Neil Blumberg

The rationale for irradiation is that congenital cardiac anomalies are associated with immune deficiency syndromes. Some of these are not easy to diagnose in the first months or even first few years of life. Our own policy is for infants and younger children (<5 years of age) to transfuse only irradiated, ABO identical red cells and the first red cell is washed. We only wash red cells <21 days of age because of data that washed red cells are associated with less inflammation and clinical complications if of shorter storage (<21 days), but greater inflammation and poorer clinical outcomes if >28 days of storage. Pediatr Crit Care Med. 2015 Mar;16(3):227-35 Despite the long standing policy of using "fresher" red cells for these patients, the safest red cells are probably about 10-21 days of storage according to our data and meta-analyses of the randomized trials. Fresher red cells are associated with a higher incidence of post-operative infections, the major cause of morbidity and mortality in this population. I would never transfused red cells <7-10 days old to any patient at this point in time. We have some mechanistic data that is as yet unpublished that the mechanism is dysregulation of oxidation/reduction in freshly collected red cells. Blood. 2016 Jan 28;127(4):400-10 Washed red cells reduce the risk of post-operative inflammation in the only published randomized trial and there is also a trend towards reduced mortality in the washed arm of the study. This may be controversial but it's the only data we have to go on, certainly the only randomized trial. Pediatr Crit Care Med. 2012 May;13(3):290-9.

Are you sure someone didn't transfuse this patient elsewhere with A positive red cells? Sometimes patients relapse and another hospital transfuses them according to their current type (which may have been mixed field with no anti-A). The vast majority of transplant patients in similar situations do not make anti-A. The graft is presumably tolerized by all the A antigen present on non-lymphohematopoietic cells and in soluble form (even in non-secretors). Worth getting a history in these instances.

"Did leukoreduction not work? Or are we still fighting the same complications because some of the US still has not adopted universal leukocyte reduction? Leukocyte reduction seems to have helped our patients a lot." The short (sort of) answer is that while leukoreduction reduces acute transfusion reactions, likely including TRALI and TACO, reduces alloimmunization to white cell and red cell alloantigens, reduces the risk of GVHD, reduces the risk of organ failure due to inflammation, etc. it does not completely abrogate these risks. Platelet transfusions still cause inflammatory type reactions in about 1% of transfusions due to soluble mediators in the plasma such as IL-6 and CD40L. There is still lots of stored plasma in red cells and, in particular, platelets, allogeneic antigen, both soluble and cell associated, mediators such as VEGF, CD40L, IL-6, etc. that are not removed by leukoreduction at the time of manufacture. The red cells and platelets deteriorate and release mediators such as free hemoglobin, free heme, platelet granule contents, etc. that are both biologically and clinically active, causing some of these complications even after leukoreduction. There are some residual viable white cells, if not irradiated, so even minimal amounts of allogeneic white cells may have effects. We don't know. Then there is the routine, inventory driven, unfortunate use of ABO non-identical plasma and cells that creates immune complexes that almost certainly cause bleeding, endothelial damage and inflammation. Iatrogenic immune complex disease, if you will, that contributes to cellular damage and organ injury. Thus there are still plenty of candidate mediators for harm. Nonetheless, I would suggest leukoreduction is the most important advance in transfusion practice since the invention of serologic testing (Coombs test) and infectious disease testing to prevent hemolytic reactions and viral disease transmission respectively. It is our speculation, and we have randomized trial evidence in acute leukemia and pediatric cardiac surgery, that removal of stored supernatant immediately prior to transfusion by washing, along with leukoreduction and ABO identical can strikingly improve clinical outcomes by reducing immunomodulation and inflammation. When ABO identical red cells or platelets are not available, we remove 95% of the supernatant from group O red cells or platelets for non-O patients. References on request.

While I would not use leukoreduction as the primary method of preventing transfusion associated graft versus host disease in high risk patients, there is evidence that it reduces the incidence of this complication in patients not conventionally thought to be immunosuppressed. These data are from the UK haemovigilance reports. Lymphocytes are not killed by irradiation, but they cannot successfully proliferate, which is necessary for graft versus host disease to occur. These UK data make one wonder what the heck the USA experts (AABB and FDA) are thinking in not mandating universal leukoreduction 20 years after it was implemented in France, UK, Canada, etc. So little cost, so many benefits. Three FDA committees have voted overwhelmingly that universal leukoreduction is clinically sound policy. No action. Many pleas to the AABB. No action. This is one of the most cost-effective and important innovations in transfusion safety in the last half century. It reduces suffering, morbidity and mortality. It's cheap and easy. The impact of universal leukodepletion of the blood supply on hemovigilance reports of posttransfusion purpura and transfusion-associated graft-versus-host disease. Williamson LM, Stainsby D, Jones H, Love E, Chapman CE, Navarrete C, Lucas G, Beatty C, Casbard A, Cohen H. Transfusion. 2007 Aug;47(8):1455-67.

No eluates, ever on neonates. Won't change therapy in any way. There are essentially no cases of autoimmune red cell disease in neonates, and the only source of IgG is mom. If we didn't have a maternal specimen, or a history from the birthing facility I suppose we might do one, but there's really no clinical mileage in doing so.

Don't believe you need a variance or validation. Just relabel the product before 24 hours is up. The product is liquid plasma, not FFP after 24 hours.

The INR is a largely useless predictor of bleeding risk except for those on coumadin/warfarin, and not so good a predictor in those patients. It is known that the range of 2-3 is a reasonably safe and effective one for anti-coagulation to prevent recurrent thrombosis (usually DVT or PE). Beyond that, INR numbers like 6 or 12 tell us next to nothing except that factor VII is quite low, which may or may not be clinically important. The INR of liquid plasma or FFP is around 1.6-1.8, and is not affected by the citrate anticoagulant, since exogenous excess calcium is added in the performance of the INR. INRs of 1.5 to about 2.0 are not associated with substantial increases in bleeding, either spontaneous or procedure related, and do not need to be corrected at all, in my view, and this opinion is supported by an extensive observational literature. FFP will not correct such an INR in any case, and thus represents risk without benefit. Medical specialty society recommendations for INRs of 1.5 prior to procedures are without any evidence support whatever, and represent old, no longer valid expert opinion. If an INR needs correction for any reason, factor concentrates are more effective and less likely to harm the patient than FFP. FFP should never be used to reverse warfarin/coumadin in my opinion, because of these efficacy and safety issues. Unfortunately factor concentrates are also much more expensive than plasma/FFP. However, this considers only the cost of the product, not the cost of any clinical complications such as thrombosis, volume overload, ICU admission, etc., not to mention death, all of which are more likely with plasma/FFP. Meta-analyses of randomized trials of FFP vs. factor concentrate, demonstrate that FFP is associated with a two fold mortality increase. 'Nuf said. One ICU admission for a few days can balance the increased costs of factor concentrates for the overall health system. Factor concentrates, preferably II, VII, IX, X concentrates that also contain some protein S and C; in the USA=Kcentra; in Europe=Beriplex are preferred over three factor concentrates, but both are superior to FFP.

Two other approaches that should be considered, likely employed are (1) minimizing blood draws and minimizing volume of any blood draws and (2) consideration to prophylactic use of EPO and/or intravenous iron. Both have been shown to help maintain hemoglobin/hematocrit levels in bleeding patients.

TACO is not just volume overload, contrary to conventional wisdom. Half the patients considered to have TACO have fever as well as signs of congestive heart failure/pulmonary dysfunction along with transfusion. Thus it's clear that TACO has an inflammatory component in many or most patients, as well as problems in dealing with the water and protein volume. It's probably not terribly different from some cases of TRALI, which are both antibody and cytokine/mediator in etiology. These distinctions are more pedagogic/nosologic than physiologic/biologic, in my view. In any case, a patient with functioning kidneys can rapidly excrete the salt and water that come with the crystalloid wash. The body has no mechanism for rapidly getting rid of the plasma protein infused with the typical platelet or plasma transfusion (about a quarter of a liter). In about 100,000+ washed components we have yet to see a case of TACO or TRALI, granted the usual passive reporting (knock on wood). When we instituted universal leukoreduction, reports of congestive heart failure signs and symptoms (TACO) dropped 50% and stayed there, and reports of TRALI dropped 80% (and stayed there). That, amongst other data, tells me that both TACO and TRALI are mediated by immunologic mechanisms (other than antibody) that haven't been elucidated.

I'm not aware of any data suggesting that psoralen treated platelets predispose to allergic reactions in adults, who are more likely to be atopic than children. If one is concerned about the toxicity of platelet transfusions there are two major ways of reducing the toxicity (inflammation, impairment of platelet function, immunomodulation, organ failure, TRALI, TACO, febrile and allergic reactions). The first is to always give ABO identical platelets and the second is to remove the supernatant prior to transfusion (e.g., washing). Happy to provide references if anyone wants them.

Not mention that isoagglutinins may be absent entirely in the first half year to year of life, and in patients receiving intensive immunosuppressive/myeloablative therapy. So the source of your plasma may make a difference, if it was from patients in a hospital, as opposed to healthy blood donors.

Some individuals have very low titer/affinity antibodies, and this probably explains your negative results. Not all that surprising or uncommon.

Vox Sang. 2009 May;96(4):316-23. doi: 10.1111/j.1423-0410.2009.01167.x. Epub 2009 Feb 24. Post-transfusion mortality among recipients of ABO-compatible but non-identical plasma. Shanwell A1, Andersson TM, Rostgaard K, Edgren G, Hjalgrim H, Norda R, Melbye M, Nyrén O, Reilly M. Author information Abstract BACKGROUND AND OBJECTIVES: The consequences of ABO-compatible non-identical plasma for patient outcome have not been studied in randomized clinical trials or large cohort studies and use varies widely in the absence of evidence-based policies. We investigated if transfusion with compatible instead of identical plasma confers any short-term survival disadvantage on the recipients. MATERIALS AND METHODS: The cohort of all 86 082 Swedish patients who received their first plasma transfusion between 1990 and 2002 was followed for 14 days and the risk of death in patients exposed to compatible non-identical plasma compared to recipients of only identical plasma. RESULTS: After adjustment for potential confounding factors, there was an increased mortality associated with exposure to ABO-compatible non-identical plasma, with the excess risk mostly confined to those receiving 5 or more units (relative risk, 1.15; 95% confidence interval, 1.02-1.29). Stratification by blood group indicated higher risks in group O recipients, especially when the compatible plasma was from a group AB donor. CONCLUSIONS: This study suggests that ABO-compatible non-identical plasma is less safe than identical plasma. Subanalyses by blood group suggest a role for circulating immune complexes. Our findings may have policy implications for improving transfusion safety.

"I do find it difficult to accept the need for expensive washed group O red cells, resuspended in AB plasma, in such a situation (particularly as any manipulation of a unit of red cells, and/or plasma, is a situation where a bacterial [and/or viral, fungal and/or parasitic] contamination may be introduced, however asceptic the technique used may have proved in the past. Surely, in a situation where anti-A1, not detected by standard serological techniques, blood found to be compatible by an IAT cross-match at 37oC is efficacious?" We don't use AB plasma as universal donor unless the blood type of the recipient is unknown. We believe giving AB plasma to group O individuals in large amounts probably increases morbidity and mortality through an immune complex mechanism (see reference below). I agree that anti-A1 not reactive at 37 degrees and/or IAT can be safely ignored. anti-A1 reactive at 37 degrees or IAT probably should be honored by full crossmatch compatible group A red cells, or, if essential with washed group O red cells. At least, that is our approach.

In general we do our best to not detect antibodies that do not react at 37 degrees and IAT, but obviously reverse grouping is performed at room temperature, so you are occasionally going to find an anti-A1. We would probably not ignore this, despite the evidence that clinically evident hemolysis is very unlikely to nil. Our approach would probably be washed group O red cells. The reasoning is to minimize the infusion of incompatible soluble antigen and antibody from the ABO blood group. It may well be overkill in this setting, but we are now convinced that the use of so-called universal donor group O red cells and group AB plasma is likely harming some patients by increasing bleeding, multi-organ failure and infection through an immune complex/hemolysis mechanism. Traditionally, hematologists and transfusion professionals are only worried about massive hemolysis. Recent work by many groups suggests that low levels of hemolysis (say 10-50 mg/dl) are not benign. Free hemoglobin, heme and iron are clearly not benign in animal models. We know from experiments of nature such as sickle cell anemia and paroxysmal noctural hemoglobinuria that these sorts of "invisible" levels of hemolysis likely cause vasculopathy, platelet activation and thrombosis and predispose to nosocomial infection. Hence we are trying to never give transfusions that may contribute to hemolysis by infusing incompatible ABO antibody or soluble/cellular antigen. Hence the saline washing of group O red cells in some instances in order to avoid both antibody as well as antigen incompatibility. We have randomized trial data that this approach is safe (no excess bleeding) and reduces inflammation in cardiac surgery and improves survival in acute myeloid leukemia. Moreover use of ABO identical and washed (and leukoreduced) transfusions almost completely abrogates the last platelet refractoriness seen in patients with hematologic malignancy. Yes it's extra work and costs a bit more, but HLA matched platelets are expensive too :). Finally, since converting to this policy of ABO identical everything for all recipients we have seen our febrile and allergic transfusion rates decrease substantially, and our red cell alloimmunization rates to CcEe and K have decreased by 50% or so. We consider this good news. One reason patients with sickle cell anemia have such high alloimmunization rates, we suspect, is the tendency to use group O red cells (unwashed) which creates low levels of ABO immune complexes in non-O recipients that predispose to immune activation. No data on this, just suspicion and extrapolation from our clinical data.