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Why irradiate liquid plasma when RBCs for trauma patients aren't irradiated?


Mabel Adams

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Can anyone explain the justification for irradiating liquid plasma (never frozen) used for trauma patients when we don't irradiate the red cell units they get?  I know the RBCs are leukoreduced so don't contain many viable lymphocytes but there were cases of GVHD if LR units weren't irradiated.  Our liquid plasma is made using a hard spin so I would think that there aren't many WBCs in it but no one seems to be able to tell me how the number of lymphocytes in liquid plasma compares to the number in a LR red cell unit.  Maybe this is because the big places irradiating their plasma have their own irradiators.  For us, it would nearly double the price of the plasma unit so I need justification.

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Where I was, I preferred both to be irradiated.  It's not so easy to irradiate and ship over state lines though.  ARC (their primary supplier) offers irradiated licensed RBC products, so they purchase those.  They do not offer licensed irradiated LP, but FDA allows you to irradiate it for emergencies.

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5 hours ago, Ensis01 said:

I can see that irradiating plasma for reconstituted whole blood makes sense if the LIS needs both the RBC and plasma to be irradiated for consistency. I see no other reason to irradiate plasma due to the manufacturing process

Hi @Ensis01, @Mabel Adams was referring to irradiating liquid plasma for trauma patients.  You may or may not know the immune state of the patient when issuing.  Liquid plasma is likely leukoreduced, but it's never frozen, so there may be viable WBCs; hence, irradiation.

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If you are not irradiating red cells, irradiating plasma makes little sense, since there are likely many more residual leukocytes in red cells that have been leukoreduced than in liquid plasma. I don't have exact data so you may want to confirm that. I don't know the methods currently in use, but the ideal would be to leukoreduce whole blood so the plasma made afterward would have many fewer white cells.  White cells are bad for patients, causing platelet refractoriness, transfusion reactions, immunomodulation predisposing to sepsis/infection and probably TRALI and TACO.  So we want to transfuse as few white cells as possible, regardless of irradiation.

Why are you using liquid instead of frozen stored plasma, out of curiosity?  Price? The factor VIII/vwF content is likely quite a bit lower, which may not be a big deal, but isn't likely an advantage.  

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1 hour ago, Neil Blumberg said:

If you are not irradiating red cells, irradiating plasma makes little sense, since there are likely many more residual leukocytes in red cells that have been leukoreduced than in liquid plasma. I don't have exact data so you may want to confirm that. I don't know the methods currently in use, but the ideal would be to leukoreduce whole blood so the plasma made afterward would have many fewer white cells.  White cells are bad for patients, causing platelet refractoriness, transfusion reactions, immunomodulation predisposing to sepsis/infection and probably TRALI and TACO.  So we want to transfuse as few white cells as possible, regardless of irradiation.

Why are you using liquid instead of frozen stored plasma, out of curiosity?  Price? The factor VIII/vwF content is likely quite a bit lower, which may not be a big deal, but isn't likely an advantage.  

I agree with almost all you said, but would ask why residual leukocytes would have any bearing on TACO please?

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On 1/26/2022 at 10:39 AM, Malcolm Needs said:

why residual leukocytes would have any bearing on TACO please?

The mechanisms of what have been termed TRALI (actually a subset of acute lung injury/acute respiratory distress syndrome) and TACO (actually something very common, congestive heart failure) have been widely misunderstood due to unjustified assumptions/dogma. There are many biologic mediators other than antibodies that can cause lung injury after venous infusion which directly subjects the lung vascular endothelium to these mediators (antibodies, activated cells, lipids, mediators such as sCD40L, DNA/histones).  Likewise there are many mediators that can cause or exacerbate cardiac failure after venous infusion (inflammatory mediators, excess volume).  Cardiac failure is not just volume overload, but can be caused by fever, inflammatory cytokines and vascular/myocardial muscle dysfunction.  The notion that these are distinct entities is also at variance with clinical experience.  Many patients have signs of both cardiac failure and pulmonary failure simultaneously.  So the definitions and pathophysiology used in reviews and texts are lacking in validity and just plain oversimplified and wrong, in my view.  There are compelling data to support these iconoclastic contentions for TRALI, and some for TACO.

Most germane (see attachment), when we introduced universal leukoreduction, we saw a sustained 83% drop in reports of TRALI and 50% in TACO over the following years.  This suggests that white cells/DNA/histones play a role in causing lung and heart inflammation and dysfunction.  This clinical observation was confirmed in animal studies from Denisa Wagner's lab at Harvard demonstrating that neutrophil extracellular traps (NETS) infused intravenously can cause acute lung injury (see attachment).  To me these observations are convincing evidence that leukoreduction alters cardiorespiratory injury and failure post-transfusion and represents one of the strongest arguments for universal leukoreduction.  Needless to say, this challenge to dogma has been ignored by the transfusion medicine community which continues, at least in the USA, to infuse deadly white cells and their degradation products (free DNA/histones) to patients, one of the great tragedies of the last 20 years in the USA blood bank field.  We got this entirely wrong and tens of thousands of patients have probably died unnecessarily due to complications of non-leukoreduced transfusions.

ULR TRALI TACO PMC version.pdf NETS and TRALI Wagner 2012.pdf

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On 1/26/2022 at 8:49 AM, Neil Blumberg said:

If you are not irradiating red cells, irradiating plasma makes little sense, since there are likely many more residual leukocytes in red cells that have been leukoreduced than in liquid plasma. I don't have exact data so you may want to confirm that. I don't know the methods currently in use, but the ideal would be to leukoreduce whole blood so the plasma made afterward would have many fewer white cells.  White cells are bad for patients, causing platelet refractoriness, transfusion reactions, immunomodulation predisposing to sepsis/infection and probably TRALI and TACO.  So we want to transfuse as few white cells as possible, regardless of irradiation.

Why are you using liquid instead of frozen stored plasma, out of curiosity?  Price? The factor VIII/vwF content is likely quite a bit lower, which may not be a big deal, but isn't likely an advantage.  

We stock liquid plasma to save the thawing time in urgent situations.  It has prevented waste of thawed plasma units that were not needed by the time we thawed them.  We can assign the liquid plasma and place it back in inventory with its full shelf life (28 days)when not needed.  Works well for us as a level 2 trauma hospital that often stabilizes and transfers patients.  We do not use the liquid plasma for routine orders because it may have viable leukocytes.

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We convert plasma frozen within 24 hours (our standard plasma product) to liquid plasma for standby and keep some A and O units thawed at all times.  For routine orders, we just thaw units as needed. The freezing and thawing of what becomes "liquid plasma" in our setting means we don't worry about graft versus host disease.  By the way AB plasma is not universal donor as it is associated with worse clinical outcomes in a variety of observational studies.  Lots of incompatible soluble antigen that reacts with anti-A and anti-B in 95% of recipients, injuring platelets, red cells and endothelium.  We only use ABO identical plasma.  Just another approach.

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  • 1 month later...

Dr. Blumberg, I have long been impressed with your amazing knowledge.  I keep some of what I have learned from you in my head even though the mainstream has never accepted it. Thanks for sharing so much all of these years.  If we were to use liquid plasma, it would be group A and have an expiration of 26 days from collection (5 days beyond the whole blood it started as).  It would be in our small hospitals because they lack time to thaw plasma when a trauma lands at their door. The flight services that serve our area are carrying liquid plasma now along with O neg red cells. As the cost and availability of O red cells has become more of a problem, we are looking for ways to start out our trauma or MTP patients with plasma instead of red cells.  The trauma surgeons like the idea of having some clotting factors given first (although liquid plasma on day 26 will have low levels of several labile factors). We would plan to never give more than 2 units of liquid plasma to a given patient.  We are a smallish, remote, level 2 trauma center.  We currently keep 2 units of thawed, group A, 5 day plasma at our main hospital for traumas/MTPs.  Our small hospitals would use it so rarely that 5 day plasma would go to waste too often.  We also have MTPs that don't turn out to be massive.  The patient gets maybe 3 units of uncrossmatched red cells and then they realize they weren't that bad after all.  If we start with 2 units of plasma, they may not even use any red cells.  Are you thawing plasma and keeping it for more than 5 days as "liquid plasma"?  Another question: irradiating liquid plasma won't necessarily mitigate the WBC issues that you describe, will it?  The lymphocytes can't multiply but the WBC antigens, biologic mediators etc. would still be present to wreak the havoc you described, wouldn't they (depending somewhat on leukoreduction, of course)?   Sorry to ramble so.

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Thanks for your generous comments Mabel.

"The trauma surgeons like the idea of having some clotting factors given first (although liquid plasma on day 26 will have low levels of several labile factors)."

In general I think we have overestimated the need for clotting factors and underestimated the risks of giving plasma to trauma patients, so I would disagree.  Most of our level I trauma patients are hypercoagulable on TEG, not hypocoagulable.  A marginally elevated PT or aPTT is not a coagulopathy and does not account for bleeding.  Plasma, like red cells and platelets is likely pro-inflammatory and pro-thrombotic, although there are almost no data, unlike for red cells and platelets, where it is clear they are pro-inflammatory and prothrombotic.  So we do not begin 1:1:1 MTP until after 8 units of red cells or we receive a call from the surgeon saying this patient is clinically hypocoagulable (the bleeding is diffuse and not proportional to the injury in their clinical judgement).  I realize this goes against the expert opinion, but expert opinion has ignored the toxicity of plasma, platelets and possibly cryo.  Obviously red cells are needed for massive hemorrhage, but I am less convinced that we are doing patients any good by starting plasma, platelets and cryo early. I think we are likely doing more harm than good.  That's an advantage of low titer whole blood group O.  We're not giving them unnecessary, ABO mismatched soluble and platelet cellular antigen with mismatched plasma (group AB) and platelets (group A usually).

 "Are you thawing plasma and keeping it for more than 5 days as "liquid plasma"? 

No, we are not, but we probably should be.  No reason not to.  Only factor VIII is lacking and these patients do not need factor VIII as their factor VIII levels are usually very high due to the trauma effect on release of factor VIII from endothelial cells.

"Another question: irradiating liquid plasma won't necessarily mitigate the WBC issues that you describe, will it?  The lymphocytes can't multiply but the WBC antigens, biologic mediators etc. would still be present to wreak the havoc you described, wouldn't they (depending somewhat on leukoreduction, of course)?"

That's correct. There is no evidence that irradiating plasma mitigates against issues of immune modulation due to allogeneic transfusion.  The reasoning for leukoreduction to my way of thinking is avoiding allogeneic white cells which cause derangements in both innate (neutrophil, monocyte, macrophage and NK cell function) and adaptive (T and B cells) immunity.  Not for the better in that host defenses against infection are impaired after allogeneic transfusion.  White cells also fall apart during storage so we are infusing histones and DNA which in animal models cause lung injury.  When we went to universal leukoreduction our rate of TRALI went down by 83% and the rate of TACO went down 50% and stayed that way for 20 years.  So leukoreduction has multiple benefits and no downside clinically.  The use of non-leukoreduced whole blood is a mistake in my mind although there are no data to support it or argue against it.  White cells from allogeneic donors only rarely benefit patients (decreased rejection of renal transplants is the only substantive benefit). 

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We also use liquid plasma for our trauma patients. Prevents us from keeping thawed 5 day on hand and having to waste it, since for a large level 1 center, we really don't transfuse plasma that much! We provide type A liquid plasma, though we do keep some AB on hand as well. It is not irradiated, just as the O neg or O pos units we give traumas are not irradiated. This is based on the theory that those patients who are massively bleeding will not notice a WBC or two the same way they don't notice a mismatch in blood type (thinking of B and AB patients here). I understand that plasma that is never frozen could have WBCs in it, hence why it may be good to irradiate it, but when giving to trauma patients to help staunch massive bleeding it seems overkill, especially with Dr. Blumberg's point about WBC antigens being present in irradiated products. 

We also have a whole blood program for our traumas, providing O pos low titer LR (with a platelet sparing filter) as the first units in an MTP, when we have it in stock of course!

 

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