Age of Blood in Sickle Cell Transfusion

Sickle Cell Disease Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03704922
• Other study ID #: 21-0018
• Secondary ID: K23HL136787-01
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: October 4, 2017
• Est. completion date: March 31, 2024

Study information

• Verified date: April 2023
• Source: University of North Carolina, Chapel Hill
• Contact: Matthew Karafin, MD
• Phone: 414-937-6809
• Email: MKarafin[@]Versiti.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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, the investigators 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, at most, 3 consecutive outpatient transfusions. Subjects will be randomized in blocks of 5 and stratified by age: at least 10 subjects from each of the age ranges 16-30 and 31-60 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: March 31, 2024
• Est. primary completion date: March 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 60 Years

Eligibility

Inclusion Criteria:

• age 16 to 60 years

• have diagnosis of sickle cell disease

• receiving outpatient red cell transfusion therapy

• outpatient at the time of transfusion

Exclusion criteria:

• history of reactions to transfusion therapy that cannot be adequately managed by antihistamines

• do not have crossmatch compatible red cells

• participation in another therapeutic trial for SCD

• pregnant

• HIV positive

• uncontrolled inter-current illness, or psychiatric illness/social situations that would limit compliance with study requirements.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Biological:
• Transfusion
Red cell units for transfusion

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Versiti Wisconsin	Milwaukee	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in the concentration of CD62L positive circulating monocytes	Change in CD62Lcirculating monocyte/macrophage MFI at 2 hours post-transfusion compared to the subject pre-transfusion. The investigators 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.	through third transfusion, an average of 18 weeks
Other	Percentage of infections in adults	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.; The investigators 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. The investigators will compare groups using a Fisher exact test. Power: A difference of 20% will be of clinical interest. The investigators do not expect to have adequate power for this pilot study but at an alpha of 0.05 with 20 subjects in each group the investigators will be able to detect a difference of 47% between the proportions.	through fourth transfusion, an average of 24 weeks
Primary	Proportion of biochemically old red cell units	The investigators 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), the investigators will have at least 80% power (a=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). The investigators 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.	through third transfusion, an average of 18 weeks