Prevention and treatment of infection in patients with an absent or hypofunctional spleen: A British Society for Haematology guideline.

Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen were published by the British Committee for Standards in Haematology in 1996 and updated in 2002 and 2011. With advances in vaccinations and changes in patterns of infection, the guidelines required updating. Key aspects included in this guideline are the identification of patients at risk of infection, patient education and information and immunisation schedules. This guideline does not address the non-infective complications of splenectomy or functional hyposplenism (FH). This replaces previous guidelines and significantly revises the recommendations related to immunisation. Patients at risk include those who have undergone surgical removal of the spleen, including partial splenectomy and splenic embolisation, and those with medical conditions that predispose to FH. Immunisations should include those against Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus) and influenza. Haemophilus influenzae type b (Hib) is part of the infant immunisation schedule and is no longer required for older hyposplenic patients. Treatment of suspected or proven infections should be based on local protocols and consider relevant anti-microbial resistance patterns. The education of patients and their medical practitioners is essential, particularly in relation to the risk of serious infection and its prevention. Further research is required to establish the effectiveness of vaccinations in hyposplenic patients; infective episodes should be regularly audited. There is no single group ideally placed to conduct audits into complications arising from hyposplenism, highlighting a need for a national registry, as has proved very successful in Australia or alternatively, the establishment of appropriate multidisciplinary networks.

Missed irradiation of cellular blood components for vulnerable patients: Insights from 10 years of SHOT data.

BACKGROUND: Irradiation of cellular blood components is recommended for patients at risk of transfusion-associated graft-vs-host disease (TA-GvHD). Prestorage leucodepletion (LD) of blood components is standard in the UK since 1999. STUDY DESIGN AND METHODS: Analysis of 10 years' reports from UK national hemovigilance scheme, Serious Hazards of Transfusion (2010-2019), where patients failed to receive irradiated components when indicated according to British Society for Haematology guidelines (2011). RESULTS: There were 956 incidents of failure to receive irradiated components all due to errors. One hundred and seventy two incidents were excluded from analysis, 125 of 172 (72.7%) because of missing essential information. No cases of TA-GvHD were reported in this cohort. The 784 patients received 2809 components (number unknown for 67 incidents). Most failures occurred in patients treated with purine analogues (365) or alemtuzumab (69), or with a history of Hodgkin lymphoma (HL) (192). Together these make up 626 of 784 (79.9%). Poor communication is an important cause of errors. CONCLUSION: Leucodepletion appears to reduce the risk for TA-GvHD. None of 12 cases of TA-GvHD reported to SHOT prior to introduction of LD occurred in patients with conditions recommended for irradiated components by current guidelines. Irradiation indefinitely for all stages of HL is not based on good evidence and is a difficult guideline to follow. Further research on long-term immune function in HL is required. Variation between different national guidelines reflects the very limited evidence.

Transfusion errors - can they be eliminated?

The Serious Hazards of Transfusion haemovigilance scheme has documented adverse transfusion incidents for 22 years. Transmission of infection (three in 2018), transfusion-related lung injury (one in 2018) and transfusion-associated graft-versus-host disease (none since 2012) are rare. Despite national recommendations, guidelines and protocols, most incidents more than 85% of incidents are still due to errors in the transfusion process. European regulation and mandatory competency assessments have been associated with a reduction in ABO-incompatible transfusion, but errors continue to put patients at risk. What can be done? Errors are reduced by the use of electronic identification systems. Exploration of human factors and ergonomics (HFE) results in amended approaches away from blaming individuals to a full review of the systems and environment. Research examining how transfusion is performed (work-as-done) compared to work-as-imagined (set out in protocols and guidelines) discovers where variability results in either resilience or error. All staff require HFE training, but this should be alongside employment of suitably qualified and experienced HFE professionals. Good teamwork is key and is undermined by insufficient staffing and poor morale. The five choosing wisely recommendations for transfusion (to ensure appropriate use) need to be widely disseminated to medical staff in all specialties to ensure patients participate in the decision-making.

The World Federation of Hemophilia Annual Global Survey 1999-2018.

INTRODUCTION: The World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non-governmental national organizations. AIM: To describe the development, methodology and achievements of the WFH AGS over the past 20 years. METHODS: The AGS is a yearly cross-sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues. RESULTS: Over the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient-level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry. CONCLUSION: The AGS has provided evidence to support research, programme planning and development activities of the WFH.

Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency.

Individuals with Factor XI (FXI) deficiency have a variable bleeding tendency that does not correlate with FXI:C levels or genotype. Comparing a range of sample conditions, we tested whether the thrombin generation assay (TGA) could discriminate between control subjects (n = 50) and FXI-deficient individuals (n = 97), and between those with bleeding tendency (n = 50) and without (n = 24). The comparison used platelet-rich plasma (PRP) and platelet-poor plasma (PPP), either with or without corn trypsin inhibitor (CTI) to prevent contact activation, over a range of tissue factor (TF) concentrations. When contact activation was inhibited and platelets were absent, FXI:C levels did not correlate with thrombin generation parameters, and control and FXI-deficient individuals were not distinguished. In all other sample types, the best discrimination was obtained using TF 0.5 pM and assay measures: endogenous thrombin potential (ETP) and peak height. We showed that although a number of conditions could distinguish differences between the groups tested, TGA measured in PRP with CTI best differentiated between bleeders and nonbleeders. These measures provided high sensitivity and specificity (peak height receiver operating characteristic [ROC] area under the curve [AUC] = 0.9362; P < .0001) (ETP ROC AUC = 0.9362; P < .0001). We conclude that by using sample conditions directed to test specific pathways of FXI activation, the TGA can identify bleeding phenotype in FXI deficiency.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

Wrong blood in tube - potential for serious outcomes: can it be prevented?

'Wrong blood in tube' (WBIT) errors, where the blood in the tube is not that of the patient identified on the label, may lead to catastrophic outcomes, such as death from ABO-incompatible red cell transfusion. Transfusion is a multistep, multidisciplinary process in which the human error rate has remained unchanged despite multiple interventions (education, training, competency testing and guidelines). The most effective interventions are probably the introduction of end-to-end electronic systems and a group-check sample for patients about to receive their first transfusion, but neither of these eradicates all errors. Further longer term studies are required with assessment before and after introduction of the intervention. Although most focus has been on WBIT in relation to blood transfusion, all pathology samples should be identified and linked to the correct patient with the same degree of care. Human factors education and training could help to increase awareness of human vulnerability to error, particularly in the medical setting where there are many risk factors.

Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS).

Long-term follow-up of children with immune thrombocytopenia (ITP) indicates that the majority undergo remission and severe thrombocytopenia is infrequent. Details regarding bleeding manifestations, however, remain poorly categorized. We report here long-term data from the Intercontinental Cooperative ITP Study Group Registry II focusing on natural history, bleeding manifestations, and management. Data on 1345 subjects were collected at diagnosis and at 28 days, 6, 12, and 24 months thereafter. Median platelet counts were 214 × 10(9)/L (interquartile range [IQR] 227, range 1-748), 211 × 10(9)/L (IQR 192, range 1-594), and 215 × 10(9)/L (IQR 198, range 1-598) at 6, 12, and 24 months, respectively, and a platelet count <20 × 10(9)/L was uncommon (7%, 7%, and 4%, respectively). Remission occurred in 37% of patients between 28 days and 6 months, 16% between 6 and 12 months, and 24% between 12 and 24 months. There were no reports of intracranial hemorrhage, and the most common site of bleeding was skin. In patients with severe thrombocytopenia we observed a trend toward more drug treatment with increasing number of bleeding sites. Our data support that ITP is a benign condition for most affected children and that major hemorrhage, even with prolonged severe thrombocytopenia, is rare.

Serious Hazards of Transfusion (SHOT) haemovigilance and progress is improving transfusion safety.

The Serious Hazards of Transfusion (SHOT) UK confidential haemovigilance reporting scheme began in 1996. Over the 16 years of reporting, the evidence gathered has prompted changes in transfusion practice from the selection and management of donors to changes in hospital practice, particularly better education and training. However, half or more reports relate to errors in the transfusion process despite the introduction of several measures to improve practice. Transfusion in the UK is very safe: 2·9 million components were issued in 2012, and very few deaths are related to transfusion. The risk of death from transfusion as estimated from SHOT data in 2012 is 1 in 322,580 components issued and for major morbidity, 1 in 21,413 components issued; the risk of transfusion-transmitted infection is much lower. Acute transfusion reactions and transfusion-associated circulatory overload carry the highest risk for morbidity and death. The high rate of participation in SHOT by National Health Service organizations, 99·5%, is encouraging. Despite the very useful information gained about transfusion reactions, the main risks remain human factors. The recommendations on reduction of errors through a 'back to basics' approach from the first annual SHOT report remain absolutely relevant today.

The rare inherited coagulation disorders.

The rare inherited coagulation disorders (RICD) are uncommon and thus not well-defined in terms of severity or management. Inheritance is autosomal; in some of these disorders in the heterozygote state affected individuals may be mildly symptomatic. Severe deficiencies are more common in association with consanguinity. Factor X and factor XIII deficiency have the most severe manifestations, while factor XI deficiency is the least severe. Factor VII and factor XI deficiencies show a poor relationship between the factor level and bleeding risk. Unlike hemophilia, women are equally affected by these RICD and can have problems related to menstruation and childbirth.

Tissue factor pathway inhibitor is a potential modifier of bleeding risk in factor XI deficiency.

BACKGROUND: Factor (F) XI deficiency is associated with increased bleeding risk in some individuals. Neither FXI levels nor clinical clotting assays predict the bleeding risk. Compared with controls, FXI-deficient bleeders have reduced clot formation, decreased fibrin network density, and increased susceptibility to fibrinolysis. Tissue factor pathway inhibitor (TFPI) was recently implicated as a modifying factor in individuals with bleeding of unknown cause. OBJECTIVES: To determine the potential of TFPI in modifying the bleeding risk in FXI-deficient individuals. METHODS: The effects of TFPI on thrombin generation and clot formation, structure, and fibrinolysis in FXI-deficient plasma were measured in vitro in the absence or presence of inhibitory anti-TFPI antibody or exogenous recombinant TFPIα. Total plasma TFPI concentration was measured in 2 independent cohorts of controls and FXI-deficient individuals classified as bleeders or nonbleeders (cohort 1: 10 controls and 16 FXI-deficient individuals; cohort 2: 48 controls and 57 FXI-deficient individuals) and correlated with ex vivo plasma clot formation and fibrinolysis parameters associated with bleeding risk. RESULTS: In an in vitro FXI deficiency model, inhibition of TFPI enhanced thrombin generation and clot formation, increased the network density, and decreased fibrinolysis, whereas an increase in TFPI had the opposite effects. Compared with controls, plasma from FXI-deficient bleeders had higher TFPI concentration. Total plasma TFPI concentrations correlated with parameters from ex vivo clotting and fibrinolysis assays that differentiate FXI-deficient bleeders and nonbleeders. CONCLUSION: Coagulation and fibrinolysis parameters that differentiate FXI-deficient nonbleeders and bleeders were altered by plasma TFPIα. Total plasma TFPI was increased in FXI-deficient bleeders. TFPI may modify the bleeding risk in FXI-deficient individuals.

Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update.

Guidelines on hereditary spherocytosis (HS) published in 2004 (Bolton-Maggs et al, 2004) are here replaced to reflect changes in current opinion on the surgical management, (particularly the indications for concomitant splenectomy with cholecystectomy in children with mild HS, and concomitant cholecystectomy with splenectomy in those with asymptomatic gallstones). Further potential long term hazards of splenectomy are now recognised. Advances have been made in our understanding of the biochemistry of the red cell membrane which underpins the choice of tests. Biochemical assays of membranes proteins and genetic analysis may be indicated (rarely) to diagnose atypical cases. The diagnostic value of the eosin-5-maleimide (EMA) binding test has been validated in a number of studies with understanding of its limitations.

Rare bleeding disorders.

Rare bleeding disorders (RBDs) include the inherited deficiencies of fibrinogen, factor (F)II, FV, FV+FVIII, FVII, FX, FXI and FXIII. There have been remarkable advances in understanding the molecular profiles that lead to each type of coagulation factor deficiency. However, as a consequence of their rarity, clinical data regarding the characteristics of bleeding symptoms and their management remain limited. The clinical manifestations in different RBDs are heterogeneous, and the residual plasma coagulant factor level does not always predict bleeding tendency. In this review, we describe the general features and recent advances in understanding three such deficiencies: FXI, FVII and fibrinogen deficiencies.

Cognitive symptoms are common in immune thrombocytopenia and associate with autonomic symptom burden.

OBJECTIVES: People with adult immune thrombocytopenia (ITP) are commonly thought to have an isolated blood disorder, but many also describe memory and concentration problems. Cognitive impairment commonly associates with autonomic dysfunction. Here, we quantified cognitive symptoms in a large cohort of patients with ITP compared with controls and explored the relationship with autonomic symptoms. METHODS: Patients with ITP were approached in the UK via the national ITP Support Association and invited to complete Composite Autonomic Symptom Scale (COMPASS; measure of autonomic symptoms) and Cognitive Failures Questionnaire (CFQ) together with one from a friend of similar age and sex without ITP. RESULTS: Three hundred and ninety-eight patients with ITP completed measures with paired data from a representative group of 189 patients and controls (47%). Both autonomic and cognitive symptom burden were higher in ITP compared with controls (COMPASS score (48 ± 14 vs. 38 ± 12; P > 0.0001); CFQ (43 ± 17 vs. 36 ± 13; P < 0.0001). A positive relationship was seen between increasing cognitive symptoms and higher COMPASS score (P < 0.0001; r(2) = 0.1). Increasing cognitive symptoms did not associate with platelet count (P = 0.08, r(2) = 0.008). Multivariate analysis confirmed age and COMPASS independently associated with higher CFQ but not platelet count. CONCLUSION: Immune thrombocytopenia is more than a bleeding disorder; cognitive symptoms are common and independently associate with autonomic symptoms but not disease severity.

Review of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen: prepared on behalf of the British Committee for Standards in Haematology by a working party of the Haemato-Oncology task force.

Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen were first published by the British Committee for Standards in Haematology (BCSH) in 1996 and formally reviewed in 2002. Although the guidelines originated from discussion within the BCSH, the intended readership is wide given the multidisciplinary nature of the management of hyposplenism.