Age of Blood in Sickle Cell Transfusion
Age of Blood in Sickle Cell Transfusion
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.
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.
Inclusion Criteria:

 1. age 16 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.