Serum Complement Levels in Immune Thrombocytopenia: Characterization and Relation to Clinical Features

Cheloff, Abraham Z.; Kuter, David J.

doi:10.1182/blood-2019-125341

Cited by 3 publications

(2 citation statements)

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“…[76][77][78] Cytotoxic T cells (CTLs) and the complement system may also play a role in ITP but CTLs may more effectively decrease platelets via targeting megakaryocytes in the bone marrow. [79][80][81] Recently, anti-αvβ3 autoantibodies, as seen in chronic ITP, have shown to have a selective inhibitory impact on megakaryocyte migration, 82 contributing to a decreased rate of thrombopoiesis in addition to platelet destruction. Glycoprotein Ib-IX (GPIb-IX) complex and GPIIbIIIa (αIIbβ3), the platelet receptors for VWF and fibrinogen, are the two most abundantly expressed platelet surface receptors and the most common autoantibody targets seen in ITP.…”

Section: Pl Atele T and Meg Ak Aryo C Y Te Cle Ar An Ce: Inadequate Under S Tand Ing Of Tp O Reg Ul Ati On In Itpmentioning

confidence: 99%

“…IgG autoantibodies are thought to be the predominant mediators of platelet destruction in the spleen 35,75 and have been found in the bone marrow of patients with ITP, likely interfering with megakaryopoiesis and thrombopoiesis 76‐78 . Cytotoxic T cells (CTLs) and the complement system may also play a role in ITP but CTLs may more effectively decrease platelets via targeting megakaryocytes in the bone marrow 79‐81 . Recently, anti‐αvβ3 autoantibodies, as seen in chronic ITP, have shown to have a selective inhibitory impact on megakaryocyte migration, 82 contributing to a decreased rate of thrombopoiesis in addition to platelet destruction.…”

Section: Platelet and Megakaryocyte Clearance: Inadequate Understanding Of Tpo Regulation In Itpmentioning

confidence: 99%

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GPIbα is the driving force of hepatic thrombopoietin generation

Karakas

2021

Research and Practice in Thrombosis and Haemostasis

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Thrombopoietin (TPO), a glycoprotein hormone produced predominantly in the liver, plays important roles in the hematopoietic stem cell (HSC) niche, and is essential for megakaryopoiesis and platelet generation. Long‐standing understanding proposes that TPO is constitutively produced by hepatocytes, and levels are fine‐tuned through platelet and megakaryocyte internalization/degradation via the c‐Mpl receptor. However, in immune thrombocytopenia (ITP) and several other diseases, TPO levels are inconsistent with this theory. Recent studies showed that platelets, besides their TPO clearance, can induce TPO production in the liver. Our group also accidentally discovered that platelet glycoprotein (GP) Ibα is required for platelet‐mediated TPO generation, which is underscored in both GPIbα −/− mice and patients with Bernard‐Soulier syndrome. This review will introduce platelet versatilities and several new findings in hemostasis and platelet consumption but focus on its roles in TPO regulation. The implications of these new discoveries in hematopoiesis and the HSC niche, particularly in ITP, will be discussed.

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Section: Pl Atele T and Meg Ak Aryo C Y Te Cle Ar An Ce: Inadequate Under S Tand Ing Of Tp O Reg Ul Ati On In Itpmentioning

confidence: 99%

Section: Platelet and Megakaryocyte Clearance: Inadequate Understanding Of Tpo Regulation In Itpmentioning

confidence: 99%

GPIbα is the driving force of hepatic thrombopoietin generation

Karakas

2021

Research and Practice in Thrombosis and Haemostasis

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Recent advances in the mechanisms and treatment of immune thrombocytopenia

Semple

2022

eBioMedicine

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Primary immune thrombocytopenia is an autoimmune disease associated with a reduced peripheral blood platelet count. The phenotype is variable with some patients suffering no bleeding whilst others have severe bleeding which may be fatal. Variability in clinical behaviour and treatment responses reflects its complex underlying pathophysiology. Historically the management has relied heavily on immune suppression. Recent studies have shown that the older empirical immune suppressants fail to alter the natural history of the disease and are associated with a poor quality of life for patients. Newer treatments, such as the thrombopoietin receptor agonists, have transformed ITP care. They have high efficacy, are well tolerated and improve patients' quality of life. A greater understanding of the underlying pathophysiology of this disorder has helped develop a number of new targeted therapies. These include inhibitors of the neonatal Fc receptor inhibitors, Bruton tyrosine kinase and complement pathway. Here we discuss the mechanisms underlying ITP and the new approach to ITP care.

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Antagonism of the Platelet-Activating Factor Pathway Mitigates Inflammatory Adverse Events Driven by Anti-erythrocyte Antibody Therapy in Mice

Won,

Gil Gonzalez,

Cruz-Leal

et al. 2024

The Journal of Immunology

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Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts primarily due to antiplatelet autoantibodies. Anti-D is a donor-derived polyclonal Ab against the rhesus D Ag on erythrocytes used to treat ITP. Unfortunately, adverse inflammatory/hypersensitivity reactions and a Food and Drug Administration–issued black box warning have limited its clinical use. This underscores the imperative to understand the inflammatory pathway associated with anti-erythrocyte Ab-based therapies. TER119 is an erythrocyte-specific Ab with anti-D-like therapeutic activity in murine ITP, while also exhibiting a distinct inflammatory signature involving production of CCL2, CCL5, and CXCL9 but not IFN-γ. Therefore, TER119 has been used to elucidate the potential mechanism underlying the adverse inflammatory activity associated with anti-erythrocyte Ab therapy in murine ITP. Prior work has demonstrated that TER119 administration is associated with a dramatic decrease in body temperature and inflammatory cytokine/chemokine production. The work presented in the current study demonstrates that inhibiting the highly inflammatory platelet-activating factor (PAF) pathway with PAF receptor antagonists prevents TER119-driven changes in body temperature and inhibits the production of the CCL2, CCL5, and CXCL9 inflammatory cytokines in CD-1 mice. Phagocytic cells and a functional TER119 Fc region were found to be necessary for TER119-induced body temperature changes and increases in CXCL9 and CCL2. Taken together, this work reveals the novel requirement of the PAF pathway in causing adverse inflammatory activity associated with anti-erythrocyte Ab therapy in a murine model and provides a strategy of mitigating these potential reactions without altering therapeutic activity.

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Serum Complement Levels in Immune Thrombocytopenia: Characterization and Relation to Clinical Features

Cited by 3 publications

References 0 publications

GPIbα is the driving force of hepatic thrombopoietin generation

GPIbα is the driving force of hepatic thrombopoietin generation

Recent advances in the mechanisms and treatment of immune thrombocytopenia

Antagonism of the Platelet-Activating Factor Pathway Mitigates Inflammatory Adverse Events Driven by Anti-erythrocyte Antibody Therapy in Mice

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