Publications by authors named "Rick Kapur"

57 Publications

Pancreatic involvement in murine antibody-mediated transfusion-related acute lung injury?

Transfusion 2021 Mar;61(3):987-989

Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.16240DOI Listing
March 2021

Matching epitopes in platelet refractoriness.

Authors:
Rick Kapur

Blood 2021 Jan;137(3):283-284

Sanquin Research; Landsteiner Laboratory.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009283DOI Listing
January 2021

Biological stratification of clinical disease courses in childhood immune thrombocytopenia.

J Thromb Haemost 2021 Apr 18;19(4):1071-1081. Epub 2021 Mar 18.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Background: In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes.

Objective: To predict the response to intravenous immunoglobulins (IVIg) and ITP disease course using genetic and immune markers.

Methods: Children aged younger than 7 years with newly diagnosed ITP (N = 147) from the Treatment With or Without IVIG for Kids with ITP study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies.

Results: In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 × 10 /L) that lasted for at least 1 month (complete sustained response [CSR]) and 32 exhibited no or a temporary response (absence of a sustained response [ASR]). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: (1) hemoglobin; (2) platelet count; (3) genetic polymorphisms of Fc-receptor (FcγR) IIc; (4) the presence of immunoglobulin G (IgG) anti-platelet antibodies; and (5) preceding vaccination. The ASR sensitivity was 0.91 (95% confidence interval, 0.80-1.00) and specificity was 0.67 (95% confidence interval, 0.53-0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during 1 year of follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses.

Conclusions: The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15232DOI Listing
April 2021

Megakaryocytes listen for their progeny's progeny during inflammation.

J Thromb Haemost 2021 Mar 21;19(3):604-606. Epub 2020 Dec 21.

Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986206PMC
March 2021

Monocytes as potential therapeutic sensors in glucocorticoid-treated newly diagnosed immune thrombocytopenia.

Authors:
Rick Kapur

Br J Haematol 2021 01 18;192(2):233-234. Epub 2020 Dec 18.

Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17204DOI Listing
January 2021

New Emerging Developments of Platelets in Transfusion Medicine.

Transfus Med Rev 2020 10 7;34(4):207-208. Epub 2020 Oct 7.

Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden; Clinical Immunology and Transfusion Medicine, Office of Medical Services, Region Skåne, Lund, Sweden; Departments of Pharmacology and Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmrv.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538989PMC
October 2020

A clinical prediction score for transient versus persistent childhood immune thrombocytopenia.

J Thromb Haemost 2021 01 27;19(1):121-130. Epub 2020 Nov 27.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Essentials There is a need for improved tools to predict persistent and chronic immune thrombocytopenia (ITP). We developed and validated a clinical prediction model for recovery from newly diagnosed ITP. The Childhood ITP Recovery Score predicts transient vs. persistent ITP and response to intravenous immunoglobulins. The score may serve as a useful tool for clinicians to individualize patient care. ABSTRACT: Background Childhood immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The prognosis (transient, persistent, or chronic ITP) remains difficult to predict. The morbidity is most pronounced in children with persistent and chronic ITP. Clinical characteristics are associated with ITP outcomes, but there are no validated multivariate prediction models. Objective Development and external validatation of the Childhood ITP Recovery Score to predict transient versus persistent ITP in children with newly diagnosed ITP. Methods Patients with a diagnosis platelet count ≤ 20 × 10 /L and age below 16 years were included from two prospective multicenter studies (NOPHO ITP study, N = 377 [development cohort]; TIKI trial, N = 194 [external validation]). The primary outcome was transient ITP (complete recovery with platelets ≥100 × 10 /L 3 months after diagnosis) versus persistent ITP. Age, sex, mucosal bleeding, preceding infection/vaccination, insidious onset, and diagnosis platelet count were used as predictors. Results In external validation, the score predicted transient versus persistent ITP at 3 months follow-up with an area under the receiver operating characteristic curve of 0.71. In patients predicted to have a high chance of recovery, we observed 85%, 90%, and 95% recovered 3, 6, and 12 months after the diagnosis. For patients predicted to have a low chance of recovery, this was 32%, 46%, and 71%. The score also predicted cessation of bleeding symptoms and the response to intravenous immunoglobulins (IVIg). Conclusion The Childhood ITP Recovery Score predicts prognosis and may be useful to individualize clinical management. In future research, the additional predictive value of biomarkers can be compared to this score. A risk calculator is available (http://www.itprecoveryscore.org).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839442PMC
January 2021

The Immune Nature of Platelets Revisited.

Transfus Med Rev 2020 10 19;34(4):209-220. Epub 2020 Sep 19.

Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden; Clinical Immunology and Transfusion Medicine, Office of Medical Services, Region Skåne, Lund, Sweden. Electronic address:

Platelets are the primary cellular mediators of hemostasis and this function firmly acquaints them with a variety of inflammatory processes. For example, platelets can act as circulating sentinels by expressing Toll-like receptors (TLR) that bind pathogens and this allows platelets to effectively kill them or present them to cells of the immune system. Furthermore, activated platelets secrete and express many pro- and anti-inflammatory molecules that attract and capture circulating leukocytes and direct them to inflamed tissues. In addition, platelets can directly influence adaptive immune responses via secretion of, for example, CD40 and CD40L molecules. Platelets are also the source of most of the microvesicles in the circulation and these miniscule elements further enhance the platelet's ability to communicate with the immune system. More recently, it has been demonstrated that platelets and their parent cells, the megakaryocytes (MK), can also uptake, process and present both foreign and self-antigens to CD8+ T-cells conferring on them the ability to directly alter adaptive immune responses. This review will highlight several of the non-hemostatic attributes of platelets that clearly and rightfully place them as integral players in immune reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmrv.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501063PMC
October 2020

Evolution and Utility of Antiplatelet Autoantibody Testing in Patients with Immune Thrombocytopenia.

Transfus Med Rev 2020 10 16;34(4):258-269. Epub 2020 Sep 16.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands; Sanquin Research, Center for Clinical Transfusion Research, Leiden, the Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.

To this day, immune thrombocytopenia (ITP) 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmrv.2020.09.003DOI Listing
October 2020

Evaluation of Platelet Responses in Transfusion-Related Acute Lung Injury (TRALI).

Transfus Med Rev 2020 10 16;34(4):227-233. Epub 2020 Sep 16.

Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Platelets are versatile cells which are capable of eliciting nonhemostatic immune functions, especially under inflammatory conditions. Depending on the specific setting, platelets may be either protective or pathogenic in acute lung injury and acute respiratory distress syndrome (ARDS). Their role in transfusion-related acute lung injury (TRALI) is less well defined; however, it has been hypothesized that recipient platelets and transfused platelets both play a pathogenic role in TRALI. Overall, despite conflicting findings, it appears that recipient platelets may play a pathogenic role in antibody-mediated TRALI; however, their contribution appears to be limited. It is imperative to first validate the involvement of recipient platelets by standardizing the animal models, methods, reagents, and readouts for lung injury and taking the animal housing environment into consideration. For the involvement of transfused platelets in TRALI, it appears that predominantly lipids such as ceramide in stored platelets are able to induce TRALI in animal models. These studies will also need to be validated, and moreover, the platelet-derived lipid-mediated mechanisms leading to TRALI will need to be investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmrv.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493815PMC
October 2020

An update on the pathophysiology of immune thrombocytopenia.

Curr Opin Hematol 2020 11;27(6):423-429

Sanquin Research, Department of Experimental Immunohematology, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder mediated by antiplatelet autoantibodies and antigen-specific T cells that either destroy platelets peripherally in the spleen or impair platelet production in the bone marrow. There have been a plethora of publications relating to the pathophysiology of ITP and since January of 2019, at least 50 papers have been published on ITP pathophysiology.

Purpose Of Review: To summarize the literature relating to the pathophysiology of ITP including the working mechanisms of therapies, T-cell and B-cell physiology, protein/RNA/DNA biochemistry, and animal models in an attempt to unify the perceived abnormal immune processes.

Recent Findings: The most recent pathophysiologic irregularities associated with ITP relate to abnormal T-cell responses, particularly, defective T regulatory cell activity and how therapeutics can restore these responses. The robust literature on T cells in ITP points to the notion that ITP is a disease initiated by faulty self-tolerance mechanisms very much like that of other organ-specific autoimmune diseases. There is also a large literature on new and existing animal models of ITP and these will be discussed. It appears that understanding how to specifically modulate T cells in patients with ITP will undoubtedly lead to effective antigen-specific therapeutics.

Conclusions: ITP is predominately a T cell disorder which leads to a breakdown in self tolerance mechanisms and allows for the generation of anti-platelet autoantibodies and T cells. Novel therapeutics that target T cells may be the most effective way to perhaps cure this disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MOH.0000000000000612DOI Listing
November 2020

Update on the pathophysiology of transfusion-related acute lung injury.

Curr Opin Hematol 2020 11;27(6):386-391

Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam.

Purpose Of Review: The aim of this study was to discuss recent advances regarding the pathogenesis of transfusion-related acute lung injury (TRALI), which highlight the pathogenic role of macrophages.

Recent Findings: TRALI remains a leading cause of transfusion-related fatalities, despite the success of the mitigation strategy, and therapeutic approaches are unavailable. Neutrophils (PMNs) are recognized pathogenic cells in TRALI. Macrophages have previously also been suggested to be pathogenic in mice via binding of C5a to their C5a-receptor, producing reactive oxygen species (ROS), which damages the pulmonary endothelium. Recent work has further highlighted the role of macrophages in the TRALI-pathogenesis. It has been shown that the protein osteopontin (OPN) released by macrophages is critical for pulmonary PMN recruitment in mice suffering from TRALI and that targeting OPN prevents the occurrence of TRALI. Another recent study demonstrated the importance of M1-polarized alveolar macrophages in murine TRALI induction by showing that α1-antitrypsin (AAT) overexpression prevented TRALI in mice through decreasing the polarization of alveolar macrophages towards the M1 phenotype.

Summary: Apart from PMNs, macrophages also appear to be important in the pathogenesis of TRALI. Targeting the pathogenic functions of macrophages may be a promising therapeutic strategy to explore in TRALI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MOH.0000000000000607DOI Listing
November 2020

Biological and structural characterization of murine TRALI antibody reveals increased Fc-mediated complement activation.

Blood Adv 2020 08;4(16):3875-3885

Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Transfusion-related acute lung injury (TRALI) remains a leading cause of transfusion-related deaths. In most cases, anti-leukocyte antibodies in the transfusion product trigger TRALI, but not all anti-leukocyte antibodies cause TRALI. It has been shown that the anti-major histocompatibility complex (MHC) class I antibody 34-1-2S (anti-H-2Kd) causes TRALI in BALB/c mice (MHC class I haplotype H-2Kd), whereas SF1.1.10 (anti-H-2Kd) does not. In C57BL/6 mice (MHC class I haplotype H-2Kb), TRALI only occurs when anti-MHC class I antibody AF6-88.5.5.3 (anti-H-2Kb) is administered together with a high dose of 34-1-2S. It remains unknown which specific antibody characteristics are responsible for eliciting TRALI. We therefore investigated several biological and structural features of 34-1-2S compared with other anti-MHC class I antibodies, which on their own do not cause TRALI: SF1.1.10 and AF6-88.5.5.3. No substantial differences were observed between the TRALI-causing 34-1-2S and the TRALI-resistant SF1.1.10 regarding binding affinity to H-2Kd. Regarding binding affinity to H-2Kb, only AF6-88.5.5.3 potently bound to H-2Kb, whereas 34-1-2S exhibited weak but significant cross-reactivity. Furthermore, the binding affinity to FcγRs as well as the Fc glycan composition seemed to be similar for all antibodies. Similar Fc glycosylation profiles were also observed for human TRALI-causing donor anti-HLA antibodies compared with human anti-HLA antibodies from control donors. 34-1-2S, however, displayed superior complement activation capacity, which was fully Fc dependent and not significantly dependent on Fc glycosylation. We conclude that TRALI induction is not correlated with Fab- and Fc-binding affinities for antigen and FcγRs, respectively, nor with the composition of Fc glycans; but increased Fc-mediated complement activation is correlated with TRALI induction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448591PMC
August 2020

Fine-tuning the treatment toolbox of immune thrombocytopenia: fostamatinib as a second-line therapy.

Authors:
Rick Kapur

Br J Haematol 2020 09 12;190(6):817-818. Epub 2020 Jul 12.

Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16958DOI Listing
September 2020

The contribution of recipient platelets in TRALI: has the jury reached a verdict?

Transfusion 2020 05;60(5):886-888

Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.15814DOI Listing
May 2020

Anti-D monoclonal antibodies from 23 human and rodent cell lines display diverse IgG Fc-glycosylation profiles that determine their clinical efficacy.

Sci Rep 2020 01 30;10(1):1464. Epub 2020 Jan 30.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.

Anti-D immunoglobulin (Anti-D Ig) prophylaxis prevents haemolytic disease of the fetus and newborn. Monoclonal IgG anti-Ds (mAb-Ds) would enable unlimited supplies but have differed in efficacy in FcγRIIIa-mediated ADCC assays and clinical trials. Structural variations of the oligosaccharide chains of mAb-Ds are hypothesised to be responsible. Quantitative data on 12 Fc-glycosylation features of 23 mAb-Ds (12 clones, 5 produced from multiple cell lines) and one blood donor-derived anti-D Ig were obtained by HPLC and mass spectrometry using 3 methods. Glycosylation of mAb-Ds from human B-lymphoblastoid cell lines (B) was similar to anti-D Ig although fucosylation varied, affecting ADCC activity. In vivo, two B mAb-Ds with 77-81% fucosylation cleared red cells and prevented D-immunisation but less effectively than anti-D Ig. High fucosylation (>89%) of mouse-human heterohybridoma (HH) and Chinese hamster ovary (CHO) mAb-Ds blocked ADCC and clearance. Rat YB2/0 mAb-Ds with <50% fucosylation mediated more efficient ADCC and clearance than anti-D Ig. Galactosylation of B mAb-Ds was 57-83% but 15-58% for rodent mAb-Ds. HH mAb-Ds had non-human sugars. These data reveal high galactosylation like anti-D Ig (>60%) together with lower fucosylation (<60%) as safe features of mAb-Ds for mediating rapid red cell clearance at low doses, to enable effective, inexpensive prophylaxis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-57393-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992666PMC
January 2020

Analysing therapeutic responses in immune thrombocytopaenia: shifting the focus towards immune characteristics.

Authors:
Rick Kapur

Br J Haematol 2020 06 30;189(5):811-812. Epub 2020 Jan 30.

Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16482DOI Listing
June 2020

The Role of Complement in Transfusion-Related Acute Lung Injury.

Transfus Med Rev 2019 10 18;33(4):236-242. Epub 2019 Oct 18.

Sanquin Research, Department of Experimental Immunohematology, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Transfusion-related acute lung injury (TRALI) is a life-threatening complication of acute respiratory distress occurring within 6 hours of blood transfusion. TRALI is one of the leading causes of transfusion-related fatalities and specific therapies are unavailable. Neutrophils are recognized as the major pathogenic cells, whereas T regulatory cells and dendritic cells appear to be important for protection against TRALI. The pathogenesis, however, is complex and incompletely understood. It is frequently postulated that the complement system plays an important role in the TRALI pathogenesis. In this article, we assess the evidence regarding the involvement of complement in TRALI from both human and animal studies. We hypothesize about the potential connection between the complement system and neutrophils in TRALI. Additionally, we draw parallels between TRALI and other acute pulmonary disorders of acute lung injury and acute respiratory distress syndrome regarding the involvement of complement. We conclude that, even though a role for complement in the TRALI pathogenesis seems plausible, studies investigating the role of complement in TRALI are remarkably limited in number and also present conflicting findings. Different types of TRALI animal models, diverse experimental conditions, and the composition of the gastrointestinal microbiota may perhaps all be factors which contribute to these discrepancies. More systematic studies are warranted to shed light on the contribution of the complement cascade in TRALI. The underlying clinical condition of the patient, which influences the susceptibility to TRALI, as well as the transfusion factor (antibody-mediated vs non-antibody-mediated), will be important to take into consideration when researching the contribution of complement. This should significantly increase our understanding of the role of complement in TRALI and may potentially result in promising new treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmrv.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127679PMC
October 2019

Treating murine inflammatory diseases with an anti-erythrocyte antibody.

Sci Transl Med 2019 08;11(506)

Canadian Blood Services Centre for Innovation, Ottawa, Ontario K1G 4J5, Canada.

Treatment of autoimmune and inflammatory diseases typically involves immune suppression. In an opposite strategy, we show that administration of the highly inflammatory erythrocyte-specific antibody Ter119 into mice remodels the monocyte cellular landscape, leading to resolution of inflammatory disease. Ter119 with intact Fc function was unexpectedly therapeutic in the K/BxN serum transfer model of arthritis. Similarly, it rapidly reversed clinical disease progression in collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis and completely corrected CAIA-induced increase in monocyte Fcγ receptor II/III expression. Ter119 dose-dependently induced plasma chemokines CCL2, CCL5, CXCL9, CXCL10, and CCL11 with corresponding alterations in monocyte percentages in the blood and liver within 24 hours. Ter119 attenuated chemokine production from the synovial fluid and prevented the accumulation of inflammatory cells and complement components in the synovium. Ter119 could also accelerate the resolution of hypothermia and pulmonary edema in an acute lung injury model. We conclude that this inflammatory anti-erythrocyte antibody simultaneously triggers a highly efficient anti-inflammatory effect with broad therapeutic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aau8217DOI Listing
August 2019

Transfusion-related Acute Lung Injury in the Perioperative Patient.

Anesthesiology 2019 09;131(3):693-715

From the Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada (M.J.M., J.W.S., W.M.K) Departments of Physiology and Anesthesia (M.J.M.) Pharmacology (J.W.S.) Laboratory Medicine-Pathobiology (C.C.-G.) Medicine-Division of Hematology (C.C.-G.) Anesthesia and Pain Management, University Health Network (K.K.) Physiology and Surgery (W.M.K.) University of Toronto, Toronto, Canada (C.C.-G.) Sickkids Department of Anesthesia and Pain Medicine (M.J.M.) Division of Hematology and Transfusion Medicine (R.K., J.W.S.), Lund University, Lund, Sweden Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands (R.K.) Departments of Laboratory Hematology (Blood Transfusion Laboratory), Laboratory Medicine Program (C.C.-G.) Medical Oncology and Hematology (C.C.-G.) University Health Network, Toronto, Canada (K.K.) Department of Clinical Pathology, Blood and Tissue Bank, Sunnybrook Health Sciences Centre, Toronto, Canada (C.C.-G.) Institute of Physiology, Charité University Berlin, Berlin, Germany (W.M.K.).

Transfusion-related acute lung injury is a leading cause of death associated with the use of blood products. Transfusion-related acute lung injury is a diagnosis of exclusion which can be difficult to identify during surgery amid the various physiologic and pathophysiologic changes associated with the perioperative period. As anesthesiologists supervise delivery of a large portion of inpatient prescribed blood products, and since the incidence of transfusion-related acute lung injury in the perioperative patient is higher than in nonsurgical patients, anesthesiologists need to consider transfusion-related acute lung injury in the perioperative setting, identify at-risk patients, recognize early signs of transfusion-related acute lung injury, and have established strategies for its prevention and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ALN.0000000000002687DOI Listing
September 2019

Anti-glycoprotein Ibα autoantibodies do not impair circulating thrombopoietin levels in immune thrombocytopenia patients.

Haematologica 2020 04 11;105(4):e172-e174. Epub 2019 Jul 11.

Sanquin Research, Department of Experimental Immunohematology and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.228908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109722PMC
April 2020

Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP).

Platelets 2020 30;31(3):399-402. Epub 2019 May 30.

Keenan Research Center, St. Michael's Hospital, Toronto, ON, Canada.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which autoantibodies and/or autoreactive T cells destroy platelets and megakaryocytes in the spleen and bone marrow, respectively. Thrombopoietin receptor agonists (TPO-RA e.g. Romiplostim and Eltrombopag) have made a substantial contribution to the treatment of patients with ITP, which are refractory to first-line treatments and approximately 30% demonstrate sustained elevated platelet counts after drug tapering. How TPO-RA induce these sustained responses is not known. We analyzed the efficacy of a murine TPO-RA in a well-established murine model of active ITP. Treatment with TPO-RA (10 ug/kg, based on pilot dose escalation experiments) significantly raised the platelet counts in ITP-mice. Immunomodulation was assessed by measuring serum IgG anti-platelet antibody levels; TPO-RA-treated mice had significantly reduced IgG anti-platelet antibodies despite the increasing platelet counts. These results suggest that TPO-RA is not only an efficacious therapy but also reduces anti-platelet humoral immunity in ITP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09537104.2019.1624709DOI Listing
September 2020

Osteopontin mediates murine transfusion-related acute lung injury via stimulation of pulmonary neutrophil accumulation.

Blood 2019 07 10;134(1):74-84. Epub 2019 May 10.

Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine and.

Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-related fatalities and is characterized by the onset of acute respiratory distress within 6 hours upon blood transfusion. Specific therapies are unavailable. Preexisting inflammation is a risk factor for TRALI and neutrophils (polymorphonuclear neutrophils [PMNs]) are considered to be the major pathogenic cells. Osteopontin (OPN) is a multifunctional protein expressed at sites of inflammation and, for example, is involved in pulmonary disorders, can regulate cellular migration, and can function as a PMN chemoattractant. We investigated whether OPN is involved in TRALI induction by promoting PMN recruitment to the lungs. Using a previously established murine TRALI model, we found that in contrast to wild-type (WT) mice, OPN knockout (KO) mice were resistant to antibody-mediated PMN-dependent TRALI induction. Administration of purified OPN to the OPN KO mice, however, restored the TRALI response and pulmonary PMN accumulation. Alternatively, blockade of OPN in WT mice using an anti-OPN antibody prevented the onset of TRALI induction. Using pulmonary immunohistochemistry, OPN could be specifically detected in the lungs of mice that suffered from TRALI. The OPN-mediated TRALI response seemed dependent on macrophages, likely the cellular source of OPN and OPN polymerization, and independent from the OPN receptor CD44, interleukin 6 (IL-6), and other PMN chemoattractants including macrophage inflammatory protein-2 (MIP-2). These data indicate that OPN is critically required for induction of antibody-mediated murine TRALI through localization to the lungs and stimulation of pulmonary PMN recruitment. This suggests that anti-OPN antibody therapy may be a potential therapeutic strategy to explore in TRALI patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019000972DOI Listing
July 2019

Transfusion-associated circulatory overload and transfusion-related acute lung injury.

Blood 2019 04 26;133(17):1840-1853. Epub 2019 Feb 26.

Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.

Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are syndromes of acute respiratory distress that occur within 6 hours of blood transfusion. TACO and TRALI are the leading causes of transfusion-related fatalities, and specific therapies are unavailable. Diagnostically, it remains very challenging to distinguish TACO and TRALI from underlying causes of lung injury and/or fluid overload as well as from each other. TACO is characterized by pulmonary hydrostatic (cardiogenic) edema, whereas TRALI presents as pulmonary permeability edema (noncardiogenic). The pathophysiology of both syndromes is complex and incompletely understood. A 2-hit model is generally assumed to underlie TACO and TRALI disease pathology, where the first hit represents the clinical condition of the patient and the second hit is conveyed by the transfusion product. In TACO, cardiac or renal impairment and positive fluid balance appear first hits, whereas suboptimal fluid management or other components in the transfused product may enable the second hit. Remarkably, other factors beyond volume play a role in TACO. In TRALI, the first hit can, for example, be represented by inflammation, whereas the second hit is assumed to be caused by antileukocyte antibodies or biological response modifiers (eg, lipids). In this review, we provide an up-to-date overview of TACO and TRALI regarding clinical definitions, diagnostic strategies, pathophysiological mechanisms, and potential therapies. More research is required to better understand TACO and TRALI pathophysiology, and more biomarker studies are warranted. Collectively, this may result in improved diagnostics and development of therapeutic approaches for these life-threatening transfusion reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-10-860809DOI Listing
April 2019

The Ultimate Murine Model of Immune Thrombocytopaenia.

Thromb Haemost 2019 Mar 6;119(3):353-354. Epub 2019 Feb 6.

Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1678697DOI Listing
March 2019

The Pathogenic Involvement of Neutrophils in Acute Respiratory Distress Syndrome and Transfusion-Related Acute Lung Injury.

Transfus Med Hemother 2018 Oct 21;45(5):290-298. Epub 2018 Sep 21.

Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.

The acute respiratory distress syndrome (ARDS) is a serious and common complication of multiple medical and surgical interventions, with sepsis, pneumonia, and aspiration of gastric contents being common risk factors. ARDS develops within 1 week of a known clinical insult or presents with new/worsening respiratory symptoms if the clinical insult is unknown. Approximately 40% of the ARDS cases have a fatal outcome. Transfusion-related acute lung injury (TRALI), on the other hand, is characterized by the occurrence of respiratory distress and acute lung injury, which presents within 6 h after administration of a blood transfusion. In contrast to ARDS, acute lung injury in TRALI is not attributable to another risk factor for acute lung injury. 'Possible TRALI', however, may have a clear temporal relationship to an alternative risk factor for acute lung injury. Risk factors for TRALI include chronic alcohol abuse and systemic inflammation. TRALI is the leading cause of transfusion-related fatalities. There are no specific therapies available for ARDS or TRALI as both have a complex and incompletely understood pathogenesis. Neutrophils (polymorphonuclear leukocytes; PMNs) have been suggested to be key effector cells in the pathogenesis of both syndromes. In the present paper, we summarize the literature with regard to PMN involvement in the pathogenesis of both ARDS and TRALI based on both human data as well as on animal models. The evidence generally supports a strong role for PMNs in both ARDS and TRALI. More research is required to shed light on the pathogenesis of these respiratory syndromes and to more thoroughly establish the nature of the PMN involvement, especially considering the heterogeneous etiologies of ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000492950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257140PMC
October 2018

Moving target PF4 directs HIT responses.

Blood 2018 08;132(7):678-679

Lund University.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-07-859975DOI Listing
August 2018

Gastrointestinal microbiota contributes to the development of murine transfusion-related acute lung injury.

Blood Adv 2018 07;2(13):1651-1663

Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.

Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora-depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation. DNA sequencing of amplicons of the 16S ribosomal RNA gene revealed a varying gastrointestinal bacterial composition between BF and SPF mice. BF fecal matter transferred into SPF mice significantly restored TRALI susceptibility in SPF mice. These data reveal a link between the gut flora composition and the development of antibody-mediated TRALI in mice. Assessment of gut microbial composition may help in TRALI risk assessment before transfusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018018903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039664PMC
July 2018