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Thromboembolic event is the most important complication of paroxysmal nocturnal hemoglobinuria (PNH) affecting its mortality. The pathophysiological mechanisms underlying thrombosis in PNH have not been fully clarified; multiple factors are likely to be involved. They are likely to be related to the complement activation on/around red blood cells (RBC), white blood cells, and particularly platelets. Intravascular hemolysis also contributes to the mechanisms through the release of free hemoglobin, depletion of nitric oxide (NO), and generation of RBC-derived microparticles (MP). Elevated MP in the plasma which derive from platelets, endothelial cells, and RBC, in total, enhance the prothrombotic states in the circulation. Recent researches have revealed close interactions between coagulation and complement systems, enhancing each other. Continuous activation of complement makes a vicious loop enhancing the coagulation/complement systems interacting with blood cells and endothelial cells in PNH.

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 lU/day × 9 days which obtained 0.16-0.28 lU/mL anti factor Xa activity in the plasma. On the second crisis, dalteparin was administered at 4,800 U/day × 20 days which obtained 0.04–0.07 U/mL anti-factor Xa activity. On the both crises, no thrombosis developed. Red cell transftisions 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 lU/mL) effectively inhibit C'-mediated hemolysis in PNH. Because anti-C activity of heparin is independent of its anticoagulant (AT-lII-binding) activity, heparin or its derivatives with enriched anti-C activity are potentially useful to inhibit Cmediated hemolysis as well as to prevent thrombotic complications in PNH.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder caused by PIG-A mutations. To assess clonal expansion in PNH over time, patients with serial testing by flow cytometry (interval of at least one year) were analyzed. This study involved 164 patients with PNH from Duke (DP) and 151 patients from Japan (JP). The mean fraction of PMNs deficient in CD59 (mean±SE) was 75.2±4.2% in DP and 40.0 + 8.3% (n=21) in JP at the initial analysis, and were 74.1 ±4.7% and 50.7 + 8.6% at the latest analysis (P=NS). However, in individual cases, the proportion of affected PMNs varied considerably from -84% to +98%. Some DP and JP pts, however, had a diminution in their CD59-deficient PMNs over time, which was associated with the development of overall hematopoietic failure (P=.04 for DP, P=.05 for JP). These data illustrate the complexity of clonal expansion in PNH, and the marked variability over time. GPI-deficient populations vary considerably over time for individual patients, but a decreasing PNH clone indicates impending hematopoietic failure. Correlation between clonal expansion or diminution and the development or recovery from aplasia will help our understanding of the natural history of PNH.

PNH, which is characterized by intravascular hemolysis and venous thrombosis, is an uncommon disorder of hematopoietic stem cells with an acquired somatic mutation of PIG-A. An understanding of the natural history of PNH is essential to improve therapy. To determine and to directly compare the clinical courses of PNH patients from the USA and Japan, data were collected for 385 patients with PNH. There were 176 patients from Duke (DP) and 209 patients from Japan (JP). The mean age at diagnosis (mean ± SE) was 32.8 ±1.2 years (4-80) in DP, and 45.1 ±1.3 years (10-86) in JP. The incidence of various chnical events was analyzed. These analyses provide important diagnostic and long-term data on two large cohorts of PNH patients, and identify important differences between Caucasian and Asian patients with PNH. Caucasians tend to be younger and have classical symptoms of PNH including thrombosis, while Asians tend to be older and have symptoms of aplasia. Multivariate analysis of factors influencing survival was also undertaken. By this study, estimates of PNH prognostic factors may provide a better understanding of the complications of the disease so that therapeutic interventions may be sought. Further, by noting differences in the two populations, possible genetic modifiers of the course of the disease may be identified for further investigation.