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  • Mannes, MarcoUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (author)

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

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • American Society of Hematology,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-516655
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-516655URI
  • https://doi.org/10.1182/bloodadvances.2023010817DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic events, which are largely refractory to anticoagulation and/or antiplatelet therapy. Anticomplement therapy, however, efficiently prevents thrombotic events in PNH and aHUS, but the underlying mechanisms remain unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by adenosine 5 '-diphosphate (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 the whole blood when membrane attack complex (MAC)-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation, although full complement activation, which causes hemolysis, occurred. By using an established model of mismatched erythrocyte transfusions in rats, we crossvalidated these findings in vivo using the complement inhibitor OmCI and cobra venom factor. 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 anticomplement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Pechtl, VeronikaUniv Ulm, Med Ctr, Inst Expt & Clin Pharmacol Toxicol & Pharmacol Nat, Ulm, Germany. (author)
  • Hafner, SusanneUniv Ulm, Med Ctr, Inst Expt & Clin Pharmacol Toxicol & Pharmacol Nat, Ulm, Germany. (author)
  • Dopler, ArthurUniv Ulm, Med Ctr, Inst Expt & Clin Pharmacol Toxicol & Pharmacol Nat, Ulm, Germany. (author)
  • Eriksson, Oskar,1984-Uppsala universitet,Vaskulärbiologi(Swepub:uu)osker931 (author)
  • Manivel, Vivek AnandUppsala universitet,Vaskulärbiologi(Swepub:uu)vivan468 (author)
  • Wohlgemuth, LisaUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (author)
  • Messerer, David Alexander ChristianUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (author)
  • Schrezenmeier, HubertUniv Ulm, Inst Transfus Med, Ulm, Germany.;Univ Hosp Ulm, Inst Clin Transfus Med & Immunogenet Ulm, Ulm, Germany.;German Red Cross Blood Serv Baden Wurttemberg Hess, Ulm, Germany. (author)
  • Nilsson Ekdahl, KristinaUppsala universitet,Vaskulärbiologi(Swepub:uu)krisnil (author)
  • Nilsson, BoUppsala universitet,Vaskulärbiologi(Swepub:uu)bonils (author)
  • Jacobsen, Eva -MariaUniv Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. (author)
  • Hoenig, ManfredUniv Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. (author)
  • Huber-Lang, MarkusUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (author)
  • Braun, Christian K.Univ Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany.;Univ Hosp Ulm, Dept Pediat & Adolescent Med, Eythstr 24, D-89075 Ulm, Germany. (author)
  • Schmidt, Christoph Q.Univ Ulm, Med Ctr, Inst Expt & Clin Pharmacol Toxicol & Pharmacol Nat, Ulm, Germany.;Martin Luther Univ Halle Wittenberg, Inst Pharm, Biochem Pharm Grp, Halle, Germany.;Univ Ulm, Inst Expt & Clin Pharmacol Toxicol & Pharmacol Nat, Med Ctr, Helmholtzstr 20, D-89081 Ulm, Germany. (author)
  • Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany.Univ Ulm, Med Ctr, Inst Expt & Clin Pharmacol Toxicol & Pharmacol Nat, Ulm, Germany. (creator_code:org_t)

Related titles

  • In:Blood Advances: American Society of Hematology7:20, s. 6367-63802473-95292473-9537

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