Milwaukee, Wisconsin 53226


Purpose:

The Investigators hypothesize that older red cell units trigger phagocytosis and activation of circulating macrophages with a downstream immunomodulatory cascade and release of excess Non Transferrin Bound Iron(NTBI) that leads to increased rates of infection in adults with Sickle Cell Disease(SCD). To test this hypothesis, the study staff will perform a randomized prospective clinical trial. In aim 1, the study staff will determine the biochemical differences between ≥30 day-old versus ≤10 day-old units. In aim 2, the study staff will determine the physiologic effects of the transfused blood in a patient with SCD. Lastly, in aim 3, the study staff will explore the clinical implications of receiving older red cells over a 3 month period.


Study summary:

The Investigators assembled a multidisciplinary investigative team to examine the potential effects of older red cell units in adults with Sickle Cell Disease(SCD). Study staff have preliminary data that show: 1) there is equipoise among blood bank directors about the effects of older units in adults with SCD, 2) in our institution, many adults are administered older units, 3) older units activate macrophages and 4) this physiology promoted by older units is associated with an increased risk of infection. Our team is now poised to take the next investigative step: a prospective, randomized study. In Milwaukee, 1/3 of units transfused to adults with SCD are >30 days old, but nation-wide some restrict the transfusion of older units. About four hundred adults receive care in the Adult Sickle Cell Clinic at Froedtert Hospital in Milwaukee, about 23 of who receive chronic outpatient transfusions for chronic pain or stroke prophylaxis. Transfusions are administered to adults regardless of storage age, except in the case of red cell exchange, for which there is a policy to use less than 14 day old units. In a 3-year retrospective review of transfusions administered to adults with SCD, 627 units were given via simple transfusion over 281 outpatient encounters. The overall median unit storage age was 22 days (range: 2-42 days), and 25% of the units transfused were stored 33 days or longer. To determine the opinions and policies of other hospital blood bank directors about the use of older red cell units for patients with SCD, study staff conducted a nation-wide survey (n=90). While only 23% of respondents had a storage age restriction policy for patients with SCD, 31% thought that older units were not as effective as younger units, and 65% believed that evidence-based policies were needed Adults with SCD may be susceptible to the effects of an older unit's physiology because they are prone to infection, inflamed, and poorly equipped to handle excess iron. In a cohort of 40 steady-state adults with SCD, we specifically measured markers of inflammation and iron excess. High sensitivity C-reactive protein, a marker of systemic inflammation, was found to be markedly elevated (median 5.6 mg/L, range 0.4-60 mg/L; reference range <1.0 mg/L), as was ferritin, a marker of iron stores (median 2,969 ng/ml, range 20-12,300 ng/ml; reference range 13-400 ng/ml). Forty chronically-transfused adults with SCD will be randomized in a double-blind fashion to receive ≥30 day-old or ≤10 day-old units for 3 months. Subjects will be randomized in blocks of 5 and stratified by age: at least 10 subjects from each of the age ranges 18-30 and 31-45 years will be enrolled. Pre-transfusion, sterile samples will be extracted from red cell units. Patient peripheral blood will be also obtained 1 month before randomization, immediately pre-transfusion, and 2 and 24 hours post-transfusion. Hemoglobin will be measured pre-transfusion, 2 and 24 hours post-transfusion, and 2 weeks post transfusion. Participants will complete standardized diaries daily to document symptoms of infection, SCD pain, medications and Emergency Department(ED) or hospital use. Diaries will be collected and participants will be assessed with each transfusion encounter and 4 weeks after the last transfusion. To ensure compliance, coordinators will contact subjects weekly to complete the diaries. Study staff will evaluate red cells pre- and post-transfusion for Phosphatidylserine(PE), Phosphatidylethanolamine(PS), and microparticles as above for all blood samples. White cells will be isolated with established separation techniques. The white cell populations of interest will be defined by their location on a forward scatter/side scatter plot and their positivity using key fluorochrome-labeled identity markers (macrophages: CD14, neutrophils: CD16). Once the cell populations of interest are identified, the cells will be evaluated for various markers of activation. The plasma fraction from each patient and red cell unit will be diverted to determine concentrations of free heme/hemoglobin, cytokines, and NTBI, respectively.


Criteria:

Inclusion Criteria: 1. age 18 to 45 years 2. Hemoglobin SS/Hemoglobin Sβ-thalassemia0 3. on chronic red cell transfusion therapy 4. outpatient at the time of transfusion Exclusion criteria: 1. history of reactions to transfusion therapy that cannot be adequately managed by antihistamines 2. ≥2 red cell alloantibodies 3. participation in another therapeutic trial for SCD 4. pregnant 5. HIV positive 6. uncontrolled inter-current illness, or psychiatric illness/social situations that would limit compliance with study requirements.


NCT ID:

NCT03704922


Primary Contact:

Principal Investigator
Joshua Field, MD
Blood Center of Wisconsin

Matthew Karafin, MD
Phone: 414-937-6809
Email: MKarafin@Versiti.org


Backup Contact:

Email: SABeggi@Versiti.org
Sarah Beggi
Phone: 414-937-6457


Location Contact:

Milwaukee, Wisconsin 53226
United States

Steven Frymark
Phone: 414-937-6814
Email: steven.frymark@bcw.edu

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: October 09, 2019

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