Granulocytes, a subset of white blood cells characterized by cytoplasmic granules, are part of the innate immune response. Neutrophils are the most abundant type of granulocyte. Severe and prolonged neutropenia is associated with high rates of infection-related morbidity and mortality. While awaiting endogenous neutrophil recovery, transfusion of granulocyte concentrates from healthy donors is an appealing option.
Despite its hypothetical value, the practice of granulocyte transfusion remains controversial. Due to uncertain clinical benefits as well as concerns about potential adverse effects in donors and recipients, uptake of granulocyte transfusion in Canada and other jurisdictions has been modest. However, as new indications for granulocytes are being evaluated and the processes for donation and manufacturing evolve, there is renewed interest in the clinical use of granulocytes. This chapter provides an overview of granulocytes: clinical evidence, indications, manufacturing and recent innovations in manufacturing.
Neutrophils and neutropenia
Neutrophils represent 50–70% of all circulating leukocytes. Based on classic experiments performed with re-infusion of ex vivo-labeled cells, neutrophils remain in circulation for 6–8 hours with a rapid decline in function over time.1 Neutropenia most often occurs because of impaired production of neutrophils due to therapy-related myelosuppression, autoimmune conditions, or bone marrow failure from malignant or infiltrative processes. Rarely congenital mutations can also cause either severe neutropenia, for example in Kostmann syndrome or Shwachman-Diamond syndrome, or dysfunctional neutrophils as in Neutrophil-specific granule deficiency or chronic granulomatous disease.2
Severe neutropenia is defined by an absolute neutrophil count below 0.5 x 109/L.3 Patients with either severe neutropenia or qualitative neutrophil dysfunction face an increased risk of serious infection by invasive bacteria or fungi.
Evolving practice and changing demands
Since the 1970s, granulocyte concentrates have been prepared through mobilization of donor neutrophils by corticosteroid (e.g., prednisone) stimulation. However, this technique often produces relatively low cell count yields and dose variability and may have contributed to suboptimal clinical results described in early literature.4,5 Moreover, adverse transfusion reactions and the inability to store neutrophils beyond 24 hours contributed to granulocyte transfusion falling out of favour as a therapeutic measure.
In the 1990s, granulocyte colony-stimulating factor (GCSF) given in combination with corticosteroids to donors resulted in more consistent and larger quantities of harvested neutrophils from each donor. In addition, the widespread use of automated cell separators and starch sedimentation during production of granulocyte concentrates improved the feasibility of collecting larger doses of granulocytes.1,6-9
Given increased antimicrobial resistance worldwide and limited novel antibiotic drug classes, there is a renewed interest in granulocyte transfusion as a supportive care strategy for patients with severe neutropenia. In addition, with the advent of potentially curative intensive chemotherapy regimens used alone or in combination with hematopoietic stem cell transplantation, there are substantial numbers of patients with prolonged, severe neutropenia who may be considered for granulocyte transfusion. Moreover, granulocyte collection practices have changed, including those pertaining to mobilization of donor neutrophils, the use of automated apheresis equipment, and the use of multi-donor pools derived from buffy coat production methods. Potential new indications for granulocytes in the immunomodulatory domain are also being explored.10-12
Evidence for granulocyte transfusion
Whether granulocyte transfusion improves survival in patients with invasive infections remains unresolved. Available literature consists mostly of observational data, with few prospective studies and even fewer randomized trials. The relevance of older studies is questionable because supportive care interventions and the management of invasive infections for patients with neutropenia have improved, making comparisons with modern practice difficult.
In 2017, the National Institutes of Health (NIH) published their retrospective experience between 1984 and 2012 using granulocyte transfusion in 58 granulocyte transfusion episodes among 48 patients with chronic granulomatous disease. Both localized and disseminated infections with bacteria, fungi as well as polymicrobial infections were included. Only 1% of the granulocyte transfusions were associated with adverse events. They reported a high clinical success rate and concluded that early initiation within 1 month after infection, high frequency and sustained therapy is associated with significantly better outcomes.13 A case series14 on 32 patients with severe aplastic anemia who received granulocyte transfusions reported the overall survival to hospital discharge was 58% and suggested granulocyte transfusions may play an adjunctive role in severe infections in this patient group.
In contrast, a 2016 Cochrane systematic review15 evaluated the effectiveness and safety of granulocyte transfusions for treating infections and included 10 trials with a total of 587 participants. Overall the evidence was evaluated to be of either very low or low quality. The authors found there is insufficient evidence to determine whether granulocyte transfusion affects all-cause mortality at 30 days or evidence of clinical response to infection for neutropenic patients following myelosuppressive chemotherapy or hematopoietic stem cell transplantation (HSCT). In sub-group analysis, no difference was found between those receiving higher granulocyte doses of ≥ 1 x 1010 per day when compared to those receiving <1 x 1010 per day. Interestingly, in the five trials published prior to the year 2000, there was a small but significant difference in all-cause mortality (RR 0.53, 95% CI 0.33,0.85) which was not seen in the one trial published after 2000 (see RING trial below).
Randomized controlled trials
Few randomized controlled trials of granulocyte transfusion have been performed in the therapeutic setting. Of these, a number were undertaken over 30 years ago, with small sample sizes and variable outcomes. Some concluded a potential benefit of granulocyte transfusion while other studies yielded inconclusive results or even suggested potential detrimental effects.16-21
Findings from the two more recent trials failed to demonstrate benefit from the use of therapeutic granulocyte concentrates. A 2008 phase III randomized controlled trial (RCT)22 examined granulocyte transfusion in 72 patients with hematologic or malignant diseases. There was no difference in the probability of 28-day survival, and no effect on survival until day 100 in patients with fungal or bacterial infection.
The 201518 RING (Resolving Infection in Neutropenia with Granulocytes) study examined clinical efficacy of granulocyte transfusion for established infections; it is the largest RCT of granulocyte transfusions to date, with 14 participating centres, and was one of the studies included in the Cochrane systematic review.15 The trial was terminated prematurely due to poor enrollment, with only 114 patients enrolled of the 236 targeted. Success rates (based on the primary composite outcome of survival and resolution of infection) for granulocyte and control arms did not differ within any infection type. A post-hoc analysis found improved mortality outcomes in subjects who received higher doses (>0.6 x 109 granulocytes/kg) compared with those who received lower ones. However, given there was no difference between the high-dose treatment group and the control group, many view this finding as only hypothesis generating.
Prophylactic or pre-emptive granulocyte transfusion has been used in patients considered at risk of infections, or as secondary prophylaxis to prevent recurrent or worsening infection during a short period of anticipated severe neutropenia, just before or during hematopoietic stem cell transplantation.1
A 2015 Cochrane systematic review evaluated 12 RCTs including 653 patients that used granulocyte transfusion as primary prophylaxis.23 The authors concluded that in patients who are neutropenic due to chemotherapy or hematopoietic stem cell transplantation, there was low-grade evidence that prophylactic granulocyte transfusion decreased the risk of bacteremia or fungemia. Higher doses may have been more beneficial, with a minimum dose of 1x1010 granulocytes per day being more effective. There was insufficient evidence to determine any difference in mortality rates due to infection between people receiving prophylactic granulocyte transfusions and those who did not.23
Future clinical research
Although future RCTs of therapeutic or prophylactic granulocyte transfusion are challenging to conduct, high quality evidence from prospectively collected granulocyte transfusion recipient registries is expected.
As the manufacturer of granulocyte concentrates in Canada, Héma-Québec is a participant in the UK-based ProGrES (PROspective Granulocyte usage and outcomEs Survey)24, an international registry of granulocyte transfusions that aims to primarily describe how granulocytes are being used, including patient demographics and treatment, and clinical outcomes.12,25,26
Health-care facilities generally determine local criteria for use of granulocyte transfusion since the available evidence on clinical efficacy is limited. Lack of consistent access to high quality granulocyte concentrates may also limit the use of this intervention, as clinicians may be reluctant to consider this treatment if high-dose granulocyte concentrates are not readily available at their institutions.
Children, because of their smaller size, may respond to granulocyte transfusion more favorably than adults. Although there has never been a randomized trial of granulocyte transfusion specifically in children, granulocyte transfusion is more frequently used in the pediatric setting, including for neonates.27,28
Summary of indications
There are two broad indications for which granulocyte transfusion is sometimes considered:
Invasive infection refractory to antimicrobial therapy with severe neutropenia29
Invasive infection refractory to antimicrobial therapy with neutrophil function disorders
For these indications, there is a narrow window of opportunity in which to transfuse granulocyte concentrates, due to their short half-life (<24 hours). Granulocyte transfusion, if available, may be helpful in patients who fulfil all the following criteria:12,26,29
Neutropenia (<0.5 x 109/L) due to congenital or acquired bone marrow failure syndromes
Fever (≥ 24–48 hours) with persistent morbidity
Confirmed or highly probable bacterial or fungal infection and a poor response to antimicrobial therapy demonstrated clinically, microbiologically, or radiologically
A reasonable expectation for eventual neutrophil recovery
Granulocyte transfusion is unlikely to be beneficial for:
Bone marrow failure syndromes where neutrophil recovery is not anticipated
Sepsis in the absence of either neutropenia or known neutrophil dysfunction
Fever of unknown origin
Viral infection in isolation
Patients with known anti-HLA or anti-neutrophil antibodies26
Manufacturing granulocytes for transfusion
Granulocytes can be obtained by leukapheresis from a single donor or from the buffy coat derived from whole blood donations. In Canada, granulocytes are obtained by single donor leukapheresis at Héma-Québec.29 There are advantages and disadvantages to each collection method, which are discussed below. Granulocyte concentrates must be ABO-compatible and irradiated29 to prevent graft versus host disease (TA-GVHD).
Granulocytes collected by apheresis
To obtain sufficient granulocytes for transfusion, apheresis donors are administered a corticosteroid (such as prednisone or dexamethasone) with or without granulocyte colony-stimulating factor (G-CSF). At Héma-Québec29, donors are given a single dose of prednisone the day prior to donation, without adjunctive G-CSF.24,30 Pharmacological stimulation is required for single donors to obtain an absolute neutrophil count (ANC) of at least 1x1010 granulocytes in the collected unit. This is the minimal number of granulocytes in the concentrate which is considered to offer sufficient antimicrobial protection to recipients.24
Pharmacological stimulation significantly increases the number of circulating neutrophils from 7 to 13.5-fold.28 The yield of stimulated apheresis granulocytes is typically higher than that of the pooled component, but considerable variability in dosing remains.12,30
To optimize neutrophil separation from red blood cells during leukapheresis, a sedimentation agent is added to the donor whole blood in addition to an anti-coagulant.24,25 In most centres including Héma-Québec,29 hydroxyethyl starch is used as a sedimentation agent and citrate is used as an anticoagulant. The final yield of neutrophils in granulocyte concentrates may vary due to inter-donor variability or the type of leukapheresis machine used.31-33 Although leukapheresis generates a granulocyte concentrate, these components also contain red blood cells and a varying number of other leukocytes such as monocytes and lymphocytes.34
Since leukapheresis returns remaining cells to the circulation, donors can donate more often than for a standard whole blood collection, potentially providing a continuing source of neutrophils for granulocyte concentrates throughout a course of therapy. The apheresis method is resource intensive and logistically challenging, particularly because of the need to identify appropriate donors for frequent or ongoing collections. At Héma-Québec, donors are limited to six granulocyte donations per 12 months due to the risks to the donor of cumulative exposure to hydroxyethyl starch (HES). See more on HES exposure below.
Donor selection and donor complications
Granulocyte donors have the same general eligibility criteria as donors of other labile blood components. However, at Héma-Québec donors must answer an extra set of questions regarding their eligibility to take prednisone. A donor collection centre must have the necessary infrastructure in place to ensure the consistent collection of high-yield granulocytes. Granulocyte apheresis requires expertise and experience in using HES to facilitate differential centrifugation.
Communication is crucial between the suppliers, hospital transfusion services laboratory, and the clinical team to ensure granulocyte transfusion occurs as rapidly as possible after collection (ideally within 6 hours) because neutrophil function decreases rapidly in storage. Granulocytes must be transfused within 24 hours of collection on a daily or alternating daily schedule to maintain innate immunity until the patient recovers.27,28 Granulocyte donation requires a substantial commitment from donors; use of pharmacological stimulating agents and exposure to HES adds an increased risk compared to other blood donors. Multiple donors are required to provide a steady supply of granulocyte components for transfusion and maintaining a supply can become challenging.28
Established donors with low risk for ineligibility are preferred.20,35 ABO matching is required. As each granulocyte unit contains approximately 20–50 mL of red blood cells, blood group compatibility is an important requirement, especially in pediatric patients with small blood volumes who are risk of hemolytic transfusion reactions related to recipient anti-A and/or anti-B. Granulocytes for CMV-seronegative recipients should be collected from CMV-seronegative donors.29
Granulocyte units are issued with transmissible disease testing results from the donor’s most recent blood donation (prior to granulocyte donation) and have “pending analysis” written on the ISBT label. Testing is performed on the donor’s granulocyte donation on the day following collection and the updated testing results are provided to the ordering hospital as they become available (see the FAQ on ordering granulocyte concentrates for more information).
A variety of neutrophil mobilization regimens have been evaluated. Single-agent G-CSF or G-CSF in combination with dexamethasone is more efficient than dexamethasone alone. In Canada, Héma-Québec donors undergo mobilization through use of prednisone alone29 —without G-CSF—due to possible risks to donor health associated with G-CSF36,37,29 However, follow-up studies of granulocyte donors who received recombinant G-CSF showed no adverse outcomes for donors more than three years after donation.10,36 Long-term safety of G-CSF has also been noted in donors of hematopoeitic progenitor cells who have received G-CSF.38
Fluids shifts and hypo- or hypervolemia may occur in the donor. Hypocalcemia may result from citrate administration. In addition, hydroxyethyl starch products to induce RBC rouleaux formation and enhance granulocyte collection may persist within the donor’s circulation.
Serious hazards of HES exposure have been described in hospitalized patients who received HES for hypotension associated with hypovolemia. These adverse effects include fever, fluid retention, hypertension, coagulopathy, headache, nephrotoxicity and a range of allergic reactions from urticaria to anaphylaxis. As a result of these observations in hospitalized patients, both Health Canada and the United States Federal Drug Administration (FDA) issued safety warnings about the use of HES39-41, while the European Union suspended marketing authorization for all HES products42 in May 2022.
The extent to which these safety concerns are relevant to the health of granulocyte donors is uncertain.43,44 Nonetheless, the use of HES in the production of granulocyte concentrates is not sustainable in the long term. Manufacturers of granulocyte concentrates, including Hema-Quebec, are working on alternative, HES-free manufacturing techniques using granulocytes from pooled buffy coats derived from whole blood donations.
Granulocytes derived from pooled buffy coat
As an alternative to apheresis collected granulocyte concentrates, granulocytes can be prepared from pooled buffy coat obtained from unstimulated donors.1 These whole blood-derived granulocytes are not currently available in Canada. Some countries including the UK, France and Australia provide pooled granulocyte components from whole blood-derived buffy coats.12
Variation in production
Several procedures have been developed to prepare granulocyte concentrates from residual buffy coats obtained from unstimulated blood donors. Since the number of neutrophils per individual donor derived buffy coat is not sufficiently high for a single granulocyte concentrate transfusion, between 10–20 buffy coats may be pooled to obtain the required granulocyte quantity.45 Residual buffy coats are a by-product of whole blood processing that is usually discarded. To prepare pooled granulocyte concentrates buffy coats are separated from other whole blood components by centrifugation and then pooled to obtain the required ANC for granulocyte transfusion prior to irradiation and storage.
There is significant variation in preparations of granulocyte concentrates from buffy coats, with no validated standard worldwide. Procedural differences include different storage times of the initial blood component (whole blood or individual buffy coats) prior to processing, the number of centrifugations, the equipment used for centrifuging whole blood, and the additive solutions used to dilute the product during processing. One published manufacturing method is briefly described here.44 Whole blood components are separated by centrifugation and stored for 18 hours at 22°C without agitation prior to further processing.45 Five BCs are pooled and diluted with platelet additive solution (SSP+) prior to a further centrifugation step and the reduction of the number of RBCs using the Optipress II automated blood component extractor system. Dilution of the pooled buffy coats decreases the viscosity of the cell preparation and improves blood component separation. Two enriched granulocyte preparations of five buffy coats each are then pooled and stored in autologous plasma until transfusion. The final product of approximately 200 to 250 mL contains on average 0.88 x 1010 neutrophils. Hydroxyethyl starch is not used in this protocol to sediment RBCs; in Europe hydroxyethyl starch products no longer have marketing authorization.46,47
The in vivo feasibility for use of these pooled, whole blood-derived granulocytes was evaluated, and indicated a recipient safety profile comparable to apheresis derived granulocyte concentrates.46 The method described to produce pooled, whole blood-derived granulocytes has now been adopted by the NHS BT for manufacturing of pooled granulocyte concentrates (NHS guideline 2021).26,48 RBC and platelet content remains relatively high in pooled granulocyte components.
Various protocol modifications have been adopted by other blood suppliers to decrease volume or increase the neutrophil yield.49,50 Buffy coat granulocyte concentrates prepared from the residual leukocyte unit of blood processed with the automated blood processing system Reveos have been reported.51 This procedure generates a buffy coat granulocyte concentrate of 300 mL with a lower neutrophil yield of 0.63 x 109. The buffy coat neutrophil yield can be increased by storing whole blood overnight prior to generating residual leukocyte units with the Reveos system or by increasing the number of donors in each pool (M. Girard, personal communication, July 7, 2023).
One of the major drawbacks of buffy coat granulocyte concentrate preparation is the loss of approximately 30% of neutrophils from the initial whole blood donation due to the use of a leukocyte reduction filter in whole blood processing. This technical barrier has not been uniformly resolved, although the Reveos system may offer one solution since granulocytes are collected in the residual leukocyte bag before the filtration.
Dosage and administration of granulocyte transfusion
Ideally, transfusion should take place within 6 hours of collection but may be transfused up to a maximum of 24 hours post-collection.52
For apheresis granulocyte concentrates the dose is typically 1 unit per day until a pre-determined clinical endpoint is reached. For children, every other day dosing is sometimes provided. The typical volume of 1 unit of apheresis granulocyte concentrate collected by Héma-Québec is 350 mL. The infusion time will depend on the volume of the granulocyte concentrate, the remaining infusion time prior to component expiry, and the volume tolerance and size of the transfusion recipient; infusion rate should thus be adjusted accordingly by the prescriber. Often, daily dosing over 1–2 weeks is provided although, in some cases daily doses for up to 42 days have been used.12,18
Clinical endpoints may include:
Resolution of infection;
Fever diminishes or disappears;
Absolute neutrophil count ≥ 0.5 x 109/L; or
Most Responsible Health Practitioner (MRHP) stops therapy.
Note that granulocyte transfusions rarely result in a measurable increase in the patient’s absolute neutrophil count.29
Granulocyte concentrates contain a large number of red blood cells, and bidirectional compatibility tests (major and minor) must be conducted prior to transfusion.29
Granulocytes should be administered as soon as possible after collection using a standard transfusion set. Leukocyte depletion filters trap granulocytes and must not be used in the transfusion of this component.29
Adverse transfusion reactions
The adverse reactions associated with transfusion of any blood component (see Chapter 10, Transfusion reactions) may also be associated with transfusion of granulocyte concentrates, although adverse reactions related to granulocyte transfusions are underreported in literature. The nature of granulocyte concentrates and their production also contribute to an increased risk of some specific types of adverse events. The informed consent process that occurs prior to the transfusion of granulocyte concentrates must account for the transfusion-associated risks that are specific to the use of granulocyte concentrates.
Transfusion-associated graft-versus-host-disease (TA-GvHD). The granulocyte concentrate has considerable lymphocyte contamination and inherently poses a risk for TA-GvHD. Granulocyte concentrates or pools therefore require irradiation prior to transfusion.
Transmission of infectious agents. The brief time frame from collection to transfusion prevents completion of routine laboratory-based testing for infectious diseases prior to the issue and transfusion of the granulocyte concentrate. Moreover, leukoreduction is contraindicated for granulocyte concentrates. Granulocyte-related transmission of West Nile virus and cytomegalovirus (CMV) have been reported. For CMV prevention, some suppliers or treaters select CMV seronegative donors for CMV seronegative recipients. However, CMV seronegative products may not always be available.10,20,53,54
Acute transfusion reactions. Most are described as mild reactions, but serious complications resulting in admission to an intensive care unit have been documented. In the RING trial, grade 1–2 reactions were seen in 41% of patients (fever, chills, and/or modest blood pressure changes). Grade 3–4 reactions (hypoxia, tachycardia, hypotension, allergic symptoms) were seen following at least one transfusion in 20% of patients, although this accounted for <5% of all transfusions overall. No deaths due to transfusion reactions were reported.12,18
Acute pulmonary complications. In previous decades there was concern regarding granulocyte transfusion in conjunction with the initiation of amphotericin B treatment, where a syndrome consistent with transfusion-associated acute lung injury (TRALI) was observed in one report from the NIH.55 This association has not been reproduced. Despite this, granulocyte transfusions are at times temporally separated from amphotericin B administration by a few hours. Separation of amphotericin B administration and granulocyte transfusion is not necessary and should not delay administration of either of these therapies.27,56,57
HLA Alloimmunization. Granulocytes expose recipients to additional donor HLA antigens and may provoke HLA alloimmunization. Those receiving granulocyte transfusions have higher chances of developing alloimmune platelet refractoriness.
There are few high quality randomized clinical trials to support the clinical effectiveness of granulocyte transfusion.24
Granulocyte transfusion may provide benefit as an adjunctive therapy to patients with severe neutropenia or neutrophil dysfunction. However, granulocyte transfusion may cause harm to both donors and recipients. There remains inconsistent use of granulocyte transfusion across Canadian institutions. Real-world evidence may emerge from several multinational registries that could assist in informing clinicians and blood manufacturers about the role of granulocyte transfusions.24 Additional indications for granulocyte transfusions are also under investigation.
Additional resources and further reading
This FAQ summarizes the ordering process for granulocyte concentrates, includes links to the ordering forms and provides information on delivery, storage, and reporting requirements.
These key papers offer broad perspectives on the clinical use of granulocyte concentrates:
Gea-Banacloche, J. Granulocyte transfusions: A concise review for practitioners. Cytotherapy 19, 1256-1269 (2017).
Cohen, T., Simmons, S.C., Pham, H.P., et al. Granulocyte Transfusion: Clinical Updates and a Practical Approach to Transfusion. Clin Lab Med 41, 647-657 (2021).
West, K.A. & Conry-Cantilena, C. Granulocyte transfusions: Current science and perspectives. Seminars in hematology 56, 241-247 (2019)
Morton, S., Massey, E., Elebute, M., et al. Clinical guidelines for the use of granulocyte transfusion. NHS Blood and Transplant (2021).
Morton, S., Fleming, K. & Stanworth, S.J. How are granulocytes for transfusion best used? The past, the present and the future. British journal of haematology (2022).
Continuing professional development credits
Fellows and health-care professionals who participate in the Canadian Royal College's Maintenance of Certification (MOC) program can claim the reading of the Clinical Guide to Transfusion as a continuing professional development (CPD) activity under Section 2: Self-learning credit. The reading of one chapter is equivalent to two credits.
Medical laboratory technologists who participate in the Canadian Society for Medical Laboratory Science’s Professional Enhancement Program (PEP) can claim the reading of the Clinical Guide to Transfusion as a non-verified activity.
The authors acknowledge Dr. Andrew Daly, Dr. Andrew Shih and Dr. Celina Montemayor for their detailed review of this chapter and Dr. Susan Nahirniak for advice on the chapter’s content.
Gardner E, Fernandes M, Latour C, Seftel M, Acker J, Clarke G. Granulocyte transfusion therapy. In: Khandelwal A, Abe T, editors. Clinical Guide to Transfusion [Internet]. Ottawa: Canadian Blood Services, 2023 [cited YYYY MM DD]. Chapter 19. Available from: https://professionaleducation.blood.ca
If you have questions about the Clinical Guide to Transfusion or suggestions for improvement, please contact us through the Feedback form.
- West, K.A. & Conry-Cantilena, C. Granulocyte transfusions: Current science and perspectives. Seminars in hematology 56, 241-247 (2019).
- Gyurkocza, B., Wlodarski, M., Dunbar, C.E., et al. Myeloid disorders and inherited bone marrow failure syndromes. in American Society of Hematology Self-Assessment Program 0 (American Society of Hematology Washington, DC, 2022).
- Taplitz, R.A., Kennedy, E.B., Bow, E.J., et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. Journal of Clinical Oncology 36, 3043-3054 (2018).
- Price, T.H. Granulocyte transfusion therapy: it's time for an answer. Transfusion 46, 1-5 (2006).
- Schiffer, C.A. Granulocyte transfusion therapy 2006: The comeback kid? Med Mycol 44, S383-s386 (2006).
- Bearden, J.D., 3rd, Coltman, C.A., Jr. & Ratkin, G.A. Hydroxyethyl starch and prednisone as adjuncts to granulocyte collection. Transfusion 17, 141-146 (1977).
- McCullough, J. Leukapheresis and granulocyte transfusion. CRC Crit Rev Clin Lab Sci 10, 275-327 (1979).
- Iacone, A., Di Bartolomeo, P., Di Girolamo, G., et al. Hydroxyethyl starch and steroid improved collection of normal granulocytes with continuous flow centrifugation gravity leukapheresis. Haematologica 66, 645-655 (1981).
- Eckermann, I. & Strauss, R.G. Granulocyte collection: a comparison of Fenwal CS 3000, IBM 2997, and haemonetics cell separators. Journal of clinical apheresis 2, 26-31 (1984).
- Klein, K. & Castillo, B. Historical Perspectives, Current Status, and Ethical Issues in Granulocyte Transfusion. Ann Clin Lab Sci 47, 501-507 (2017).
- Hiwarkar, P., Adams, S., Gilmour, K., et al. Cord blood CD8+ T-cell expansion following granulocyte transfusions eradicates refractory leukemia. Blood advances 4, 4165-4174 (2020).
- Morton, S., Fleming, K. & Stanworth, S.J. How are granulocytes for transfusion best used? The past, the present and the future. British journal of haematology (2022).
- Marciano, B.E., Allen, E.S., Conry-Cantilena, C., et al. Granulocyte transfusions in patients with chronic granulomatous disease and refractory infections: The NIH experience. J Allergy Clin Immunol 140, 622-625 (2017).
- Quillen, K., Wong, E., Scheinberg, P., et al. Granulocyte transfusions in severe aplastic anemia: an eleven-year experience. Haematologica 94, 1661-1668 (2009).
- Estcourt, L.J., Stanworth, S.J., Hopewell, S., et al. Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction. The Cochrane database of systematic reviews 4, Cd005339 (2016).
- Fortuny, I.E., Bloomfield, C.D., Hadlock, D.C., et al. Granylocyte transfusion: a controlled study in patients with acuute nonlymphocytic leukemia. Transfusion 15, 548-558 (1975).
- Winston, D.J., Ho, W.G. & Gale, R.P. Therapeutic granulocyte transfusions for documented infections. A controlled trial in ninety-five infectious granulocytopenic episodes. Annals of internal medicine 97, 509-515 (1982).
- Price, T.H., Boeckh, M., Harrison, R.W., et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood 126, 2153-2161 (2015).
- Cairo, M.S., Worcester, C.C., Rucker, R.W., et al. Randomized trial of granulocyte transfusions versus intravenous immune globulin therapy for neonatal neutropenia and sepsis. The Journal of pediatrics 120, 281-285 (1992).
- Cohen, E.R., Miceli, M., Ahmed, J., et al. The Safety and Efficacy of Granulocyte Transfusions in Pediatric Recipients with Severe Neutropenia. Blood 138, 2148 (2021).
- Morton, S., Boulat, C., Laing, E., et al. Use of Granulocyte Transfusions in Two National Cohorts and Association between Transfusion Dose and Patient Outcomes: The Best Collaborative Study. Blood 138, 3242 (2021).
- Seidel, M.G., Peters, C., Wacker, A., et al. Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant 42, 679-684 (2008).
- Estcourt, L.J., Stanworth, S., Doree, C., et al. Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction. The Cochrane database of systematic reviews 2015, Cd005341 (2015).
- Pagano, M.B., Morton, S., Cohn, C.S., et al. An International Registry of Granulocyte Transfusions. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 45, 318-322 (2018).
- West, K.A., Gea-Banacloche, J., Stroncek, D., et al. Granulocyte transfusions in the management of invasive fungal infections. British journal of haematology 177, 357-374 (2017).
- Morton, S., Massey, E., Elebute, M., et al. Clinical guidelines for the use of granulocyte transfusion. NHS Blood and Transplant (2021).
- Cohen, T., Simmons, S.C., Pham, H.P., et al. Granulocyte Transfusion: Clinical Updates and a Practical Approach to Transfusion. Clin Lab Med 41, 647-657 (2021).
- Héma-Québec. Circular of information. (Héma-Québec, 2021).
- Morton, S., Stanworth, S., Lozano, M., et al. Vox Sanguinis International Forum on provision of granulocytes for transfusion and their clinical use. Vox sanguinis 112, e48-e68 (2017).
- Thorausch, K., Schulz, M., Bialleck, H., et al. Granulocyte collections: comparison of two apheresis systems. Transfusion 53, 3262-3268 (2013).
- Leitner, G.C., Kolovratova, V., Horvath, M., et al. Granulocyte collection using a novel apheresis system eases the procedure and provides concentrates of high quality. Transfusion 55, 991-995 (2015).
- Cancelas, J.A., Padmanabhan, A., Le, T., et al. Spectra Optia granulocyte apheresis collections result in higher collection efficiency of viable, functional neutrophils in a randomized, crossover, multicenter trial. Transfusion 55, 748-755 (2015).
- Murru, A., Allard, M., Paré, G., et al. Comparison of Neutrophil Function in Granulocyte Concentrates From Prednisone- and G-CSF-Treated Donors: Effect of Stimulant, Leukapheresis and Storage. Front Med (Lausanne) 9, 839475 (2022).
- Dorsey, K.A., Moritz, E.D., Steele, W.R., et al. A comparison of human immunodeficiency virus, hepatitis C virus, hepatitis B virus, and human T-lymphotropic virus marker rates for directed versus volunteer blood donations to the American Red Cross during 2005 to 2010. Transfusion 53, 1250-1256 (2013).
- Cavallaro, A.M., Lilleby, K., Majolino, I., et al. Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant 25, 85-89 (2000).
- Al-Khinji, A. & Linenberger, M. Splenic infarction and G-CSF. Transfusion 55, 708 (2015).
- Shaw, B.E., Confer, D.L., Hwang, W., et al. A review of the genetic and long-term effects of G-CSF injections in healthy donors: a reassuring lack of evidence for the development of haematological malignancies. Bone Marrow Transplant 50, 334-340 (2015).
- Ambruso, D.R. Hydroxyethyl starch and granulocyte transfusions: considerations of utility and toxicity profile for patients and donors. Transfusion 55, 911-918 (2015).
- Health Canada. Health Product InfoWatch. (2021).
- U.S. Food and Drug Administration. Labeling Changes on mortality, kidney injury, and excess bleeding wiht hydroxyethyl starch products. (2021).
- European Commission. Commission Implementing Decision of 24.5.2022 concerning, in the framework of Article 107p of Directive 2001/83/EC of the European Parliament and of the Council, the marketing authorisations of medicinal products for human use which contain the active substance “hydroxyethyl starch (HES), solutions for infusion” following an assessment of a post authorisation safety study. (2022).
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