Paroxysmal nocturnal haemoglobinuria with coexisting deficiency of the ninth component of complement: lack of massive haemolytic attack

Abstract

A 47-year-old woman with paroxysmal nocturnal haemoglobinuria (PNH) was found to have an inherited deficiency in the ninth complement component (C9). In complement-sensitivity lysis tests, 80% of her erythrocytes were markedly complement-sensitive (PNH-III). Laser cytofluorimetry with a monoclonal antibody against decay-accelerating factor (DAF) revealed that 95% of her erythrocytes were DAF-negative. Surprisingly, she has suffered only mild haemolysis and has never experienced massive spontaneous haemolysis. Gross haemoglobinuria and jaundice occurred only after receiving postoperative transfusion of whole blood. In her serum, C9 was not detectable either by immunological or by functional assays. Both the Ham test and the sugar water test using normal human serum or plasma yielded marked haemolysis of the patient's erythrocytes. When the patient's serum or plasma was used, only a trace of lysis was detected. Addition of purified human C9 to her plasma fully restored haemolysis. These observations indicated that C9 may play a critical role in haemolytic attacks in patients with PNH and that characteristic haemolysis in PNH may be tempered by coexisting C9 deficiency.

A novel mechanism of complement-independent clearance of red cells deficient in glycosyl phosphatidylinositol–linked proteins

“…In fact, mild hemolysis was found in a PNH patient with inherited C9 deficiency. 33 The cause of hemolysis in this patient is unclear because deficiency of DAF alone does not cause hemolysis. [37][38][39] This suggests that in this C9-deficient PNH patient, as in the mice described here, an increased complement-independent clearance occurs that shortens the half-life of PNH RBCs.…”

“…This pathway is independent of complement and is mediated by fixed macrophages in spleen, liver, and possibly bone marrow. In patients with PNH this pathway is likely masked by the overwhelming hemolysis caused by complement; however, it might become manifest if the lytic action of complement is inhibited, for example, due to inherited C9 deficiency 33 or, more recently, due to treatment with complement inhibitors that currently are tested for the treatment of PNH. 34 Mice with PIGA Ϫ RBCs have lower hemoglobin levels and RBC counts, whereas the reticulocyte counts are higher compared to wt controls.…”

Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria

“…In this regard, slightly elevated levels of LDH have also been reported in a patient with coexistent PNH and C9 deficiency. 12 The marked reduction in transfusions demonstrated in the initial eculizumab study was sustained in the extension study. Further, patients who had good bone marrow reserve (those without cytopenia) showed greater reductions in transfusion requirements than did patients who had hypoplasia (those with cytopenia).…”

Persistently high quality of life conferred by coexisting congenital deficiency of terminal complement C9 in a paroxysmal nocturnal hemoglobinuria patient

“…7 In 1980, we found a PNH patient with a coexisting congenital deficiency of C9, still the only case globally. 8 Presently, the patient is 78 years old and has kept a high QOL (no experience of massive hemolysis, thrombotic events, critical infection, or malignant diseases) for more than 31 years after the PNH diagnosis. Of note, the patient manifests very low levels of PNH hemolysis ( Figure 1A-B) and marrow failure ( Figure 1A).…”