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The Pathogenesis and Pathology of the Hemorrhagic State in Viral and Rickettsial Infections
Published in James H. S. Gear, CRC Handbook of Viral and Rickettsial Hemorrhagic Fevers, 2019
An experimental model of AHF, infection of guinea pigs with Junin virus, results in fever, weight loss, thrombocytopenia, leukopenia, death on day 11 to 15, and hemorrhagic lesions observed at necropsy. Several observations may have importance in relation to hemostatic defects. Guinea pig megakaryocytes are infected with Junin virus, which grows in bone marrow to a titer 100-fold higher than in plasma.71 Destruction of bone marrow cells occurs with elevated serum concentrations of acid proteases on days 8 to 12 and acid and alkaline phosphatases on days 6 to 12.72 All animals died by day 12. The origin of these enzymes, which is probably leukocytic lysosomes, has been hypothesized as the heat stable, divalent cation-dependent activator of CI. The effect is consumption of C4 and depression of total complement activity.73 The results of these changes in complement activity are not clear, but vascular integrity and coagulation could be affected.
Eculizumab for the treatment of myasthenia gravis
Published in Expert Opinion on Biological Therapy, 2020
Renato Mantegazza, Paola Cavalcante
Hemolytic activity, reflecting total complement activity (CH50 and AP50), is reported as an eculizumab activity marker, along with C5 function [28,35]. For eculizumab levels of >100 µg/ml, undetectable CH50 and AP50, and normal C5 levels, with inhibited C5 function, have been reported [35]. Pharmacodynamic activity measured by free C5 concentrations <0.5 ug/mL was correlated with complete complement activity blockade in gMG, as in PNH, aHUS, and NMOSD [33]. Data from single- and multiple-dose studies across different patient populations indicated that 35 µg/ml serum eculizumab concentration is sufficient to block complement [34]. A suboptimal response to eculizumab was described in PNH patients bearing a rare missense C5 variant c.2654 G→A (p.Arg885His) able to inhibit eculizumab binding to C5 [36], suggesting that genetic factors affecting the drug efficacy should be investigated and considered for developing personalized approaches.