Anti-U. Should U Worry About It?

What is Anti-U?

Anti-U is a blood group antigen that has gained attention for its importance in blood transfusions and potential complications during pregnancy. Discovered in 1961, Anti-U is part of the MNS blood group system and is relatively rare in the general population. The presence of this antigen can impact the blood transfusion process, particularly for pregnant women of African descent. In this post, we will explore the significance of Anti-U, its association with genotype, phenotype, and race, and the unique challenges faced by pregnant women with this blood group.

Anti-U antibody is an antibody that targets the U antigen, which is part of the MNS blood group system. The MNS system is one of the most complex blood group systems, with over 40 different antigens that can cause an immune response if they are not properly matched during a blood transfusion.

Anti-U and Race

The prevalence of the Anti-U antigen varies across different populations. It is almost entirely absent in individuals of African descent, with only 1-2% of the African population having the U antigen. In contrast, the U antigen is present in approximately 99.8% of people of European origin. Consequently, the incidence of Anti-U antibodies is higher among individuals of African descent, making it an important consideration for blood transfusions and pregnancies within this demographic.

Challenges for Pregnant Women

For pregnant women with Anti-U antibodies, there is an increased risk of hemolytic disease of the fetus and newborn (HDFN). This condition occurs when maternal antibodies cross the placenta and attack the red blood cells of the developing fetus, causing anemia and potentially leading to fetal death or severe neonatal complications.

Mothers who are identified as having anti-U antibody may require specialized care to prevent HDN. The mother's blood will be screened for the presence of the antibody, and if it is found, she will need regular monitoring of her pregnancy to ensure that the fetus is not affected. This may involve frequent ultrasounds and monitoring of the fetus's blood counts.

If a mother with anti-U antibody gives birth to a baby with the U antigen, the baby may develop HDN, which can cause anemia, jaundice, and other complications. To prevent this, the baby's antigen and antibody status will be checked at birth, and if necessary, the baby may require a blood transfusion with SsU negative blood to prevent HDN.

Phenotype

U- patients are always S- and s-. This S-s-U negative phenotype is due to the patient lacking glycophorin B, which is the RBC glycoprotein responsible for S and s antigen expression. However, not all S-s- patients will be U negative. There exists a variant of the U antigen that produces seemingly incomplete epitopes of the antigen. Figure this similar to partial D patients. This is typically notated as S-s-U+var. Although the U antigen is present on the Red Cell, it has variable missing epitopes and patients can still create an Anti-U towards these missing epitopes were they to come in contact with U+ blood.

Acquiring U Negative Blood

In cases where a blood transfusion is necessary for someone with Anti-U antibodies, finding compatible blood can be challenging. The rarity of the antigen, especially among African populations, means that sourcing blood with the U antigen may be difficult. To address this issue, rare donor programs have been established to maintain frozen stocks of blood with the U antigen. These programs facilitate access to compatible blood for those in need, reducing the risk of transfusion reactions.

Many transfusion services will opt to have the unit typed for S and s as well as U, thus patients will often receive S-s-U- blood. Thankfully, as previously mentioned, if the unit is U negative, the unit very well should be S and s negative as well. It is not enough to search for S-s- units, as some may still be U+.

Identifying Anti-U

Care must be taken to properly identify an Anti-U especially in pregnant women., to ensure fetal health and safety. Many people working in a transfusion center Blood Bank may have never seen an Anti-U before, but that certainly depends on the size and population of the hospital. Those working in reference labs would obviously have a higher chance of seeing an Anti-U come through.

Anti-U initially appears to look like a panagglutinin. Generally all screening cells will be U positive, thus all screening cells will be positive. Additionally, many panels do not have a U negative cell on them. This is lot dependent of course, some do. As such, many panels will also appear as a panagglutinin due to the lack of U negative cells.

Unless you specifically knew to look for Anti-U, you'd probably be thinking Warm Autoantibody, Daratumumab interference, Anti-k? Who knows. Most people wouldn't think Anti-U. Most hospitals who didn't have a panel with a U negative cell on it would most likely end up sending the specimens to a reference lab for further workup and ID.

Those lucky enough to have a U negative cell panel will then find it very difficult to rule everything else out, prompting the need for potential send out as well. This is where keeping old expired panels in the back fridge comes in handy. If you can QC a cell and it passes, you're good as gold to use it!

We recently had an Anti-U patient, and despite finding 4 U negative panel cells (current and expired), we still couldn't rule out Jkb,Fya,C,K,E. We had to work with the Red Cross to find S-s-U-Jkb-Fya-C-K-E- blood as we weren't immediately able to send the patient out for workup as they were an outpatient scheduled for OB surgery. They came through with some previously frozen deglycerolized RBCs!

Storage Lesion

Storage Lesion in Blood Products: Understanding the Impact of Time on Transfusions

Blood transfusions have saved countless lives by replacing lost or deficient blood components, such as red blood cells (RBCs), platelets, and plasma. However, the quality and effectiveness of blood products can be affected by storage time, leading to a set of changes known as storage lesion. In this article, we'll explore what storage lesion is, how it affects blood products, and why fresher blood may be better for some people.

What is Storage Lesion in Blood Products?

Storage lesion refers to the changes that occur in blood products over time, particularly during refrigerated storage. These changes can affect the viability, function, and safety of the blood components, and may vary depending on the type of product and storage conditions. Some of the common changes associated with storage lesion in blood products include:

Reduced levels of adenosine triphosphate (ATP), which is essential for energy metabolism and cell membrane integrity;
Increased levels of reactive oxygen species (ROS), which can damage cell membranes, proteins, and DNA;
Loss of membrane flexibility and deformability, which can impair oxygen delivery and hemostasis;
Alterations in blood cell surface markers and activation status, which can affect immune responses and thrombosis;
Changes in coagulation factors, complement proteins, and cytokines, which can modulate inflammation and immune reactions.
Decreased pH: During storage, the pH of blood products can decrease, which can impair the function of enzymes and other proteins in the blood.

These changes can have important clinical implications for patients who receive transfusions, especially those who are critically ill, have underlying diseases, or require frequent transfusions. For example, storage lesion in RBCs can cause an increase in potassium levels and an increase in free hemoglobin, which can lead to hyperkalemia and hemolysis in susceptible patients. Moreover, storage lesion can compromise oxygen delivery, exacerbate inflammation, and increase the risk of transfusion-related complications, such as transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), and transfusion-transmitted infections (TTIs).

Platelet Storage Lesion

During platelet storage, several biochemical and physiological changes can occur, collectively known as the platelet storage lesion. Some of the common changes associated with the platelet storage lesion include:

Loss of platelet function: Platelets stored for longer durations may become less effective at forming blood clots or adhering to damaged blood vessels.
Activation of platelets: Platelets can become activated during storage, leading to the release of proinflammatory and procoagulant substances, such as cytokines, thromboxane A2, and platelet factor 4.
Loss of platelet viability: Platelets can undergo apoptosis or programmed cell death during storage, leading to a reduced number of viable cells.
Changes in platelet membrane structure and composition: Platelets stored for longer durations may undergo structural changes in their membranes, such as increased lipid peroxidation, which can impair their function and survival.
Bacterial contamination: Platelet storage bags and units can become contaminated with bacteria, which can cause transfusion-related infections and other complications.

Why Fresher Blood May Be Better for Some People?

Given the potential adverse effects of storage lesion in blood products, researchers and clinicians have explored various strategies to minimize its impact. One of these strategies is to use fresher blood, i.e., blood that has been stored for a shorter duration. This approach is based on the hypothesis that fresher blood has fewer storage lesions and, therefore, may be more effective and safer for some patients.

Several studies have investigated the association between blood storage time and clinical outcomes in various patient populations. For example, a randomized controlled trial published in the New England Journal of Medicine in 2015 found that transfusion of fresher RBCs (stored for less than 10 days) did not improve mortality or morbidity in critically ill adults compared to standard-issue RBCs (stored for up to 42 days). However, the study also showed that fresher blood was associated with a lower risk of new-onset multiple organ failure, suggesting a potential benefit for specific subgroups of patients.

Another study published in JAMA in 2021 analyzed data from nearly 300,000 transfusions in more than 80,000 patients and found that fresher RBCs were associated with a lower risk of in-hospital mortality and complications, especially in patients with sepsis, acute respiratory distress syndrome (ARDS), and cardiac surgery. The study also reported that fresher RBCs had higher levels of ATP, lower levels of potassium, and less hemolysis than older RBCs, supporting the hypothesis that storage lesion contributes to the adverse effects of blood transfusions.

However, using fresher blood may not be feasible or cost-effective in all settings. Physicians should order and use judiciously, and transfusion centers should be sure to double check with the physician before proceeding.

The nursing floor just requested RhIG on an Rh positive MALE? Why???

They likely want to perform a "medical splenectomy"!

Patients with ITP or idiopathic (or immune) thrombocytic purpura create an autoantibody towards antigens on platelets which subsequently marks the platelets for destruction and they are removed from circulation causing thrombocytopenia. Typically, physicians will try treatments such as steroids first, to dampen the immune systems response and see if platelet counts recover. If not, there are other options available. Very often physicians will spring for IVIg (Intravenous Immunoglobulin). The mechanism in which IVIg works in regards to platelets in ITP is not fully understood but it is postulated the immunoglobulins bind receptors on macrophages, leaving them unable to interact with platelets and target them for destruction. This inability to mark the platelets for destruction means more platelets remain in circulation.

There is another option, however, and it is still considered a first-line therapy, much like IVIg is. RhIG! Yes, Rh immune globulin, the same stuff you've been giving Rh negative pregnant mothers all this time to prevent RhD alloimmunization. WinRho SDF and Rhophylac brands are approved for IV usage in ITP situations. RhoGAM (a specific brand of RhIG) is typically given only as an IM shot. RhoGAM can ultimately be used, but patients may need multiple shots, making WinRho and Rhophylac a better choice.

To receive IV RhIG for ITP treatment, patients MUST be Rh positive, must still have a functional spleen, and should not be exhibiting signs of hemolytic anemia or DIC. Providing RhIG to Rh positive patients for treatment of ITP is known colloquially as performing a "medical splenectomy". This is because removing the spleen is a drastic measure to stop platelet sequestration and destruction, as it is where the platelets get sent for destruction once they are antibody targeted. In more medically scientific terms it is know as an Fc receptor blockade mechanism.

This mechanism can be described as such:

The anti-D from the RhIG preparation attaches to the RhD positive red cells of the recipient. Essentially, the RhIG "opsonizes" the RhD red blood cells, targeting them for destruction. The RhD positive red cells are brought through the reticuloendothelial system via phagocytic cells like macrophages where they will be destroyed in the spleen. This massive increase in antibody marked cells, coupled with the fact there are far more antigen sites on a Red Blood Cell, meaning more antibody can attach, means that the Red Cells will generally preferentially get removed from circulation rather than the platelets, allowing the platelets to remain in circulation.

Given this mechanism, it is not only possible, but likely that the patient can experience a level extravascular hemolysis leading to a mild decrease in Hemoglobin/Hematocrit levels. It's important to get a baseline, and continue to monitor these levels after administration. A drop of 1-2 grams of Hgb is possible over a few days post administration. This is also why it's important to ensure there aren't other hemolytic processes taking place beforehand (like hemolytic anemia). If a patients Hgb drops too much, it is thought that they should receive Rh negative blood for the time being, to lessen the amount of hemolysis taking place, ensuring the blood remains in circulation unscathed.

Despite these effects, use of RhIG is often quicker to infuse than IVIG, less volume than IVIG, sometimes longer duration of action when compared to IVIG, cheaper than IVIG, and a much more limited donor exposure than IVIG.

Have you ever seen RhIG used in such circumstances?

Emergent FFP for Angioedema?

You get a call from an ER nurse that they new FFP emergently on a patient in the ER. The patient's tongue and face is swelling to the point of respiratory compromise. You don't have any blood type on file so you tell the nurse, and decide that it's so emergent that you'll have to thaw AB plasma and give it emergently.

What was happening to this patient? Why was this such an emergency? What is FFP going to do to help this patient in this situation?

Angiotensin Converting Enzyme (ACE)

Millions of people in the world have diagnosed hypertension and may be prescribed an Angiotensin Converting Enzyme (ACE) inhibitors to control their elevated blood pressure. An uncommon side effect of ACE inhibitors includes angioedema, in which fluid buildup and swelling occurs underneath the skin in certain areas. Inhibiting Angiotensin Converting Enzyme can lead to a build up of an enzyme known as bradykinin, which is a potent vasodilator, but also leads to increased vascular and capillary permeabilty. This allows fluids to leave the space they should occupy and accumulate in other areas in which they shouldn't. This effect is known as ACE inhibitor-induced angioedema or ACEI-IAE.

ACEI-IAE typically presents as an emergency as airways and respiratory systems can quickly become compromised by excessive tongue, face, neck, etc., swelling. Initial treatment will include discontinuation of the drug, and potentially antihistamines, steroids, epinephrine, IVIG, etc. This may not work for all patients, however.

How Does FFP Help with Angioedema?

FFP has been used successfully in patients who do not respond to other treatments. Some patients respond quite rapidly after FFP transfusion and regain respiratory control. The idea behind FFP administration is that FFP contains ACE, sometimes referred to as Kininase II, as it's an enzyme that can break down Bradykinin. This immediate addition of Kininase II from FFP transfusion helps to breakdown the excessive bradykinin that has accumulated due to ACE inhibitor use. This is why so many patients will see a very rapid improvement post FFP administration.

Why would an Rh positive baby type as Rh negative?

Intrauterine transfusion? Sure that's possible.

This specific scenario describes more of an immunologic basis for mistyping.

Enter...the Blocked D phenomenon. It is something very rarely seen in Blood Banks, especially these days with ever increasing sensitivity of reagents, but it can still happen.

The Blocked D phenomenon may occur when a mother has created a strong IgG based allo-Anti-D and bears an Rh positive child. It is generally seen in fairly severe cases of HDFN.

A sample experiencing the blocked D phenomenon will type as Rh negative, and essentially always have a positive IgG DAT. A subsequent elution would show the maternal Anti-D coating the Red Cells of the baby. The red cells type as Rh negative because maternal Anti-D is blanketing the RhD antigens on the Red Cells, blocking the REAGENT IgM Anti-D from agglutinating the cells. As a result, a false negative Rh testing occurs. With a positive IgG DAT, it would not be possible to perform a Weak D (Du) without treating the cells either, as Weak D testing is performed at the AHG (Coombs) phase.

Cord Blood Evaluations generally arrive to the blood bank as a battery of Blood Type and Direct Coombs testing. This is why it is important to finish all testing prior to resulting. If the blood type was resulted before the DAT was completed, you may be inadvertently reporting erroneous results to the patient's Blood Bank file and chart.

How to remedy this?

Generally you would need to perform an elution, such as an acid glycine elution, to remove the bound IgG from the neonates Red Cells. Once removed, and you can prove the antibody is removed by perform another DAT to make sure the IgG is now negative, you can retest the red cells for the D antigen using your monoclonal typing reagents. You may now perform a Weak D test as well, since the DAT is no longer IgG positive.

How many of you have seen this phenomenon? While rare, it has real implications in the Blood Bank and for proper patient care. Not realizing the phenomenon taking place, can result in a delay of care. A newborn exhibiting this phenomenon may need to receive an exchange transfusion to remove their Red Cells and replenish with Rh negative cells until the maternal antibody is no longer reacting. If the phenomenon is not noticed at first, and the baby is resulted as Rh negative, it will change the clinical picture for the physician and make it more difficult for them to arrive at a diagnosis of HDFN and treat at a earlier point in time.

Fat Embolism Syndrome in Sickle Cell Disease

Blood Banks are no stranger to patients with Sickle Cell Anemia. Many patients are chronically transfused, and many of us have been there for emergent Red Blood Cell exchanges due to acute chest, stroke, etc. What you might not have been a part of is a Sickle Cell patient experiencing Fat Embolism Syndrome.

What is a Fat Embolism?

A fat embolism is exactly as it sounds, it's fat or globules of fat that for one reason or another enter the bloodstream circulation and act as a embolism (vasculature occlusion caused by a clot or similar). While not common, fat embolisms are usually seen in trauma with orthopedic / long bone fractures, such as tibia, fibula, femur, pelvis, etc. It can also be seen in patients with pancreatitis.

Fat Embolism Syndrome in Sickle Cell patients

Certain populations of Sickle Cell patients may be at risk for Fat Embolisms as well.

Fat Embolism Syndrome describes a situation in which Bone Marrow Necrosis occurs as a result of the patients Sickle Cell Disease. The necrosis is not fully understood but it's hypothesized that the microvasculature in the bone marrow may become occluded, leading to cell damage and death. As the Bone Marrow is necrosed, it is thought that this could lead to fat emboli being released into circulation, causing occlusion of vessels. Another theory proposes that fat globules released into circulation get broken down into toxic metabolites leading to a pro-inflammatory state, as evidenced by increased levels of CRP, cytokines, and free fatty acids in serum. These metabolites can be responsible for many of the symptoms seen in Fat Embolism Syndrome.

Patients may have shortness of breath/respiratory distress, tachycardia, neurologic changes from confusion up to coma, petechial rash, pain, fever, hepatic damage (with resulting jaundice), decreased urine output, etc.

Interestingly, patient's with more severe homozygous Sickle Cell Disease (HgbSS) are less likely to experience Fat Embolism Syndrome. Heterozygous Sickle Cell Disease such as HgbSC or HbS/ß-Thalassemia has a higher likelihood of exhibiting Fat Embolism Syndrome propensity. The thought behind this is that with heterozygous Sickle Cell Disease, patients tend to have a higher baseline hematocrit, and thus have a higher blood viscosity than that of a HgbSS patient whose hematocrits tend to trend on the lower end. This increased viscosity can lead to decreased perfusion and thus more damage, causing increased necrosis. HgbSC patients tend to have increased inflammatory issues as well, compared to their HgbSS counterparts.

Fat Embolism Syndrome Treatment with Apheresis

The Apheresis department plays a role in helping to treat Fat Embolism Syndrome. Essentially, the first line treatment of Fat Embolism Syndrome caused by Bone Marrow Necrosis in Sickle Cell Disease is to perform a Red Blood Cell exchange. This helps to remove the sickled cells that may be assisting in causing occlusions along side of the fat globules, but based on density, should also remove a portion of the fat globules as well.

Additionally, there is reason to believe that following up with a plasma exchange could be beneficial in treating Fat Embolism Syndrome. In some patients, RBC exchange is not enough. This study explores this idea. Given that there may be a biochemical component to Fat Embolism Syndrome, such as the increased inflammatory mediators, cytokines, free fatty acids, toxic lipid metabolites, etc., it makes sense that plasmapheresis would be beneficial in removing these from the plasma.

Have you come across a patient with FES?

PFAS and the Blood Bank -- How are they related?

Don't bust out the Optia in hopes of therapeutic PFAS level reduction apheresis just yet... however...

What are PFAS?

Are PFAS the new asbestos? You may have heard the term "forever chemicals" before. This buzzword generally refers to PFAS or Per- and polyfluorinated alkyl substances. They are deemed to be "forever chemicals" due to their propensity to hang around in the environment for an extraordinarily long period of time, seemingly forever due to them containing a strong Carbon-Fluorine bond, which lends to their "immortality". They are easily able to leach into soil and nearby waters where they pose a health risk to life.

PFAS are found in all branches of industry from textiles, fire-fighting foam, furniture, packaging, non-stick surfaces, hydrophobic surfaces/materials, paper or cardboard coating, electronics, automotive, cables, tray liners, medical products, etc. The list goes on. We are certainly not free from PFAS exposure.

Exposure to PFAS is known to cause deleterious effects to living beings. Originally, they were thought to be relatively harmless, however, repeated exposure to PFAS raises concentrations within the body to a toxic level. As PFAS usage in materials increased, so did the knowledge that PFAS may be more harmful that originally thought.

PFAS exposure may cause:

Certain cancers, especially Kidney and Testicular.
Liver disease and liver damage (may be one of the reasons Non-Alcoholic Fatty Liver Disease is increasing in the population)
Thyroid disease and/or dysfunction.
Developmental defects in fetus
Fertility issues in women
Increase in pregnancy complications
Increased cholesterol levels
Ulcerative colitis
Immune system damage/dysregulation

Studies are looking into other toxic manifestations of PFAS exposure

Blood donors who have elevated serum PFAS levels are not excluded from donating blood. PFAS are everywhere, and no threshold has been given that poses an increased risk to recipients of donated blood products. Blood authorities such as AABB and FDA should continue to monitor the evidence on the possible health effects of PFASs and consider the possible implications of increased PFAS levels in blood donors.

Plasma Donation and PFAS

An interesting new study out of Australia has shown a meaningful reduction in serum PFAS levels after donation of whole blood or plasma. The study followed Australian firefighters who regularly come in contact with PFAS through their regular use of firefighting foam which harbors large concentrations of PFAS. It has been noted in the past from other studies that firefighters typically have a higher serum PFAS level than other populations.

Throughout the year of the study, significant reduction of serum PFAS levels were observed in the firefighters who donated blood and plasma. A greater reduction of PFAS levels was seen in those who donated strictly plasma, however blood donation significantly lowered levels as well.

This is certainly an interesting discovery, given the ubiquitous nature of PFAS and difficulty in removing them from our environment once they are already there. More studies are needed to further elucidate this effect. While removing PFAS from manufacturing as a whole is the best way to remedy the situation, this can certainly be a potential valid way for those in consistent high risk groups to lower their risk of experiencing toxic PFAS effects.

It is worth noting that there are no suggested limits or guidelines as far as PFAS levels in plasma go. For all intents and purposes, blood or plasma from donors regardless of PFAS level is currently accepted into blood bank inventory. It will be interesting to see how, if at all, this will be handled in the future. It is also probably unlikely that transfusing units of blood or FFP from donors with elevated PFAS levels will increase the recipients levels to a toxic level, but again, further studies can help flesh this out. Perhaps regular plasma donation for manufacturing/research purposes, rather than transfusion purposes would be the best route for these populations to take.

Perhaps in the future therapeutic plasma exchange will be an indication for toxic PFAS exposure? Who knows!

Blood Bank Specialist -- A Medical Laboratory Science Review

Your destination for Immunohematology within the world of Transfusion Medicine

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