Valsartan impedes epinephrine-induced ICAM-4 activation on normal, sickle cell trait and sickle cell disease red blood cells.

Abnormal red blood cell (RBC) adhesion to endothelial αvβ3 plays a crucial role in triggering vaso-occlusive episodes in sickle cell disease (SCD). It is known that epinephrine, a β-adrenergic receptor (β-AR) stimulator, increases the RBC surface density of active intercellular adhesion molecule-4 (ICAM-4) which binds to the endothelial αvβ3. It has also been demonstrated that in human embryonic kidney 293 cells, mouse cardiomyocytes, and COS-7 cell lines, the β-adrenergic and renin-angiotensin systems are interrelated and that there is a direct interaction and cross-regulation between β-AR and angiotensin II type 1 receptor (AT1R). Selective blockade of AT1R reciprocally inhibits the downstream signaling of β-ARs, similar to the inhibition observed in the presence of a β-AR-blocker. However, it is not known if this mechanism is active in human RBCs. Here, we studied the effect of valsartan, an AT1R blocker, on the surface density of active ICAM-4 receptors in normal, sickle cell trait, and homozygous sickle RBCs. We applied single molecule force spectroscopy to detect active ICAM-4 receptors on the RBC plasma membrane with and without the presence of valsartan and epinephrine. We found that epinephrine significantly increased whereas valsartan decreased their surface density. Importantly, we found that pretreatment of RBCs with valsartan significantly impeded the activation of ICAM-4 receptors induced by epinephrine. The observed reduced expression of active ICAM-4 receptors on the RBC plasma membrane leads us to conjecture that valsartan may be used as a supporting remedy for the prevention and treatment of vaso-occlusive crisis in SCD

A Two-Compartment Model of Osmotic Lysis in Plasmodium falciparum-Infected Erythrocytes

We recently identified a voltage-dependent anion channel on the surface of human red blood cells (RBCs) infected with the malaria parasite, Plasmodium falciparum. This channel, the plasmodial erythrocyte surface anion channel (PESAC), likely accounts for the increased permeability of infected RBCs to various small solutes, as assessed quantitatively with radioisotope flux and patch-clamp studies. Whereas this increased permeability has also been studied by following osmotic lysis of infected cells in permeant solutes, these experiments have been limited to qualitative comparisons of lysis rates. To permit more quantitative examination of lysis rates, we have developed a mathematical model for osmotic fragility of infected cells based on diffusional uptake via PESAC and the two-compartment geometry of infected RBCs. This model, combined with a simple light scattering assay designed to track osmotic lysis precisely, produced permeability coefficients that match both previous isotope flux and patch-clamp estimates. Our model and light scattering assay also revealed Michaelian kinetics for inhibition of PESAC by furosemide, suggesting a 1:1 stoichiometry for their interaction

Patient Controlled Analgesia for Adults with Sickle Cell Disease Awaiting Admission from the Emergency Department

Background. A treatment algorithm for sickle cell disease (SCD) pain in adults presenting to a single emergency department (ED) was developed prioritizing initiation of patient controlled analgesia (PCA) for patients awaiting hospitalization. Objectives. Evaluate the proportion of ED visits in which PCA was started in the ED. Methods. A two-year retrospective chart review of consecutive SCD pain ED visits was undertaken. Data abstracted included PCA initiation, low versus high utilizer status, pain scores, bolus opioid number, treatment times, and length of hospitalization. Results. 258 visits resulted in hospitalization. PCA was initiated in 230 (89%) visits of which 157 (68%) were initiated in the ED. Time to PCA initiation was longer when PCA was begun after hospitalization versus in the ED (8.6 versus 4.5 hours, p<0.001). ED PCA initiation was associated with fewer opioid boluses following decision to admit and less time without analgesic treatment (all p<0.05). Mean pain intensity (MPI) reduction did not differ between groups. Among visits where PCA was begun in the ED, low utilizers demonstrated greater MPI reduction than high utilizers (2.8 versus 2.0, p=0.04). Conclusions. ED PCA initiation for SCD-related pain is possible and associated with more timely analgesic delivery

Annual Academy of Sickle Cell and Thalassaemia (ASCAT) conference: a summary of the proceedings

The fourteenth annual ASCAT conference was held 21-23 October 2019. The theme of the conference was 'Sickle Cell and Thalassaemia disorders new treatment horizon; while ensuring patient safety and delivering excellence in routine patient care.' Over the three-day conference, topics on current and novel models of care, advances in bone marrow transplant and gene therapy, as well as the psychosocial aspects of mind, body and health related quality of life were discussed. In addition, blood transfusion, apheresis, iron chelation therapy and acute haemolytic complications were presented. Quality standards in the diagnosis and treatment of sickle cell and thalassaemia were reviewed. Experts from Europe, the United Kingdom, the Middle East, the United States and Africa reported up-to-date scientific data, guides to comprehensive care, and current research into developing cures and advancing current therapy were described. In addition, oral and poster presentations on novel research from all over the world were shown during the conference

Identification of Risk Factors For an Unsuccessful Transition From Pediatric to Adult Sickle cell Disease Care.

Background A successful transition from pediatric to adult sickle cell disease (SCD) care is paramount to continued improvements in survival. In order to enhance transition success, our pediatric SCD transition process was modified to include combined adult and pediatric provider clinics that incorporated participation by our local SCD community‐based organization. All children ages 16 and over participated in this newly‐formed transition program. Procedure After 5 years of implementation of the modified SCD transition program, we retrospectively studied clinical and non‐clinical risk factors for an unsuccessful transition. Risk factor categories studied included patient demographics, transition clinic attendance, and disease severity. Results Thirty‐two percent of patients did not transition successfully. Demographic factors such as gender, race, and type of insurance did not influence transition outcome, although travel distance to the adult SCD center was an identifiable risk factor for an unsuccessful transition. While transition clinic attendance rate did not affect transition outcomes, older age at first modified combined transition clinic visit was a significant risk factor for lack of transition. Patients with clinical markers of milder disease severity (SC and Sβ+ genotypes and no chronic transfusion therapy) were at higher risk for an unsuccessful transition than patients with severe disease. Conclusions We have identified several risk factors for lack of transition success which will allow us to modify our transition efforts going forward to capture this highest risk subset. Pediatr Blood Cancer 2014;61:697–701. © 2013 Wiley Periodicals, Inc