The evolving use of intensive chemotherapy regimens in oncology and bone marrow/stem cell transplantation programs has increased the demand for platelet products, particularly for patients with severe thrombocytopenia or bleeding complications. The use of apheresis platelet transfusions has also increased substantially, from 352,000 units in 1989 to 1,003,000 units in 1999 (Table 1)[1-3]; this increase is being driven partly by the need for alternative platelet inventories to support cardiac surgery and peripheral blood stem cell (PBSC) transplantation programs, and partly by the use of leukoreduced platelet products.
Emerging issues are renewing interest in platelet transfusion practices. This review discusses the current risks associated with platelet transfusion and the results of recent studies of alternative strategies in platelet transfusion therapy, including: (1) reevaluation of the platelet threshold for prophylactic transfusion, (2) modification of the platelet transfusion dose, (3) the potential role of thrombopoietin therapy, and (4) current investigational and pharmacologic options for the treatment of cancer-related thrombocytopenia.
The risk of acquiring transfusion-transmitted diseases is estimated to be lower than ever (Table 2).[3,6] Nucleic acid testing has decreased the risk of viral infection by shortening the window of infectivity, and thus reducing the risk of posttransfusion infection with the hepatitis C virus and human immunodeficiency virus (HIV).
Transfusion-associated HIV infection was first reported in late 1982 and early 1983. HIV antibody testing was implemented in March 1985, and over the next 5 years, only about five cases of transfusion-associated HIV infection were reported annually. In the year before testing began, 714 cases had been reported. In late 1995, blood banks began testing donors for the p24 antigen to further decrease the risk of transfusion-transmitted HIV disease. In 1999, nucleic acid testing was introduced to close the window of infectivity (from infection to detection) by at least 50%, lowering the estimated risk of HIV transmission by transfusion to approximately 1 in 2 million units.
Labeling of blood from paid donors (a practice initiated in 1972) and the implementation of third-generation screening tests for the hepatitis B surface antigen markedly reduced transfusion-transmitted hepatitis B. By 1995, however, these measures were found to eliminate only about 10% of all posttransfusion hepatitis cases.
The incidence of non-A, non-B posttransfusion hepatitis was further reduced when potential HIV-positive donors were excluded and was reduced again when donors were tested for the surrogate markers alanine aminotransferase (a marker for acute liver inflammation) and antibody to hepatitis B core antigen (evidence of previous hepatitis B infection). Even greater reductions in the risk of transmission of non-A, non-B hepatitis were described after implementation of a test for antibody to the hepatitis C virus (Table 2).[3,10] Finally, implementation of nucleic acid testing reduced the current estimated risk of hepatitis C transmission to approximately 1 in 2,000,000 units.
Platelet Product Contamination
The estimated risk of sepsis related to apheresis platelets is 1:2,000. This risk is greater with transfusions of pooled platelet concentrates from multiple donors. Because the risk of bacterial overgrowth increases with time, the shelf life of platelets stored at 20oC to 24oC is limited to 5 days. The organisms most commonly implicated in fatalities, in descending order, are Staphylococcus aureus, Klebsiella pneumoniae, Serratia marcescens, and Staphylococcus epidermidis.
Clinical presentation of infection with bacterially contaminated platelets can range from mild fever (potentially indistinguishable from febrile, nonhemolytic transfusion reactions) to acute sepsis, hypotension, and death. Sepsis caused by transfusion of contaminated platelets is unrecognized, in part, because the organisms found in platelet contamination are often the same as those implicated in catheter-related sepsis. The overall mortality rate of identified platelet-associated sepsis is 26%.
No widely accepted test is available to detect bacterially contaminated blood products. Currently, the most promising approach is the use of psoralen and ultraviolet (UV) light to sterilize blood products. In the clinical setting, any patient who develops fever within 6 hours of receiving platelets should be evaluated, and empiric antibiotic therapy should be considered.
Cytomegalovirus (CMV) infection caused by platelet transfusions has been associated with substantial morbidity and mortality in immunocompromised oncology patients. Patients who undergo allogeneic bone marrow/stem cell transplantation are at risk of contracting the virus present in blood products due to their use of cytotoxic preparative regimens or immunosuppressive therapy (cyclosporine and corticosteroid), or graft-vs-host disease. Up to 60% of this patient population will become infected with CMV, and 50% will develop CMV disease if no preemptive therapy is administered.
The risk of developing CMV infection ranges from 28% to 57% for seronegative bone marrow transplant patients who receive standard blood products. Even with the use of CMV-negative blood products, CMV seroconversion has been reported in 1% to 4% of CMV-negative donor-recipient transplant patients.
A recent analysis of our program at Washington University identified CMV viremia in only 1 (2.5%) of 39 CMV-negative donor-recipient pairs undergoing allogeneic PBSC transplantation. Our analysis included 59 patients who had undergone allogeneic PBSC transplantation in an investigational study of prophylactic granulocyte infusions from stem cell donors. Notably, results showed that CMV-positive granulocytes did not alter the risk of viremia compared with CMV-negative granulocytes; the incidence of CMV viremia was 34.5% vs 26.6%, respectively (95% confidence interval [CI] = 0.47-4.41).
CMV infection and CMV disease occur much less commonly than other virally transmitted diseases in patients receiving conventional chemotherapy or autologous bone marrow/stem cell transplantation and are not a significant clinical problem except in CD34-selected or T-cell-depleted stem cell transplantations.
A randomized, controlled clinical trial in allogeneic bone marrow transplantation patients compared the value of CMV-seronegative blood products vs unscreened blood products subjected to bedside leukofiltration. Of 252 patients in the CMV-seronegative cohort, 4 (1.3%) developed CMV infection, with no CMV disease or fatalities; 6 (2.4%) of 250 patients in the leukoreduced cohort developed CMV disease, and 5 of these patients died. The leukoreduced cohort had an increased probability of developing CMV disease by day 100 (2.4% vs 0%, P = .03). Even when investigators eliminated the CMV infections that occurred within 21 days of transplantation, two patients in the leukoreduced arm and none in the seronegative arm died of CMV disease. The investigators’ conclusions that leukoreduced blood products are "CMV safe" remain controversial.
In a consensus conference held by the Canadian Blood Service, 7 of 10 panelists concluded that patients considered at risk for CMV disease should receive CMV-negative products, even when blood components are leukoreduced.
Debate over the merits of "universal" leukoreduction (cellular components with < 5 ´ 106 leukocytes) has focused on several potentially important clinical effects, including transfusion-related alloimmunization to platelets, febrile-associated transfusion reactions, and transfusion-related immunomodulation. Use of both leukoreduced and nonleukoreduced blood components is currently approved by the US Food and Drug Administration (FDA).
Table 3 summarizes the number of leukoreduced blood units collected in the United States from 1994 to 1999.[2,3] While the percentages of red cell transfusions remained static, the generation of leukoreduced apheresis platelets, especially by blood centers, increased substantially. For the first 9 months of 1999, 13% of all red cells transfused at our hospital were leukoreduced. Our indications for leukoreduction reflect those published previously (Table 4).
· Febrile ReactionsFebrile-associated transfusion reactions occur in only 0.5% of patients transfused with red cells, and of these, 18% and 8% experience a second and third event, respectively. Approximately 18% of all platelet transfusions are associated with febrile-associated transfusion reactions, although the prevalence of these responses can be as high as 30% in frequently transfused populations, such as oncology patients. Reactions characterized as severe occur in only 2% of platelet transfusions, and bedside leukofiltration has not reduced the overall prevalence of such effects.[22,23] Moreover, bedside leukoreduction filters can cause significant hypotensive events by activating the bradykinin/kininogen systems, particularly in patients who are receiving angiotensin-converting enzyme inhibitors.
· Alloimmunization to PlateletsTransfusion-related alloimmunization to platelets was studied in a multicenter trial in newly diagnosed leukemia patients. The study found that clinical platelet refractoriness associated with human leukocyte antigen seropositivity was reduced from 13% in patients transfused with unprocessed platelet concentrates to from 3% to 5% in patients receiving leukoreduced apheresis platelets, leukoreduced platelet concentrates, or psoralen/UV-B-treated platelets. Although this difference is statistically significant, no clinically important differences were found between patient cohorts in prevalence of transfusion reactions, hemorrhagic events, length of hospital stay, number of platelet transfusions, number of red cell transfusions, or mortality.
· ImmunomodulationTransfusion-related immunomodulation has been cited as clinically important in patients undergoing renal transplantation and in women who have had multiple miscarriages. However, a multicenter, controlled study found no evidence of such an effect, and the authors recommended against the use of allogeneic mononuclear infusions as treatment for unexplained recurrent miscarriages. Similarly, patients who received transfusions before renal transplantation had a superior 1-year renal allograft survival rate compared with untransfused patients. Nevertheless, among patients who did not receive a transfusion prior to surgery, blood transfused at the time of transplantation had no effect on 1-year renal allograft survival. Only a few prospective studies have attempted to clarify the potential immunomodulatory effects of allogeneic transfusion in other settings.
Table 4 lists the indications for leukoreduction published in a review in 1992. These guidelines continue to be applicable, pending future controlled, prospective clinical trials.