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BACKGROUND Passenger lymphocyte syndrome occurs when donor lymphocytes are transplanted with a solid organ and produce alloantibodies that react with antigens on the recipient's red blood cells (RBCs). Typically, passenger lymphocyte syndrome presents as immunoglobulin G antibody-mediated, extravascular hemolytic anemia with reticulocytosis. Often, the donor was alloimmunized before transplantation. CASE REPORT A 34-year-old Group O, D+ man with a negative antibody screen received a liver transplant from a Group O, D− donor. Twenty Group O, D+ RBC units were transfused on Postoperative Days (PODs) 0 through 2. On POD 7, the patient developed anemia, a weakly positive antibody screen, and a positive direct antiglobulin test with anti-D in the eluate. After POD 8, a D− transfusion protocol was initiated. Despite laboratory evidence of hemolysis, two initial peripheral blood smears showed no increase in schistocytes or spherocytes, the reticulocyte count was depressed, and a marrow biopsy revealed erythroid hyperplasia. Eventually, anemia resolved after a period of medication non-compliance; however, a positive direct antiglobulin test persisted to the last follow-up date (POD 233). RESULTS Other potential causes of aplastic anemia were investigated, but no alternative cause was found. History excluded passive anti-D. D+, LW− cells were reactive, excluding anti-LW. Genotyping showed no evidence of a partial D genotype. Chart review revealed that the liver donor had a history of anti-D. A diagnosis of passenger lymphocyte syndrome was reached. CONCLUSION Although antibody-mediated hemolytic anemia has been reported to cause reticulocytopenia in the presence of marrow erythroid hyperplasia, this report of passenger lymphocyte syndrome causing a similar post-transplant anemia in association with reticulocytopenia is noteworthy.

Background Thirty percent of chronically transfused patients with sickle cell disease (SCD) become alloimmunized. Antigen-matching reduces alloimmunization. Matching may be prospective (for all patients) or based on history (only for patients with an alloimmunization history). We assessed the clinical and financial value of a potential assay to identify at-risk patients to guide antigen-matching.

Background Sickle cell disease is associated with extensive health care utilization; estimated lifetime costs exceed $460,000 per patient. Approximately 30% of chronically transfused sickle cell patients become alloimmunized to red blood cell antigens, but these patients cannot be identified a priori. Prospective antigen matching can prevent alloimmunization, but is costly and may not benefit most patients. Study design and methods A Markov-based model was constructed to compare the health and financial implications of four alternative antigen-matching strategies for chronically transfused sickle cell patients. The strategies varied by the group of patients receiving matched blood (all patients prophylactically or only patients with a history of alloimmunization [history-based]), and by the extent of antigen matching (limited to C, E, and K, or extended to 11 antigens). Direct medical costs and alloimmunization events were assessed over 10- and 20-year periods, for a hypothetical cohort of initially transfusion-naive patients and for a dynamic population. Results Within a hypothetical cohort of initially transfusion-naive patients, implementing prophylactic limited matching for all chronically transfused patients instead of history-based limited matching is expected to cost an additional $765.56 million over 10 years, but result in 2072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2424 fewer alloimmunization events. Averting a single alloimmunization event using prospective matching would cost $369,482 to $769,284. Among a dynamic population over 10 years, prospective limited matching is expected to cost $358.34 million more than history-based limited matching. Conclusions While prospective matching for all transfused patients would reduce alloimmunization, this strategy requires considerable expenditure.

Background We have monitored ABO antibody titers in 53 ABO-incompatible kidney transplants (INKTs) using a time-consuming, conventional test tube (CTT) method that included a 30-minute room temperature (RT) phase, followed by incubation for 30 minutes at 37 degrees C and conversion to the anti-human globulin (AHG) phase. Our studies have indicated that AHG ABO antibody titers are critical for clinical management, but RT titers do not supplement clinical decision making. Therefore, we assessed AHG titers by two methods: 1) a revised test tube (TT) method without RT and 2) an anti-immunoglobulin G (IgG) gel microcolumn (IgG gel) method with a goal of streamlining ABO antibody titrations. Study design and methods Fifty frozen samples from our INKT collection with anti-A and/or anti-B AHG titers of 2 to 512 were titrated by revised TT method with 30 minutes at 37 degrees C and conversion to AHG and by IgG gel method with 15 minutes at 37 degrees C and centrifugation. Results The titers using the revised TT and IgG gel methods had 64 and 52% concordance, respectively, with CTT AHG titers. Neither the revised TT AHG titers nor the IgG gel titers varied by more than one standard dilution from the CTT AHG titers, which is within acceptable limits for titration techniques. Conclusions The revised TT and IgG gel titers are comparable to the CTT AHG titers. The IgG gel method offers the best titer turnaround time, eliminating 45 minutes of incubation time alone. Implementation of this technique would benefit ABO INKT patients by providing titer results in a more timely manner.

BACKGROUND: Thousands of patients with chronic renal failure die yearly without a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to permit ABO-incompatible (ABO-I) kidney transplants, but little is known about how well TPE reduces ABO antibodies or complications related to TPE in this clinical setting. STUDY DESIGN AND METHODS: This retrospective study evaluated 46 individuals that received TPE to permit ABO-I kidney transplant. The number of TPE treatments was based on a goal ABO titer at the anti-human globulin (AHG) phase of 16 or less before surgery. RESULTS: Before TPE, the median titer of recipient was 32 (range, 2-128) at room temperature (RT) phase and 64 (range, 4-1024) at AHG phase. The first TPE reduced the total agglutination reactivity score at AHG phase by 10.2 percent. Before transplantation, there was a mean of 6.2 ± 2.5 TPE treatments and total agglutination reactivity score at AHG phase was reduced by 53.5 percent. The median titer remained reduced at 3 to 6 months after transplantation at 4 (range, 0-64) at RT phase and 8 (range, 1-64) at AHG phase. TPE complications were minimal. During at least one procedure, 15 (32.6%) individuals had either urticaria or pruritis, 18 (39.1%) individuals experienced mild citrate-induced hypocalcemia, 5 (10.2%) individuals had hypotension, 6 (13.0%) individuals had nausea or vomiting, and 1 (2.2%) individual had West Nile virus encephalitis. CONCLUSIONS: With current infectious disease blood screening protocols, TPE has minimal complications and can reduce ABO antibody titers to permit ABO-I renal transplantation.

ABO incompatibility and human leukocyte antigen (HLA) sensitization remain the two largest barriers to optimal utilization of kidneys from live donors. Here we describe the first successful transplantation of patients who were both ABO incompatible and crossmatch positive with their only available donor. A preconditioning regimen of plasmapheresis (PP) and low-dose CMV hyperimmune globulin (CMVIg) was delivered every other day until donor-specific antibody (DSA) titers were reduced to a safe level and isoagglutinin titers were < or =16. Each patient received quadruple sequential immunosuppression, splenectomy and three protocol post-transplant PP/CMVIg treatments. There was no hyperacute rejection. Two of the three patients had a persistent positive cytotoxic crossmatch on the day of transplant and eliminated their DSA subsequently. Antibody-mediated rejection (AMR) in one patient was reversed by reinitiating PP/CMVIg and anti-CD20. The patients are more than 9 months post-transplant with excellent graft function. Preconditioning with PP/CMVIg results in a durable suppression of DSA and permits accommodation of the allograft to a discordant blood type. The ability to cross these two barriers simultaneously is clinically important as sensitized patients have often exhausted their blood type compatible living donors during previous transplants.

BACKGROUND: Febrile nonhemolytic transfusion reactions (FNHTR) is a relatively common complication associated with allogeneic transfusion. Because WBCs have been implicated in the mechanism of FNHTRs, it has been proposed that the transfusion of leukoreduced RBCs should be associated with a decreased incidence of FNHTRs. These reactions are generally not life threatening, but they are expensive in their management, evaluation, and associated blood-product wastage. Over the past several years, the proportion of leukoreduced RBCs has increased at Johns Hopkins Hospital in an effort to move toward complete leuko-reduction. A retrospective analysis is reported here of FNHTRs in RBC recipients as the inventory increased in percentage of leukoreduced RBC units.

Neonatal alloimmune thrombocytopenia (NAIT) results from maternal immunization against fetal platelet antigens and can occur during the first pregnancy. The most common complications of NAIT are neonatal thrombocytopenia, intracerebral hemorrhage, and fetal death. Most cases of NAIT in Causasians are caused by anti-HPA-1a (PlA1). Anti-HPA-5b (Bra) accounts for only 4.3 percent of all NAIT cases. NAIT due to anti-HPA-5b is thought to be milder and have fewer complications than NAIT caused by anti-HPA-1a because of the lower number of HPA-5b antigenic sites per platelet. This report describes a severe case of NAIT due to anti-HPA-5b that was treated by intrauterine platelet transfusion.

BACKGROUND: Thousands of patients with chronic renal failure die yearly and are unable to have a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to remove ABO antibodies and permit ABO-incompatible (ABO-I) kidney transplants, but there is only limited research within this area and a lack of standardized protocols for TPE. This article reviews the literature to provide a historical perspective of TPE for ABO-I kidney transplantation and also provides the Johns Hopkins Hospital protocol with a focus on both titers and TPE. STUDY DESIGN AND METHODS: The TPE treatment plan is based on ABO titers with the goal of a titer of 16 or less at the anti-human globulin (AHG) phase before surgery. Pretransplant therapy consists of every-other-day TPE followed immediately by cytomegalovirus hyperimmune globulin. ABO antibody titers are closely monitored before and after transplantation. After transplantation, TPE therapy is performed for all patients to prevent rebound of anti-A and anti-B titers until tolerance or accommodation occurs. TPE is discontinued and reinstituted based on the clinical criteria of creatinine levels, biopsy results, and ABO titer. RESULTS: Fifty-three ABO-I kidney transplants have been completed with no episodes of hyperacute antibody-mediated rejection (AMR) and only three episodes of AMR. One-year death-censored graft survival is 100 percent and patient survival is 97.6 percent. CONCLUSIONS: While randomized clinical trials are needed to evaluate the optimal method and protocol to remove ABO antibodies, the current literature and our results indicate a critical role for TPE in ABO-I renal transplantation.

BACKGROUND: A murine model would be useful to identify which immune mechanisms could be manipulated to treat or prevent red blood cell (RBC) alloimmunization in patients who become sensitized to multiple or widely expressed antigens. STUDY DESIGN AND METHODS: Transgenic mice (B6CBAF1/J-Tg-Fy b ) expressing the human Fy b antigen of the Duffy (Fy) blood group were donors. Recipient B6CBA-F1 mice received four weekly intravenous (IV) transfusions: either 0.3 mL of washed buffy coat-depleted RBCs or 0.3 mL of RBCs with spleen cells. Titers of immunoglobulin M (IgM) and immunoglobulin G (IgG) were measured in recipient serum samples by flow cytometry with RBCs from donor mice as target cells. Recipient serum samples were also tested against human RBCs of various Fy phenotypes. Additionally, RBC survival studies were performed in alloimmunized mice utilizing biotin-labeled Fy b transgenic mouse RBCs. RESULTS: B6CBA-F1 mice receiving washed buffy coat-depleted RBCs first made IgM, followed by IgG alloantibodies to transgenic mouse Fy b -positive RBCs. Recipients of Fy b -positive RBCs mixed with spleen cells also produced IgM and IgG alloantibodies, but at a slower rate than recipients of washed buffy coat-depleted RBCs. Serum samples showed specificity for Fy3, Fy b , and Fy6. Decreased survival of transfused RBCs was evident at 24 hours after transfusion. CONCLUSIONS: It is possible to elicit the formation of anti-Fy alloantibodies by IV transfusion in mice that lack Fy antigens. The transfusion of RBCs alone was adequate to stimulate alloantibody production in B6CBA-F1 recipient mice. The survival of transfused Fy b -positive RBCs is diminished in sensitized mice. This model will be useful in further studies of RBC alloimmunization.

The majority of preconditioning protocols developed to allow ABO-incompatible (ABOi) renal transplantation include concurrent splenectomy as a prerequisite to successful engraftment. Our center has developed a preconditioning protocol that includes plasmapheresis (PP), low-dose CMV hyperimmune globulin (CMVIg), and anti-CD20 monoclonal antibody (rituximab) to allow ABOi renal transplantation without splenectomy. Our initial experience has included treatment of six recipients and successful transplantation from blood group A(1), A(2), and group B living donors. Mean (+/- SD) serum creatinine was 1.3 +/- 0.1 mg/dL among the six recipients and no episodes of antibody-mediated rejection (AMR) occurred at a median follow-up of 12 months. ABO antibody titers have remained below pretreatment levels. The absence of AMR and stable allograft function in this series show the potential of this preconditioning protocol to increase ABOi renal transplantation. The use of rituximab, allowing avoidance of splenectomy, may further remove one of the significant disincentives to ABOi transplantation, and eliminate the risk of post-splenectomy infections.

A 7-year-old Caribbean-American boy with a 5-month history of hemophagocytic lymphohistocytosis and previous ceftriaxone exposure presented with fever. He was empirically given amikacin and ceftriaxone after 1:00 PM on Day 1 and acutely developed back and abdominal pain, vomiting, hematuria, and hypotension. Both plasma (see figure, top panel) and urine showed hemolysis. The peripheral blood smear showed diffuse agglutination of RBCs without schistocytes (see figure, lower left). Serum LDH was elevated (1787 U/L); urine was negative for myoglobin. The patient's Hb dropped from 11.7 to 4.4 g/dL in 32 hours. The symptoms, hemolysis, and agglutination resolved (see figure, lower right) with discontinuation of ceftriaxone and two double-volume whole blood exchange transfusions. Immunohematology studies demonstrated a positive DAT due to C3 only, and serologic drug studies were positive with ceftriaxone, but not with amikacin. The RBC agglutination seen on peripheral smear was most likely due to drug/antidrug immune complexes, a theory supported by the finding of IgM ceftriaxone-dependent antibodies (titer = 32) at presentation. The titer decreased to 8 on Day 2 and to 0 by Day 5, suggesting that the antibody was consumed by the RBCs and/or removed by treatment. Drug-induced immune hemolytic anemia (DIHA) due to ceftriaxone-dependent antibodies is uncommon, but well described. The majority of documented cases have occurred in children with a history of exposure to ceftriaxone. Autoagglutination may be a feature of DIHA due to ceftriaxone. It is important to recognize and treat DIHA early, since it can be fatal, but is reversible with treatment.