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... Show moreBackground: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. Show less
Amini, S.N.; Nelson, V.S.; Porcelijn, L.; Netelenbos, T.; Zwaginga, J.J.; Haas, M. de; ... ; Kapur, R. 2022
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with an incompletely understood pathophysiology, but includes platelet-clearance in the spleen and liver via T-cells and/or platelet... Show moreImmune thrombocytopenia (ITP) is an autoimmune bleeding disorder with an incompletely understood pathophysiology, but includes platelet-clearance in the spleen and liver via T-cells and/or platelet-autoantibodies. Strikingly, thrombopoietin (TPO) levels remain low in ITP. Platelet-glycoprotein (GP)Ibα has been described to be required for hepatic TPO generation, however, the role of GPIb-antibodies in relation to platelet hepatic sequestration and TPO-levels, with consideration of platelet counts, remains to be elucidated. Therefore, we performed a study in which we included 53 chronic and non-splenectomized ITP patients for which we conducted indium labeled autologous platelet scintigraphy, measured platelet-antibody profiles and TPO-levels. Upon stratification towards the severity of thrombocytopenia, no negative association was observed between GPIb/IX-antibodies and TPO levels, suggesting that GPIb/IX-antibodies do not inhibit or block TPO levels. Surprisingly, we observed a positive association between GPIb/IX-antibody levels and TPO levels, and GPIb/IX-antibodies and platelet hepatic sequestration, in patients with severe thrombocytopenia, but not in patients with mild or moderate thrombocytopenia. In addition, platelet hepatic sequestration and TPO levels were positively associated. This collectively indicates that GPIb/IX-antibodies may be associated with an increased platelet hepatic sequestration and elevated TPO levels in severe thrombocytopenic ITP patients, however, further research is warranted to elucidate the pathophysiological mechanisms. Show less
Amini, S.N.; Porcelijn, L.; Sobels, A.; Kartachova, M.; Haas, M. de; Zwaginga, J.J.; Schipperus, M.R. 2022
Antiglycoprotein (anti-GP) antibodies play an important role in the pathophysiology of immune thrombocytopenia (ITP). The sequestration pattern of platelets in the spleen and liver can be studied... Show moreAntiglycoprotein (anti-GP) antibodies play an important role in the pathophysiology of immune thrombocytopenia (ITP). The sequestration pattern of platelets in the spleen and liver can be studied with In-111-labeled autologous platelet scans. No studies have investigated the role of anti-GP antibodies in sequestration patterns in ITP patients. In this study, we examined the association between antibodies and (1) platelet sequestration site and (2) clearance rate of platelets. All ITP patients receiving an In-111-labeled autologous platelet study between 2014 and 2018 were included. Antibodies were measured using the direct MAIPA method to determine the presence and titer of anti-GPIIb/IIIa, anti-GPIb/IX, and anti-GPV antibodies. Multivariate regression models were used to study the association between anti-GP antibodies, sequestration site, and clearance rate. Seventy-four patients were included, with a mean age of 36 years. Forty-seven percent of the patients showed a predominantly splenic sequestration pattern, 29% mixed, and 25% a hepatic pattern. In 53% of the patients, anti-GP antibodies were detected. Regression models showed a significant association between splenic sequestration and GPV autoantibodies. Furthermore, in patients where antibodies were present, the clearance rate was higher in patients with a splenic sequestration. Anti-GPV antibodies are associated with a splenic sequestration pattern in ITP patients. These associations provide insight into the possible pathophysiological mechanisms of ITP, which may lead to better detection and treatment of this partly idiopathic and prevalent disease. Show less
Background and Objectives: Limited data are available to guide physicians on how to determine the red blood cell (RBC) transfusion regimen in chronically transfusion-dependent patients. The lack of... Show moreBackground and Objectives: Limited data are available to guide physicians on how to determine the red blood cell (RBC) transfusion regimen in chronically transfusion-dependent patients. The lack of clarity on thresholds and targets to be used for transfusion could easily result in either under or over transfusion in these patients. The aim of our survey is to investigate (1) transfusion thresholds; (2) number of RBC units given per transfusion episode; (3) interval between transfusions and (4) patient factors, like decreased cardiac function modulating the former. Materials and Methods: We sent a web-based 44-question survey to members of the Dutch Haematology Association. Results: Fifty physicians responded between June and October 2020 (response rate 30%), well-distributed between community and academic hospitals. A wide variation in transfusion strategies was reported: Most patients have transfused 1-2 RBC units (range: 0-3 units) every 2-4 weeks (range: 1-12 weeks) with a median threshold of 8.0 g/dl ranging from 6.4 to 9.6 g/dl. Patient-specific clinical factors that are most frequently reported to influence the transfusion strategy are angina pectoris, cardiac failure and dyspnoea, softer parameters that are of influence are the quality of life and self-sustainability. Conclusion: The results of this survey indicate a broad variation in RBC transfusion strategies in Dutch patients with chronic transfusion dependency. While the current variation in transfusion strategies may be unavoidable in an individualized approach, randomized trials and better defined usable parameters to evaluate the effect of transfusion strategies are required to reach a consensus on how to determine the transfusion strategy. Show less
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at least involve autoantibody... Show moreImmune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at least involve autoantibody-dependent and/or cytotoxic T cell mediated platelet clearance and impaired megakaryopoiesis. In addition, T cell imbalances involving T regulatory cells (Tregs) also appear to play an important role. Intriguingly, over the past years it has become evident that platelets not only mediate hemostasis, but are able to modulate inflammatory and immunological processes upon activation. Platelets, therefore, might play an immuno-modulatory role in the pathogenesis and pathophysiology of ITP. In this respect, we propose several possible pathways in which platelets themselves may participate in the immune response in ITP. First, we will elaborate on how platelets might directly promote inflammation or stimulate immune responses in ITP. Second, we will discuss two ways in which platelet microparticles (PMPs) might contribute to the disrupted immune balance and impaired thrombopoiesis by megakaryocytes in ITP. Importantly, from these insights, new starting points for further research and for the design of potential future therapies for ITP can be envisioned. Show less
Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare, commonly fatal complication of transfusion preventable by irradiation of blood units. The revision of the Dutch transfusion... Show moreTransfusion-associated graft-versus-host disease (TA-GVHD) is a rare, commonly fatal complication of transfusion preventable by irradiation of blood units. The revision of the Dutch transfusion guideline addressed the question whether irradiation is still necessary if blood components are prestorage leukodepleted. We searched for published cases of TA-GVHD following transfusion of prestorage leukodepleted blood and through contacting haemovigilance systems. Six presumed cases were found, dating from 1998 to 2013. Four out of six patients had received one or more non-irradiated units despite recognised indications for irradiated blood components. In the countries providing information, over 50 million prestorage leukodepleted, non-irradiated, non-pathogen-reduced cellular components were transfused in a 10-year period. Potential benefits of lifting indications for irradiation were considered. These include reduced irradiation costs (euro 1.5 million annually in the Netherlands) and less donor exposure for neonates. Findings were presented in an invitational expert meeting. Recommendations linked to human leukocyte antigen similarity between donor and recipient or intra-uterine transfusion were left unchanged. Indications linked to long-lasting deep T-cell suppression were defined with durations of 6 or 12 months after end of treatment (e.g. autologous or allogeneic stem cell transplantation). Need for continued alertness to TA-GVHD and haemovigilance reporting of erroneous non-irradiated transfusions was emphasised. Show less
Tonino, R.P.B.; Wilson, M.; Zwaginga, J.J.; Schipperus, M.R. 2021
Background and Objectives While iron deficiency (ID) is the most common cause of anaemia, little is known about the prevalence and type of ID in preoperative surgical patients. The aims of the... Show moreBackground and Objectives While iron deficiency (ID) is the most common cause of anaemia, little is known about the prevalence and type of ID in preoperative surgical patients. The aims of the present study were to investigate the prevalence and types of ID in a large cohort of surgical patients, and how these are related to perioperative blood use after correction for confounders such as haemoglobin level. Materials and Methods Data were retrospectively extracted from electronic case records of all patients who underwent elective surgery between September 2016 and November 2017 (n = 2711). Iron parameters, haemoglobin and details of perioperative red cell transfusions were collected. Results Of 2711 patients, 618 (22.8%) were iron deficient (= transferrin saturation [TSAT] < 16%) preoperatively, 173 (6.4% of the cohort) had an absolute iron deficiency (AID; TSAT < 16% and ferritin < 30 mu g/L) and 445 (16.4%) had functional/mixed ID (TSAT < 16% and ferritin >= 30 mu g/L). Corrected for Hb level, iron-deficient patients received significantly more red cell units than patients without ID (p = 0.026). AID was not associated with a significantly higher incidence of transfusions (7.5% of patients transfused; p = 0.12 after correction for Hb) than patients without ID, whereas patients with functional/mixed deficiency did receive significantly more transfusions (6.1%; p = 0.021) as compared to patients without ID (1.7%). Conclusion Preoperative ID, in particular the functional/mixed type, was associated with a higher risk of receiving perioperative red cell transfusions as compared to patients without ID. Adequately treating ID might, therefore, reduce the need for perioperative red cell transfusions. Show less
Jolink, A.T.C.; Nelson, V.S.; Schipperus, M.R.; Amini, S.N.; Vidarsson, G.; Schoot, C.E. van der; ... ; Kapur, R. 2021
Autologous platelet sequestration pattern is associated with post-splenectomy platelet response in patients with immune thrombocytopenia (ITP). However, published results are contradictory, and... Show moreAutologous 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. Show less
Plasma transfusion is indicated for replenishment of coagulative pro- teins to stop or prevent bleeding. In 2014, the Netherlands switched from using similar to 300mL fresh frozen plasma (FFP)... Show morePlasma transfusion is indicated for replenishment of coagulative pro- teins to stop or prevent bleeding. In 2014, the Netherlands switched from using similar to 300mL fresh frozen plasma (FFP) units to using 200mL Omniplasma, a solvent/detergent treated pooled plasma (SD plasma), units. We evaluated the effect of the introduction of SD plasma on clinical plasma use, associated bleeding, and transfusion reaction incidences. Using diagnostic data from six Dutch hospitals, national blood bank data, and national hemovigilance data for 2011 to 2017, we compared the plasma/red blood cell (RBC) units ratio (f) and the mean number of plasma and RBC units transfused for FFP (similar to 300mL) and SD plasma (200mL) for various patient groups, and calculated odds ratios comparing their associated transfusion reaction risks. Analyzing 13,910 transfusion episodes, the difference (Delta f = f(SD) (-) f(FFP)) in mean plasma/RBC ratio (f) was negligible (Delta f(entire-cohort) = 0.01 [95% confidence interval (CI): -0.02 - 0.05]; P=0.48). SD plasma was associated with fewer RBC units transfused per episode in gynecological (difference of mean number of units -1.66 [95% CI: -2.72, -0.61]) and aneurysm (-0.97 [-1.59, -0.35]) patients. SD plasma was further associated with fewer anaphylactic reactions than FFP (odds ratio 0.37 [0.18, 0.77; P<0.01]) while the differences for most transfusion reactions were not statistically significant. SD plasma units, despite being one third smaller in volume than FFP units, are not associated with a higher plasma/RBC ratio. SD plasma is associated with fewer anaphylactic reactions than FFP plasma/RBC units ratio. Show less
Hout, F.M.A. van; Middelburg, R.A.; Meer, P.F. van der; Pors, A.; Wiersum-Osselton, J.C.; Schipperus, M.R.; ... ; Bom, J.G. van der 2019
BACKGROUND Reports on the clinical consequences of longer storage time of platelet concentrates are contradictory. The objective of this study was to assess whether longer storage times are... Show moreBACKGROUND Reports on the clinical consequences of longer storage time of platelet concentrates are contradictory. The objective of this study was to assess whether longer storage times are associated with a higher risk of transfusion reactions. STUDY DESIGN AND METHODS We gathered storage times of pooled platelet concentrates related to transfusion reactions reported to the national hemovigilance office from 2004 to 2015. These were combined with storage times of platelet concentrates in the reference population to compare incidences of transfusion-associated circulatory overload, transfusion-related acute lung injury, allergic reactions, febrile nonhemolytic reactions, and "other" reactions between storage time categories. RESULTS A total of 567,053 platelet concentrates and 1870 transfusion reactions were analyzed. Among platelet additive solution (PAS)-B platelet recipients, the odds ratio of a storage time of 4 to 5 days compared to 1 to 3 days was 1.60 (95% confidence interval [CI], 1.17-2.18) for allergic, and 1.47 (1.09-1.98) for febrile reactions. For PAS-C platelet recipients, the odds ratio for allergic reactions was 3.78 (95% CI, 1.31-10.9) for 4 to 5 days, and 4.57 (95% CI, 1.57-13.4) for 6- to 7-day-old platelets when compared to 1- to 3-day-old units. In all other studied reaction types, no statistically significant association was observed in platelets in plasma, PAS-B, and PAS-C. CONCLUSIONS In plasma platelets, longer storage time was not associated with a higher incidence of transfusion reactions. In PAS platelets, longer storage time was associated with higher transfusion reaction incidences, in particular for allergic reactions with both PAS fluids and febrile reactions with PAS-B. This indicates that the effect of storage time is different for different reaction types and depends on the storage fluid. Show less
Hout, F.M.A. van; Meer, P.F. van der; Wiersum-Osselton, J.C.; Middelburg, R.A.; Schipperus, M.R.; Bom, J.G. van der; Kerkhoffs, J.L. 2018
