International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology: Cancun report (2012).

The International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology convened during the International congress in Cancun, July 2012. This report details the newly identified antigens in existing blood group systems and presents three new blood group systems.

Haemolytic anaemia and renal failure associated with antibodies to trimethoprim and sulfamethoxazole.

AIM: The aim of this study was to support a clinical diagnosis of drug-induced immune haemolytic anaemia (DIIHA). BACKGROUND: DIIHA is rare and has only been described twice with the antibiotic combination of trimethoprim (TMP) and sulfamethoxazole (SMX). METHODS/MATERIALS: Serologic tests for drug antibodies were performed using methods previously published by our laboratory. RESULTS: A 44-year-old woman experienced body aches, chills, chest pressure, nausea and a rash while receiving TMP-SMX; a week later her haemoglobin was low and she was in renal failure. At the hospital, the direct antiglobulin test (DAT) was positive (C3 only) and the serum reacted with all red blood cells (RBCs) by the gel method only (TMP-SMX is present in the RBC diluent used for the gel method). At the Red Cross immunohaematology laboratory, the patient's serum was reactive in the presence of TMP-SMX (haemolysis and positive antiglobulin test), pure TMP (positive antiglobulin test using anti-IgG only) and pure SMX (haemolysis and positive antiglobulin test using both anti-IgG and anti-C3). The patient was treated with transfusions and haemodialysis and was discharged after a week in stable condition. CONCLUSION: We describe a patient who appeared to have haemolytic anaemia and renal failure associated with antibodies to both TMP and SMX.

Clinical evaluation for lymphoproliferative disease prompted by finding of IgM warm autoanti-IT in two cases.

Anti-IT is an unusual specificity originally described as a naturally occurring cold agglutinin. The antibody reacts strongly with cord RBCs, weakly with adult I RBCs, and most weakly with the rare adult i RBCs. IgG anti-IT in patients with hemolytic anemia has been associated with Hodgkin's lymphoma. Difficulties in blood grouping tests and the presence of a warm reactive agglutinin in samples from two patients with hemolytic anemia led to further serologic studies and the identification of anti-IT. In both cases, the anti-IT was a rarely encountered IgM warm reactive agglutinin; in one case, the IgG component was also anti-IT, whereas in the second case the IgG antibody was broadly reactive. The unusual serologic finding of anti-IT prompted further clinical evaluation for lymphoproliferative disease in these two patients.

Neurologic abnormalities in HTLV-I- and HTLV-II-infected individuals without overt myelopathy.

BACKGROUND: Human T-lymphotropic virus (HTLV) type I is the causative agent of HTLV-associated myelopathy (HAM)/tropical spastic paraparesis, and a number of HAM cases with HTLV-II infection have also been reported. However, despite some reports, it is unclear whether HTLV-I or -II infection is associated with other neurologic manifestations. METHODS: An analysis of medical histories and screening neurologic examinations from a prospective cohort of 153 HTLV-I, 388 HTLV-II, and 810 HTLV-seronegative individuals followed up for means of 11.5, 12.0, and 12.2 years was performed. Participants diagnosed with HAM were excluded. We calculated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race or ethnicity, income, educational attainment, body mass index, alcohol and cigarette consumption, injection drug use, diabetes, and hepatitis C virus status, using generalized estimating equations for repeated measures. RESULTS: HTLV-I and -II participants were more likely than seronegative participants to have leg weakness (ORs 1.67 [95% CI 1.28-2.18] and 1.44 [1.16-1.78]), impaired tandem gait (ORs 1.25 [95% CI 1.07-1.47] and 1.45 [1.27-1.64]), Babinski sign (ORs 1.54 [95% CI 1.13-2.08] and 1.51 [1.18-1.93]), impaired vibration sense (ORs 1.16 [95% CI 1.01-1.33] and 1.27 [1.14-1.42]), and urinary incontinence (ORs 1.45 [95% CI 1.23-1.72] and 1.70 [1.50-1.93]). For both HTLV-I and -II participants, higher odds of sensory neuropathy by monofilament examination were no longer significant after adjustment for confounding. CONCLUSIONS: These results provide strong evidence that human T-lymphotropic virus (HTLV)-I and -II are associated with a spectrum of predominantly motor abnormalities in patients without overt HTLV-associated myelopathy. Further investigation of the clinical course and etiology of these abnormalities is warranted.

Modulating the red cell membrane to produce universal/stealth donor red cells suitable for transfusion.

Two approaches have been used to produce universal group O donor red blood cells (RBCs) from groups A, B, and AB RBCs. The first involves cleavage of the terminal immunodominant sugars from carbohydrate chains on the RBC membrane, using specific enzymes, to produce so-called enzyme-converted group O (ECO) RBCs. ECO RBCs have been produced from whole units of B RBCs and transfused successfully to humans. Group A RBCs (especially A(1) RBCs) have been more difficult. New sources of enzymes have produced ECO RBCs from A(1) and A(2) RBCs that do not react with powerful monoclonal anti-A. Unfortunately, there are still problems encountered with polyclonal human antibodies (i.e. cross-matching). The second approach interferes with an antibody reaching its specific antigen on the RBC membrane by bonding polyethylene glycol (PEG) to the RBC. PEG will attract water molecules, yielding a combination that may block most RBC antigens, including A and B antigens. Initial excitement generated by preliminary reports of the possibility of producing 'stealth' PEG-RBCs were tempered by the findings of in vitro serological problems and possible reduced in vivo RBC survival. Many of these problems were solved, but recent findings that PEG is immunogenic in animals and humans, and that PEG antibodies can shorten the survival of PEG-RBCs (in rabbits) and pegylated proteins (e.g. PEG-asparaginase) in humans, are disturbing, suggesting that 'stealth' RBCs may never become a reality.

The James Blundell Award Lecture 2007: do we really understand immune red cell destruction?

We have learned a great deal about immune red blood cell (RBC) destruction since the elaboration of biochemical/immunological interactions of antibodies, complement and macrophages during the past 50 years. We first learned about the direct lysis of RBCs involving complement. We then learned of the role of the macrophage (particularly in the spleen and the liver) in initiating phagocytosis and antibody-dependent cytotoxicity of antibody-coated RBCs. Later, as the complexities of the human complement system were unravelled, we learned that complement-coated RBCs that were not directly haemolysed could interact with macrophages and that specific complement molecules on the RBC membrane could lead to a phagocytic event or the RBC (although heavily coated with complement) could survive normally. The application of isotope-labelling procedures (e.g. (51)Cr) for RBC survival (starting in the 1950s) advanced our knowledge considerably. Advances in knowledge in immunology helped us understand the complexity of the immunoglobulins (e.g. subclasses) and the specific receptors on macrophages and their role in immune haemolysis. Nevertheless, after more than 30 years researching this area, I am sometimes embarrassed to realize how much I cannot explain. Why do some patients have severe haemolytic transfusion reactions because of antibodies that are only detectable by one technique or not detectable by any? How do we explain autoimmune haemolytic anaemia with negative direct antiglobulin tests (DATs)? Why do RBCs strongly coated with immunoglobulin (Ig)G1 or IgG3 sometimes have normal survival? Are cells, other than macrophages, involved in immune RBC destruction? Could the relative amount of cytotoxicity vs. phagocytosis explain different clinical findings and response to treatment? How do we explain 'hyperhaemolysis' in sickle cell disease? Could novel mechanisms involving IgG glycosylation, CD47, 'armed' macrophages, bystander lysis, antibody activated reactive oxygen species, natural killer cells or antibody perturbation of RBC membrane be involved? Why do RBCs die after circulating for 100-120 days in healthy individuals? How should we define a 'clinically significant' antibody; how do we evaluate this? So many questions, so little time!

Late onset neonatal anaemia due to maternal anti-Ge: possible association with destruction of eythroid progenitors.

There have been no reports of severe haemolytic disease of the newborn (HDN) due to Gerbich (Ge) antibodies. Two babies with HDN due to anti-Ge3, both born to the same mother, are described. The anti-Ge appeared in the first pregnancy and was not detectable in the first trimester, the babies' reticulocyte and bilirubin values were not greatly elevated (similar to HDN due to Kell antibodies), and the anaemia in both cases was either not apparent or not severe until 2 to 4 weeks after birth. Ge antigens are found on glycophorins (GPs) C and D; GPC, like Kell, has been shown to be expressed early on erythroid progenitor cells. The maternal anti-Ge3 was shown to promote phagocytosis of Ge+ early erythroid progenitors by monocytes (similar to what has been reported with anti-K and K+ progenitor cells). Thus, anti-Ge3 may cause immune destruction of erythroid progenitors and possibly suppression of erythropoiesis (which would explain the reticulocyte and bilirubin values seen in both cases). Anti-Ge3 appears to be capable of causing severe HDN. We suggest that babies born to mothers with anti-Ge should have their haemoglobin concentrations monitored for signs of anaemia for several weeks after birth. Functional assays may prove useful.

First year donation patterns predict long-term commitment for first-time donors.

BACKGROUND AND OBJECTIVES: Converting first-time donors to become regular donors continues to be a challenge facing blood centres. We examined whether first-time donors with frequent return in the first 12 months were more likely to become regular donors. SUBJECTS AND METHODS: The donation histories of 179 409 community whole-blood donors, whose first-time donation in 1991 was negative on donor screening tests, were evaluated. Donors were categorized by the number of donations made in the 12 months after (and including) their first donation. The donor return pattern in the subsequent 6 years, and its association with first-year donation frequency and demographics, was evaluated by using logistic regression analysis. A 'regular donor' was defined as one who returned to donate in at least 4 of the 6 years of follow-up. RESULTS: First-year donation frequency was significantly correlated with long-term donor return (P < 0.0001). Among those giving 1, 2, 3, 4 and > or = 5 donations in the first year, 4%, 11%, 21%, 32% and 42%, respectively, became regular donors (P < 0.0001). Similar associations between donation pattern and donor return behaviour were observed after adjusting for demographic variables (P < 0.0001). CONCLUSIONS: Strategies aimed at encouraging current donors to donate more frequently during the first year may help to establish a regular donation behaviour.

Tazobactam-induced haemolytic anaemia, possibly caused by non-immunological adsorption of IgG onto patient's red cells.

A patient with pneumonia was treated with Tazocin (piperacillin/tazobactam). However, the expected haemoglobin (Hb) increment after transfusion was not achieved. Plasma bilirubin and lactate dehydrogenase were raised. The direct antiglobulin test (DAT) was positive (4+) for immunoglobulin G (IgG) only, but no RBC antibodies were demonstrable in the plasma or an eluate from the patient's RBCs. Drug-induced haemolysis was suspected. After discontinuing Tazocin administration, Hb and bilirubin levels returned to expected values. The patient's plasma gave a positive (3+) indirect antiglobulin reaction only with RBCs pretreated with tazobactam. However, random patient plasmas also gave weak (+/- to 1+) reactions, indicating non-immunological adsorption of IgG onto RBCs rather than specific anti-tazobactam antibodies. Subsequently, plasma samples with varying IgG levels (0.8-89.7 g L(-1)) were tested against RBCs pretreated with tazobactam. The amount of plasma IgG non-immunologically adsorbed onto the drug-coated RBCs was found to correlate directly with the plasma IgG level. The patient had a high plasma IgG level (41.6 g L(-1)) which explains why the antiglobulin test was stronger with the patient's plasma than with random plasma samples. Previous reports (Garratty & Arndt, (1998) British Journal of Haematology, 100, 777-783; Arndt & Garratty (2000) Transfusion, 40, 29S) suggested that non-immunological coating of RBCs with IgG may affect RBC survival; our results would support that suggestion. This is the first reported case of haemolytic anaemia associated with tazobactam.

Prevalence and clinical features of HTLV neurologic disease in the HTLV Outcomes Study.

BACKGROUND: Almost 20 years after its discovery, the prevalence and clinical course of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM, also known as tropical spastic paraparesis [TSP]) remain poorly defined. Whereas the causative association of HTLV-I and HAM/TSP is generally recognized, controversy still surrounds the relationship between HTLV-II and HAM/TSP. METHODS: The HTLV Outcomes Study (HOST-formerly Retrovirus Epidemiology Donor Study [REDS]) is a prospective cohort study including 160 patients with HTLV-I, 405 patients with HTLV-II, and 799 uninfected controls who have been followed every 2 years since 1990-1992. Clinical outcomes are measured by health interviews and examinations, and blood samples are obtained. RESULTS: Six cases of HTLV-I-associated myelopathy (3.7%, 95% CI 1.4 to 8.0) and four cases of HTLV-II myelopathy (1.0%, 95% CI 0.3 to 2.5) have been diagnosed since the formation of the cohort. There have been no cases of HAM/TSP diagnosed among HTLV-negative subjects (0.0%, 95% CI 0.0 to 0.5). Clinical features of the cases include lower extremity hyperreflexia, variably associated with weakness, spasticity, and bladder dysfunction. CONCLUSIONS: Systematic screening of HTLV-infected blood donors reveals a high prevalence of HAM/TSP. The clinical course of HAM/TSP appears highly variable. HTLV-II-associated myelopathy generally presents with milder and more slowly progressive signs and symptoms.