrome (OSA) in children with sickle cell disease (SCD) is higher than in the general pediatric population. Adenotonsillectomy involves significantly increased risks in patients with SCD because of the need for general anesthesia,which could induce a vaso-occlusive event. Various preoperative regimens have been suggested to reduce peri-operative risks for SCD patients. Objective: We retrospectively reviewed the perioperative management for pediatric SCD patients undergoing adenotonsillectomy. We sought to identify the optimal preoperative hemoglobin (Hb) level for patients to have lowest risk of post-operative complications. Methods: Children between 1 and 18 years old with SCD including HbSS, HbSC, HbS beta thalassemia (Sβ0 and Sβ+) who underwent adenotonsillectomy from 2007 to 2017 were identified at Holtz Children's Hospital. Patients without these diseases who underwent the procedures were collected as a control. The study was approved by the University of Miami Institutional Review Board (IRB). De-identified data were exported to GraphPad Prism version 5.02 to perform the statistical analyses. Means were analyzed by student t test, rates by Chi-squared test. p = 11.5 g/dL (11.5% vs 60%, p=0.04; see Figure 1). Complication rates were also lower in the Hb 9-11.5 g/dL group, but without statistical difference (19.2% vs 40%, p=0.3). Data is limited by small sample size in the SCD group. Conclusion(s): We concluded that for pediatric SCD patients planning for adenotonsillectomy, it is better to keep the posttransfusion Hb level at least above 9 mg/dL but less than 11.5 g/dL before procedure to avoid significant post operational complications. If pretransfusion Hb level is above 9 mg/dL, exchange transfusion by partial phlebotomy or simple transfusion (not to exceed 11.5 g/dL) may be considered. Disclosures No relevant conflicts of interest to declare