Patients with severe infection have an increased risk of cardiovascular events. A possible underlying mechanism is inflammation-induced platelet aggregation. We investigated whether... Show morePatients with severe infection have an increased risk of cardiovascular events. A possible underlying mechanism is inflammation-induced platelet aggregation. We investigated whether hyperaggregation occurs during infection, and whether aspirin inhibits this. In this multicentre, open-label, randomised controlled trial, patients hospitalised due to acute infection were randomised to receive 10 days of aspirin treatment (80 mg 1dd or 40 mg 2dd) or no intervention (1:1:1 allocation). Measurements were performed during infection (T1; days 1-3), after intervention (T2; day 14) and without infection (T3; day > 90). The primary endpoint was platelet aggregation measured by the Platelet Function Analyzer (R) closure time (CT), and the secondary outcomes were serum and plasma thromboxane B2 (sTxB2 and pTxB2). Fifty-four patients (28 females) were included between January 2018 and December 2020. CT was 18% (95%CI 6;32) higher at T3 compared with T1 in the control group (n = 16), whereas sTxB2 and pTxB2 did not differ. Aspirin prolonged CT with 100% (95%CI 77; 127) from T1 to T2 in the intervention group (n = 38), while it increased with only 12% (95%CI 1;25) in controls. sTxB2 decreased with 95% (95%CI - 97; - 92) from T1 to T2, while it increased in the control group. pTxB2 was not affected compared with controls. Platelet aggregation is increased during severe infection, and this can be inhibited by aspirin. Optimisation of the treatment regimen may further diminish the persisting pTxB2 levels that point towards remaining platelet activity. This trial was registered on 13 April 2017 at EudraCT (2016-004303-32). Show less
Rhun, E. le; Oppong, F.B.; Bent, M. van den; Wick, W.; Brandes, A.A.; Taphoorn, M.J.B.; ... ; Weller, M. 2022
BackgroundThrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of... Show moreBackgroundThrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine in recurrent glioblastoma.MethodsWe performed a retrospective analysis of the associations of thrombocytopenia with treatment delivery and outcome in EORTC 26101, a randomised trial designed to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma.ResultsA total of 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients (57%) of group 1 and 187 patients (66%) of group 2 experiencing at least one episode of thrombocytopenia, 36 patients (16%) in group 1 and 93 (33%) in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. On adjusted analysis accounting for major prognostic factors, dose modification induced by thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumours in groups 1 and 2. This effect was noted for overall survival, too, but only for group 2 patients. Conclusion: Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine chemotherapy in recurrent glioblastoma. Mitigating thrombocytopenia to enhance lomustine exposure might improve outcome in patients with MGMT promoter-methylated tumours. Show less
Rijnhout, T.W.H.; Noorman, F.; Horst, R.A. van der; Tan, E.C.T.H.; Viersen, V.V.A.; Waes, O.J.F. van; ... ; Hoencamp, R. 2022
Background The Netherlands Armed Forces have been successfully using deep-frozen (- 80 degrees C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere... Show moreBackground The Netherlands Armed Forces have been successfully using deep-frozen (- 80 degrees C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere environments since 2001. However, high-quality evidence for the effectiveness and safety of DTCs is currently lacking. Therefore, the MAssive transfusion of Frozen bloOD (MAFOD) trial is designed to compare the haemostatic effect of DTCs versus room temperature-stored platelets (RSP) in the treatment of surgical bleeding. Methods The MAFOD trial is a single-blinded, randomized controlled non-inferiority trial and will be conducted in three level 1 trauma centres in The Netherlands. Patients 12 years or older, alive at hospital presentation, requiring a massive transfusion including platelets and with signed (deferred) consent will be included. The primary outcome is the percentage of patients that have achieved haemostasis within 6 h and show signs of life. Haemostasis is defined as the time in minutes from arrival to the time of the last blood component transfusion (plasma/platelets or red blood cells), followed by a 2-h transfusion-free period. This is the first randomized controlled study investigating DTCs in trauma and vascular surgical bleeding. Discussion The hypothesis is that the percentage of patients that will achieve haemostasis in the DTC group is at least equal to the RSP group (85%). With a power of 80%, a significance level of 5% and a non-inferiority limit of 15%, a total of 71 patients in each arm are required, thus resulting in a total of 158 patients, including a 10% refusal rate. The data collected during the study could help improve the use of platelets during resuscitation management. If proven non-inferior in civilian settings, frozen platelets may be used in the future to optimize logistics and improve platelet availability in rural or remote areas for the treatment of (massive) bleeding trauma patients in civilian settings. Show less
Porcelijn, L.; Schmidt, D.E.; Oldert, G.; Hofstede-van Egmond, S.; Kapur, R.; Zwaginga, J.J.; Haas, M. de 2020
To this day, immune thrombocytopenia (HT) remains a clinical diagnosis made by exclusion of other causes for thrombocytopenia. Reliable detection of platelet autoantibodies would support the... Show moreTo this day, immune thrombocytopenia (HT) remains a clinical diagnosis made by exclusion of other causes for thrombocytopenia. Reliable detection of platelet autoantibodies would support the clinical diagnosis, but the lack of specificity and sensitivity of the available methods for platelet autoantibody testing limits their value in the diagnostic workup of thrombocytopenia. The introduction of methods for glycoprotein-specific autoantibody detection has improved the specificity of testing and is acceptable for ruling in ITP but not ruling it out as a diagnosis. The sensitivity of these assays varies widely, even between studies using comparable assays. A review of the relevant literature combined with our own laboratory's experience of testing large number of serum and platelet samples makes it clear that this variation can be explained by variations in the characteristics of the tests, including in the glycoprotein-specific monoclonal antibodies, the glycoproteins that are tested, the platelet numbers used in the assay and the cutoff levels for positive and negative results, as well as differences in the tested patient populations. In our opinion, further standardization and optimization of the direct autoantibody detection methods to increase sensitivity without compromising specificity seem possible but will still likely be insufficient to distinguish the often very weak specific autoantibody signals from background signals. Further developments of autoantibody detection methods will therefore be necessary to increase sensitivity to a level acceptable to provide laboratory confirmation of a diagnosis of ITP. (C) 2020 The Author(s). Published by Elsevier Inc. Show less
Membrane-exposed sulfatides are proposed to contribute to P-selectin-dependent platelet aggregation. Here, we demonstrated that P-selectin-mediated platelet aggregation on a collagen-coated surface... Show moreMembrane-exposed sulfatides are proposed to contribute to P-selectin-dependent platelet aggregation. Here, we demonstrated that P-selectin-mediated platelet aggregation on a collagen-coated surface under flow indeed depended on sulfatides and that this interaction differed considerably from the interaction of P-selectin with P-selectin Glycoprotein Ligand-1 (PSGL-1), which underlies leukocyte-endothelium adhesion.\n= 7-12 μM).\nOur data suggest that the sulfatide/P-selectin interaction implicates multiple binding pockets, which only partly overlap with that of PSGL-1. These observations open ways to selectively interfere with sulfatide/P-selectin-dependent platelet aggregation without affecting PSGL-1-dependent cell adhesion. Show less
Fustolo-Gunnink, S.F.; Huisman, E.J.; Bom, J.G. van der; Hout, F.M.A. van; Makineli, S.; Lopriore, E.; Fijnvandraat, K. 2019
The majority of platelet transfusions are given to patients with a hematological malignancy to prevent or treat bleeding complications. The adhered transfusion trigger for patients with an... Show moreThe majority of platelet transfusions are given to patients with a hematological malignancy to prevent or treat bleeding complications. The adhered transfusion trigger for patients with an increased risk of bleeding varies among hematologists. Although almost 20.000 donors are HLA typed in the Netherlands, adequate transfusion support cannot be guaranteed for all immunized patients, especially not for patients from a non-Caucasian background. From a clinical perspective, major hemorrhage is the most relevant outcome to measure effectiveness of platelet transfusions. We developed a model consisting of drop in hemoglobin, transfusion support, and CT-brain to enable the identification of major hemorrhage among leukemic patients in routinely recorded data. In the Netherlands, the standard platelet concentrate is derived from buffy coats and resuspended in plasma or platelet additive solution (PAS) and can be stored for seven days. Storage has a negative effect on safety and efficacy of platelet transfusions. Using routinely collected health care data, we demonstrated a lower risk of a positive blood culture after transfusion of platelet concentrates stored for five to seven days. Using the database of TRIP, we showed an increased risk of transfusion transmitted bacterial infections for platelet concentrates stored in PAS compared to those stored in plasma. Show less
C. Caram-Deelder’s thesis explores the potential of secondary data – data that was generated for a different purpose than the research itself - to answer questions regarding safety and efficacy of... Show moreC. Caram-Deelder’s thesis explores the potential of secondary data – data that was generated for a different purpose than the research itself - to answer questions regarding safety and efficacy of blood products. By combining datasets of several hospitals, she demonstrated that receiving red cell transfusions from a female donor who has been pregnant is associated with increased mortality among male patients under the age of 50. Also using data from hospitals she demonstrated that old platelets shorter the time between platelets transfusions, resulting in an increased total number of transfusions on a population level. This increase is, however, unlikely to outweigh the benefit of reduced outdating and wastage. By meta-analysing studies it is shown that old platelets are inferior to fresh platelets for platelet related counts, time between transfusions and the need of additional platelet transfusions. Additionally the thesis discusses the methodological issue of the use of the terms ‘prospective’ and ‘retrospective’ in clinical observational research. These terms are still broadly used in spite of the recommendation to refrain from using them by guidelines and journals’ editorial boards. The usage of the terms was, however, not associated with the quality of the report. Show less
Atherothrombosis is a complication of atherosclerosis that causes acute cardiovascular events such as myocardial infarction and stroke. Circulating lipid levels are highly correlated with... Show moreAtherothrombosis is a complication of atherosclerosis that causes acute cardiovascular events such as myocardial infarction and stroke. Circulating lipid levels are highly correlated with atherosclerotic plaque development. In addition, experimental evidence suggests that lipids also directly influence thrombosis and influence the risk and the outcome of acute cardiovascular events. Plasma lipoproteins influence three aspects important to atherothrombosis: endothelial function, platelet aggregation (primary coagulation) and secondary coagulation. Overall, VLDL, LDL and oxLDL promote thrombus formation, whereas HDL shows antithrombotic actions. In this review we will address the current knowledge about modulation of atherothrombosis by lipoproteins, summarizing findings from in vitro and in vivo animal studies, as well as from observational and interventional studies in humans. We will conclude with future perspectives for lipid modulation in the prevention of atherothrombosis. Show less
This thesis details our studies assessing the role of the endothelial-enriched miRNA-126 in the regulation of vascular homeostasis. In Chapter 2 the current insight in the role of miRNA-126 in... Show moreThis thesis details our studies assessing the role of the endothelial-enriched miRNA-126 in the regulation of vascular homeostasis. In Chapter 2 the current insight in the role of miRNA-126 in vascular homeostasis is reviewed. Chapter 3 focuses on the role of miRNA-126 in ischemia induced angiogenesis, followed by Chapter 4 which describes the potential role of miRNA-126 the mobilization of vasculogenic progenitor cells upon ischemia. Both chapters utilize antagomir-technology to specifically silence miRNA-126 in vivo. This approach to silence miRNA-126 was also used in Chapter 5 to elucidate the regulatory role of miRNA-126 in vascular cell adhesion molecule-1 expression in the kidney vasculature. Chapter 6 details our findings that circulating miRNA-126 in the periphery is not exclusively derived from endothelial cells but can also originate from platelets. Consequently, the use of aspirin has to be taken into account when relating circulating miRNA-126 levels to the progression of cardiovascular disease. Chapter 7 demonstrates that the angiogenic potential of miRNA-126 as described in Chapter 3 might reach beyond the presence of this pro-angiogenic miRNA in endothelium, but that neovascularization can also be supported by miRNA-126 expressed in circulating cells. Finally, Chapter 8 provides a summary of research presented in this thesis, presents the major conclusions that could be drawn and further discusses the role of miRNA-126 in vascular homeostasis. Show less
According to current guidelines, patients with thrombocytopenia due to myelosuppression are supported with platelet concentrates in order to prevent and treat bleeding complications using... Show moreAccording to current guidelines, patients with thrombocytopenia due to myelosuppression are supported with platelet concentrates in order to prevent and treat bleeding complications using algorithms which include the level of thrombocytopenia as well as varying clinical parameters, e.g. concomitant infection, the use of anticoagulant drugs, specific interventions. In the last three decades, mainly driven by safety issues, several platelet product changes were made with leukoreduction in the eighties of the previous century, plasma reduction and the use of additive solution in the nineties and the use of pathogen reduction in the first decade of this century.This thesis is mainly based on two randomised controlled trials testing the clinical efficacy of the use of additive solutions and pathogen reduction, essentially showing a decreased clinical efficacy as well as a decrease in adverse transfusion events. A bette r understanding of the pathophysiology of bleeding, thrombocytopenia and platelet transfusion refractoriness will lead to improvements in supportive care as well as patient survival, the common goal of all physicians. Show less
Red blood cells (RBCs) are probably the most frequently used drug given to very preterm infants; more than 90% of infants with a birth weight <1000 grams receive one or more RBC transfusions.... Show moreRed blood cells (RBCs) are probably the most frequently used drug given to very preterm infants; more than 90% of infants with a birth weight <1000 grams receive one or more RBC transfusions. Except for reduction of the amount of blood drawn for laboratory tests and use of a single donor program, no measures have been shown to be an irrefutable safe way to reduce donor exposure. Preventative measures for anemia should be used to reduce the number of RBC transfusions needed. Alternatives for allogenic RBC transfusions, such as autologous RBC cord blood transfusion, should be further explored and implemented. A restrictive transfusion strategy does not seem harmful for the children in short term or long term outcome. Thrombocytopenia is also a frequently encountered problem in neonatal medicine with an increased risk for hemorrhage. Thrombocytopenia, irrespective of the severity, increases the incidence of intraventricular hemorrhage. A more restrictive platelet transfusion policy significantly reduces the number of infants receiving a platelet transfusion without a difference in occurrence of (severe) hemorrhage. We state that both for red blood cell and platelet transfusions in (premature) newborn infants, safe thresholds are still not established. Transfusions may have (late) detrimental effects. Safe thresholds for both erythrocytes and platelets need to be found by large prospective randomized trials focusing not only on the direct effects but also on the long-term effects. Show less
In the Netherlands 1 of 1.000 inhibitants undergo cardiac surgery annually. To compensate blood loss these patients receive often blood transfusions, which can cause unexpected adverse reactions.... Show moreIn the Netherlands 1 of 1.000 inhibitants undergo cardiac surgery annually. To compensate blood loss these patients receive often blood transfusions, which can cause unexpected adverse reactions. Allogeneic leukocytes may play a prominent role in the development of these adverse reactions. We found in a randomized trial in cardiac valve surgery that patients receiving buffy-coat depleted (which contain 20-30% donor leukocytes) red blood cell (RBC) transfusions had dose-dependently higher hospital-mortality and postoperative infections than patients receiving leukocyte-depleted RBCs. Cost-effectiveness analysis revealed that leukodepletion of RBCs reduces the costs after cardiac valve surgery. Additional analyses revealed that plasma transfusions were associated with mortality and platelet transfusions with postoperative infections and longer ICU-stay. Patients who received more than 3 red blood cell units had significantly higher cytokine IL-6 concentrations after leukocyte-containing, buffy-coat depleted red blood cells (RBC) as compared to patients who had received similar numbers of leukocyte-depleted RBC units. Patients who developed postoperative infections and multiple-organ-dysfunction-syndrome showed, respectively, increased concentrations of cytokines IL-6 and IL-12 in the group that received leukocyte-containing RBCs. This laboratory analysis suggests that buffy-coat depleted erythrocytes may affect the development of postoperative complications by modulation of the postoperative proinflammatory response after cardiac surgery. Show less
Cardiovascular disease are a leading cause of mortality and morbidity in the Western world. Platelets play an important role in the development of cardiovascular disease, not only in the acute... Show moreCardiovascular disease are a leading cause of mortality and morbidity in the Western world. Platelets play an important role in the development of cardiovascular disease, not only in the acute onset of thrombosis after atherosclerotic plaque rupture but also in the initiation and progression of atherosclerosis and plaque formation. In recent years, the awareness has grown that platelet function may vary among individuals and that high platelet reactivity may increase the risk of cardiovascular events. This thesis addresses variation in platelet reactivity in relation to occurrence of cardiovascular events. We show that high platelet reactivity in subjects with cardiovascular disease using aspirin or clopidogrel as well as in antiplatelet drug-na_ve healthy subjects is related to the risk of cardiovascular events. We also revealed several genetic and clinical risk factors of high platelet reactivity. Moreover, we show that the 110-year old antiplatelet drug aspirin has interesting time-dependent pleiotropic effects on various pressor systems underlying blood pressure. As discussed in this thesis, although promising results have been published, routine platelet reactivity testing in daily clinical practice would currently be premature. Future studies are warranted to further investigate the clinical applicability of platelet reactivity testing in subjects at risk for cardiovascular events. Show less
