Universal leukoreduction and ABO identical transfusions reduce HLA alloimmunization by transfusion to near zero

[Neil Blumberg]

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.

[Cliff]

Thank you Neal.

Are you allowed to post the entire article?

We are a large facility and transfuse about 40 - 60 platelets a day.  Many of these are transitioning ABO due to transplant.  I see matching ABO as a daunting task, and with the current environment of Med Tach shortages, more worrisome to think of volume reducing them.

[Neil Blumberg]

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/

[Sonya Martinez]

Working in a children's hospital we only give ABO compatible platelets or type AB but our first choice is identical.  In most cases we use ABO identical and we have a very detailed Selection of Appropriate Component policy.  For patients who received or will be receiving BM/HPC transplants we give compatible based on matching donor and recipient types, or type AB only (example patient type A receiving type O transplant gets either A or AB platelets).  Also our listed ABO incompatible heart transplant candidates we will only give type O RBC and type AB plasma containing products until transplant and then ABO compatibility is determined by donor to recipient type.  I attached our transfusion guidelines for non-transplant patients and BM/HPC transplants.  

 

It has been over 15 years since I've worked in an adult hospital so I'm not sure how hard it would be to implement our policies but I know we have a white board where we keep track of the platelets so we can easily look and make sure we have what we need at a glance.

[Ensis01]

Hi Neil, I have been following your RBC and platelet transfusion observations, and your resulting evolution of policies with interest and I agree with ABO matching platelets (also my observations). I guess however I am one of these that see too many problems for implementation, even gradual.  Yes the Med Techs select the platelet, but mostly it has to be the shortest date first to minimize waste (a major concern/factor every where I have worked). A policy to only give ABO identical to a patient (one, all, or a percentage) will result in occasions where the ABO matched platelet can not be obtained locally (and may not be obtainable at all). While you mentioned both these issues and suggested solutions my experience leads me to believe it an unsurmountable task for many hospitals unless there is agreement among the physicians and/or the transfusion Medical Director can override orders (and not just advise). I can not see that happening in most institutions especially larger ones. 

[Neil Blumberg]

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.  

[Ensis01]

14 hours ago, Neil Blumberg said:

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.  

Agreed to all the above; as you say you have implemented a policy that prioritizes clinical benefit over inventory control and waste reduction, which the hospital (physicians, Med Techs and bean counters) follow. My experience, however, is disciplinary action taken over product wastage. So unless a hospital implements a policy similar to the one you outline, which the Med Techs can follow, giving only ABO specific platelets will be problematic. 

[Neil Blumberg]

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.