Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria

Wiedmer, T; Hall, SE; Tl, Ortel; Kane, WH; Rosse, WF

doi:10.1182/blood.v82.4.1192.bloodjournal8241192

Cited by 8 publications

(9 citation statements)

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“…However, it is possible that anti‐platelet antibodies damage or alter the platelet membrane so that cell‐bound complement regulators, CD55 and CD59, are lost or modified. This would enhance anti‐platelet antibody‐mediated complement activation resulting in direct membrane injury and vesiculation as has been observed in platelets from patients with PNH 23 …”

Section: Complement Disorders Associated With Thrombocytopeniamentioning

confidence: 89%

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Complement in immune thrombocytopenia (ITP): The role of complement in refractory ITP

Weitz,

Liebman

2023

Br J Haematol

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SummaryImmune thrombocytopenia (ITP) is a disorder characterized by low platelets due to increased clearance and decreased platelet production. While ITP has been characterized as an acquired disorder of the adaptive immune system, the resulting platelet autoantibodies provide ancillary links to the innate immune system via antibody interaction with the complement system. Most autoantibodies in patients with ITP are of the IgG1 subclass, which can be potent activators of the classical complement pathway. Antibody‐coated platelets can initiate complement activation via the classical pathway leading to both direct platelet destruction and enhanced clearance of C3b‐coated platelets by complement receptors. Similar autoantibody interactions with bone marrow megakaryocytes can also result in complement injury and ineffective thrombopoiesis. The development of novel therapeutic complement inhibitors has revived interest in the role of complement in autoantibody‐mediated disorders, such as ITP. A recent early‐phase clinical trial of a classical complement pathway inhibitor has demonstrated efficacy in a subset of ITP patients refractory to conventional immune modulation. In this review, we will analyse the role of complement in refractory ITP.

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Section: Complement Disorders Associated With Thrombocytopeniamentioning

confidence: 89%

“…This would enhance anti-platelet antibody-mediated complement activation resulting in direct membrane injury and vesiculation as has been observed in platelets from patients with PNH. 23…”

Section: Com Pl E M E N T Disor Der S As Soci Ate D W Ith Throm Boc Y...mentioning

confidence: 99%

Complement in immune thrombocytopenia (ITP): The role of complement in refractory ITP

Weitz,

Liebman

2023

Br J Haematol

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“…22,23 Deficiency or absence of CD55 and CD59 thus results in chronic complement-mediated hemolysis in patients with PNH, and a greater than 90% reduction in the lifespan of PNH RBCs as compared to normal RBCs. 24 Complement can be activated through multiple pathways (i.e. classical, alternative, and lectin) that converge at the complement component C3, which is the central protein in the complement cascade.…”

Section: An Overview Of Pnh Pathophysiologymentioning

confidence: 99%

Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria

Wong

2022

Therapeutic Advances in Hematology

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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by complement-mediated hemolysis, thrombosis, and various degrees of bone marrow dysfunction. Until recently, C5 inhibition with eculizumab or ravulizumab represented the only therapies approved for patients with PNH by the United States Food and Drug Administration (US FDA). Although C5-inhibitors reduce PNH-related signs and symptoms, many patients continue to exhibit persistent anemia and require frequent blood transfusions. In May 2021, pegcetacoplan became the third US FDA-approved treatment for adults with PNH, and the first to target C3, a complement component upstream of C5. The novel strategy of inhibiting proximal complement activity with pegcetacoplan controls C5-mediated intravascular hemolysis and prevents C3-mediated extravascular hemolysis. Here, we review the results from multiple pegcetacoplan clinical studies on the efficacy and safety of pegcetacoplan treatment in adults with PNH. This review summarizes findings from three studies in complement-inhibitor-naïve patients with PNH (PADDOCK [phase Ib], PALOMINO [phase IIa], PRINCE [phase III; pegcetacoplan versus standard treatment excluding complement-inhibitors]), and one phase III study (PEGASUS) that compared eculizumab to pegcetacoplan in patients who remained anemic (hemoglobin levels < 10.5 g/dL) despite stable eculizumab treatment (⩾3 months). These studies found that pegcetacoplan contributed to superior improvements in primary and secondary endpoints related to hemoglobin levels and other hematologic parameters and provided effective management of anemia and anemia-related complications (i.e. transfusion burden, reticulocyte production, and fatigue). Furthermore, we summarize results from the 32-week open-label period from the PEGASUS trial, which confirmed the long-term safety and durable efficacy of pegcetacoplan as demonstrated by sustained improvements in clinical and hematologic outcomes in pegcetacoplan-treated patients. Pegcetacoplan is approved for the treatment of adults with PNH in the United States (Empaveli™) and for adult patients who remain anemic after at least 3 months of stable C5-inhibitor therapy in the European Union (Aspaveli®) and Australia (Empaveli; also approved for patients intolerant to C5-inhibitors).

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“…C3 −/− mice have prolonged bleeding time and diminished platelet activation, further proving a direct link between complement and platelet activation (22,23). Besides, the anaphylatoxin C3a and its derivative C3adesArg directly induced platelet activation and aggregation (24). In comparison to C3 −/− mice, C5 −/− mice have no apparent defect in platelet activation, platelet deposition in the vessel wall, and the initial hemostasis (22).…”

Section: The Effect Of the Complement System On Platelet Activationmentioning

confidence: 99%

Complement in Hemolysis- and Thrombosis- Related Diseases

Luo

Wang

et al. 2020

Front. Immunol.

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The complement system, originally classified as part of innate immunity, is a tightly self-regulated system consisting of liquid phase, cell surface, and intracellular proteins. In the blood circulation, the complement system, platelets, coagulation system, and fibrinolysis system form a close and complex network. They activate and regulate each other and jointly mediate immune monitoring and tissue homeostasis. The dysregulation of each cascade system results in clinical manifestations and the progression of different diseases, such as sepsis, atypical hemolytic uremic syndrome, C3 glomerulonephritis, systemic lupus erythematosus, or ischemia-reperfusion injury. In this review, we summarize the crosstalk between the complement system, platelets, and coagulation, provide integrative insights into how complement dysfunction leads to hemopathic progression, and further discuss the therapeutic relevance of complement in hemolytic and thrombotic diseases.

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Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria

Cited by 8 publications

References 0 publications

Complement in immune thrombocytopenia (ITP): The role of complement in refractory ITP

Complement in immune thrombocytopenia (ITP): The role of complement in refractory ITP

Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria

Complement in Hemolysis- and Thrombosis- Related Diseases

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