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• W2768066832 abstract "As a resident rotating through the transfusion medicine service at Children's National Medical Center in Washington, DC, many years ago, I had a session with Naomi Luban, about T-activation and its importance for pediatric transfusion. At that time, lectins were readily available commercially, and the AABB's Technical Manual had a procedure dedicated to their use. I learned the importance of identifying T-activation in children and then providing the appropriate transfusion therapy. Decades later I became aware of the ongoing controversy surrounding the presence of T-activation and whether it had a direct role in red blood cell (RBC) destruction after transfusion. In this issue of TRANSFUSION, Moh-Klaren and colleagues1 present a case of an infant with necrotizing enterocolitis (NEC) and T-activation who died in temporal relationship to receiving blood products. To gain a better understanding of this patient's outcome, they performed a prospective study to more closely examine the relationship between NEC, T-activation, and hemolysis in patients in the neonatal intensive care unit (NICU). As stated in their introduction, “the causal relationship between T-activation and hemolysis has been called into question by many clinicians and serologists.”1 Their work adds more information to this provocative topic and also presents prospective data with more detailed laboratory testing than many previous studies. The first observations of polyagglutination of RBCs date back to the 1920s when RBCs were unexpectedly agglutinated by normal human adult sera that were ABO-compatible; this reaction did not occur with sera from newborns.2, 3 Hübener initially studied the phenomenon of polyagglutination secondary to in vitro contamination of blood samples with bacteria.4 Thomsen noticed that RBCs could change types from one day to the next and they could even be agglutinated with AB plasma, causing typing discrepancies. He called this characteristic “panagglutinable” and theorized it was secondary to RBCs agglutinating with bacteria.5 His student, Friedenreich, then showed that enzymes released from bacteria caused changes in RBC membranes that made them agglutinate. Due to the routine practice of using uncapped specimens that stood at room temperature for many hours, these laboratories, performing pioneering work in RBC serology, frequently saw polyagglutination secondary to environmental contamination by bacteria. This phenomenon could also be used to potentiate reactivity in the cold, also demonstrating the first uses of enzyme treatment to aid in antibody identification.4-6 Later, Friedenreich discovered that certain hidden antigens became exposed due to the actions of bacterial enzymes, and these hidden or “crypt-” antigens were responsible for the unexpected agglutination. This series of observations was called the Thomsen-Hübener-Friedenreich phenomenon and later T-activation, after Dr Thomsen.7-9 In 1938, the first in vivo case of polyagglutination was described in a 4-year-old with pneumococcus. The etiology was felt to be a soluble substance from the bacteria or medications used to treat the patient's infection.3 A variety of bacteria and viruses have been associated with polyagglutination, in vitro, including Pneumococcus, Streptococcus, Staphylococcus, Clostridia, Escherichia coli, Vibrio cholera, and influenza viruses.6 Alterations in the RBC membrane resulting in polyagglutination can occur due to the action of enzymes or incomplete biosynthesis of RBC membrane components or through inheritance of an uncommon haplotype.3 The T-antigen is normally masked by a structure composed of terminal N-acetyl neuraminic acid (NeuAc or sialic acid), d-galactose, N-acetyl-d-galactosamine (GalNac), and serine or threonine. Upon the cleavage of the terminal NeuAc by neuraminidase produced by microbial agents, the T-antigen is uncovered, leaving behind d-galactose, GalNac, and serine or threonine.2 This antigen is carried on the M and N sialoglycoproteins. The exposed galactose residues, in the correct three-dimensional state, become the receptor for anti-T. Th activation appears to represent an earlier and milder form of T-activation, where less sialic has been cleaved from the RBC surface. This type of activation is most common in newborns and their mothers.2, 6, 9 Tk activation is due to the action of bacterial B-galactosidases rather than neuraminidase.3, 9 Tx activation has been described in children with pneumococcal infection. Tn activation is the result of a somatic mutation. In contrast with the other forms of T-activation, which are transient, Tn activation is persistent.6 When polyclonal reagents were in common use, T-activation could be identified through routine testing and was usually first recognized by discrepancies in cell and serum types. Now, with the use of monoclonal reagents, other techniques have to be employed to seek out and detect T-activation. The various forms of T-activation can be identified and distinguished from each other by treatment with various plant lectins. T-activation is characterized by reactivity with both the peanut lectin, Arachis hypogaea, and the soy lectin, Glycine soya. After 2 months of age, infants start to develop anti-T, reaching adult levels by the ages of 2 to 5 years old. Anti-T is believed to develop due to exposure of bacterial gut flora, similar to the appearance of the isoagglutinins anti-A and anti-B. There was also speculation that their formation is the result of childhood immunizations.2 The appearance of anti-T is transient, lasting weeks to months. Anti-T is an immunoglobulin (Ig)M antibody, most active at 4°C (not usually active at 37°C), and does not fix complement. Based on these characteristics, it is unlikely that anti-T can cause clinically significant hemolysis.2, 3, 6 Anti-T is not always present in adults with T-activated RBCs, possibly due to neutralization by T-activated substances in the patient's plasma.2, 8 The serologic properties of anti-T do not support its role as a cause of clinically significant hemolysis. There are a variety of nonimmunologic mechanisms that can cause RBC hemolysis, which may occur in infected patients. The direct effect of toxins, such as phospholipase C (PLC), released from bacteria can damage the RBC membrane and lead to hemolysis. This effect is demonstrated in a report of an adult with sepsis secondary to Clostridia perfringens, E. coli, and enterococci, without evidence of T-activation, who died after massive hemolysis. In this patient, PLC was found to increase in concordance with levels of lactate dehydrogenase.10 The pore-forming toxin perfringolysin O, a cholesterol-dependent cytolysin, is more effective as cells age, pointing toward a role in RBC destruction at the end of their life span. Likewise, pneumolysin, another cholesterol-dependent cytolysin, can cause membrane pore formation in RBCs leading to hemolysis. With antibiotic use, as well as in the setting of sepsis, there can be increases in susceptibility to cholesterol-dependent cytolysin. When treatment with antimicrobials begins, there is an increase in the release of cytotoxins from lysis of bacteria that bind to membrane cholesterol that increase the risk of RBC membrane lysis.11-13 Finally, there are case reports of drugs such as cephalosporins causing acute hemolysis through their actions on RBCs.14 Hemolysis by anti-T is usually weak and only significant when there is profound desialylation of RBCs. Anti-T hemolysin has been found to be weaker than anti-A and anti-B hemolysins, speaking against its clinical significance. Using an in vitro system to assess anti-T-mediated hemolysis, Des Roziers and colleagues15 showed that hemolysis can significantly increase, independent of T antigen expression. These investigators showed that hemolysis after plasma administration is a rare event in patients with T-activation and NEC, possibly due to the weakness of anti-T, exhibiting titers less than 64. Low titers of anti-T are in contrast with anti-A and anti-B in group O plasma, which are usually much higher in titer, but still only rarely cause hemolysis when passively transfused. Likewise, Issitt and Anstee2 found only weak titers of 2, 4, and 8 in tested plasma. They likened anti-T to anti-P1 and Leb, antibodies that are not considered clinically significant.7, 15, 16 With sialic acid expression correlating with hemolysis of T-activated RBCs, there is no need for special blood products, except with profound desialylation and use in plasma exchange.15 Neuraminidase released by bacteria will break down sialic acid (NeuAc) in the RBC membrane, resulting in damage that causes hemolysis. Early reports in animals showed that T-activated RBCs had decreased survival and increased clearance in the presence of anti-T. To induce T-activation, the RBCs were exposed to either neuraminidase or influenza virus.7 This nonimmune mechanism of hemolysis, in the setting of T-activation, can be explained by understanding the RBC structure. Sialic acid appears to protect RBC membranes from degradation. When sialic acid is removed by hydrolysis, there is increased binding with A. hypogaea, showing that physically removing sialic acid, as opposed to immunologic actions, can destabilize the RBC membrane.17 Therefore, anti-T binding to the T-antigen is not causing the hemolysis, but it is the breakdown of sialic acid that causes RBC membrane damage and subsequent hemolysis. The presence of sialic acid is important to prevent complement-mediated lysis. Sialic acid binds to complement factor H, enhancing its affinity for C3b, inhibiting C3 convertase of the alternate pathway. The enhancement of the classic pathway on cell surfaces by desialylation has been reported.15, 18, 19 Further evidence from animal models and models using RBCs from healthy human blood donors show that there is desialylation as RBCs age, which plays a role in RBC senescence. This pathway provides additional evidence of the important role of sialic acid in maintaining RBC integrity.15, 20 Therefore, anti-T-mediated hemolysis is dependent on the degree of desialylation of RBCs, without the presence of anti-T.15 T-activation is most common in infants and young children with bacterial infections, in particular in the setting of NEC with C. perfringens and nondiarrheal hemolytic uremic syndrome (HUS) with Streptococcus pneumoniae. There are also case reports of T-activation in adults with bacterial infection.10, 21 It is important to recognize that hemolysis is more difficult to diagnose and assess in newborns and young children. Since normal ranges for analytes are different from adults, there should be caution in interpreting laboratory values. Sick newborns are subject to various fluid shifts due to therapy and blood draws that can lead to variability of hemoglobin levels.8 In addition, since pretransfusion testing of neonates is truncated to reduce iatrogenic blood loss, there are fewer opportunities to uncover T-activation. It is always important to formulate a broad differential diagnosis to rule out all other causes of hemolysis, when evaluating these very ill, complex infants.7, 8 There have been decades of case reports, case series, and discussions of the association between NEC in infants, T-activation, hemolysis, and hemolysis after transfusion. Many cases of hemolysis reported in patients with NEC occurred in patients infected with C. perfringens. In this setting, neuraminidase from C. perfringens cleaves sialic acid from the RBC membrane, exposing the T-antigen. In some patients who are T-activated and transfused with blood products from adults, whose plasma contains anti-T, severe and even deadly hemolysis has been reported. In one study of four patients, two children received standard transfusions before the diagnosis of NEC; one died and the other required two RBC exchanges, using washed RBCs suspended in albumin. Two patients who were transfused after the diagnosis and only received washed RBCs, washed platelets (PLTs), albumin, or protein fraction had no evidence of increased RBC destruction. Since this publication7-9, 22-25 and others cite worse outcomes due to T-activation and the temporal relationship with the transfusion and hemolysis, some have called for exclusive use of washed and lower-risk blood products. Conversely, some posit that T-activation is actually a marker of severity of disease, being associated with an increased risk for the need for surgery, worse outcomes including higher mortality, and the presence of C. perfringens and that the transfusion is not related to hemolysis.1, 7, 9, 24, 26-28 Although some publications show an association between T-activation and transfusion, there is no consistency in these reports. In some of the reports, serologic data, such as testing to confirm presence of anti-T, the direct antiglobulin test (DAT), and temperature of testing may be missing or contradictory. The reported cases are not consistent; some patients with T-activation do not hemolyze, some without T-activation hemolyze, some with T-activation hemolyze with unwashed products, and some with T-activation hemolyze with washed products. It is important to remember that T-activation is rare and hemolysis with T-activation is rare.1, 7-9, 16, 26, 27, 29-31 If there is a true linkage between T-activation, transfusion, and hemolysis, this variation should not exist. Nondiarrheal HUS has also been associated with T-activation, primarily in children infected with P. pneumoniae.32 As with NEC, it is associated with a reduction in sialic acid in the RBC membrane, secondary to neuraminidase, leading to hemolysis. Huang and colleagues33 have shown that T-activation is a sensitive marker for HUS in invasive pneumococcal disease, in both HUS and invasive pneumococcal disease with hemolytic anemia. They recommend that early testing can be helpful to serve as a marker of invasive disease once pneumococcus is diagnosed, since T-activation appears to precede microangiopathic anemia and thrombocytopenia. Galectins, soluble proteins that have an affinity for T-antigen, may also serve as an additional marker for T-activation.32 T-antigen is present not only on RBCs, but also on PLTs and renal glomerular cells, possibly having a role in the thrombocytopenia and renal failure seen in HUS, although these findings may be solely related to the microangiopathic changes of HUS.3, 7, 34, 35 There are case reports where children with severe HUS, who are only transfused with washed blood products and undergo plasma exchange with albumin to avoid plasma, have good outcomes.35-38 As with NEC, there are conflicting and incomplete data, creating controversy as to whether or not washed components and low anti-T-titer plasma products improve outcomes; T-activation is associated with hemolysis whether or not the patient has received a transfusion; reports of no hemolysis after transfusion of anti-T-containing products; and reports of patients receiving only low-risk products with poor outcomes.4, 7-9, 34, 39 Waters and associates34 found that using fresh-frozen plasma (FFP) or albumin for plasma exchange did not seem to have an impact on patient outcomes. Therefore, with decades of data, much of it conflicting, where are we left? Can we make some decisions and feel comfortable that these decisions will yield the best patient outcomes? In the report by Moh-Klaren and coworkers in this issue of TRANSFUSION, their patient received antibiotics and FFP due to low fibrinogen and then developed hemolysis, with tests showing T-activation; the DAT and eluate were negative. Due to worsening clinical status, the patient underwent an exchange transfusion with washed RBCs suspended in 4% albumin. The infant then developed renal failure, disseminated intravascular coagulation, and multiple organ failure leading to his death. Additional studies showed that the transfused FFP agglutinated neuraminidase-treated RBCs at 4 and 22°C, but only weakly at 37°C. DTT treatment showed that the anti-T was IgM and the titer at 4°C was 8. No hemolysis of neuraminidase-treated RBCs was observed in vitro with a serum sample from the plasma donor.1 Their accompanying prospective study included 266 infants in the NICU who were tested for T-activation. Fifty-six of 238 patients without NEC were septic or were suspected of sepsis; only mild Th activation was detected in one of these patients. Of 28 patients with NEC, three had 4+ reactivity with lectins. They received unwashed RBCs and plasma-containing blood products without evidence of hemoglobinuria; all patients were discharged from the hospital.1 Based on these findings, Moh-Klaren and coworkers concluded that the poor outcome of their patient was not due to passively transfused anti-T to their patient, but was due to nonimmune destruction. Therefore, they concluded that there is no convincing evidence for routine screening for T-activation in infants with NEC and there is no reason for the use of plasma-containing blood products to be withheld from infants with NEC, even in the presence of T-activation. The strict avoidance of plasma could be harmful, especially in the setting of coagulopathy, and manipulations of cellular products and plasma could create potentially dangerous delays.1 I am in agreement with Moh-Klaren and coworkers. There are many robust mechanisms that account for the nonimmune RBC destruction. In addition, patients studied have infections with exposure to bacterial toxins and are being treated with antibiotics that can play a role in increased RBC destruction. Reports of children with the highest risk of T-activation and hemolysis show that those children are usually the sickest, with multiple comorbidities. Some patients might have needed early transfusion before T-activation was identified, due to the severity of their disease, explaining poorer outcomes in transfused patients.7 I believe that T-activation may represent a correlate of the degree of toxin present and serve as a possible marker for disease severity. This information could be helpful for patients and their parents to understand when discussing possible prognosis and outcomes. It is difficult to find fault with practitioners trying to follow a conservative course of treatment for sick children, fragile newborns and premature infants by providing special blood products. On the other hand, there are no consistent data that transfusion of blood products with anti-T is the etiology for hemolytic events. The serologic principles we adhere to show that anti-T is not clinically significant and titers are usually low; there is also no proven “safe” threshold. Since anti-T begins to appear in infants after the age of 2 months and those older than 2 years may already have adult levels that do not appear to be causing hemolysis, it seems unlikely that passive anti-T is dangerous. Striving to work toward evidence-based treatments that result in the best patient outcomes, I think we can conclude that there is not good evidence for worsening outcomes being directly caused by transfusing standard blood products in the setting of T-activation in patients with NEC and HUS. Due to the rarity of hemolysis with T-activation and reports from various colleagues of the inability to consistently have commercial reagents readily available, conducting a randomized controlled trial may not be feasible. We are in an era of changes in the paradigms of medical practice. There are many efforts to reduce unnecessary laboratory testing and unnecessary medical interventions, understanding that doing more is not necessarily doing better. As transfusion medicine practitioners, we have been brought up with the precautionary principle that any risk needs to be mitigated, but based on literature that is more than 50 years old and more current studies, like that of Moh-Klaren and colleagues, we have not proven causality. It may be time to consider that testing to determine the need for special blood products, and supplying special blood products for the treatment of infants and children with T-activation is not necessary. The author has disclosed no conflicts of interest. Susan D. Roseff Department of Pathology VCU School of Medicine Richmond, VA e-mail: [email protected]" @default.
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• W2768066832 date "2017-11-01" @default.
• W2768066832 modified "2023-09-27" @default.
• W2768066832 title "Cryptantigens: time to uncover the real significance of T-activation" @default.
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