Any of the causes of hypersplenism increased activity of the spleen , such as portal hypertension. Acquired hemolytic anemia is also encountered in burns and as a result of certain infections e. Lead poisoning or poisoning by arsine or stibine causes non-immune hemolytic anemia. Red blood cells without right and middle and with left hemolysis. If as little as 0. In vitro hemolysis can be caused by improper technique during collection of blood specimens, by the effects of mechanical processing of blood, or by bacterial action in cultured blood specimens.
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This results in the deposition of the opsonic fragment C3b on the RBC and may, upon increasing opsonization, lead to the formation of membrane attack complexes MAC. Complement-opsonized RBC are cleared extravascularly via complement receptor-mediated phagocytosis mainly by liver macrophages, whereas IgG-opsonized RBC are phagocytosed via Fc-gamma receptors by splenic macrophages. Additionally, intravascular hemolysis may occur due to complement-induced MAC formation on the RBC membrane as a consequence of strong complement activation by, for example, IgM auto-antibodies causing direct hemolysis in the circulation.
A significant proportion of patients with AIHA have IgM auto-antibodies that are not detectable using the most common diagnostic techniques and complement activation accompanied by intravascular hemolysis. However, they do not act immediately and some patients are unresponsive.
Currently, the only available therapeutic complement inhibitors are eculizumab, used for the treatment of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and generalized myasthenia gravis, and C1 esterase inhibitor C1-INH , approved for the treatment of hereditary angioedema.
Eculizumab inhibits complement activation at the level of C5 and blocks MAC formation, thereby preventing intravascular hemolysis; however, it does not halt opsonization or extravascular hemolysis, which renders this drug less suitable for AIHA patients.
Due to the low-affinity interaction with its substrates, high doses of C1-INH are needed. Sutimlimab, a humanized monoclonal antibody directed against human C1s, specifically blocks the classical pathway of complement. Although sutimlimab has been recently shown to be safe in a randomized first-in-human study in healthy volunteers, antidrug antibodies were detected in some of the treated volunteers, which could compromise the inhibitory capacity of this antibody.
Cp40 targets complement activation at the level of C3 and is therefore expected to block both extra- and intravascular hemolysis. Cp40 has been previously shown to inhibit C3 deposition on RBC in an in vitro malaria model 10 and complement opsonization and hemolysis of RBC from patients with paroxysmal nocturnal hemoglobinuria.
Although complement deposition was observed with all tested sera, opsonization levels differed among patients, presumably due to variability in titer and the subclass of the opsonizing auto-antibodies in the sera from the different patients Figure 1A. This reduction was stronger than that achieved with C1-INH and similar to the levels observed when a monoclonal antibody against C1q was used and in the ethylenediaminetetraacetic acid EDTA control Figure 1C , the latter of which blocks all complement activity.
No inhibition was observed with a sequence-scrambled Cp40 control peptide. As reported previously, higher levels of C4b were detected on the RBC membrane in the presence of Cp40 Figure 1D , probably due to enhanced detection of C4b in the absence of surrounding C3b.
This inhibition was comparable to that observed in sera treated with eculizumab or EDTA, whereas the scrambled Cp40 control did not inhibit MAC formation. Previous studies have shown that Cp40 blocks C3 deposition and hemolysis of RBC in the context of malaria and paroxysmal nocturnal hemoglobinuria, which are both antibody-independent diseases.
Mecanismos de destrucción de los hematíes
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