Familial pseudohyperkalemia in blood donors: a novel mutation with implications for transfusion practice.

BACKGROUND: Familial pseudohyperkalemia (FP) is a dominantly inherited condition in which red blood cells (RBCs) have an increased cold-induced permeability to monovalent cations. Potassium leaks into the supernatant of all stored blood with time, but FP RBCs leak potassium more rapidly. We investigated two unrelated blood donors whose RBC donations demonstrated unexpectedly high potassium after 5 and 6 days' storage. We matched the observed pattern of RBC cation leak to a previously recognized family with FP (FP-Cardiff) and investigated the likely cause with targeted DNA analysis. STUDY DESIGN AND METHODS: Cation leakage from the donor RBCs and from standard donor units was measured. DNA analysis of donors and family members with FP-Cardiff was performed. Allele frequencies were obtained from human variation databases. RESULTS: Both implicated donors were found to have increased cold-induced potassium leak identical in pattern to affected members of the family with FP-Cardiff. We found a heterozygous substitution Arg723Gln in the ATP-binding cassette, Subfamily B, Member 6 protein that segregated with FP in the Cardiff family and was also present in both blood donors. Arg723Gln is listed in human variation databases with an allele frequency of approximately 1:1000. CONCLUSIONS: We describe a novel FP mutation that may affect 1:500 European blood donors and causes rapid loss of potassium from stored RBCs. This finding has implications for neonates and infants receiving large-volume RBC transfusions. Genomic screening of donors could be used to identify donors with this mutation and potentially improve the quality and safety of donor units.

Transfusion-related Acute Lung Injury: 36 Years of Progress (1985-2021).

The term transfusion-related acute lung injury (TRALI) was coined in 1985 to describe acute respiratory distress syndrome (ARDS) after transfusion, when another ARDS risk factor was absent; TRALI cases were mostly associated with donor leukocyte antibody. In 2001, plasma from multiparous donors was implicated in TRALI in a randomized controlled trial in Sweden. In 2003 and in many years thereafter, the U.S. Food and Drug Administration reported that TRALI was the leading cause of death from transfusion in the United States. In 2003, the United Kingdom was the first among many countries to successfully reduce TRALI using male-predominant plasma. These successes are to be celebrated. Nevertheless, questions remain about the mechanisms of non-antibody TRALI, the role of blood products in the development of ARDS in patients receiving massive transfusion, the causes of unusual TRALI cases, and how to reduce inaccurate diagnoses of TRALI in clinical practice. Regarding the latter, a study in 2013-2015 at 169 U.S. hospitals found that many TRALI diagnoses did not meet clinical definitions. In 2019, a consensus panel established a more precise terminology for clinical diagnosis: TRALI type I and TRALI type II are cases where transfusion is the likely cause, and ARDS are cases where transfusion is not the likely cause. For accurate diagnosis using these clinical definitions, critical care or pulmonary expertise is needed to distinguish between permeability versus hydrostatic pulmonary edema, to determine whether an ARDS risk factor is present, and, if so, to determine whether respiratory function was stable within the 12 hours before transfusion.

Ten years of hemovigilance reports of transfusion-related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma.

BACKGROUND AND METHODS: From 1996 through 2006, 195 cases were reported as transfusion-related acute lung injury (TRALI) to the Serious Hazards of Transfusion scheme and from 1999 onward classified by probability, using clinical features and HLA and/or HNA typing. From late 2003, the National Blood Service provided 80 to 90 percent of fresh-frozen plasma (FFP) and plasma for platelet (PLT) pools from male donors. RESULTS: Forty-nine percent of reports were highly likely/probable TRALI, and 51 percent possible/unlikely. Of 96 investigations, donor antibodies recognizing recipient antigens were found in 73 cases (65%), with HLA Class I in 25 of those (40%), HLA Class II antibodies in 38 (62%), and granulocyte antibodies in 12 (17%). A review in 2003 revealed that the TRALI risk/component was 6.9 times higher for FFP and 8.2 times higher for PLTs than for red blood cells, and that in donors of implicated FFP/PLTs, white blood cell antibodies were found 3.6 times more often than by chance (p

Acute lung injury after ruptured abdominal aortic aneurysm repair: the effect of excluding donations from females from the production of fresh frozen plasma.

OBJECTIVES: Transfusion-related acute lung injury may contribute to the development of acute lung injury in the critically ill, due to plasma from female donors containing antileukocyte antibodies. In July 2003, the U.K. National Blood Service stopped using female donor plasma for the production of fresh frozen plasma. Patients undergoing repair of a ruptured abdominal aortic aneurysm receive large amounts of fresh frozen plasma and often develop acute lung injury. We investigated whether the change to male fresh frozen plasma was associated with a change in the frequency of acute lung injury in these patients. DESIGN: A retrospective, before and after, observational, single-center study. SETTING: Tertiary care center and a regional blood center. PATIENTS: The study included 211 patients undergoing open repair of a ruptured abdominal aortic aneurysm between 1998 and 2006. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was the development of acute lung injury in the first 6 hrs after surgery. Secondary outcomes were significant hypoxia (PaO2/FiO2 ratio <300), time to extubation, and survival at 30 days. Groups were well matched and received similar volumes of intravenous fluids and blood components. There was significantly less acute lung injury following the change to male fresh frozen plasma (36% before vs. 21% after, p = .04). At 6 hrs after surgery, fewer patients were hypoxic (87% before vs. 62% after, p < .01). In multivariate analysis, the change in donor policy was associated with a decreased risk of developing acute lung injury (odds ratio 0.39; 95% confidence interval, 0.16-0.90). Time to extubation and survival at 30 days were not statistically different between groups. CONCLUSIONS: The policy to exclude female donors from the production of fresh frozen plasma was associated with a decrease in the frequency of acute lung injury in patients undergoing repair of a ruptured abdominal aortic aneurysm.

Serious hazards of transfusion: a decade of hemovigilance in the UK.

The Serious Hazards of Transfusion (SHOT) scheme is a UK-wide, independent, professionally led hemovigilance system focused on learning from adverse events. SHOT was established in 1996 as a confidential reporting system for significant transfusion-related events, building an evidence base to support blood safety policy decisions, clinical guidelines, clinician education, and improvements in transfusion practice. Recommendations are formulated by an independent steering group drawn from medical royal colleges and professional bodies. Ten years after its inception, SHOT has analyzed 2630 transfusion safety events, published 8 annual reports with recommendations, and presented data nationally and internationally. These recommendations have underpinned key initiatives, in particular the UK Department of Health "Better Blood Transfusion" strategy. SHOT has encouraged open reporting of adverse events and "near-misses" in a supportive, learning culture, vigilance in hospital transfusion practice, and evaluation of information technology to support this process. The importance of education and training has been emphasized. Detailed analysis of events has identified weaknesses in the transfusion chain. A collaborative initiative between SHOT, the Chief Medical Officer for England's National Blood Transfusion Committee, and the National Patient Safety Agency aims to reduce ABO-incompatible transfusions by improving bedside practice. Cumulative SHOT data have documented the decline in transfusion-related graft vs host disease after implementation of leucodepletion and have highlighted transfusion-related acute lung injury and bacterial contamination of platelets as important causes of death and morbidity. The UK blood services have developed strategies to reduce these risks. Future SHOT data will evaluate the success of these and other blood safety improvements.

Donor CD31 genotype impacts on transplant complications after human leukocyte antigen-matched sibling allogeneic bone marrow transplantation.

Mismatch for the adhesion molecule CD31 (PECAM-1) has been associated in some studies with graft-versus-host disease (GVHD), suggesting a role for CD31 as a minor histocompatibility antigen. We examined polymorphisms of the CD31 (PECAM-1) gene in 74 patients and their human leukocyte antigen-matched sibling donors, comparing CD31 genotype with outcomes of occurrence of GVHD and survival using regression analysis. Polymorphisms in codon 125, 563, and 670 are strongly linked forming conserved haplotypes. Donor CD31 (val/asn/gly) haplotype was associated with acute GVHD (P=0.004, odds ratio 7.5). In addition, donor heterozygosity at codon 563 was significantly associated with worse overall survival after correcting for other known variables by regression modeling. Peptide binding predictions support the hypothesis that CD31 could act as a minor histocompatibility antigen. Assessment for CD31 gene status may be of value in pretransplant assessment of bone marrow transplant recipients and donors for prediction of likely transplant-related complications.

Enhanced engraftment of a very low-dose cord blood unit in an adult haemopoietic transplant by addition of six mismatched viable cord units.

The report describes the feasibility of the addition of multiple viable HLA-mismatched unrelated cord blood units, to a low cell number matched unrelated cord, to assist clinical engraftment. An ablative stem cell transplant was performed in an adult with relapsed acute lymphoblastic leukaemia (ALL), using a single HLA-matched cord blood unit (mononuclear cell dose 0.8 × 10(7)), supported by six mismatched cord blood units (one unit per 10 kg recipient weight). No adverse reaction occurred following the infusion of mismatched units and engraftment of the suboptimal-dose matched unit occurred rapidly, with no molecular evidence of engraftment of mismatched cords. Early molecular remission of ALL was demonstrated using a novel PCR for a mitochondrial DNA mutation in the leukaemic clone. The cell dose of the matched cord was well below that recommended to engraft a 70 kg recipient. We suggest that a factor or factors in the mismatched cords enhanced/supported engraftment of the matched cord.

The impact of universal leukodepletion of the blood supply on hemovigilance reports of posttransfusion purpura and transfusion-associated graft-versus-host disease.

BACKGROUND: The pathogenesis of posttransfusion purpura (PTP) and transfusion-associated graft-versus-host disease (TA-GVHD) involves patient exposure to donor platelets (PLTs) and T lymphocytes, respectively, which are removed during blood component leukodepletion (LD). STUDY DESIGN AND METHODS: Reports of PTP and TA-GVHD to the UK hemovigilance scheme Serious Hazards of Transfusion (SHOT) from 1996 to 2005 were compared before and after implementation of universal LD during 1999. RESULTS: There were 45 reports of PTP, with a mean of 10.3 per year before universal LD and 2.3 per year afterward (p < 0.001). All patients had received red cells, but before universal LD, only 1 of 31 (3%) cases had also received PLTs, compared to 8 of 14 (57%) afterward (p < 0.001). Thirty-four cases (76%) had human platelet antigen (HPA)-1a antibodies, whereas 11 had antibodies to other HPA specificities, only 1 of which occurred after LD. Two cases reported before LD also had heparin-dependent PLT antibodies. There were 13 reports of TA-GVHD, all fatal, of which only 2 cases of undiagnosed immunodeficiency met current UK criteria for irradiated components. Eight others had one or more risk factors: B-cell malignancy (6), steroids (1), fresh blood (1), and donor-recipient HLA haplotype share (4). Eleven cases were due to non-LD and 2 to LD components (p < 0.001). No cases have been reported since 2001. In an additional 405 cases, nonirradiated components were transfused in error to high-risk recipients, mainly on fludarabine, but none developed TA-GVHD. CONCLUSIONS: These findings suggest that universal LD has further reduced the already low risk of TA-GVHD in immunocompetent recipients and has altered the profile of PTP cases.

Long-term survival after blood transfusion: a population based study in the North of England.

BACKGROUND: Blood transfusion may transmit infectious diseases with long incubation periods. Estimation of the risks of transmission of such disease requires know-ledge of long-term survival of transfused patients. No such information is available in the UK, where there is particular concern about possible transmission by trans-fusion of variant CJD. STUDY DESIGN AND METHODS: Information on survival after transfusion and demographics was collected for all patients transfused during June 1994 in a population of 2.9 million served by a single blood center. RESULTS: A total of 2899 patients were transfused with 10,760 units of RBCs (99% of RBCs issued during the study period). Follow-up to death or 5 years was completed for 98.2 percent, and 46.9 percent of all transfusion recipients were alive at 5 years; 41 percent of transfused RBC units and 36 percent of transfused FFP were given to patients who were alive at 5 years. Median age at transfusion was 67 years (mean, 60.9 years). Shorter patient survival was associated with increasing patient age, increasing numbers of RBC units transfused, trans-fusion of plasma or PLTs, and nonsurgical indications for transfusion. CONCLUSIONS: Posttransfusion survival is lower than estimated in previous decades in other countries. This is probably due to a relative increase in use of transfusion for older patients and for medical indications. Our figures may be used to predict and stratify the risk of infections, such as variant CJD, amongst different groups of transfusion recipients.

Single hospital experience of TRALI.

BACKGROUND: TRALI is a serious adverse effect of blood transfusion. There is evidence that the condition is underrecognized and underreported. STUDY DESIGN AND METHODS: This study was an observational study carried out in a single hospital. RESULTS: Eleven cases of TRALI were recognized over 12 years. In 10 cases the implicated donor unit was FFP and in 1 case uncertain. All implicated donors were parous women. In 4 cases the presumed causative antibodies were to an HLA class II antigen only. Specific anti-neutrophil antibodies, possibly causative, were detected in 1 case only. Ten of the 11 cases required mechanical ventilatory support. Five persons died as a result of the TRALI. The observed incidence of TRALI caused by FFP is 1 in 7900 units transfused. CONCLUSION: TRALI is the most common serious adverse effect of blood transfusion in our hospital. Antibodies to HLA class II antigens should be looked for routinely when investigating a possible case of TRALI.