Extravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment

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• 作者：Marta Subí ; as Hidalgo^a ; Hector Martin Merinero^a ; Alicia Ló ; pez^a ; Jaouad Anter^a ; Sheila Pinto Garcí ; a^a ; Fernando Ataú ; lfo Gonzalez-Ferná ; ndez^b ; Rafael Foré ; s^c ; Margarita Lopez-Trascasa^d ; Ana Villegas^b ; Emilio Ojeda^c ; Santiago Rodrí ; guez de Có ; rdoba^a ; ^{srdecordoba@cib.csic.es}
• 关键词：PNH ; Complement ; extravascular hemolysis ; Complement receptor 1 ; Eculizumab
• 刊名：Immunobiology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：222
• 期：2
• 页码：363-371
• 全文大小：1275 K
• 卷排序：222

文摘

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n = 12) for signs of hemolysis and assessed complement biomarkers. Patients were also genotyped for complement receptor 1 (CR1, CD35) and C5 polymorphisms and evaluated for free eculizumab in plasma. We report that 10 patients (83%) present parameters suggesting persistent hemolysis, although they did not require additional transfusions. Seven of them (58%) become direct Coombs-test positive as a consequence of treatment, including all patients carrying the low-expression CR1-L allele. CH50 and sC5b-9 assays demonstrate that the persistent low-level hemolysis identified in our treated patients is not a consequence of incomplete C5 blockade, supporting that this hemolysis, as has been suggested previously, results from the extravascular removal of C3 opsonized PNH erythrocytes. We also show that continuous alternative pathway activation in eculizumab-treated individuals carrying the CR1-L allele results in abnormally decreased levels of C3 in plasma that could, potentially, increase their susceptibility to bacterial infections. Finally, we encourage a routine evaluation of free eculizumab levels and terminal pathway activity to personalize eculizumab administration.