Basic weapons to degrade C3a and C5a

Foley, Jonathan H.; Conway, Edward M.

doi:10.1111/jth.13999

Cited by 6 publications

(5 citation statements)

References 34 publications

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“… 10 , 21 , 22 , 23 , 24 This is in line with data from animal studies using cobra venom factor (CVF) to decomplement animals via an exhaustive fluid phase consumption of C3 and C5 which apparently occurs without any ill effect to the animal. 10 , 25 , 26 , 27 However, these conclusions from clinical practice in humans and animal studies using CVF are contrasted by a plethora of published data from in vitro or animal studies that suggest a direct mechanistic link between complement activation and coagulation and/or prothrombotic cell activation (reviewed previously 4 , 10 , 11 , 28 , 29 ).…”

Section: Introductionmentioning

confidence: 99%

Complement and platelets: prothrombotic cell activation requires membrane attack complex–induced release of danger signals

Mannes,

Pechtl,

Hafner

et al. 2023

Blood Advances

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Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic syndrome (aHUS) results in cytolysis and fatal thrombotic events which are largely refractory to anticoagulation and/or antiplatelet therapy. Anti-complement therapy, however, efficiently prevents thrombotic events in PNH and aHUS but the underlying mechanisms remained unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by ADP. Blockage of C3 or C5 abolished platelet activation. We found that human platelets failed to respond functionally to the anaphylatoxins C3a and C5a. Instead, complement activation did lead to prothrombotic cell activation in whole blood when MAC-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation although full complement activation, causing hemolysis, occurred. By employing an established model of mismatched erythrocyte transfusions in rats, we cross-validated the above findings in vivo utilizing the complement inhibitor OmCI and cobra venom factor (CVF). Consumptive complement activation in this animal model only led to a thrombotic phenotype when MAC-mediated cytolysis occurred. In conclusion, complement activation only induces substantial prothrombotic cell activation if terminal pathway activation culminates in MAC-mediated release of intracellular ADP. These results explain why anti-complement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.

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Section: Introductionmentioning

confidence: 99%

Complement and platelets: prothrombotic cell activation requires membrane attack complex–induced release of danger signals

Mannes,

Pechtl,

Hafner

et al. 2023

Blood Advances

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“…Whether or not complement activation occurs after blood contact with a biomaterial also reflects whether the material has good blood compatibility. After complement activation, anaphylatoxins such as C3a and C5a are produced, and thus, the concentration of these anaphylatoxins can be detected in plasma after contact with a material, reflecting the degree of complement activation …”

Section: Resultsmentioning

confidence: 99%

“…After complement activation, anaphylatoxins such as C3a and C5a are produced, and thus, the concentration of these anaphylatoxins can be detected in plasma after contact with a material, reflecting the degree of complement activation. 49,50 The results of contact activation, including complement activation, are shown in Figure 5. As shown in Figure 5A, PF4 concentrations were no larger than the value for noncontacted plasma for all modified membranes, indicating that platelet activation did not occur after contact of the modified membranes with blood.…”

Section: Clotting Time (Aptt and Tt) Detectionmentioning

confidence: 99%

Improvement in the blood compatibility of polyvinylidene fluoride membranes via in situ cross‐linking polymerization

Nie

Zeng

Qin

et al. 2018

Polymers for Advanced Techs

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In this study, we have provided a highly efficient, convenient, and universal protocol for preparing polyvinylidene fluoride (PVDF) membranes with low blood contact activation via in situ cross‐linking copolymerization of 2‐hydroxyethl methacrylate (HEMA) and acrylic acid (AA) in a solution of PVDF. The modified membranes were prepared from PVDF solution by phase inversion technology. The composition and morphology of the modified membranes were confirmed by attenuated total reflectance‐Fourier transform infrared (ATR‐FTIR) spectroscopy, thermogravimetric (TG) analysis, and scanning electron microscopy (SEM). Protein adsorption, clotting time, and contact activation on the modified PVDF membranes were systematically studied, the results indicating that after the incorporation of AA and HEMA, the modified PVDF membranes possessed anticoagulant properties in addition to low contact activation of blood components when in contact with blood. Therefore, fluorinated PVDF membranes with surfaces enriched with carboxyl and hydroxyl groups possessed the potential for use in long‐term blood‐contacting devices.

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“…It is worthy of expectation for preclinical studies on recombinant CPB to suppress the unrestrained in ammation and reduce the clinical severity of COVID-19. Notably, the endogenous CPB2 was also known as thrombin-activatable brinolysis inhibitor (TAFI) to inhibit brinolysis and thereby reduce the binding of plasminogen to the brin clot [23]. An excessive supplement of recombinant CPB may upset the balance between coagulation and brinolysis.…”

Section: Discussionmentioning

confidence: 99%

“…The resulting C5a des-Arg retains 1-10% of the in ammatory activity of C5a, and C3a des-Arg is devoid of any proin ammatory activity [21]. Recently, Carboxypeptidase B2 (CPB2, encoded by human CPB2 gene) was demonstrated to be an important regulator in reducing in ammatory response and organ damage by degrading plasma anaphylatoxins [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Carboxypeptidase B Inhibits Over-activation of Anaphylatoxin-neutrophil Extracellular Trap Axis in COVID-19 Patients

Zhang¹,

Han²,

Du³

et al. 2020

Preprint

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Background: Thrombosis and coagulopathy are highly prevalent in severe patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. Neutrophil extracellular traps (NETs) are primary components of immunothrombosis, whereas the mechanism of NET formation remains unclear. We aim to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19.Methods: We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase-DNA. We detected complement-induced NET formation by immunofluorescent staining and evaluated the cytotoxicity to vascular endothelial HUVEC cells by CCK-8 assay.Results: We found that the plasma levels of complements (C3 and C5) and NETs were closely related to coagulopathy and multiple organ dysfunction in patients with COVID-19. By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products.Conclusions: Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.

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Basic weapons to degrade C3a and C5a

Cited by 6 publications

References 34 publications

Complement and platelets: prothrombotic cell activation requires membrane attack complex–induced release of danger signals

Complement and platelets: prothrombotic cell activation requires membrane attack complex–induced release of danger signals

Improvement in the blood compatibility of polyvinylidene fluoride membranes via in situ cross‐linking polymerization

Carboxypeptidase B Inhibits Over-activation of Anaphylatoxin-neutrophil Extracellular Trap Axis in COVID-19 Patients

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