Transfusion-related immunomodulation: gamma irradiation alters the effects of leukoreduction on alloimmunization
Nelson KA, Aldea GS, Warner P, Latchman Y, Gunasekera D, Tamir A, Gernsheimer T, Bolgiano D, Slichter SJ
BACKGROUND Adverse events following blood transfusion include allosensitization and generalized immunosuppression, collectively referred to as transfusion-related immune modulation. We evaluated the immunological effects of red blood cell (RBC) and platelet transfusions on alloantibody responses and on immunoregulatory cells in nonimmunosuppressed patients undergoing cardiovascular surgery. STUDY DESIGN AND METHODS Patients were randomized to receive standard unmodified (STD), leukoreduced (LR), or leukoreduced and gamma-irradiated (LRgamma) RBCs. Patients received only apheresis platelets that were in-process LR and were gamma-irradiated for the third arm. Nontransfused patients served as controls for the effects of surgery itself on immunologic changes. Antibodies to HLA were assessed with use of solid-phase assays. The effects of transfusion on adaptive and innate immunity were evaluated by assessing T regulatory cells (Tregs) and invariant natural killer T (iNKT) cells. RESULTS LR of blood products reduced the development of human leukocyte antigen (HLA) alloantibodies, but only in patients without preexisting HLA antibodies. However, if LR blood products were gamma-irradiated, HLA antibody production was not reduced. Compared to nontransfused patients, recipients of STD or LR transfusions showed a significant increase in CD4+CD25(hi) T cells expressing FoxP3 or CTLA4 and also of iNKT cells producing interleukin-4. In contrast, recipients of LRgamma blood products showed markedly lower increases in all three cellular assays. CONCLUSION LR decreased HLA alloantibody production in naive recipients, but did not reduce the immunosuppressive effects of transfusion. LRgamma reduced immunosuppression and was not associated with decreased HLA alloantibody production.
Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial
Uhl L, Assmann SF, Hamza TH, Harrison RW, Gernsheimer T, SlichterSJ
Bleeding remains a significant problem for many thrombocytopenic hematology/oncology patients in spite of platelet transfusions. Factors that might contribute to bleeding were analyzed for 16320 patient-days on or after their first platelet transfusion in 1077 adult patients enrolled in the Platelet Dose (PLADO) trial. All patients had a greatly increased risk of bleeding at platelet counts of <=5 x 109/L (odds ratio [OR], 3.1; 95% confidence interval [CI], 2.0-4.8) compared with platelet counts >=81x 109/L. Platelet counts between 6 x 109/L and 80 x 109/L were also associated with a somewhat elevated bleeding risk in patients receiving allogeneic stem cell transplants (SCTs) or chemotherapy but not in those undergoing autologous SCTs. Other significant laboratory predictors of bleeding were hematocrit <=25% (OR, 1.29; 95% CI, 1.11-1.49), activated partial thromboplastin time (aPTT) 30 to <=50 seconds (OR, 1.40; 95% CI, 1.08-1.81; P = .01), aPTT >50 seconds (OR, 2.34; 95% CI, 1.54-3.56), international normalized ratio (INR) 1.2 to 1.5 (OR, 1.46; 95% CI, 1.17-1.83), and INR >1.5 (OR, 2.05; 95% CI, 1.43-2.95). Transfusion of either platelets or red blood cells (RBCs) on days with bleeding was often not sufficient to change bleeding outcomes on the following day. Because bleeding occurred over a wide range of platelet counts among patients undergoing allogeneic SCT or chemotherapy and because platelet transfusions may not prevent bleeding, other risk factors may be involved. These may include low hematocrit and coagulation abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT00128713.Copyright © 2017 by The American Society of Hematology.
Platelet transfusion: a systematic review of the clinical evidence
Kumar A, Mhaskar R, Grossman BJ, Kaufman RM, Tobian AA, Kleinman S, Gernsheimer T, Tinmouth AT, Djulbegovic B, AABB Platelet Transfusion Guidelines Panel
BACKGROUND Platelet (PLT) transfusion is indicated either prophylactically or therapeutically to reduce the risk of bleeding or to control active bleeding. Significant uncertainty exists regarding the appropriate use of PLT transfusion and the optimal threshold for transfusion in various settings. We formulated 12 key questions to assess the role of PLT transfusion. STUDY DESIGN AND METHODS We performed a systematic review (SR) of randomized controlled trials (RCTs) and observational studies. A comprehensive search of PubMed, Web of Science, and Cochrane registry of controlled trials was performed. Methodologic quality of included studies was assessed and a meta-analysis was performed if more than two studies with similar designs were identified for a specific question. RESULTS Seventeen RCTs and 55 observational studies were included in the final SR. Results from RCTs showed a beneficial effect of prophylactic compared with therapeutic transfusion for the prevention of significant bleeding in patients with hematologic disorders undergoing chemotherapy or stem cell transplantation. We found no difference in significant bleeding events related to the PLT count threshold for transfusion or the dose of PLTs transfused. Overall methodologic quality of RCTs was moderate. Results from observational studies showed no evidence that PLT transfusion prevented significant bleeding in patients undergoing central venous catheter insertions, lumbar puncture, or other surgical procedures. The methodologic quality of observational studies was very low. CONCLUSION We provide a comprehensive assessment of evidence on the use of PLT transfusions in a variety of clinical settings. Our report summarizes current knowledge and identifies gaps to be addressed in future research.Copyright © 2014 AABB.
Effects of prophylactic platelet (Plt) dose on transfusion (Tx) outcomes (PLADO Trial)
Slichter SJ, Kaufman RM, Assmann SF, Brecher ME, Gernsheimer T, Hillyer CD, McCullough J, Strauss RG, Triulzi D
Blood. 2008;112((11):): Abstract No. 285.
Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients
Slichter SJ, Davis K, Enright H, Braine H, Gernsheimer T, Kao KJ, Kickler T, Lee E, McFarland J, McCullough J, et al
A variety of patient and product-related factors influenced the outcome of 6379 transfusions given to 533 patients in the Trial to Reduce Alloimmunization to Platelets (TRAP). Responses measured were platelet increments, interval between platelet transfusions, and platelet refractoriness. Patient factors that improved platelet responses were splenectomy and increasing patient age. In contrast, at least 2 prior pregnancies, male gender, splenomegaly, bleeding, fever, infection, disseminated intravascular coagulation, increasing height and weight, lymphocytotoxic antibody positivity, an increasing number of platelet transfusions, or receiving heparin or amphotericin were associated with decreased posttransfusion platelet responses. Platelet factors that were associated with improved platelet responses were giving ABO-compatible platelets, platelets stored for 48 hours or less, and giving large doses of platelets while ultraviolet B (UV-B) or gamma irradiation decreased platelet responses. However, in alloimmunized lymphocytoxic antibody-positive patients, the immediate increment to UV-B-irradiated platelets was well maintained, whereas all other products showed substantial reductions. Refractoriness to platelet transfusions developed in 27% of the patients. Platelet refractoriness was associated with lymphocytotoxic antibody positivity, heparin administration, fever, bleeding, increasing number of platelet transfusions, increasing weight, at least 2 pregnancies, and male gender. The only factors that reduced platelet refractoriness rates were increasing the dose of platelets transfused or transfusing filtered apheresis platelets.
Factors influencing moderate to severe reactions to PLT transfusions: experience of the TRAP multicenter clinical trial
Enright H, Davis K, Gernsheimer T, McCullough JJ, Woodson R, Slichter SJ
BACKGROUND During the Trial to Reduce Alloimmunization to Platelets (TRAP Trial), data were prospectively collected for 8769 PLT transfusions regarding the frequency of moderate to severe PLT transfusion reactions. STUDY DESIGN AND METHODS At seven centers, 598 patients were randomly assigned to receive unmodified pooled random-donor PLT concentrates (PCs), UV-B-irradiated PCs, filtered PCs, or filtered random-donor apheresis PLTs. RESULTS Moderate to severe transfusion reactions were an increase in temperature of at least 2 degrees C, chills with rigors, extensive urticaria, dyspnea, cyanosis, or bronchospasm. These reactions occurred with 2.2 percent of the transfusions in 22 percent of the patients. Transfusion reactions were associated with WBC counts of more than 5 x 10(6) per transfusion (p = 0. 002) and transfusions stored for more than 48 hours (p = 0. 02). PLT counts before transfusion were significantly lower for transfusions associated with reactions (p = 0. 005). Neither UV-B irradiation nor apheresis PLTs independently influenced reaction rates. The PLT increment at 1 hour after transfusion was lower for transfusions associated with reactions (p = 0. 004), and the frequency of reactions was higher in PLT refractory patients (p < 0. 001). CONCLUSIONS The provision of either fresh and/or WBC-reduced PLTs may decrease the frequency of PLT transfusion reactions and improve PLT transfusion efficacy.
The transfusion trigger and number of units transfused in patients with HIV: associations with disease stage and functional status
Kennedy MS, Kalish LA, Mohandas K, Gernsheimer T, Townsend-McCall D, Viral Activation Transfusion Study Group
BACKGROUND The influence of quality of life (QOL), physical functioning, and HIV disease stage on the transfusion trigger and the number of units transfused was investigated. STUDY DESIGN AND METHODS The Viral Activation Transfusion Study, a randomized, double-blind study at 11 participating sites, enrolled HIV-positive patients with anemia who required RBC transfusion; 428 patients were included in the analysis of the first transfusion. The QOL scores, Perceived Health Index, Karnofsky score, CD4+ cell count, HIV viral load, and site were analyzed for relationships with the Hb level and the number of units transfused. RESULTS The transfusion trigger was lower in patients with higher levels of Karnofsky score, Perceived Health Index, CD4+ cell count, and a number of QOL scales. Both the Hb trigger and the number of units transfused had a significant site variation. Males were transfused at a significantly lower Hb level than females. In multivariate analysis, the CD4+ cell count remained significant, but the Karnofsky score or the Perceived Health Index did not. The number of RBC units transfused was associated with the Hb level, CD4+ cell counts, and Karnofsky scores in unadjusted analysis but with only Hb in adjusted analysis. CONCLUSIONS In this group of HIV+ patients, lower CD4+ cell counts prompted transfusion at higher Hb levels. However, after controlling for the Hb level, the number of units transfused was associated with only the Hb level. The HIV stage appears to influence the decision to transfuse at a particular Hb level but not to influence the number of RBC units transfused. The functional status does not appear to influence the decision to transfuse.
Signs and symptoms associated with the transfusion of WBC-reduced RBCs and non-WBC-reduced RBCs in patients with anemia and HIV infection: results from the Viral Activation Transfusion Study
Lane TA, Gernsheimer T, Mohandas K, Assmann SF
BACKGROUND RBC transfusion is associated with fever and other reactions in some patients. The Viral Activation Transfusion Study randomly assigned patients to receive either unmodified or WBC-reduced RBCs and thus offered an opportunity to assess the effect of WBC-reduced RBCs on the incidence of transfusion reactions prospectively. STUDY DESIGN AND METHODS This prospective, randomized, double-blind, multicenter study compared prestorage WBC-reduced RBCs to unmodified RBCs in HIV-infected, CMV-seropositive, and transfusion-naive persons who required transfusions for anemia. Primary endpoints were survival and change in the plasma HIV RNA level at 7 days after transfusion. The incidence of transfusion reactions was prospectively evaluated. RESULTS The two groups had similar baseline characteristics and study endpoints; 3864 RBC units (median storage age, 9 days) were administered to 531 patients during 1745 transfusions. The most frequent signs reported were elevated temperature and hypotension. Subjects who reported fever within the week prior to transfusion were more likely to have an elevation in temperature associated with transfusion. The administration of RBCs that were less than 10 days old was associated with a marginal increase in the incidence of transfusion-associated temperature elevation among recipients of unmodified RBCs, but not among recipients of WBC-reduced RBCs. Caregivers reported fewer instances of both elevated temperature and hypotension than were identified by review of transfusion records. CONCLUSIONS The incidence of elevated temperature and hypotension associated with transfusion in this population was unexpectedly high. Use of WBC-reduced RBCs had no effect on the overall rates of elevated temperature or hypotension associated with transfusion of RBCs. The occurrence of a pre-existing fever was associated with a higher frequency of transfusion-associated elevated temperature.
Leukocyte-reduced red blood cell transfusions in patients with anemia and human immunodeficiency virus infection: the Viral Activation Transfusion Study: a randomized controlled trial
Collier AC, Kalish LA, Busch MP, Gernsheimer T, Assmann SF, Lane TA, Asmuth DM, Lederman MM, Murphy EL, Kumar P, et al
CONTEXT Allogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in vitro and of HIV in small pilot studies. Retrospective studies suggest that transfusions adversely affect the clinical course of HIV. Data in selected non-HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells (RBCs). OBJECTIVE To compare the effects of leukoreduced and unmodified RBC transfusions on survival, complications of acquired immunodeficiency syndrome, and relevant laboratory markers in HIV-infected patients. DESIGN AND SETTING Double-blind randomized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999, with a median follow-up of 12 months (24 months in survivors). PATIENTS A total of 531 persons infected with HIV and CMV, aged 14 years or older, who required transfusions for anemia; 259 received leukoreduced transfusions and 262 received unmodified transfusions (10 did not receive the planned transfusion). MAIN OUTCOME MEASURES Survival and change in plasma HIV RNA level 7 days after transfusion, compared by type of transfusion. RESULTS At entry, the groups were similar in demographic, clinical, and relevant laboratory characteristics. A total of 3864 RBC units were transfused. Two hundred eighty-nine deaths occurred (151 with leukoreduced transfusion; 138 with unmodified transfusion); median survival was 13.0 and 20.5 months, respectively (relative hazard [RH], 1.20; 95% confidence interval [CI], 0.95-1.51; log-rank P =.12). Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction (RH, 1.35; 95% CI, 1.06-1.72). There was no difference in time to new opportunistic event/death or frequency of transfusion reactions. No changes in plasma HIV RNA level were seen in either group at days 7, 14, 21, or 28, even in patients not taking antiretroviral drugs. There were no differences in trends between groups in CMV DNA, CD4 cell counts, activated (CD38% or human leukocyte antigen-DR) CD8 cell counts, or plasma cytokine levels. CONCLUSIONS We found no evidence of HIV, CMV, or cytokine activation following blood transfusion in patients with advanced HIV infection. Leukoreduction provided no clinical benefit in these patients. These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient populations, since smaller studies in other patient populations have suggested leukoreduction may be beneficial.
WBC reduction in RBC concentrates by prestorage filtration: multicenter experience
Yomtovian R, Gernsheimer T, Assmann SF, Mohandas K, Lee TH, Kalish LA, Busch MP, Viral Activation Transfusion Study Group
BACKGROUND As universal leukocyte (WBC) reduction (ULR) is being considered as a new standard, few data are available on the performance of WBC-reduction filtration in routine practice. The performance of WBC-reduction in RBCs, using varied filtration practices, in meeting the current FDA requirement (<5 x 10(6)), Council of Europe (EC) recommendation, the proposed FDA requirement (<1 x 10(6)), and a more stringent proposal (<5 x 10(5)) for residual WBCs per RBC unit was assessed and compared. STUDY DESIGN AND METHODS Participating facilities were the 11 sites of the Viral Activation Transfusion Study (VATS), a prospective study of the impact of transfusion with and without WBC-reduction on survival and HIV viral load in HIV-1-infected patients. Patients randomly assigned to undergo WBC reduction were required to receive RBCs < or =14 days old that had undergone prestorage (within 72 hours of collection) WBC-reduction filtration by a method devised to achieve a postfiltration WBC count of <5 x 10(6). Residual WBC quantitation was performed by PCR in the central VATS laboratory by using frozen WBC-reduced RBC samples obtained at issue for transfusion. RESULTS A total of 1869 WBC-reduced RBC units were studied. Filtration practices varied within and between sites. There were significant differences in mean residual WBC counts at the 11 sites (p<0.001). Among the WBC-reduced RBC units, 0.8 percent exceeded 5 x 10(6) WBCs per unit, 8.3 percent exceeded 1 x 10(6) WBCs per unit, and 14.3 percent exceeded 5 x 10(5) WBCs per unit. CONCLUSION Residual WBCs in WBC-reduced RBC units vary within and between sites. WBC reduction was successful, in that over 99 percent and 91 percent of VATS WBC-reduced RBC units met US and EC thresholds, respectively. However, the small but measurable failure rate indicates that not every unit will meet these guidelines.