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      Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis

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          Abstract

          Background

          Severe leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thrombocytopenia, but also to platelet dysfunction, and that increased binding of von Willebrand factor (VWF) to platelets is involved in both platelet dysfunction and increased platelet clearance.

          Methodology/Principal findings

          A prospective study was carried out in Semarang, Indonesia, enrolling 33 hospitalized patients with probable leptospirosis, of whom 15 developed clinical bleeding, and 25 healthy controls. Platelet activation and reactivity were determined using flow cytometry by measuring the expression of P-selectin and activation of the α IIbβ 3 integrin by the binding of fibrinogen in unstimulated samples and after ex vivo stimulation by the platelet agonists adenosine-diphosphate (ADP) and thrombin-receptor activating peptide (TRAP). Platelet-VWF binding, before and after VWF stimulation by ristocetin, as well as plasma levels of VWF, active VWF, the VWF-inactivating enzyme ADAMTS13, thrombin-antithrombin complexes (TAT) and P-selectin were also measured. Bleeding complications were graded using the WHO bleeding scale. Our study revealed that platelet activation, with a secondary platelet dysfunction, is a feature of patients with probable leptospirosis, especially in those with bleeding manifestations. There was a significant inverse correlation of bleeding score with TRAP-stimulated P-selectin and platelet-fibrinogen binding (R = -0.72, P = 0.003 and R = -0.66, P = 0.01, respectively) but not with platelet count. Patients with bleeding also had a significantly higher platelet-VWF binding. Platelet counts were inversely correlated with platelet-VWF binding (R = -0.74; P = 0.0009. There were no correlations between platelet-VWF binding and the degree of platelet dysfunction, suggesting that increased platelet-VWF binding does not directly interfere with the platelet α IIbβ 3 signaling pathway in patients with probable leptospirosis.

          Conclusion/Significance

          Platelet dysfunction is common in probable leptospirosis patients with manifest bleeding. Increased VWF-platelet binding may contribute to the activation and clearance of platelets.

          Author summary

          Bleeding is a frequent complication of leptospirosis, a disease caused by the pathogenic spirochaete Leptospira. Although thrombocytopenia is common, studies have shown that it does not fully explain the bleeding events seen in these patients. We hypothesized that platelet dysfunction plays a role in the development of bleeding complications. The present study involved 33 hospitalized patients with probable leptospirosis and 25 healthy controls. We report that circulating platelets from patients with severe, probable leptospirosis were activated, but less reactive to ex vivo activation. The degree of this platelet dysfunction was associated with bleeding, in contrast to the degree of thrombocytopenia. Platelets of leptospirosis patients also demonstrated increased binding with von Willebrand factor (VWF), and a strong negative correlation with platelet count suggesting that this binding is important for platelet clearance.

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          Most cited references57

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          Leptospirosis: a zoonotic disease of global importance.

          In the past decade, leptospirosis has emerged as a globally important infectious disease. It occurs in urban environments of industrialised and developing countries, as well as in rural regions worldwide. Mortality remains significant, related both to delays in diagnosis due to lack of infrastructure and adequate clinical suspicion, and to other poorly understood reasons that may include inherent pathogenicity of some leptospiral strains or genetically determined host immunopathological responses. Pulmonary haemorrhage is recognised increasingly as a major, often lethal, manifestation of leptospirosis, the pathogenesis of which remains unclear. The completion of the genome sequence of Leptospira interrogans serovar lai, and other continuing leptospiral genome sequencing projects, promise to guide future work on the disease. Mainstays of treatment are still tetracyclines and beta-lactam/cephalosporins. No vaccine is available. Prevention is largely dependent on sanitation measures that may be difficult to implement, especially in developing countries.
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            The ITP syndrome: pathogenic and clinical diversity.

            Immune thrombocytopenia (ITP) is mediated by platelet autoantibodies that accelerate platelet destruction and inhibit their production. Most cases are considered idiopathic, whereas others are secondary to coexisting conditions. Insights from secondary forms suggest that the proclivity to develop platelet-reactive antibodies arises through diverse mechanisms. Variability in natural history and response to therapy suggests that primary ITP is also heterogeneous. Certain cases may be secondary to persistent, sometimes inapparent, infections, accompanied by coexisting antibodies that influence outcome. Alternatively, underlying immune deficiencies may emerge. In addition, environmental and genetic factors may impact platelet turnover, propensity to bleed, and response to ITP-directed therapy. We review the pathophysiology of several common secondary forms of ITP. We suggest that primary ITP is also best thought of as an autoimmune syndrome. Better understanding of pathogenesis and tolerance checkpoint defects leading to autoantibody formation may facilitate patient-specific approaches to diagnosis and management.
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              ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions.

              Thrombotic thrombocytopenic purpura (TTP) is a devastating thrombotic disorder caused by widespread microvascular thrombi composed of platelets and von Willebrand factor (VWF). The disorder is associated with a deficiency of the VWF-cleaving metalloprotease, ADAMTS-13, with consequent accumulation of ultralarge (UL) VWF multimers in the plasma. ULVWF multimers, unlike plasma forms of VWF, attach spontaneously to platelet GP Ibalpha, a component of the GP Ib-IX-V complex. We have found that ULVWF multimers secreted from stimulated endothelial cells (ECs) remained anchored to the endothelial surface where platelets and Chinese hamster ovary cells expressing the GP Ib-IX-V complex attached to form long beads-on-a-string structures in the presence of fluid shear stresses in both the venous (2.5 dyne/cm(2)) and arterial (20 and 50 dyne/cm(2)) ranges. Although measurement of the activity of the ADAMTS-13 VWF-cleaving metalloprotease in vitro requires prolonged incubation of the enzyme with VWF under nonphysiologic conditions, EC-derived ULVWF strings with attached platelets were cleaved within seconds to minutes in the presence of normal plasma (containing approximately 100% ADAMTS-13 activity) or in the presence of partially purified ADAMTS-13. By contrast, the strings persisted for the entire period of perfusion (10 minutes) in the presence of plasma from patients with TTP containing 0% to 10% ADAMTS-13 activity. These results suggest that cleavage of EC-derived ULVWF multimers by ADAMTS-13 is a rapid physiologic process that occurs on endothelial cell surfaces.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: Data curationRole: Investigation
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                21 September 2017
                September 2017
                : 11
                : 9
                : e0005915
                Affiliations
                [1 ] Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
                [2 ] Center for Tropical and Infectious Disease (CENTRID), Faculty of Medicine Diponegoro University, Dr Kariadi Hospital, Semarang, Indonesia
                [3 ] National Reference Laboratory for Leptospira, Dr. Kariadi Hospital, Semarang, Indonesia
                [4 ] Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, The Netherlands
                University of California Davis, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-6168-4758
                Article
                PNTD-D-16-02286
                10.1371/journal.pntd.0005915
                5626517
                28934202
                aac8b3de-8e0c-41d9-a4a3-7efc308a0a74
                © 2017 Tunjungputri et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 December 2016
                : 28 August 2017
                Page count
                Figures: 4, Tables: 1, Pages: 18
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Platelets
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Platelets
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Platelets
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Platelets
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                Platelets
                Medicine and Health Sciences
                Hematology
                Blood Coagulation
                Platelet Activation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Vascular Medicine
                Hemorrhage
                Medicine and Health Sciences
                Infectious Diseases
                Bacterial Diseases
                Leptospirosis
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Leptospirosis
                Medicine and Health Sciences
                Infectious Diseases
                Zoonoses
                Leptospirosis
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Hematology
                Thrombocytopenia
                Medicine and Health Sciences
                Hematology
                Blood Coagulation
                Platelet Aggregation
                Biology and Life Sciences
                Biochemistry
                Glycobiology
                Glycoproteins
                Fibrinogen
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-10-03
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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