Neil Blumberg

IVIgG can contain detectable rbc alloantibodies, although it would be unusual to be anything other than anti-A and anti-B.

N Engl J Med. 2010 Feb 18;362(7):600-13. doi: 10.1056/NEJMoa0904084. Dose of prophylactic platelet transfusions and prevention of hemorrhage. Slichter SJ1, Kaufman RM, Assmann SF, McCullough J, Triulzi DJ, Strauss RG, Gernsheimer TB, Ness PM, Brecher ME, Josephson CD, Konkle BA, Woodson RD, Ortel TL, Hillyer CD, Skerrett DL, McCrae KR, Sloan SR, Uhl L, George JN, Aquino VM, Manno CS, McFarland JG, Hess JR, Leissinger C, Granger S. Author information Abstract BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

For platelets you can cut the dose in half with no worsening of clinical outcomes. Randomized trial in NEJM called the PLADO (platelet dose) study some years ago (Sherrill Slichter was the senior author). Most platelets do little or no good, so this is actually a good idea for patients and helps with inventory in times of shortage. Try to give ABO identical as the increment is higher, the duration of increment is longer and the patients bleed less.

Probably the primary stimulation was not the fetus, but previous pregnancy, transfusion, tattooing, needle sharing, non-sterile tattooing, etc. Pregnancy is a situation in which B cells are upregulated (type 2 immunity) and T cells down regulated (roughly speaking) and pregnancy may have increased B cell activity to the point where previously undetectable antibodies are now detectable. Just a theory ;).

Duplication

Best guess is that the antigenic stimulation (at least primary) was not the fetus. Sharing needles, tattooing, blood sharing ceremonies and transfusions the patient was not aware of may have been the sources of stimulation of the primary immune response. Pregnancy stimulates Type 2 immunity (B cells mostly) which may increase the detectability of previously existing antibodies, at least in theory.

This is where having a transfusion service director who knows something about clinical medicine and hematology comes in very handy. It shouldn't be the medical technologists' job to triage requests. Many transfusions do more harm than good, so it's not that difficult to figure out which patients urgently need transfusion and which can wait, but this requires a knowledgeable and tenacious physician to handle the individual requests and screen them. As a field, pathology has paid little attention to the need for those who can do such tasks, as compared with surgical pathology skills, cytopathology, etc. You may need to involve your institution's hematologist(s), intensivist(s), surgeons and anesthesiologists to help make these decisions if your lab physician(s) aren't up to the task.

The vast majority of trauma patients only need TEG/ROTEM as these are the only assays shown to improve clinical outcomes when used to drive transfusion therapy. For patients who don't respond well (keep bleeding), it's important to have the fibrinogen level, platelet count, PT, PTT as well. The individual factor assays are largely irrelevant and unneeded. Hemophilia A and B are vanishingly rare diseases, and vWF is usually mild to moderate in most patients so individual factor analyses would be needed very uncommonly. A test of platelet function such as the closure time (PFA-100) might be a useful thing to have too, but less relevant in trauma patients.

I am aware of no rationale for not using this product in neonates.

The decision that a patient is in immediate risk of exsanguination and death is one that can only made at the bedside. That said, I think many trauma patients are overtransfused these days, particularly with plasma and platelets being given in most hospitals along with the first red cells. So I'd be very clear that the ordering practitioner believes that death is imminent without transfusion. And hopefully the patient would have already received tranexamic acid, and probably DDAVP as well to mitigate or even stop bleeding. These are evidence based, inexpensive, effective and safe drugs that can make the difference between surviving and not surviving, and between needing only a few units of red cells versus many more. Not all physicians have accepted these data, even trauma surgeons in some cases.

Our typical training period in slightly larger hospital is about 3 months (twice as long as yours). Most of our trainees are recent graduates (MT).

We are persuaded that sending plasma and platelets in a first cooler harms more patients than it helps. We actually wait to provide plasma and platelets/cryo until we are told this is a massively bleeding patient or 8 red cells have been sent. First cooler is 4 red cells. Second cooler is 4 red cells, if needed. Almost all the time, none or few of them are used. We are the only level I trauma center within 70-80 miles. Thus including plasma and platelets, which are highly toxic products, associated with nosocomial infection, multi-organ failure, thrombosis and mortality, will likely lead to the occasional patient receiving them along with one or a few red cells. A recipe for increased harm with no benefit. I realize this goes against the grain of what is being recommended, but the experts in surgical trauma are resolutely unaware or in denial about the risks of transfusion in patients in whom transfusions are not life saving. Reasonable, to my way of thinking, to reserve plasma/platelets and cryo for patients who are truly massively bleeding and will die without transfusion. Even then, I'd recommend tranexamic acid and/or DDAVP, and possibly fibrinogen concentrate (or cryo) long before transfusing plasma and platelets to bleeding patients, based upon randomized trial evidence to date. Remember that early use of plasma and platelets has never been tested against these other modalities in randomized trials. Platelet transfusion in particular, has promoted bleeding and mortality in randomized trials to date, and should be avoided if possible. Particularly ABO non-identical transfusions which almost certainly make bleeding worse, not better.

While our knowledge of the molecular structure of blood group antigens has certainly advanced during the last 20-25 years, our clinical practices have not changed much, if at all. The clinically significant antibodies are still clinically significant and those that rarely cause hemolytic reactions or HDN still are of little concern ;). While gel and other technologies have fostered automation, tube testing is still the cheapest, fastest, most appropriate methodology in my view for many clinical situations. I'm interested in hearing opinions as to what truly clinically relevant things have changed since the 4th edition. I cannot think of any at the moment, but I'm getting old. We still aren't certain what the molecular findings in the Rh system mean for clinical practice in my view.

Just to state the obvious, if you are using pathogen reduced platelets, no testing is needed. That has been our choice due to (1) it's a superior method for preventing viral, bacterial, parasite transmission and (2) the logistics of testing 20-30 platelets per day are formidable and not without significant expense for materials, labor, QC, proficiency and competency. If your supplier provides the option of pathogen reduced, I would go that direction despite the increased expense.

As for pediatrics, we have an attached children's hospital, Golisano Children's Hospital of the University of Rochester. We have a blood management program but it has proven difficult to find evidence based transfusion criteria for the main blood components, red cells, platelets and plasma. There has been some reluctance to change practice lacking evidence, which is understandable. Pediatric practice, with perhaps the exception of anesthesiology and critical care, seems based upon older understandings of transfusion that it was "very effective and not very risky." The reverse is almost certainly true in most clinical settings, other than life threatening bleeding and/or anemia. Therapeutic minimalism, rather than maximalism is called for, in my view. Witness the use of 20-30 ml/kg of red cells or whole blood in the recent NEJM trial in Africa. These doses would be fatal to a substantial number of adult patients. Thus changing practice in pediatrics should probably focus initially on appropriate dosing to start with. Our typical adult doses for red cells are in the range of 3-5 ml/kg and for platelets and plasma not much more, and certainly not more than 10 ml/kg. Since there is a dose dependent increase in nosocomial infection, thrombosis, inflation and mortality with red cell transfusion that is in part causal, these practices are likely not in the patient's best interest, despite representing "state of the art 1985 expert opinion." There is not a shred of evidence that WHO's guideline of 20 ml/kg is effective and safe, to my knowledge. The general guidance of hemoglobin 7 and hematocrit of 21 as boundaries for numbers (as opposed to clinically) driven red cell transfusion has reasonably strong evidence based (randomized trials) in children. Platelet transfusion and plasma transfusion have minimal evidence base, but the prophylactic threshold of 10,000/µl for non-bleeding children with hematologic malignancies seems reasonably evidence based. There is essentially no evidence to guide plasma transfusion, so my general approach is "don't do it" unless there is life threatening bleeding not treatable by anything other than massive transfusion.

And to give credit where credit is due, whatever I have achieved has been with the invaluable contributions of my collaborators, including physicians, scientists, medical technologists and nurses. In particular, my most important collaborator has been my wife, Dr. Joanna Heal MBBS, MRCP, whose brilliance and dedication to patient care made all the difference. That's her in the picture :).

Malcolm, my sincere appreciation of your kind words. I've enjoyed and learned from your comments on this website.

And to answer the initial question, yes, one monitors such features as service line specific use of blood transfusions, correcting for case mix and hospital days. Examples of metrics are red cells per admission or platelets per hospital day. Monitored quarterly or semi-annually. Change is slow so there is no need to monitor things on a daily, weekly or monthly basis in most cases. Can verify the improvement in clinical outcomes by metrics such as complication rates (central line infections, UTIs, etc.).

Patient Blood Management is a comprehensive, multi-modal approach to reduce/prevent anemia prevalence and reduce transfusions to only those that are life saving or absolutely essential. While the AABB has some materials and interest, they are relatively less likely to explain to you that the primary rationale is that anemia and transfusions are mostly harmful to patients in current practices. The pre-eminent organization in the USA in this matter is SABM. The founders of PBM include anesthesiologists such as Aryeh Shander at Englewood Hospital and Tim Hannon at St. Vincents, who saw that (1) Jehovah's Witnesses who refused transfusions actually had better outcomes than similar transfused patients and (2) transfused patients had dose dependent increases in nosocomial infection, thrombosis, multi-organ failure and mortality in the literature and their own practices. In other words, less is better. None is best when possible. Needless to say, the initial reaction in the blood banking and transfusion medicine community was lukewarm at best when these ideas were first put forward a couple of decades ago. But preventing anemia by doing fewer lab tests, and less frequent lab tests has begun to catch on in some places. See: https://www.sabm.org/patient-blood-management-programs/ Good place to get some initial education and join if of interest. A typical PBM program will include a part-time medical director (often an anesthesiologist, intensivist or hematologist, but also surgeons, transfusion medicine physicians, and other specialties) and one or more full-time nurses or medical technologists who focus on educating practitioners about current practices. You need a clinical champion at the bedside who other practitioners respect and will listen to. Changing practices is arduous and sometimes rather unpleasant work. When Bernard Fisher showed that the Halstead radical mastectomy for breast cancer was harmful to patients, the initial reaction was anger, disbelief and pushback. So it sometimes is with PBM. Physicians change their practices slowly or not at all. At our institution, PBM is heavily weighted towards collaborations between specialties, including, for example, an anemia management program prior to cardiac surgery, advocating restrictive transfusion practices where there is evidence (and there is tons of evidence that liberal practices are lethal at worst, wasteful at best). Happy to answer further questions.

"Leukoreduction reduces platelet function drastically on whole blood therefore it is not leuko reduced." I don't believe the word drastically is correct. The differences are slight and, as I recall, only in platelet aggregation, which has no known relationship to clinical efficacy of platelet transfusions. Absence of leukoreduction will almost certainly increase the risk of nosocomial infection, multi-organ failure and mortality for the patients who survive the hemorrhagic emergency. In addition, non-leukoreduced whole blood will have higher levels of hemolysis in vitro and likely in the patient due to damage to the red cells. Free hemoglobin, heme and iron levels in the patient are associated with increased mortality in recipients of transfusions. I would suggest the choice not to leukoreduce will cause net harm to patients. The minimal changes, if any are of clinical relevance, in platelet efficacy are not worth the risk, in my opinion, of well documented complications of allogeneic leukocyte infusion.

Pathogen reduction prevents lymphocyte proliferation and thus is practically speaking equivalent to irradiation. Whole blood platelets are pathogen reduced in some parts of Europe, but the manufacturers have not put forward these methods for FDA approval in the USA. A serious mistake and waste of resources. In any case, apheresis platelets carry a higher rate of some transfusion adverse events (TRALI, for example) in French hemovigilance data, so why one would preferentially use pathogen reduced platelets that are single donor rather than pooled whole blood is beyond me. We used to use 100% whole blood platelets as a socially responsible use of donor resources, particularly as apheresis platelets carry no proven health benefits for patients (donor exposure is a straw man in this instance, given the low risk of infectious disease transmission, and it's irrelevance in the pathogen reduction era). We are using close to 100% apheresis simply because that's the only pathogen reduced platelet product available. As I said, a terrible mistake in my view. But better apheresis platelets than non-pathogen reduced is our decision. We'd welcome use of whole blood pathogen reduced platelets as a much more responsible use of donor's time and safety given that whole blood platelets are essentially now a wasted, low cost scrap product. Much less expensive, and we think safer than apheresis platelets for most patients.

The simplest solution and the clinically superior one is to use pathogen reduced platelets (at the cost of $100+ more per transfusion). Bacterial testing will not prevent all bacterial contamination events in any case, and pathogen reduction pretty much will do that. In addition, pathogen reduction is the future of transfused blood (and no lesser expert than Harvey Alter, the co-discoverer of both Hepatitis B and C, has stated this). There will be viruses we don't know about and cannot immediately test for that come around the way HIV did, and pathogen reduction addresses these future pathogens, including present realities such as babesiosis, malaria, etc. We then could stop testing for pretty much everything if we wanted to, including useless tests like syphilis, Zika, etc. (These diseases are not known to be transfusion transmitted with current practices). That would save a little money, but awaits (1) pathogen reduction technology for whole blood and (2) the FDA and various states agreeing the redundant testing makes no sense from a clinical standpoint. Good luck with the latter :). We are close to 100% pathogen reduced for platelets in our center, and the cost was about $500,000 per year. Of course, one or two cases of post-platelet transfusion sepsis in a patient with neutropenia will pay for that in avoiding ICU stays, etc. If you are a small hospital and transfuse a few platelets per month, the extra few thousand dollars per year for pathogen reduction is easily recouped in reduced staff training time for bacterial testing, logistic nightmares and other complexities. Plus it's a superior approach to reducing risk to patients. To me, it's a no brainer, but your mileage may vary.

As long as the low titer whole blood is really low titer (say <50 or so; not 200), I don't see any major disadvantage in using low titer group O whole blood for trauma patients of unknown ABO type. For those of known ABO type, ABO identical is no doubt preferable, whether whole blood or components. We really don't have any comparative data except in trauma patients of unknown ABO type. Comparisons of ABO identical components versus low titer group O whole blood for everyone are simply not available in any form, to my knowledge. Would make a very important and useful randomized trial, but no one seems particularly interested in doing the work and incurring the expense, including the military who have sponsored most of this work. Lots of assumptions being made, but not much data at present. We know AB plasma given to group O recipients (about 45% of trauma transfusions) is associated with a significant increase in mortality from Swedish national data, so perhaps group O whole blood, if low titer, may actually be safer than traditional component resuscitation in patients of unknown ABO type. At least the 45% of patients are group O will be getting ABO identical instead of the 5% now occurring (thanks to our giving AB plasma to everyone).

If you read the paper carefully, the major difference in outcomes is reoperation and other complications clearly unrelated to transfusion triggers. Poor choice of endpoints and data analysis and totally non-credible conclusion regarding clinical outcomes in my view. The immense body of data showing that restrictive transfusion is not only safer but likely superior tells us this is a small pilot study with little to no real meaning for clinical practice. Cannot imagine what the reviewers were thinking when they let them publish this with these conclusions in the current form.

Most patients with IgA deficiency and even with anti-IgA do not have anaphylactic or allergic reactions. Unless she has a history of anaphylaxis/atopy I wouldn't worry. In an hemorrhagic emergency, just transfuse and, as always, have some epinephrine on hand for reactions. It's well established now that most anaphylactic reactions happen in atopic patients and IgA deficiency has nothing to do with it, in general. See work by Gerald Sandler, et al. on the subject or listen to the Blood Bank Guy podcast by Sandler. Be happy, don't worry.