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.

The effect of intravenous iron therapy on long-term survival in anaemic colorectal cancer patients: Results from a matched cohort study.

INTRODUCTION: Intravenous iron therapy has been shown to be advantageous in treating anaemia and reducing the need for blood transfusions. Iron treatment, however, may also be hazardous by supporting cancer growth. Present clinical study explores, for the first time, the effect of preoperative intravenous iron therapy on tumour prognosis in anaemic colorectal cancer patients. METHODS: A retrospective cohort study was performed on consecutive patients who underwent surgery for colorectal cancer between 2010 and 2016 in a single teaching hospital. The primary outcomes were 5-year overall survival (OS) and disease-free survival (DFS). Survival estimates were calculated using the Kaplan-Meier method and patients were matched based on propensity score. RESULTS: 320 (41.0%) of all eligible patients were anaemic, of whom 102 patients received preoperative intravenous iron treatment (31.9%). After propensity score matching 83 patients were included in both intravenous and non-intravenous iron group. The estimated 1-, 3-, and 5-year OS (91.6%, 73.1%, 64.3%, respectively) and DFS (94.5%, 86.7%, 83.4%, respectively) in the intravenous iron group were comparable with the non-intravenous iron group (p = 0.456 and p = 0.240, respectively). In comparing patients with an event (death or recurrence) and no event in the intravenous iron group, a distinct trend was found for decreased transferrin in the event group (median 2.53  g/L vs 2.83  g/L, p = 0.052). CONCLUSION: The present study illustrates that a dose of 1000-2000 mg preoperative intravenous iron therapy does not have a profound effect on long-term overall and disease-free survival in anaemic colorectal cancer patients. Future randomised trials with sufficient power are required to draw definite conclusions on the safety of intravenous iron therapy.

Iron therapy as treatment of anemia: A potentially detrimental and hazardous strategy in colorectal cancer patients.

In colorectal cancer patients, iron therapy, and especially intravenous iron therapy, is increasingly used to treat anemia and reduce the use of blood transfusions. However, iron has also been shown to be an essential nutrient for rapidly proliferating tissues and cells. In this respect, anemia of inflammation, characterized by limited duodenal iron uptake and sequestration of iron into the reticuloendothelial system, might be regarded as a potentially effective defense strategy of the human body against tumor growth. We therefore hypothesize that iron therapy, by supporting colorectal tumor growth and increasing the metastatic potential, may worsen tumor prognosis in colorectal cancer patients. This hypothesis is particularly supported for colorectal cancer by laboratory, epidemiological and animal studies, demonstrating the role of iron in all aspects of tumor development growth. Compared to non-malignant colon cells, tumor cells differ in the levels and activity of many iron import and export proteins, resulting in an increase in intracellular iron level and enhanced proliferation. In addition, it is demonstrated that iron is able to amplify Wnt signaling in tumors with Apc mutation, a critical mutation in the development of colorectal cancer. If our hypothesis is to be confirmed, current practice of iron administration, as treatment for anemia and as replacement of blood transfusions, can be hazardous and should be completely reconsidered.

The role of preoperative iron deficiency in colorectal cancer patients: prevalence and treatment.

BACKGROUND: In preoperative blood management of colorectal cancer patients, intravenous iron therapy is increasingly used to treat anaemia and prevent red blood cell transfusions. However, while iron deficiency is the most common cause of anaemia, little is known about the prevalence and namely type of iron deficiency in this population, whereas both types of iron deficiency (i.e. absolute and functional iron deficiency) are recommended to be treated differently by international cancer guidelines. OBJECTIVE: The aim of present study is to investigate the prevalence and namely type of iron deficiency in colorectal cancer patients, and to assess its clinical relevance. METHODS: Preoperative iron status, clinical parameters (i.e. age, ASA classification, tumour location, tumour stage) and postoperative complications were retrospectively collected for all newly diagnosed colorectal cancer patients in our institution over a 3-year period. RESULTS: Iron deficiency was observed in 163 (48.1%) of 339 patients. Of these iron-deficient patients, 3.7% had an isolated absolute iron deficiency (AID) and 15.3% a functional iron deficiency (FID), while the rest had a combination of AID and FID. Anaemia was present in 66.1% of iron-deficient patients. Iron deficiency was significantly associated with an increased postoperative complication rate (univariable OR 1.94, p = 0.03, multivariable OR 1.84, p = 0.07), with right-sided tumours (p < 0.001), high ASA classification (p = 0.002), advanced tumour stage (p = 0.01) and advanced age (p = 0.04). In comparing clinical parameters between patients with AID and FID, advanced age was significantly associated with FID (p = 0.03), and the presence of anaemia with AID (p = 0.02). CONCLUSION: In preoperative colorectal cancer patients, there is a high prevalence of iron deficiency, including a high percentage of patients with-a component of-functional iron deficiency, associated with the increased postoperative complication rate. As both types of iron deficiency require a different treatment strategy, our results illustrate the therapeutic potential of especially intravenous iron supplementation in patients with severe iron deficiency and stress the urgency of routinely monitoring preoperative iron status and differentiation between types of iron deficiency. As iron therapy may also be potentially harmful in respect to stimulation of tumour growth, future clinical trials assessing the long-term effect of iron therapy are necessary.

Long-term prognostic value of preoperative anemia in patients with colorectal cancer: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the long-term prognostic factor of preoperative anemia in colorectal cancer patients. BACKGROUND: Anemia is frequently observed in colorectal cancer patients, with a case incidence of 30 to 67 percent. Besides an indicator of tumor-induced blood loss and inflammation, anemia in cancer is also suggested to be a cause of inferior outcome, possibly via worsening of tumor hypoxia. As surgery is likely to enhance anemia, the long-term prognostic value of preoperative anemia seems most interesting. METHODS: Comprehensive searches were carried out in all relevant databases, including MEDLINE, Embase and Web-of-Science. To include studies addressing overall survival, follow-up had to be at least 24 months or till death. For pooling of survival results, a mixed-linear (fixed-effects) model was fit to the reported hazard ratios (HRs) to calculate a pooled estimate and confidence interval. RESULTS: We included 12 studies comprising 3588 patients to estimate the association between preoperative anemia and overall survival (OS) and disease-free survival (DFS). In a fixed-effects meta-analysis of eight studies, including both colon and rectal cancer, preoperative anemia was significantly associated with poor OS (HR 1.56; 95% CI 1.30 to 1.88; p < 0.001). A meta-analysis of seven studies also showed that preoperative anemia was significantly associated with poor DFS (HR 1.34; 95% CI 1.11 to 1.61; p = 0.002). Restricted to studies exclusively on colon cancer or rectal cancer, HRs for OS were 1.25 (95% CI 1.00 to 1.55; p = 0.05) and 2.59 (95% CI 1.68 to 4.01; p < 0.001), respectively, while HRs for DFS were 1.21 (95% CI 0.96 to 1.52; p = 0.11) and 1.61 (95% CI 1.18 to 2.21; p = 0.003). CONCLUSION: The present meta-analysis reveals that preoperative anemia is significantly associated with decreased long-term OS and DFS in rectal cancer, but not in colon cancer patients, although this meta-analysis is mainly based on retrospective studies with high heterogeneity. These results justify raised awareness about the impact of preoperative anemia on long-term survival.

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.

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.

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.

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.

New therapeutic options for immune thrombocytopenia.

Understanding of the mechanisms and aetiology of immune thrombocytopenia (ITP) has progressed significantly in recent years. It is now recognised to be an autoimmune condition, involving not only platelet destruction, but also deficits in platelet production. This has led to widespread research exploring potential mechanisms for therapy, the result of which has been the development of romiplostim and eltrombopag. These new treatments target the thrombopoietin receptor (TPO-R), promoting formation of megakaryocytes and survival of platelets. Furthermore, the advances in the understanding of ITP have led to the production of guidelines to assist healthcare professionals in the diagnosis and treatment of ITP. This review examines the recommendations made in these guidelines, particularly the American Society of Haematology (ASH) 2011 evidence-based practice guidelines. In addition, searches were carried out to retrieve information on clinical trials of new molecules and off-label treatments for ITP. Corticosteroids, anti-Rho(D) immunoglobulins (anti-D), intravenous immunoglobulins (IVIg) and splenectomy are well-established treatments and continue to be recommended in the guidelines. The recently available romiplostim and eltrombopag, which are specific for treatment of IT P, are also included in the recommendations. The only off-label therapy to be recommended in the guidelines is the chimeric monoclonal antibody rituximab. However, investigations are ongoing into products approved for other indications, which may be beneficial to patients suffering from refractory ITP.

Triggers and appropriateness of red blood cell transfusions in the postpartum patient--a retrospective audit.

BACKGROUND AND OBJECTIVE: Despite published guidelines, a proportion of red blood cell (RBC) transfusions seem unnecessary. To evaluate the indications for and the appropriateness of RBC transfusions in the postpartum patient, we performed a retrospective audit over a 1-year period in two Dutch hospitals. STUDY DESIGN AND METHODS: Observational study of transfused obstetric patients, admitted in 2006 to the Departments of Obstetrics of a university and a general hospital, was carried out. Relevant clinical and laboratory data were recorded. The appropriateness of RBC transfusions was assessed using the national and age-based transfusion guidelines for the general population; for the studied group the transfusion threshold haemoglobin (Hb) value was 6.4 g/dl for non-massive and 8.1 g/dl for massive blood loss. From these we derived target Hb levels. RESULTS: Ninety patients received one or more RBC units within 48 h of delivery. Mean pretransfusion Hb level was 6.9 [SD 1.2] g/dl. Median number of transfusions was 2. Mean Hb level at discharge was 9.7 [SD 1.1] g/dl. Taking threshold Hb and the derived target Hb level into account, 68% (n = 61) of the patients may have received one or more RBC units inappropriately. Of 311 RBC units transfused, 143 units (46%) were possibly inappropriate, partly due to over-transfusion. CONCLUSION: A significant proportion of postpartum RBC transfusions are possibly inappropriate, partly due to over-transfusion. If current guidelines would be more specific, in particular, with respect to the target Hb levels, the total amount of RBC transfusions may be considerably decreased.

[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.