Neil Blumberg

Malcolm, I agree this was truly insensitive and arrogant behavior, not atypical of physicians in many periods of history, granted. I do believe this is very different from our use of about to be discarded cord blood specimens used for laboratory testing, but I'm sure some would disagree. Our human subjects review boards generally consider laboratory testing blood specimens from patients that would otherwise be discarded may be used for research purposes or quality control purposes without informed consent.

We have yet to see a patient on daratumamab who has made an anti-K antibody after years of transfusing red cells without regard to K antigen status. We use cord red cells in an antibody screen to rule out significant antibodies to allogeneic red cells (they are CD38 negative) as our method of dealing with this issue of pan-reactivity from daratumumab. I know this practice isn't allowed in the UK due to the over the top regulations that followed the infant parts kerfuffle. We detect plenty of anti-K's, just NOT in patients receiving anti-B cell therapies. In fact, I cannot recall a single new red cell alloantibody in myeloma or lymphoma patients receiving daratumumaub, rituximab, etc. No B cells equals dramatically reduced risk of alloimmunization, so you may be worrying about something that is pretty unlikely to happen. Just another approach.

Blood ABO major incompatible platelets increase bleeding in intracranial hemorrhage . 2021 May 13;137(19):2699-2703. doi: 10.1182/blood.2020008381.

I think the evidence (mostly adults) is that AB plasma is no safer than A plasma, probably because it is soluble antigen incompatible with 95% of patients compared with 60% for A plasma. Obviously ABO identical is safest and probably most effective. With platelets, giving ABO major incompatible platelets increases bleeding in adults so I would definitely not be preferring AB platelets which are incompatible with 95% of recipients. At this point, group O may be safest and most effective for initial transfusions until ABO identical can be transfused. We've worried about hemolysis but have neglected to detect that transfusing incompatible antigen (A and B cellular and soluble antigen) forms immune complexes that contribute to hemolysis even when the incompatible antigen isn't from red cells. This is a rapidly evolving field with not a lot of clinical outcome data, much less randomized trials. Nonetheless, it appears we've gotten the ABO system wrong when it comes to what is safest. And it isn't AB plasma, which, in adults, is associated with with increased sepsis, lung injury and mortality in group O patients. There are no data, but I assume the same would be true for AB platelets given to O recipients. So our choice would be O red cells (or low titer group O whole blood), A plasma and A or O platelets. We would never use AB plasma or platelets except for AB patients, given the bad outcomes in adult patients. Arch Surg . 2010 Sep;145(9):899-906. doi: 10.1001/archsurg.2010.175. Vox Sang . 2009 May;96(4):316-23. doi: 10.1111/j.1423-0410.2009.01167.x. Epub 2009 Feb 24.

I think the evidence (mostly adults) is that AB plasma is no safer than A plasma, probably because it is soluble antigen incompatible with 95% of patients compared with 60% for A plasma. Obviously ABO identical is safest and probably most effective. With platelets, giving ABO major incompatible platelets increases bleeding in adults so I would definitely not be preferring AB platelets which are incompatible with 95% of recipients. At this point, group O may be safest and most effective for initial transfusions until ABO identical can be transfused. We've worried about hemolysis but have neglected to detect that transfusing incompatible antigen (A and B cellular and soluble antigen) forms immune complexes that contribute to hemolysis even when the incompatible antigen isn't from red cells. This is a rapidly evolving field with not a lot of clinical outcome data, much less randomized trials. Nonetheless, it appears we've gotten the ABO system wrong when it comes to what is safest. And it isn't AB plasma, which, in adults, is associated with with increased sepsis, lung injury and mortality in group O patients. Arch Surg . 2010 Sep;145(9):899-906. doi: 10.1001/archsurg.2010.175. Sang . 2009 May;96(4):316-23. doi: 10.1111/j.1423-0410.2009.01167.x. Epub 2009 Feb 24.

Disciplinary action over product wastage sounds like it is perhaps well intentioned but ignorant bureaucrats, not health care workers running the show. That's a big part of the problem in many institutions these days. We are fortunate in that the senior decision makers in our hospital are all physicians, nurses, etc., including the CEO, CMO, COO. Washing your hands before delivering babies turns out to be inconvenient but a better idea. Universal leukoreduction and avoiding infusion of ABO incompatible antigen and antibody are also better ideas than what we have done for decades or longer. These practices will save lives, reduce need for transfusions and actually save the system money overall, albeit at greater expense in the transfusion service. You are no doubt correct that there will be pushback from transfusion service staff used to doing things the old, easy, but harmful way, and hospital administrators who prioritize the wrong things such as budgetary tunnel vision over reduced harm. And blood centers are not likely to initially be all that interested in changing practices. But when the data says patients do better with universal leukoreduction and ABO matching, hopefully, in the long run the dogma will be replaced by data driven practices. May take a while.

Once clinicians understand that ABO mismatched platelets not only do not provide hemostasis, but make bleeding more likely/worse, they will be less willing to accept infusion of ABO mismatched antibody/antigen. Once blood transfusion services realize that infusing ABO mismatched platelets increases utilization by two fold, they will be more interested in making the effort to give ABO identical or remove incompatible plasma by washing. Doing the right thing for patients is never the wrong answer to the question. Our current practices are convenient for us and minimize waste. We need to prioritize clinical benefit over inventory control and waste reduction. What we are doing now is providing little to no benefit and actually harming patients in many instances. The bleeding rate in the PLADO (platelet dose study) in NEJM was 70%. That's not exactly a clinical triumph. Our bleeding rate is probably less than 5-10% employing ABO identical/washed platelets.

Cannot post the entire article due to copyright restrictions, but most institutions have access to NEJM through their library. If not, shoot me an email at neil_blumberg@urmc.rochester.edu and I'll send along the .pdf. If you are transfusing 40-60 platelets a day, giving ABO identical to group O and A individuals should be relatively easy. When patients are changing ABO blood group it becomes more difficult. We avoid transfusion ABO antigen and/or antibody that is incompatible with either original recipient type or donor type. Usually means washed group O red cells and platelets. That's the bad news. It does require time and effort, and as you say, med techs are in short supply. Here's the good news. If you transfuse ABO identical or washed compatible platelets you will use between 30-50% fewer platelets per patient, increasing your supply and decreasing your cost/problems. You will also use next to no HLA matched platelets (we used 3 out of 6,000 one recent year), you will have fewer febrile and allergic transfusion reactions, you will have fewer red cell as well as HLA antibodies made in recipients, and you may reduce TRALI and TACO. Obviously you have to have universal leukoreduction to start with. Selective leukoreduction misses about 50% of the patients who will become refractory, probably due to missed or delayed diagnosis of hematologic malignancy, aplastic anemia, etc. But the big attraction is you will have less bleeding, although that mainly affects the patients and the docs and nurses at the bedside. When you transfuse ABO major incompatible, which seems to be the default due to fear of hemolysis from minor incompatible, you don't get any increments, you use lots of platelets and the patients bleed more. (see references below) Bleeding causes lots of harm, but also impacts the blood transfusion service for obvious reasons. So figure out a way to start giving patients with aplastic anemia and acute myeloid leukemia who are newly diagnosed only ABO identical platelets and that will be a great start for the patients and the transfusion service. Those patients will bleed less, need fewer platelet transfusions, have fewer transfusion reactions, will not have positive DATs, and will likely survive their hospitalization and disease at higher rates if our experience is typical. And if you cannot give ABO identical or washed platelets free of incompatible cellular and soluble antigen and free of incompatible ABO antibody, start out with minor incompatible platelets (e.g., O to A) rather than ABO major incompatible (e.g., A to 0). The risks of hemolysis are not negligible (about 1 in 800) but are less serious and severe than having life threatening bleeding or refractoriness which occur more rapidly with ABO major incompatible in all likelihood. There's a ton of antibody that is incompatible with antigen transfused when we give A platelets to O recipients which means each antigen winds up with a ton of antibody making huge immune complexes. When we transfuse antibody incompatible we are transfusing a small amount of antibody into a recipient with huge amounts of antigen, so the size and number of immune complexes is probably smaller. These are my best guesses that we've been making exactly the wrong decision when we give ABO mismatched platelets. Best to avoid any, but major mismatched provides no hemostasis, minimal to no increment and is associated with increased bleeding mortality in the study from Columbia (David Roh and colleagues https://pubmed.ncbi.nlm.nih.gov/33649761/). But ABO identical is not that hard for larger centers for the 85% of patients who are group O or A. You just have to start small, get the hang of it, and then extend to other blood groups and other diseases than leukemia, MDS and aplastic anemia (including transplants, particularly allo--transplants). All those tables of how to select ABO mismatched platelets for transplant recipients are well intentioned but scientifically without evidence. Avoid infusing incompatible antigen and antibody as much as possible, and delay transfusion when ABO identical will be available within hours. Give priority to patient well being over inventory management. Give reduced doses, which work just as well. Get a Terumo or Haemonetics washing device and wash with PAS. It's a big set of changes, but neither terribly expensive nor rocket science. The dogmas and expert opinion about universal leukoreduction and ABO matching of transfusions are now proven to be tragically mistaken. https://www.ashclinicalnews.org/news/from-the-blood-journals/written-in-blood/outcomes-abo-incompatible-platelet-transfusions-patients-intracerebral-hemorrhage/ https://pubmed.ncbi.nlm.nih.gov/11399821/ https://pubmed.ncbi.nlm.nih.gov/21414009/

Research letter in NEJM describes our findings. https://www.nejm.org/doi/full/10.1056/NEJMc2034764?fbclid=IwAR1BQRvpaHBAMDaHxCPY07xBjPQHlIHoJCOmpjoT_pBNvQsV7pzzDVdLYaY Table 1. HLA-Matched Platelets as a Percentage of All Platelet Transfusions, According to the Initiation of Other Protocols.* Protocol and Timing of Initiation No. of Years HLA-Matched Platelets Difference from Previous Period (95% CI) median % (IQR) percentage points No leukoreduction and no ABO matching (1985–1990) 6 12.5 (4.2–13.7) NA Leukoreduction and ABO matching for patients with leukemia and MDS (1991–1999)† 5 2.9 (2.0–3.6) 9.6 (9.4–9.8) Universal leukoreduction (2001–2004) 4 1.4 (1.1–2.0) 1.5 (1.4–1.6) Universal ABO matching (2005–2015) 11 0.4 (0.2–0.8) 1.0 (1.0–1.1) Pathogen reduction of platelets (2016–2019)‡ 4 1.7 (0.8–1.8) ND The practical fact is that this can only be implemented by medical technologists, not physicians, and this is a daunting prospect. But the reality is that ABO mismatched platelet transfusions probably exacerbate rather than prevent bleeding, so waiting for ABO identical is likely better than just transfusing whatever is available. This is going to require a major change of approach because the (incorrect) dogma, based upon no data, is that ABO doesn't matter for platelets. I understand why many people's instant reaction is this is not feasible. But it is once technical experts in your transfusion service figure out how to implement it gradually. In our randomized trial back in 1993 (see ref below), the ABO identical group only required <50% the number of platelet transfusions (every other day instead of every day on average) compared with the usual first in, first out regardless of ABO type group. ABO mismatched transfusions create a hostile environment with gigantic immune complexes that compromise subsequent transfusion that may be ABO identical. Avoiding this is key. Our suggestion is to start gradually. Pick new previously untransfused patients with aplastic anemia and good prognosis AML (young, favorable or normal cytogenetics), groups O or A, and start with them. Eminently doable since your platelet supply is 45% O and 40% A, just like your patients, on average. Get the hang of doing this and prioritizing ABO for at least some patients. Once you get this in place, extending it to other patients and eventually all patients can happen. We use washed O or A platelets and red cells for group B and AB recipients when we don't have group B or AB platelets. No increase in bleeding and fewer transfusion reactions, lung injury and congestive heart failure (what we call TRALI and TACO). In the end, you have more surviving patients and fewer headaches and transfuse many fewer platelets per patient and essentially no HLA if you can get your referring hospitals to stop our current standard harmful practices. Godspeed. Heal JM, Rowe JM, McMican A, Masel D, Finke C, Blumberg N. The role of ABO matching in platelet transfusion. Eur J Haematol. 1993 Feb;50(2):110-7. doi: 10.1111/j.1600-0609.1993.tb00150.x. PMID: 8440356. Happy to have discussions or visitors so our technical experts can show you how it is feasible.

I've summarized the data in this letter: https://www.bmj.com/content/366/bmj.l4968 In randomized trials, the fresher blood arm is associated with a higher incidence of nosocomial infection (immunomodulation, presumably). There has never been any data examining clinical outcomes that actually favors using very fresh blood. Mostly just "expert opinion" and "it seemed like a good idea." That's not good enough now, in my view. Two key references (one only published in abstract form) are: Alexander PE, Barty R, Fei Y, et al . Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis. Blood2016;127:400-10. doi:10.1182/blood-2015-09-670950 pmid:26626995 Abstract/FREE Full TextGoogle Scholar ↵ Schmidt A, Gore E, Cholette JM, et al . Oxidation reduction potential (ORP) is predictive of complications following cardiac surgery in pediatric patients[abstract]. Transfusion2016;56(Supplement S4):20A-1A. Google Scholar

Our neonatal intensive care transfusions are all irradiated because many severe immunodeficiency states are not evident until weeks to months after birth. These are rare, and leukoreduced transfusions probably mitigate the risk of GVHD somewhat, but we are erring on the side of caution. We irradiate just before transfusion so the storage based problems with irradiated red cells are less of a concern. We define fresh as <21 days of storage, because the data suggest very fresh blood is actually more dangerous to patients than blood stored 7-21 days or so. Seat of the pants, to be sure, but somewhat data driven. No one knows for sure, but very fresh blood (<7 days storage) is totally unnecessary in terms of proven benefit and may actually be more dangerous, for reasons that are largely unknown.

All you need to do is document platelet recovery (should be at least 80%) and pH. Nothing else is required. No platelet function tests, etc. since these are not used with unwashed platelets. Would recommend washing in platelet additive solution rather than saline.Washed platelet buffy coat platelet additive manual.pdf

Should mention that Terumo has a similar process that is licensed in Europe using riboflavin. Both Cerus and Terumo have licenses for whole blood platelets but for some reason these have not been introduced in the USA, so only apheresis platelets are pathogen reduced at present. Which makes little sense from a resource or cost standpoint. There are no clinical advantages to pathogen reduced apheresis platelets over whole blood platelets and apheresis platelets carry a greater risk of acute lung injury due to the five fold increase in plasma from a single "dangerous" donor.

Pathogen reduced platelets are treated with a Cerus Corp. method of using light to activate a photo-activated psoralen compound that cross links DNA and RNA, thus making it impossible for cells to replicate, and, more importantly, viruses, bacteria and fungi to replicate. Thus the risks of bacterial infection after platelet transfusion become near zero. Increases the cost by about $150 from your blood supplier. Saves the occasional life threatening post-transfusion bacterial septic infection, and may reduce line infections too I'd guess.

There is absolutely no scientific or clinical reason that a vaccine could not be stored with frozen blood components. That doesn't mean you won't get some overly officious inspector who will decide it's a bad idea. But currently there are no regulatory or accreditation issues that I am aware of.

We used to do universal irradiation but then became aware of two things. One, irradiation of red cells causes increased hemolysis during storage. That's been known for some time. But in recent years, the toxic effects of infusing free hemoglobin or increasing hemolysis in vivo have become evident (e.g., sickle cell anemia; levels of hemolysis correlating with morbidity in surgical patients). So we stopped irradiating everything at that point. Just per protocol. Leukoreduction reduces GVH in the British data.

No one knows what to do for sure. We keep such patients on irradiated for life, since these recipients are not immunologically normal in many cases. But there are no data to support or refute this practice. Seems low risk and prudent to us.

I would not be performing one hour post-transfusion vital signs unless the patient has signs or symptoms that require assessment. I would not be reacting to one hour post-transfusion data unless they were consonant with a transfusion reaction. If fever was the only sign or symptom, it's probably not transfusion related in the vast majority of cases. Routine vital signs in the absence of a clinical rationale are a problem, not a solution.

Agree with Malcolm. We would tend to give Rh negative blood transfusions so we can tell when the recipient's cells are largely gone. We might do this in particular if the recipient is a female of child bearing age or younger. But we would not be giving Rh immune globulin in the vast majority of settings for the reason that Malcom mentioned.

IM injections hurt. IV hurt much less. Both acutely and over the next day or two. That's the likely motivation. Most physicians don't administer IV meds in their office as it requires more time and skill.

Obviously worth repeating. Sample mixup, technical error are other possibilities.

Should add that individuals with sickle trait have % S that is usually less than 50%. At those levels, even patients with SS disease usually are asymptomatic. Sickle trait individuals do not have symptoms under anything less than extreme physiologic stress, although some believe that occasional individuals have had complications when severely hypoxic or stressed. These case reports tend to neglect the fact that individuals who do not have S hemoglobin can have similar symptoms under extreme physiologic or hypoxic stress, so it's not clear these individuals with sickle trait are truly at greater risk. Larger cohort studies have sometimes suggested a higher rate of symptoms among AS (sickle trait) individuals, but there remains some doubt, at least in my mind :).

Sounds like a good plan. Reducing needless work is a great idea. I find it absurd to require busy practitioners to attest to the urgency of a clinical request by installing bureaucratic obstacles. It may be required by regulators and accreditation agencies, but it is bureaucratic nincompoopery (sic) to my mind, serving no real purpose. A discussion of the pros and cons of giving out red cells without an antibody screen should occur with every such request when time allows. Almost no one does a physical crossmatch these days anyway, to my knowledge, except if alloantibodies are present. This requirement is obsolete. Documenting in the medical record what you did and why should be the priority, not filling out forms taking responsibility for that which one is obviously entirely responsible. The transfusion service doesn't decide when to transfuse patients, so obviously a decision to urgently transfuse partially tested or untested blood is the responsibility of the ordering practitioner. Duh.

Patients with sickle trait do not have sickle crises at all, except in very rare cases when they become seriously hypoxic. There are rare cases reported in military personnel and athletes. It's not clear whether they are sickle crises in some cases or just similar symptoms seen in non-sickle cell patients. These are truly rare cases, and usually at higher stress than an altitude of 8,000 feet, which really isn't terribly high. No personal experience. In extreme circumstances, patients heterozygous for S may be slightly more susceptible to symptoms like mountain sickness, just like everyone else. Don't know for sure. They have lower hematocrits and this may be one factor. Distinguishing between sickle cell symptoms and mountain sickness may be difficult for some clinicians. Lots of people get sick at altitude, especially if they exert themselves or make the ascent rapidly, or are dehydrated. I would guess that is what happened to this group. There is no need for hemoglobin S negative units for routine transfusions to non-sickle cell, hemoglobin homozygous patients.

People heterozygous for hemoglobin S have no clinical level problems with transporting oxygen, so there is no need (except for being overly cautious) to provide hemoglobin S tested blood for newborns, or, as I mentioned above, anyone who is not being monitored for % S. Another one of those "it seemed like a good idea at the time" but not evidence based approaches.