Treatment of PNH hemolytic crisis with heparin or low-molecular weight heparin by its dual (anti-complement and anti-coagulant) activity

The anti-complement (C') activity of heparin has been well demonstrated, but its clinical use as anti-C' drug has been limited by its anticoagulant activity. A 34-year-old man with PNH was complicated by two episodes of hemolytic crisis in 1999 and in 2000, triggered by infections. Because hemolytic crisis is often followed by thrombotic complications in PNH, we treated the crises with heparin or low-molecular weight heparin (dalteparin) by expecting dual effects on the C' and coagulation systems. On the first crisis, heparin was administered at 8,000 IU/day x 9 days which obtained 0.16-0.28 IU/mL anti factor Xa activity in the plasma. On the second crisis, dalteparin was administered at 4,800 U/day x 20 days which obtained 0.04-0.07 U/mL anti-factor Xa activity. On the both crises, no thrombosis developed. Red cell transfusions were required under heparin administration, but not under dalteparin. In the both courses of crises, biochemical data returned to the levels before the crises in 14-20 days. In vitro experiment demonstrated that heparin or dalteparin (> 0.6 IU/mL) effectively inhibit C'-mediated hemolysis in PNH. Because anti-C' activity of heparin is independent of its anticoagulant (AT-III-binding) activity, heparin or its derivatives with enriched anti-C' activity are potentially useful to inhibit C'-mediated hemolysis as well as to prevent thrombotic complications in PNH.