Treasures of Transfusion Medicine
Significant blood banking advances are in progress and experts predict this trend will continue.
By Jay E. Menitove, MD
Blood bankers, or as some prefer, transfusion medicine specialists, face extraordinary changes. New infectious disease testing procedures and expanded use of state-of-the-art leukocyte-reduction filtration processes further reduce transfusion-transmitted infection risks and potentially obviate transfusion-related immunologic adverse events.1,2 Concomitant with these advances, automated blood collection equipment and breakthroughs in information technology facilitate public and professional information exchange about blood.3
Tempering these advances, however, are emerging threats of new infectious agents (e.g., new variant Creutzfeldt Jacob Disease [nvCJD]) and an erosion of the blood donor base.4,5 Cost containment, affecting all aspects of health care, restricts choices but exerts a salutary effect by focusing attention on outcomes and best practices.6
New Viral Testing
Nucleic acid amplification testing (NAT) began in the United States by spring 1999 under Food and Drug Administration (FDA)-approved Investigational New Drug (IND) applications. Rather than detecting human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infected donors by antibody testing, NAT detects genomic HIV and HCV RNA sequences.
NAT’s benefit relates to shortening the “window” between infection and sero-detection (i.e., the interval in which donors transmit HIV or HCV but lack anti-HIV or anti-HCV antibodies).1 Based on reports involving more than 5 million donations screened by NAT, 1 per 250,000 donors was found anti-HCV negative/HCV NAT positive.7,8 This approximates the residual risk estimate of HCV transmission by anti-HCV negative blood of 1 per 120,000 units and presumably lowers the risk substantially.9
As of November 1999, only one donor out of more than 5 million was HIV antibody negative/HIV NAT positive. Taken together, NAT appears effective in improving transfusion therapy safety. This accomplishment, conducted under the FDA-approved IND, occurred when testing was performed on plasma aliquots pooled from several donors. Pooling reduces cost but may decrease sensitivity through dilution. At this time, it’s unclear when single donor testing will replace pooled testing and how this change will affect the current $60 million to $80 million annual expenditure attributed to NAT.
Testing detects known pathogenic viruses but does not prevent transmission of emerging and newly discovered pathogens. It also does not eliminate transfusion-associated bacterial infections. For these reasons, intense efforts to develop techniques that destroy viral and bacterial pathogens are under way.
For example, the solvent/detergent viral inactivation process effectively prevents transmission of lipid envelope-containing viruses (e.g., HIV and HCV) by plasma and plasma derivatives such as factor VIII and factor IX concentrates. Non-lipid enveloped viruses such as the hepatitis A and parvovirus B19 are not inactivated by the solvent/detergent process, although these agents can be detected by NAT.
Viral inactivation techniques for platelet concentrates and red blood cells are in development and early clinical trials. While these developments hold promise, potential toxicities caused by the chemicals used in the treatment process must be evaluated before wide-scale implementation is approved by the FDA.10
From a risk/benefit vantage point, most agree that 5.0 x 106 or more white cells per unit provide no benefit while adding some risk to red blood cell or platelet transfusions.2 The contaminating white cells are implicated causally in the pathogenesis of febrile, nonhemolytic transfusion (“chill-fever”) reactions, alloimmunization and refractoriness to platelet transfusions, cytomegalovirus (CMV) transmission and transfusion-related immunomodulation.2,11,12 The latter refers to reports linking transfusion to an increased rate of postoperative infections and transfusion with a shortened disease-free interval following tumor surgery.
Leukocyte reduction filtration prior to component storage–or performing leukocyte reduction at blood collection facilities before distributing the components to hospitals–provides standardized procedures, achieves economies of scale through uniform processes and removes white cells before cytokine production and leukocyte fragmentation. Leukocyte reduction lowers the rates of febrile reactions, alloimmunization and CMV transmission.
The evidence for preventing transfusion-related immunomodulation is less clear. It is noteworthy that randomized, clinical trials investigating the relative risk of transfusion-related immunomodulation and possible benefits of leukocyte reduction provide inconclusive results about both of these issues.13,14
Recently released results of the NIH-sponsored multi-center Viral Activation Transfusion Study trial refute concerns that transfusion activates HIV and CMV in patients infected with these viruses.15 HIV and CMV activation did not occur among recipients of nonleukocyte-reduced or leukocyte-reduced red blood cell transfusions. Logistic advantages and presumed enhancements to patient care accrue by adopting universal leukocyte reduction. Cost constraints, however, argue for limiting leukocyte reduction to clinical situations most likely to benefit from this procedure. There’s a potential $500 million annual expenditure associated with universal leuko-reduction.
Of note, the FDA’s Blood Products Advisory recommended universal leukocyte reduction, preferably done prior to storage, in September 1998. During an FDA-sponsored workshop in December 1999, a consensus emerged to achieve universal leukocyte reduction of all blood components within two years. Red cells will be leukocyte reduced by filtration and platelets, most likely, will be supplied as leukocyte-reduced platelet apheresis components.
Outcomes, Benchmarking, Best Practices
Clearly, health care reimbursement cutbacks create an environment in which all decisions undergo fiscal scrutiny.6 Choices require justification by showing positive outcomes and patient benefits. Blood bankers now increasingly rely on evidence-based decision making, compare their practices with others and use this information for selecting the best practices. This advance in blood banking, more subtle than other advances, provides an important opportunity for progress.
Changes in the Donor Base
Seventy-five percent to 80 percent of blood donors are repeat donors; those identified as carriers of infectious agents are deferred from future donations. Since the seroconversion rate is low in repeat donors, the effect translates into increases in transfusion safety.
The number of persons willing to donate blood has declined in recent years. The National Blood Data Resource Center found allogeneic donations had decreased 3 percent between 1994 and 1997 while whole blood/red cell transfusions increased 3.7 percent.5
A decline in discarded units, attributed to fewer positive screening test results and lower outdating, helped maintain inventory levels. Without an increase in blood donations, shortages are predicted. Fortunately, preliminary information suggests an increase in donations during 1999, but greater numbers of donations are needed. Use of advanced, automated (apheresis) blood collection devices that permit collection of two units of red cells within 45 minutes, two doses of apheresis platelets within 60 to 100 minutes, “jumbo” plasma units within 30 to 45 minutes or combinations of these procedures maximize the donor’s contribution and provide more components from the existing donor base.3 It’s likely that blood collections using automated blood devices will increase, especially in light of plans for universal leukocyte reduction within the next two years.
Hematopoietic Progenitor Cell Activities
Assuming blood banking is a support service for surgeons and oncologists, a natural extension of current activities includes hematopoietic stem cell collection, preservation and storage for treatment of hematologic and oncologic conditions. Advances in this arena include umbilical cord blood banking.16 Cord blood is enriched in stem cells and has been demonstrated to be a useful source of hematopoietic progenitor cells for patients without related histocompatible donors. Several blood centers, academic institutions and free-standing organizations have organized cord blood banks and provide cord blood units to transplant centers. *
Dr. Menitove is executive director and medical director of the Community Blood Center of Greater Kansas City (MO).
1. Sun R, Schilling W, Jayakar H, et al. Simultaneous extraction of hepatitis C virus (HCV), hepatitis B virus, and HIV-1 from plasma and detection of HCV RNA by a reverse transcriptase-polymerase chain reaction assay designed for screening pooled units of donated blood. Transfusion 1999;39:1111-19.
2. Transfusion-associated immunomodulation and universal white cell reduction: Are we putting the cart before the horse? Transfusion 1999;39:665-670.
3. Rugg N, Pitman C, Menitove JE, et al. A feasibility evaluation of automated blood component collection system platelets and red cells. Transfusion 1999;39:460-65.
4. Collinge J. Variant Creutzfeldt-Jacob disease. Lancet 1999;354:317-23.
5. Sullivan MT, Wallace EL, Umana WO, Schreiber GB. Trends in the collection and transfusion of blood in the United States, 1987-1997. Transfusion 1999;39:1S(P2-020C).
6. AuBuchon JP. Blood transfusion options: Improving outcomes and reducing costs. Arch Pathol Lab Med 1997;121:40-7.
7. Stramer SL, Waldman KJ, Brodsky JP, et al. Investigational screening of whole blood donations for HIV-1 and HCV by nucleic acid testing (NAT). Transfusion 1999;39:84S(S381-030F).
8. Caglioti S, McAuley J, Spizman R, Busch MP. Value of sorting samples for NAT based on first time and repeat donation status. Transfusion 1999;39:93S(S422-030J).
9. Recommendations for prevention and control of hepatitis C (HCV) infection and HCV-related chronic disease. CDC MMRR 1998;47:RR-19.
10. Lin L, Cook DN, Wiesehahn GP, et al. Photochemical inactivation of viruses and bacteria in platelet concentrates by use of a novel psoralen and long-wavelength ultraviolet light. Transfusion 1997;37:423-35.
11. Trial to Reduce Alloimmunization to Platelets (TRAPS) Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med 1997;337:1861-9.
12. Bowden RA, Slichter SJ, Sayers M, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood 1995;86:3598-3603.
13. Vamvakas EC. Transfusion-associated cancer recurrence and postoperative infection: Meta-analysis of randomized, controlled clinical trials. Transfusion 1996; 36:175-186.
14. McAlister FA, Clark HD, Wells PS, Laupacis A. Perioperative allogeneic blood transfusion does not cause adverse sequelae in patients with cancer: A meta-analysis of unconfounded studies. Brit J Surg 1998;85:171-78.
15. Busch MP, Collier A, Gernsheimer T, et al. The Viral Activation Transfusion Study (VATS): Rationale, objectives, and design overview. Transfusion 1996;36:854-859.
16. Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 1998;339:1565-77.