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Age of Blood in Sickle Cell Transfusion

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03704922
Recruitment Status : Recruiting
First Posted : October 15, 2018
Last Update Posted : September 21, 2021
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Matthew Karafin, University of North Carolina, Chapel Hill

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Biological: Transfusion Phase 2 Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Age of Blood in Sickle Cell Transfusion -The Effects of Phosphotidylserine Expression on Older Red Cell Units in Adults With Sickle Cell Disease
Actual Study Start Date : October 4, 2017
Estimated Primary Completion Date : February 28, 2023
Estimated Study Completion Date : February 28, 2023

Arm Intervention/treatment
Experimental: ≤10 day Blood
Subjects in this group will receive only blood stored ≤10 days for 3 consecutive transfusion events.
Biological: Transfusion
Red cell units for transfusion

Experimental: ≥30 day Blood
Subjects in this group will receive only blood stored ≥30 days for 3 consecutive transfusion events.
Biological: Transfusion
Red cell units for transfusion

Primary Outcome Measures :
  1. Proportion of biochemically old red cell units [ Time Frame: 7 years ]
    We will compare the transfusions provided to the two groups (the proportion of biochemically old units when stored ≥30 days compared to when stored ≤10 days) using a Fisher exact test at an alpha of 0.05. Power: With a total sample size of 40 patients (20 in each group), we will have at least 80% power (α=0.05) to detect a difference of at least 47% between the two randomized groups for biochemically old red cell units (close to a 100% difference is expected). We will compare the secondary endpoints plasma free hemoglobin, heme, and NTBI and also PS, PE, and microparticle concentrations using a two sided two sample t-test at an alpha of 0.05.

Other Outcome Measures:
  1. Change in the concentration of CD62L positive circulating monocytes [ Time Frame: 7 years ]
    Change in CD62Lcirculating monocyte/macrophage MFI at 2 hours post-transfusion compared to the subject pre-transfusion. We will compare the two groups using a two sample two-sided t-test of the log at an alpha of 0.05. Power: In addition, we will use a general(ized) linear model to include biochemically old units transfused, regardless of unit age, as a covariate in our analysis. Other co-variates will include free heme, cell free hemoglobin, and NTBI from the transfused unit. We will similarly compare secondary activation endpoints: activation markers for neutrophils and measured cytokine concentrations. Lastly, as an exploratory aim, we will evaluate the in vivo change in recipient red cell PE/PS positivity at 2 and 24 hours post transfusion. When possible, donor and recipient red cells will be differentiated in S-antigen negative patients who are by chance provided S-positive heterozygous or homozygous donor red cells.

  2. Percentage of infections in adults [ Time Frame: 7 years ]

    The primary endpoint is the percentage of infections in adults who receive ≥30 day-old units as compared to ≤10 day-old units. The presence of an indwelling catheter will be used as a key co-variate in this analysis.

    We will further explore the relationship of blood age and transfusion of biochemically old red cell units on the change in Hb and HbS% over time, daily pain scores, opioid use and dose, ED and hospitalization rate, infection symptoms, new alloantibody formation, and antibiotic use during the 3-month study period. We will compare groups using a Fisher exact test. Power: A difference of 20% will be of clinical interest. We do not expect to have adequate power for this pilot study but at an alpha of 0.05 with 20 subjects in each group we will be able to detect a difference of 47% between the proportions.

Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03704922

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Contact: Matthew Karafin, MD 414-937-6809
Contact: David Wichlan 919-966-6876

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United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Hailly Butler, RN    404-712-8895   
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: David Wichlan    919-966-6876   
United States, Wisconsin
Versiti Wisconsin Completed
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Jane Little, MD University of North Carolina, Chapel Hill
Principal Investigator: Matthew Karafin, MD, MS University of North Carolina, Chapel Hill
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Responsible Party: Matthew Karafin, Principal Investigator, University of North Carolina, Chapel Hill Identifier: NCT03704922    
Other Study ID Numbers: 00026112
K23HL136787-01 ( U.S. NIH Grant/Contract )
First Posted: October 15, 2018    Key Record Dates
Last Update Posted: September 21, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to make Individual Participant Data (IPD) available.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Matthew Karafin, University of North Carolina, Chapel Hill:
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn