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.

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.

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.

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.

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.

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 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?

Platelet transfusions: trigger, dose, benefits, and risks.

Over the last half century, platelet transfusion has been an effective therapy for the prevention and treatment of bleeding, particularly in patients with hematologic malignancies. Recent randomized trials have demonstrated that current practices may be suboptimal in a number of ways. The rationale for parsimony in the use of this powerful therapy includes previously described severe and fatal adverse outcomes (including refractoriness, hemolysis from ABO-mismatched transfusions, acute lung injury, and bacterial sepsis), newly described serious potential risks (including thrombosis and earlier leukemic recurrence), difficulty in maintaining adequate supplies of platelets, the need to place volunteer donors on cell separators to provide the product, and cost. Recent findings demonstrate that the platelet count threshold for prophylactic transfusion can be as low as 10,000/µL, and a therapeutic rather than a prophylactic strategy of transfusion for bleeding manifestations only may be equally safe for most patients. Another recently completed study suggests that very low doses of platelet transfusions (the equivalent of half a unit of apheresis platelets or two to three units of whole blood-derived platelets) are as effective at preventing bleeding as much higher doses. One question for which there are no randomized trial data is at what threshold prophylactic platelet transfusion should be given before invasive procedures or major surgery. The typically recommended threshold of 50,000/µL is based only on expert opinion, and substantial observational data indicate that this threshold leads to many transfusions that are likely unnecessary and therefore represent risk with little or no additional benefit.