Transfusion medicine: A research agenda for the coming years.

The important scientific and clinical advances of the last century in transfusion medicine include methods for avoiding hemolytic transfusion reactions and preventing transmission of viral infectious diseases. The next great clinical advances will require improving the efficacy and safety of transfusions, as well as acknowledgement of the now proven serious complications of transfusion, including nosocomial infection, thrombosis, inflammation and multi-organ failure. Possible strategies include (1) universal leukoreduction to mitigate transfusion immunomodulation effects and improve storage conditions, (2) minimizing transfusion of ABO incompatible antibodies and cellular/soluble antigens, (3) substituting use of safer solutions for normal saline during apheresis, component infusion and washing (4) new techniques to improve the efficacy and safety of blood components, including improved storage solutions/conditions, supernatant removal by washing, and rejuvenation and (5) maximizing the risk to benefit ratio of transfusions by employing more restrictive and physiologic indications for transfusion (including patient blood management) and improving clinical decision making through novel laboratory and bedside tests such as thromboelastography.

0.9% NaCl (Normal Saline) - Perhaps not so normal after all?

Crystalloid infusion is widely employed in patient care for volume replacement and resuscitation. In the United States the crystalloid of choice is often normal saline. Surgeons and anesthesiologists have long preferred buffered solutions such as Ringer's Lactate and Plasma-Lyte A. Normal saline is the solution most widely employed in medical and pediatric care, as well as in hematology and transfusion medicine. However, there is growing concern that normal saline is more toxic than balanced, buffered crystalloids such as Plasma-Lyte and Lactated Ringer's. Normal saline is the only solution recommended for red cell washing, administration and salvage in the USA, but Plasma-Lyte A is also FDA approved for these purposes. Lactated Ringer's has been traditionally avoided in these applications due to concerns over clotting, but existing research suggests this is not likely a problem. In animal models and clinical studies in various settings, normal saline can cause metabolic acidosis, vascular and renal function changes, as well as abdominal pain in comparison with balanced crystalloids. The one extant randomized trial suggests that in very small volumes (2 l or less) normal saline is not more toxic than other crystalloids. Recent evidence suggests that normal saline causes substantially more in vitro hemolysis than Plasma-Lyte A and similar solutions during short term storage (24 hours) after washing or intraoperative salvage. There are now abundant data to raise concerns as to whether normal saline is the safest replacement solution in infusion therapy, red cell washing and salvage, apheresis and similar uses. In the USA, Plasma-Lyte A is also FDA approved for use with blood components and is likely a safer solution for these purposes. Its only disadvantage is a higher cost. Additional studies of the safety of normal saline for virtually all current clinical uses are needed. It seems likely that normal saline will eventually be abandoned in favor of safer, more physiologic crystalloid solutions in the coming years.

How do we forecast tomorrow's transfusion? - Next generation transfusion practices to improve recipient safety.

Recipient safety measures play a key role in overall transfusion efficacy. The key advances in safety over the first century of transfusion medicine have been the development of techniques to prevent hemolytic transfusion reactions, hemolytic disease of the newborn and transmission of viral pathogens. While these risks remain important, they affect many fewer patients than previously. We propose that some of the most important current safety issues relate to toxicities broadly encompassed by the immunomodulatory effects of allogeneic transfusion. These include (1) universal leukoreduction to mitigate nosocomial infections, inflammation and organ injury, (2) removal of stored supernatant and its attendant toxic contents that cause dysfunctional immunity and organ injury, (3) avoiding infusing ABO incompatible antigen and antibody that can lead to bleeding, platelet refractoriness and inflammation, (3) minimizing prophylactic transfusions (particularly of plasma and platelets) except where benefit is proven, and (4) avoiding use of normal saline which is linked to renal failure and possibly hemolysis. Accompanying these safety measures will be the continued growth of one of the most important safety measures, patient blood management, which has as one benefit the avoidance of unnecessary and harmful transfusions. Reducing the toxicity of transfusions will enhance the improved clinical outcomes seen with patient blood management.

Providing ABO-identical platelets and cryoprecipitate to (almost) all patients: approach, logistics, and associated decreases in transfusion reaction and red blood cell alloimmunization incidence.

BACKGROUND: There are multiple benefits to transfusing only ABO-identical blood components. Historically our institution routinely transfused ABO-nonidentical platelets (PLTs) and cryoprecipitate to surgical patients. In April 2005, we implemented a policy of transfusing only ABO-identical components whenever feasible, regardless of outdating or logistic considerations. STUDY DESIGN AND METHODS: Technical staff closely monitored product usage and adjusted blood center orders based on recent utilization and planned transfusions. When unable to provide ABO-identical PLTs, ABO-compatible PLTs were washed to remove incompatible plasma. Data on outdating were collected for 18 months before and after implementation. We compared transfusion reaction and red blood cell (RBC) alloimmunization incidence for 4 years preceding (2001-2004) and subsequent (2006-2009) to implementation. RESULTS: In the year after implementation, only 11 of 410 surgical patients received ABO-nonidentical PLTs (2.7%). There was a 5.6% increase in outdating of PLTs. Transfusing ABO-identical components was associated with significant reductions in febrile (-46%; 8.0 to 4.3 per 10,000 components; p < 0.0001) and allergic transfusion reactions (-23%; from 7.0 to 5.4 per 10,000 components; p = 0.025). A progressive reduction in de novo RBC alloimmunization incidence also occurred (-50% by 2009; p = 0.03). CONCLUSIONS: Providing ABO-identical PLTs to almost all patients was feasible in our setting by changing ordering and inventorying procedures and making the ABO-identical policy a staff priority. Unexpected and striking reductions in febrile and allergic reactions and RBC alloimmunization were observed, of uncertain causal relationship to this ABO policy change, which will require further study.

Utilization of blood transfusion among older adults in the United States.

BACKGROUND: While there have been epidemiologic studies of blood donors, the characteristics of individuals who receive transfusions have not been well described for the US population. STUDY DESIGN AND METHODS: Subjects were from the nationally representative Health and Retirement Study whose data were linked to Medicare files from 1991 through 2007 (n = 16,377). A cohort study was conducted to assess the frequency of transfusion in older Americans over time and to describe the characteristics of blood recipients. RESULTS: Thirty-one percent (95% confidence interval [CI], 30%-33%) of older Americans received at least one transfusion within a 10-year period and 5.8% (95% CI, 5.4%-6.2%) experienced repeated transfusion-related visits within 30 days. The mean number of transfusion-related visits was 2.3 over a 10-year period (95% CI, 2.2-2.4). Older Americans who lived in the South were most likely to receive a transfusion (34%), independent of demographic and health-related factors, while those who lived in the western United States were the least likely (26%). Predictors of transfusion included smoking, low body mass index, and a history of cancer, diabetes mellitus, end-stage renal disease, and heart disease. African-Americans and Mexican-Americans had greater rates of blood utilization than other races and other Hispanics (respectively). There were also differences in transfusion utilization by education, marital status, religion, and alcohol use. CONCLUSIONS: Transfusion is common in older Americans. Regional variations in blood use are not explained by patient characteristics alone.

An association of ABO non-identical platelet and cryoprecipitate transfusions with altered red cell transfusion needs in surgical patients.

BACKGROUND: Transfusion of ABO non-identical plasma, platelets and cryoprecipitate is routine practice even though adverse effects can occur. METHODS AND MATERIALS: Our hospital changed transfusion practice in 2005 and adopted a policy of providing ABO-identical blood components to all patients when feasible. We retrospectively compared the transfusion requirements, length of stay and in-hospital mortality in relation to ABO blood group in surgical patients who received platelet transfusions before and after this change to determine whether it resulted in any benefit. RESULTS: Prior to the change in practice, both group B and AB patients received more ABO non-identical platelet transfusion (P=0·0004), required significantly greater numbers of red cell transfusions (P=0·04) and had 50% longer hospital stays (P=0·039) than group O and A patients. Following the policy change, there was a trend for fewer red cell transfusions (P=0·17) and length of stay in group B and AB patients than group O or A patients. Overall, the mortality rate per red cell transfusion decreased from 15·2 per 1000 to 11·0 per 1000 (P=0·013). CONCLUSIONS: These results, in the context of previous findings, suggest that providing ABO-identical platelets and cryoprecipitate might be associated with reduction in transfusion requirements and improve outcomes in surgical patients.

An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions.

BACKGROUND: Cardiopulmonary adverse events after transfusion include transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), which are potentially lethal and incompletely understood. STUDY DESIGN AND METHODS: To determine whether the incidence of TRALI and TACO was affected by leukoreduction we conducted a retrospective, before-and-after study of acute transfusion reactions for the 7years before and after introduction of universal leukoreduction in 2000, involving 778,559 blood components. RESULTS: Substantial decreases occurred in the rates of TRALI (-83%; from 2.8 cases per 100,000 components before to 0.48 after universal leukoreduction; p=0.01), TACO (-49%; 7.4 to 3.8 cases per 100,000; p=0.03), and febrile reactions (-35%; 11.4 to 7.4 cases per 10,000; p<0.0001). The incidence of allergic reactions remained unchanged (7.0 per 100,000 before and after universal leukoreduction). These outcomes were primarily attributable to decreased TRALI and/or TACO associated with red blood cell (RBC) and platelet (PLT) transfusions (-64%) with notably smaller decreases associated with fresh-frozen plasma or cryoprecipitate transfusions (-29%). The incidence of TRALI and/or TACO after 28,120 washed RBC and 69,325 washed transfusions was zero. CONCLUSION: These data suggest novel hypotheses for further testing in animal models, in prospective clinical trials, and via the new US hemovigilance system: 1) Is TACO or TRALI mitigated by leukoreduction? 2) Is the mechanism of TACO more complex than excessive blood volume? and 3) Does washing mitigate TRALI and TACO due to PLT and RBC transfusions?

Increased risk of infection and mortality in women after cardiac surgery related to allogeneic blood transfusion.

BACKGROUND: Infection and mortality rates are greater in women than in men after cardiac surgery. This study was conducted to assess whether allogeneic blood transfusion could partially account for this gender difference, as transfusion has been associated with immunomodulation. METHODS: A cohort study was conducted in 380 patients at the University of Rochester Medical Center. Subjects were adult patients who underwent primary coronary artery bypass graft (CABG) surgery, primary valve replacement surgery, or both. Information was collected about blood components transfused, as well as postoperative infection, pulmonary dysfunction, and in-hospital mortality. RESULTS: Women were more likely to receive allogeneic red blood cells (RBCs) or platelets than men (odds ratio [OR] 21.6, 95% CI 3.8, 124.2) and a greater quantity of blood than men. Patients who received allogeneic blood were 4.4 times more likely to develop an infection than those who did not (95% CI 1.5, 13.2). There was a positive linear correlation between number of units of blood received and number of days with fever (p<0.001) and hospital length of stay (p<0.001). This was particularly evident in patients who received four or more units of nonleukoreduced blood components. Women had a greater risk of infection (p=0.005), pulmonary dysfunction (p=0.005), and mortality (p=0.007) than men during hospitalization. CONCLUSIONS: One reason for the greater mortality in women after cardiac surgery may be the increased likelihood of receiving nonleukoreduced allogeneic RBCs and platelets. Transfusion increased the risk of infection; infection, then, increased the likelihood of pulmonary dysfunction and mortality.

ABO identical and washed blood transfusions as candidate strategies to reduce early mortality in acute promyelocytic leukemia.

BACKGROUND: Despite dramatically improved long term outcomes seen with all-trans retinoic acid therapy, and now arsenic trioxide, in acute promyelocytic leukemia (APL), early mortality remains a substantial challenge. Recent data from a single center study and the Surveillance, Epidemiology and End Results (SEER) registry report 30day mortality rates of 26% (n=18 of 70) and 17% (n=238 of 1400), respectively. Early deaths are predominately due to hemorrhage. Patients with APL invariably have abnormal laboratory hemostasis tests. The standard of practice is to prophylactically transfuse platelets, plasma and cryoprecipitate to mitigate abnormal platelet counts, PT/PTT and fibrinogen levels. Standard blood bank practice is to transfuse platelets, plasma and cryoprecipitate largely without regard to ABO blood group (platelets, cryoprecipitate), and, in some centers, transfusing ABO non-identical universal donor group AB plasma. Evidence from observational studies suggests that use of ABO non-identical blood components may be associated with increased bleeding. We hypothesized that use of ABO identical blood components and saline washed transfusions (red cells and platelets) would be associated with reduced early mortality in APL by avoidance of transfusion induced hemostatic dysfunction. METHODS: This is a single center cohort study of APL patients treated in an 800 bed university community and referral hospital. Novel approaches to transfusion support, based upon randomized trials, include implementation of ABO identical platelet transfusions for all patients with acute leukemia in 1990, use of only ABO identical cryoprecipitate in 2005, and washed transfusions of red cells and platelets for all patients with acute leukemia <50years of age beginning in 2006. Plasma transfusion has always been ABO identical. Two comparison populations were recent literature reports and the New York State Cancer Registry. We characterized 30 day mortality in APL patients seen in our institution since 2000 as a convenience sample comparable to literature reports, beginning approxcimately when ATRA therapy became uniform for induction therapy. Only patients receiving their induction therapy in our hospital were included. RESULTS: Of 41 patients there were 2 early (30 day) deaths (5%; a 71-81% reduction from expected). Early mortality at 100 days was 7% (n=3). The 30 day mortality in the younger cohort <50years of age (n=16) receiving washed transfusions was 0%. Restricting the analysis to patients treated since 2006 (ABO identical transfusions, mostly washed) (n=27; mean age 43 years; median 41 years; range 12-79), the early mortality rate at 30days was 3.7%. Long-term survival (5 years) of our APL patients was similar to New York State Cancer Registry and literature reports (80-83%). DISCUSSION: APL patients supported with transfusion regimens including ABO identical blood components, with or without washing, experienced early mortality at 30 days that was strikingly improved (71% to 86% lower) compared with that reported in the recent literature (3.7% to 5% vs. 17% to 26%). If these observed low rates of early mortality are related to transfusion practices, avoidance of ABO immune complex formation, and subsequent interference with hemostasis, is a plausible contributing mechanism. These favorable results provide a rationale for randomized trials of relatively simple and inexpensive approaches to reducing early hemorrhagic mortality in APL: use of ABO identical transfusions and washing to remove supernatant plasma.

Management of Platelet Disorders and Platelet Transfusions in ICU Patients.

Thrombocytopenia or receipt of antiplatelet drugs, with or without bleeding, is a common indication for platelet transfusions in the ICU. However, there is almost no evidence base for these practices other than expert opinion. Also common is use of platelet transfusions prior to invasive procedures or surgery in patients with thrombocytopenia. Likewise, there is no high-quality evidence that such practices are efficacious or safe. Recently, it has become clear that, whether causal or not, patients receiving prophylactic platelet transfusions experience high rates of nosocomial infection, thrombosis, organ failure, and mortality, which increase the urgency and need for randomized trials to assess these practices. Investigational methods of improving the safety and efficacy of platelet transfusions include use of alternate strategies such as antifibrinolytics; use of ABO-identical, leukoreduced, and washed platelet transfusions; and improved storage solutions.

Platelet transfusion - the new immunology of an old therapy.

Platelet transfusion has been a vital therapeutic approach in patients with hematologic malignancies for close to half a century. Randomized trials show that prophylactic platelet transfusions mitigate bleeding in patients with acute myeloid leukemia. However, even with prophylactic transfusions, as many as 75% of patients, experience hemorrhage. While platelet transfusion efficacy is modest, questions and concerns have arisen about the risks of platelet transfusion therapy. The acknowledged serious risks of platelet transfusion include viral transmission, bacterial sepsis, and acute lung injury. Less serious adverse effects include allergic and non-hemolytic febrile reactions. Rare hemolytic reactions have occurred due to a common policy of transfusing without regard to ABO type. In the last decade or so, new concerns have arisen; platelet-derived lipids are implicated in transfusion-related acute lung injury after transfusion. With the recognition that platelets are immune cells came the discoveries that supernatant IL-6, IL-27 sCD40L, and OX40L are closely linked to febrile reactions and sCD40L with acute lung injury. Platelet transfusions are pro-inflammatory, and may be pro-thrombotic. Anti-A and anti-B can bind to incompatible recipient or donor platelets and soluble antigens, impair hemostasis and thus increase bleeding. Finally, stored platelet supernatants contain biological mediators such as VEGF and TGF-ß1 that may compromise the host versus tumor response. This is particularly of concern in patients receiving many platelet transfusions, as for acute leukemia. New evidence suggests that removing stored supernatant will improve clinical outcomes. This new view of platelets as pro-inflammatory and immunomodulatory agents suggests that innovative approaches to improving platelet storage and pre-transfusion manipulations to reduce toxicity could substantially improve the efficacy and safety of this long-employed therapy.

Optimizing platelet transfusion therapy.

Platelet transfusions are widely used. Prophylactic transfusions are employed in severely thrombocytopenic patients without evidence of bleeding, but no randomized trial data prove the safety or efficacy of this approach. Randomized trials have demonstrated the equivalence of transfusion triggers of 10,000 and 20,000/microl for prophylactic transfusions. The former threshold is potentially safer for the patient, conservative of donor resources and leads to lower costs, with perhaps a slightly greater risk of minor hemorrhage. Randomized trials have demonstrated the equivalence of pheresis or whole blood-derived platelet transfusions. The former present a lower risk for infectious agents, and the latter are less expensive and a more efficient use of limited donor resources. Randomized trials prove that leukoreduced and ABO identical platelet transfusions reduce the risks of HLA alloimmunization and platelet transfusion refractoriness (both leukoreduction and ABO matching), transfusion reactions (leukoreduction) and CMV transmission (leukoreduction). Leukoreduction and ABO matching of platelet transfusions also have been associated in preliminary observational studies with reduced morbidity and mortality in surgical patients and reduced infections in patients with leukemia. These results require further investigation. Future challenges include (1) determining the best approach to bacterial contamination of platelets, whether by detection methods or pathogen inactivation and (2) determining the threshold for prophylactic platelet transfusions in thrombocytopenic patients undergoing surgery or invasive procedures.

ABO incompatibility between donor and recipient and clinical outcomes in allogeneic stem cell transplantation.

We performed a retrospective, cohort study to evaluate the impact on recipient survival of ABO incompatibility between recipient and donor after allogeneic stem cell transplantation, primarily involving marrow-derived cells. No statistically significant difference was noted in survival for 153 patients with acute or chronic leukemia or myelodysplastic syndrome receiving ABO identical or ABO mismatched allografts. Five patients who had allografts that were bidirectionally incompatible (both donor cells and plasma incompatible) did have significantly poorer survival than the other recipients, similar to the experience reported in one other cohort study. However, these patients had other risks for mortality, including being older and receiving transplants from matched, unrelated donors. Our data do not support a significant role for ABO donor-recipient matching in allogeneic stem cell transplantation.