Directive: Implementation of Prestorage Leukoreduction of Cellular Blood Components

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Directive: Implementation of Prestorage Leukoreduction of Cellular Blood Components (PDF Version, 112 kb)
Date: 1999-06-30

DATE: November 2, 1998

FROM: Director General, Therapeutic Products Programme

TO: Licensed Canadian Blood Establishments

SUBJECT: Implementation of Prestorage Leukoreduction of Cellular Blood Components

1. PURPOSE

The purpose of this Directive is to advise all licensed Canadian blood establishments to take the necessary steps to implement prestorage leukoreduction of all allogeneic red blood cell and platelet components as soon as operationally feasible, but no later than June 30, 1999.

2. BACKGROUND

The use of leukocyte-reduced blood and blood components for the management of transfusion-related complications has expanded considerably in the past several years. In Canada, leukocyte removal from all random donor platelets by filtration is currently performed prior to storage by the manufacturers of blood and blood components. A licence amendment for prestorage leukoreduction of apheresis platelets was also approved by the Therapeutic Products Programme (TPP) in August 1998. With regard to red blood cells, leukocyte removal by filtration is performed in hospitals poststorage for selected indications for which the beneficial effects of leukoreduction have been clearly established. Currently, these include the prevention of alloimmunization and recurrent non-hemolytic febrile transfusion reactions in patients requiring long-term transfusion therapy (1-5).

The improvements in leukocyte reduction techniques, and the increased knowledge about the role of leukocytes in many adverse transfusion reactions favor the extension of the indications for prestorage leukoreduced blood components. For example, accumulating data from preclinical (6,7) and clinical (8-12) studies suggest that leukoreduction may be effective in reducing the incidence of cancer recurrence and postoperative infections in surgical patients transfused with allogeneic blood components. Leukocytes also serve as a reservoir for certain viruses that can be transmitted through blood, and it has been demonstrated in several clinical studies that the removal of leukocytes from allogeneic blood significantly reduces the risk of transfusion-associated cytomegalovirus transmission (1,2,4,13,14). Thus, leukoreduction could potentially reduce or eliminate the transfusion-associated transmission of other leukotropic viruses. This is particularly significant in cases where screening tests for the infectious agents are not effective, or have yet to be developed.

To date, few disadvantages have been associated with the use of leukoreduced blood components. These include (i) an average red cell and platelet loss of 14 to 23% and 20 to 24%, respectively (15,16); and (ii) an increase in bradykinin concentration in some platelet and red cell components due to the activation of the contact system of coagulation factors by some brands of negatively charged filters (17, 18). A number of reports suggest that bradykinin may play a role in hypotensive reactions in patients on angiotensin-converting enzyme inhibitor therapy receiving blood components filtered at the bedside with negatively charged filters (19).

While the advantages of prestorage leukoreduction over poststorage leukoreduction have not been proven in randomized controlled clinical trials, results from animal studies clearly show that prestorage leukoreduction is superior to poststorage leukoreduction for the prevention of tumor growth (7) and alloimmunization (20). The superiority of prestorage leukoreduction for the prevention of non-hemolytic febrile transfusion reactions has also been demonstrated in non-randomized prospective and retrospective clinical studies (21,22). Furthermore, prestorage leukoreduction enables the removal of leukocytes before they disintegrate and release potentially harmful substances such as cytokines, membrane fragments containing human leukocyte antigens, and other metabolites into blood components (23-28). Finally, data from experimental studies indicate that prestorage leukoreduction reduces or prevents bacterial proliferation in blood components (29-33), and significantly reduces transfusion-associated Trypanosoma cruzi infection in mice (34).

The TPP is cognizant of some controversies regarding the efficacy of prestorage leukoreduction in preventing some of the deleterious effects of blood transfusions (2,4,12, 35-40). However, it believes that the evidence suggesting that a majority of transfusion recipients could potentially benefit from leukoreduced blood and blood components far outweighs the disadvantages associated with leukoreduction. The TPP also believes that the current practice of removing leukocytes from stored blood components just before transfusion is less desirable than prestorage leukoreduction in a manufacturing environment, as the latter appears to produce a better product, is more amenable to process and quality control, and provides a uniform standard for all blood components.

For the reasons stated above, the TPP has decided to introduce a requirement for the prestorage leukoreduction of all red blood cell and platelet components as a general safety enhancement. On October 8, 1998, the TPP's Expert Advisory Committee on Blood Regulation advised the TPP to proceed with this initiative.

3. RECOMMENDATION

The leukoreduced blood and blood components should be prepared by a method known to reduce the residual leukocyte content to levels below 5 x 106 cells per component.

4. SCOPE

This Directive applies to all licensed Canadian blood establishments involved in the manufacturing of allogeneic red blood cell and platelet components.

5. LICENSING REQUIREMENTS

Blood establishments are required to submit a Licence Amendment Submission to the Bureau of Biologics and Radiopharmaceuticals for review. This information is required as soon as possible but no later than February 1, 1999.

6. COMPLIANCE DATE

The TPP expects full implementation of prestorage leukoreduction across Canada by June 30, 1999.

7. ADDITIONAL INFORMATION

Questions concerning the Directive for Prestorage Leukoreduction of Blood Components should be directed to:

Director, Bureau of Biologics and Radiopharmaceuticals
3rd Floor LCDC Building #6
Postal Locator 0603C
Tunney's Pasture
Ottawa, Ontario
KIA 0L2

Attention: Blood and Tissues Division.

8. APPENDIX 1: List of References

Dann M. Michols

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3. Higgins VL. Leukocyte-reduced blood components: patient benefits and practical application. Oncol Nurs Forum 23:659-67 (1996).
4. Sirchia G, Rebulla P. Evidence-based medicine: the case for white cell reduction. Transfusion 37:543-9 (1997).
5. The Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusion. N Engl J Med 337:1861-9 (1997).
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20. Blajchman MA, Bardossy L, Carmen RA, Goldman M, Heddle NM, Singal DP. An animal model of allogeneic donor platelets refractoriness: The effect of the time of leukodepletion. Blood 79:1371-5 (1992).
21. Muir JC, Jacobson S, Herschel L, Aubuchon JP. Does prestorage leukocyte reduction of blood components reduce the risk of febrile reactions in sensitized patients? Blood 84 (10 Suppl 1):464a (1994).
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26. Shanwell A, Kristiansson M, Remberger M, Ringdén O. Generation of cytokines in red cell concentrates during storage is prevented by prestorage white cell reduction. Transfusion 37:678-83 (1997).
27. Nielsen HJ, Skov F, Dybkjaer E, Reimert CM, Pedersen AN, et al. Leucocyte and platelet-derived bioactive substances in stored blood: Effect of Prestorage leucocyte filtration. Eur J Haematol 58:273-8 (1997).
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32. Dzik W. Use of leukodepleted filters for the removal of bacteria. Immunol Invest 24:95-115 (1995).
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38. Houbiers JG, van de Velde CJ, van de Watering LM, Hermans J, Schreuder S, et al. Transfusion of red cells is associated with increased incidence of bacterial infection after colorectal surgery: A prospective study. Transfusion 37:126-34 (1997).
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