Hemoglobin modulation affects physiology and patient reported outcomes in anemic and non-anemic subjects: An umbrella review.

Background: An abnormal hemoglobin concentration has a substantial effect on a person's quality of life and physiology. Lack of tools that effectively evaluate hemoglobin-related outcomes leads to uncertainty regarding optimal hemoglobin levels, transfusion thresholds and treatment targets. We therefore aim to summarize reviews that assess the effects of hemoglobin modulation on the human physiology at various baseline hemoglobin levels, and identify gaps in existing evidence. Methods: We conducted an umbrella review of systematic reviews. PubMed, MEDLINE (OVID), Embase, Web of Science, Cochrane Library and Emcare were searched from inception to the 15th of April 2022 for studies that reported on physiological and patient reported outcomes following a hemoglobin change. Results: Thirty-three reviews were included of which 7 were scored as of high quality and 24 of critically low quality using the AMSTAR-2 tool. The reported data generally show that an increase in hemoglobin leads to improvement of patient reported and physical outcomes in anaemic and non-anaemic subjects. At lower hemoglobin levels, the effect of a hemoglobin modulation on quality of life measures appears more pronounced. Conclusion: This overview has revealed many knowledge gaps due to a lack of high-quality evidence. For chronic kidney disease patients, a clinically relevant benefit of increasing the hemoglobin levels up until 12 g/dL was found. However, a personalized approach remains necessary due to the many patient-specific factors that affect outcomes. We strongly encourage future trials to incorporate physiological outcomes as objective parameters together with subjective, but still very important, patient reported outcome measures.

Autologous platelet scintigraphy and clinical outcome of splenectomy in immune thrombocytopenia: A systematic review and meta-analysis.

Autologous platelet sequestration pattern is associated with post-splenectomy platelet response in patients with immune thrombocytopenia (ITP). However, published results are contradictory, and have not been systematically reviewed. Our aim is to systematically review and meta-analyse the association between sequestration pattern and post-splenectomy platelet response. Articles were selected from MEDLINE when they a) included ITP patients, b) performed scintigraphy, and c) included post-splenectomy platelet response. The 23 included studies (published between 1969-2018) represented 2966 ITP-patients. Response to splenectomy occurred most frequently in patients with a splenic pattern (87.1 % in splenic versus 47.1 % in mixed and 25.5 % in hepatic patterns). A pooled analysis of 8 studies showed an odds ratio of 14.21 (95 % CI: 3.65-55.37) for platelet response in the splenic versus the hepatic group. Our findings indicate that a splenic sequestration pattern is associated with better response after splenectomy. Platelet sequestration patterns may be useful in the clinical decision-making regarding splenectomy.

International haemovigilance: what have we learned and what do we need to do next?

The International Haemovigilance Network (IHN) defines haemovigilance as 'a set of surveillance procedures covering the whole transfusion chain (from the collection of blood and its components to the follow-up of recipients), intended to collect and assess information on unexpected or undesirable effects resulting from the therapeutic use of labile blood products, and to prevent their occurrence or recurrence'. IHN, the International Society of Blood Transfusion and World Health Organization work together to support both developing and established haemovigilance systems. Haemovigilance systems provide valuable data on a range of adverse events related to blood donation and clinical transfusion, from donor syncopal events to transfusion-transmitted infections, immunological complications and the impact of human errors. Harmonised definitions for most adverse reactions have been developed and validated internationally. Definitions of pulmonary complications are again under review. Haemovigilance data have resulted in changes in policy, products and practice, and can complement and inform clinical audit and research, leading to improved blood donor safety, optimised product use and better clinical outcomes after transfusion. However, more work is needed. Not all countries have haemovigilance systems in place. More robust data and careful analysis are required to improve the understanding of the causes, occurrence and clinical outcomes of these events. Wider dissemination of results will facilitate health policy development internationally, and implementation of haemovigilance recommendations will support further important progress in blood safety.

Quality indicators for the hospital transfusion chain: a national survey conducted in 100 dutch hospitals.

BACKGROUND: The 2011 Dutch Blood Transfusion Guideline for hospitals incorporates seven internal quality indicators for evaluation of the hospital transfusion chain. The indicators aim to measure guideline compliance as shown by the instatement of a hospital transfusion committee and transfusion safety officer (structural indicators), observance of transfusion triggers and mandatory traceability of labile blood components (process indicators). STUDY DESIGN AND METHODS: Two voluntary online surveys were sent to all Dutch hospitals for operational years 2011 and 2012 to assess compliance with the guideline recommendations. RESULTS: Most hospitals had a hospital transfusion committee and had appointed a transfusion safety officer (TSO). In 2012, only 23% of hospitals complied with the recommended minimum of four annual transfusion committee meetings and 8 h/week for the TSO. Compliance with the recommended pretransfusion haemoglobin threshold for RBC transfusion was achieved by 90% of hospitals in over 80% of transfusions; 58% of hospitals measured the pretransfusion platelet count in over 80% of platelet transfusions and 87% of hospitals complied with the legally mandatory traceability of blood components in over 95% of transfusions. CONCLUSION: With the current blood transfusion indicators, it is feasible to monitor aspects of the quality of the hospital transfusion chain and blood transfusion practice and to assess guideline compliance. The results from this study suggest that there are opportunities for significant improvement in blood transfusion practice in the Netherlands. These indicators could potentially be used for national and international benchmarking of blood transfusion practice.

Presence of medication taken by blood donors in plasma for transfusion.

BACKGROUND AND OBJECTIVES: The TRIP national hemovigilance and biovigilance office receives reports on side-effects and incidents associated with transfusion of labile blood products. Anaphylactic reactions accounted for the largest number of serious transfusion reactions in the period 2008-2012. In most cases, no cause is found for these reactions. TRIP data show that anaphylactic reactions occur relatively frequently with transfusion of plasma or platelet concentrates. Data from blood services show that 10% or more of plasma donors regularly use medication which is permitted under donation guidelines. It is conceivable that medication taken by the donor in plasma for transfusion could cause an anaphylactic transfusion reaction in the recipient. This exploratory study investigated the presence of drugs or drug metabolites in donor plasma. MATERIALS AND METHODS: Samples (5 ml) were taken from thawed, quarantine fresh frozen plasma units (FFP) which had to be rejected for transfusion because of leaks or length of time after thawing. The samples were analysed for approximately 1000 drugs and drug metabolites using a toxicological screening method. RESULTS: Eighty-seven samples were analysed. Toxicological screening was positive in fourteen samples (16%). In eleven samples, one substance was found, and in three samples, the presence of two or three drugs was detected. CONCLUSION: After freezing, storage and thawing of fresh FFP, it is possible to detect medication taken by the donor. Further investigation is recommended to analyse whether donors' medication in plasma can be implicated in some cases of allergic or anaphylactic reactions in transfusion recipients.

Variation between hospitals in rates of reported transfusion reactions: is a high reporting rate an indicator of safer transfusion?

BACKGROUND AND OBJECTIVES: It has been suggested that the rate of reported transfusion reactions is positively correlated with safety of the transfusion chain in a hospital. We evaluated this assumption in the Transfusion Reactions in Patients Dutch National Hemovigilance Office database taking reported incorrect blood component transfused as a proxy for unsafe transfusion. METHODS: Reports from 2006 to 2010 and annual numbers of transfused blood components from the 103 hospitals were analysed. The rate of transfusion reactions per 1000 blood components was calculated per hospital. Logistic regression analysis was performed between reporting of at least one incorrect blood component and tertile of transfusion reaction rate. RESULTS: Out of the 103 hospitals, 101 had complete data in some and 93 in all 5years. In all, 72 had reported at least one incorrect blood component transfused; this was associated with blood use level and also with rate of reported transfusion reactions: odds ratio 4·2 (95% confidence interval, 1·3-13·7) in the highest vs. the lowest tertile after adjustment for blood use level. CONCLUSION: Hospitals in the Netherlands which report more transfusion reactions per 1000 units are also more likely to have reported incorrect blood component transfused. The data do not support that hospitals with a higher rate of transfusion reaction reports are safer.

Quality validation of data in national haemovigilance systems in Europe: report of a survey on current state of practice.

European Union member states must have national haemovigilance reporting of serious adverse reactions and events. We sent national competent authorities an email questionnaire about data validation. Responses were received from 23/27 countries. Nine previously had no national haemovigilance system. In 13 (57%), the serious adverse reactions and events can be verified. Coverage of blood establishments is documented in 20 systems (87%) and of hospitals in 15 systems (65%). Although all member states have implemented haemovigilance systems, there are currently wide variations in data quality assurance, not allowing comparisons between countries.

Allo-exposure status and leucocyte antibody positivity of blood donors show a similar relation with TRALI.

INTRODUCTION: The fraction of transfusion-related acute lung injury (TRALI) cases preventable by deferral of allo-exposed donors has previously been estimated, under the assumption this indirectly estimated the contribution of leucocyte antibodies to the occurrence of TRALI. Our aim was to estimate the fraction preventable by deferral of leucocyte antibody positive donors and to investigate the validity of allo-exposure as a marker for leucocyte antibodies. METHODS: All donors involved in a series of previously published TRALI patients were tested for leucocyte antibodies. The observed number of antibody positive donors was compared to the expected number. From this comparison we estimated the contribution of leucocyte antibodies to the occurrence of TRALI and compared this to the previously reported estimate for allo-exposed donors. RESULTS: Sixty-one TRALI patients were included. Of 288 involved donors 43 were expected and 67 were observed to be leucocyte antibody positive. The observed percentage of positive donors was 8.3% (95% confidence interval (CI): 5.1-11.5%) in excess of the expected. Overall 59% (95% CI: 34-85%) of TRALI cases was estimated to be preventable by the exclusion of all leucocyte antibody positive donors. For plasma-poor products this was 16% (95% CI: -5.0 to 36%). CONCLUSIONS: These estimates were similar to those previously published for allo-exposed donors. This suggests allo-exposure status can effectively be used in donor deferral strategies.

[Transfusion-related acute lung injury (TRALI) in the Netherlands in 2002-2005]. / Transfusiegerelateerde acute longbeschadiging (TRALI) in Nederland in 2002-2005.

OBJECTIVE: To determine the number of reported cases of transfusion-related acute lung injury (TRALI) in the Netherlands in 2002-2005 and to determine how many cases were associated with incompatibility between leukocyte-reactive antibodies in the donor plasma and leukocytes or antigens in the recipient. DESIGN: Retrospective national case review. METHOD: Cases of TRALI reported in 2002-2005 were assessed according to the national clinical definition of TRALI, and the relationship between TRALI and transfusion was assessed. Additional clinical details were requested from the treating hospital as necessary. The results of leukocyte serological tests from donors and recipients were linked to clinical cases. For cases with positive leukocyte serological tests, the relevant blood components and the sex of the donor were recorded. RESULTS: Of the 46 cases reported, 6 had insufficient information. 8 cases did not meet the definition or had another more likely diagnosis. There was a trend toward an increase in the number of reports: 12 cases were reported in 2005, corresponding with 1:60,000 blood components. Of the 40 evaluable cases, 32 (80%) met the definition of TRALI and were deemed to be definitely (n = 16), probably (n = 5) or possibly (n = 11) related to transfusion. Severity ranged from moderate to life-threatening, and there was one TRALI-related death. Leukocyte serology was fully investigated in 18 cases: 13 (72%) had leukocyte incompatibility and in 5 cases exclusively fresh frozen plasma from a female donor was implicated.

Duration of meconium passage in preterm and term infants.

BACKGROUND: First passage of stool after birth, meconium, is delayed in preterm infants compared to term infants. The difference in duration of meconium passage until transition to normal stools has however never been assessed in preterm and term infants. HYPOTHESIS: Preterm infants have prolonged duration of passage of meconium (PoM) compared to term infants. METHODS: Between August and November 2006, all infants born in an academic and non-academic hospital with gestational age (GA) 25-42 weeks and without metabolical, congenital diseases or gastrointestinal disorders, were included. Infants were divided into four groups: (A) GA < or =30 weeks; (B) GA between 31 and 34 weeks; (C) GA between 35 and 36 weeks; (D) GA > or = 37 weeks (term born). RESULTS: A total of 198 infants (102 males); 32, 62, 33 and 71 infants in groups A, B, C and D, respectively, were included. With decreasing gestation a trend was found for delayed first PoM (p<0.001). Compared to term infants 79% (56/71), less preterm infants passed their first stool within 24 h after birth--group A: 44% (14/32); group B: 68% (42/62); and group C: 73% (24/33). With decreasing gestation a trend for prolonged PoM was found (p<0.001). The mean (SD) PoM duration was prolonged in group A: 7.8 days (2.5); group B: 4.3 days (2.4); and group C: 2.9 days (1.3) compared to term infants. Furthermore, PoM was associated with birth weights < or =2500 g (p = 0.03) and morphine therapy (p = 0.03). Duration of PoM was not associated with type of feeding, small for gestational age, large for gestational age or need for respiratory support. CONCLUSION: PoM was not only delayed but also prolonged in preterm infants. Duration of PoM was associated with GA, birth weight and morphine therapy.

Experience with alemtuzumab in treatment of chronic lymphocytic leukaemia in the Netherlands.

BACKGROUND: Alemtuzumab (MabCampath) is a monoclonal antibody against CD52, indicated as third-line treatment of chronic lymphocytic leukaemia (CLL). As most important side effect opportunistic infections are mentioned. It is, however, unknown whether these complications often lead to problems in general patient care in the Netherlands. METHODS: To gain insight into the use and complications of alemtuzumab therapy, the alemtuzumab-treated CLL patients in 15 hospitals in the Netherlands were evaluated by means of a questionnaire. RESULTS: In the period from 31 October 2001 until 17 November 2005, 27 patients with CLL or prolymphocytic leukaemia (PLL), RAI stage I to IV, Binet stage A to C, received 32 treatments with alemtuzumab. The time from diagnosis until start of alemtuzumab treatment was 6 +/- 4.5 years (mean +/- SD ). The treatment lasted 11 +/- 7 weeks. Of the treatments, 41% could be administered for the full 12 weeks. The most frequent adverse events were fever (72%), shivering (47%), fatigue (22%) and dyspnoea (16%). Haematological side effects consisted of leucopenia (75%), thrombocytopenia (44%), and anaemia (13%). Infectious complications occurred in 12 of 32 (38%) treatments: pneumonia (25%; of which one Pneumocystis carini pneumonia and four Aspergillus infections), sepsis (9%; of which one Listeria), herpes zoster (9%), herpes simplex (6%), CMV reactivation (6%), meningitis (3%) and Guillain Barre (3%). The overall response was 53%, with complete remission in 13%, partial remission in 41%, stable disease in 25% and progressive disease in 13%, and lasted for 8.3 +/- 7.3 months. CONCLUSION: Treatment with alemtuzumab is often terminated prematurely, leading to a suboptimal treatment effect. Fear of severe uncontrollable opportunistic infections seems unjustified.

T-lymphocyte reconstitution following rigorously T-cell-depleted versus unmodified autologous stem cell transplants.

We compared the kinetics of T-cell recovery after extensive ex vivo and in vivo T-cell depleted autologous stem cell transplantation (SCT) for multiple sclerosis (MS; n=8) with unmodified SCT for hematological malignancies (HM; n=39). Both patient group showed a very protracted recovery of 'naive' CD4(+), 45R0(-) ( approximately CD45RA(+)) T-cells. Within the 'primed' CD4(+), 45R0(+) T-cells, the 'central memory' cells expressing the CD62L and CD27 markers were the slowest to recover. The repopulating T-cells were highly activated, as shown by increased expression of HLA-DR and the apoptosis marker CD95. The capability of CD4(+) and CD8(+) T-cells to produce IFN-gamma, IL-2 and TNF-alpha had reached normal ranges from 2 months post SCT onwards. Unexpectedly, the kinetics of T-cell recovery between 3 and 12 months post transplant was similar in T-depleted and unmodified SCT. Before SCT, the HM patients showed lymphopenia of all T-cell subsets, upregulated HLA-DR and CD95 expression and increased cytokine responses. We suggest that the similar kinetics of T-cell recovery in the two patient groups may be explained by the susceptibility to apoptosis of the activated CD4(+) T-cells in the autografts of the HM patients. This susceptibility to apoptosis would interfere with a swift and sustained CD4(+) T-cell regeneration post SCT.

[Transfusion reactions in patients: haemovigilance reports to the Dutch National Haemovigilance Office in 2003]. / Transfusiereacties bij patiënten: hemovigilantiemeldingen aan het Landelijk Hemovigilantiebureau over 2003.

OBJECTIVE: National registration and analysis of unexpected side effects and incidents associated with blood transfusion (together termed 'transfusion reactions') in 2003 in order to arrive at recommendations to improve safety in the transfusion chain. DESIGN: Observational METHOD: A uniform national reporting form with definitions and a reporting manual were sent to all Dutch hospitals in the spring of 2003 with the request to report transfusion reactions retroactively to January 2003 to the Dutch National Haemovigilance Office 'Transfusion reactions in patients' (TRIP). TRIP is an independent organisation managed by representatives of professional societies that are involved in blood transfusion. Each hospital was given a reporting code. The reports were in principle voluntary and anonymous with regard to both the patient and the attending physician. Transfusion reactions were assessed for severity as well as for the level of probability with which they could be ascribed to the transfusion. RESULTS: Reports were received from 82 (80%) of the hospitals; 9 hospitals informed the TRIP explicitly that there had been no transfusion reactions in 2003. A total of 267 reports were received. Of these, 803 (63%) were graded for severity and of these 803, 52 (6%) were grade 2 ('moderate to severe morbidity') or worse. In the categories involving possible infectious complications, there were 2 reports of bacterial contamination that were judged, on review, to be due 'with certainty' to the transfusion. 34 reports concerned transfusion of the wrong blood product, resulting in a total of 9 transfusion reactions (4 of grade 2). The total number of reports concerning 2003 was 1.6/1000 blood products. CONCLUSION: The participation by the hospitals was high in the first year of national reporting, 2003. Most of the reports were of non-serious reactions known to be possible side effects of blood transfusion; 52 reports were rated as grade 2 or worse.

Feasibility of a restrictive red-cell transfusion policy for patients treated with intensive chemotherapy for acute myeloid leukaemia.

Red-cell transfusions are required for symptomatic treatment of severe anaemia caused by intensive chemotherapy. Concerns about the transfusion-related complications, such as infections (e.g. the very low risk of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) transmission and the risk of postoperative infections), haemolytic transfusion reaction, immunological effects and the costs, prompt a reevaluation of the transfusion practice. Retrospective analysis of prospectively collected data on 84 patients with acute myeloid leukaemia (AML), who were treated with combination chemotherapy between June 1, 1997 and December 7, 2001, was performed. The use of red-cell transfusions with a restrictive transfusion policy (haemoglobin = 7.2-8.8 g dL(-1), dependent on age and symptoms, n = 38) was compared with a more liberal transfusion trigger (haemoglobin = 9.6 g dL(-1), n = 46). The number of units transfused was recorded. Signs and symptoms of anaemia, chemotherapy-related effects and complications were investigated for both transfusion policies. The more restrictive transfusion policy led to a significant decrease of 11% of red blood cell (RBC) transfusions in patients with AML. No significant differences were found in the incidence of infections, number of platelet units transfused, bleeding complications, cardiac symptoms or response to chemotherapy. The more restrictive transfusion policy was feasible in this clinical setting, and it might be concluded that a restrictive transfusion policy is safe in supporting clinical patients treated with intensive chemotherapy for AML.

Quality of life measurement in patients with transfusion-dependent myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are clonal disorders characterized by dysplasia in at least two myeloid cell lines. Fatigue is one of the most significant symptoms. MDS patients are treated with blood transfusions to improve their health-related quality of life (HRQoL). A cross-sectional pilot study was performed for psychometric evaluation of three internationally established HRQoL measures in MDS patients, and for investigation of the association between the severity of chronic anaemia and HRQoL. Fifty consecutive MDS patients completed the Short Form 36, the Multidimensional Fatigue Inventory and the EuroQoL-5D Visual Analogue Scale. Hb level was measured during the same visit. Psychometric analysis focused on feasibility, construct validity and reliability. The questionnaires showed a high feasibility, reliability and validity. MDS patients had worse HRQoL scores than the age- and sex-matched general population. We found a positive correlation between haemoglobin (Hb) level and HRQoL. This study provides insights into the suitability of established HRQoL measures for the evaluation of interventions in MDS patients. Hb value and HRQoL are complementary variables for evaluation of the severity of chronic anaemia in patients with MDS.

Stroma-supported progenitor production as a prognostic tool for graft failure following autologous stem cell transplantation.

To analyse the involvement of a possible numerical or qualitative stem cell defect in the development of sustained graft failure after autologous transplantation, we have determined the graft content of CD34+ nucleated cells, colony-forming cells and cobblestone area-forming cell subsets, as well as transplant ability to produce progenitors using the long-term culture colony-forming cell (LTC-CFC) assay. We evaluated material from the graft reference ampoules of 13 graft failure patients after bone marrow transplantation (BMT), four graft failure patients and four isolated thrombocytopenia patients after peripheral blood stem cell transplantation (PBSCT). We compared these data with those from six successfully engrafted BMT patients and 20 engrafted PBSCT patients respectively. In the BMT setting, the LTC-CFC 6-week assay represented a highly significant graft failure predictor. In the PBSCT setting, the total number of 2-week and 6-week LTC-CFCs transplanted per kg bodyweight (BW) showed the highest significant difference between the engrafted and the graft failure patients, as well as between the engrafted patients and the patients suffering from isolated thrombocytopenia after transplantation. These data show that the ability of a graft to generate progenitors in vitro rather than the number of primitive progenitors transplanted can have prognostic value for post-transplant haematological reconstitution.