Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 17)

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Bone Marrow Failure—Relationship between PNH and AA It is not unusual that patients with firmly established PNH have a previous history of well-documented AA. On the other hand, sometimes a patient with PNH becomes less hemolytic and more pancytopenic and ultimately has the clinical picture of AA. Since AA is probably an organ-specific autoimmune disease in which T cells cause damage to hematopoietic stem cells, the same may be true of PNH, with the specific proviso that the damage spares PNH stem cells. Skewing of the T cell repertoire in patients with PNH supports this notion. In addition, in...

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Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 17) Bone Marrow Failure—Relationship between PNH and AA It is not unusual that patients with firmly established PNH have a previous history of well-documented AA. On the other hand, sometimes a patient with PNH becomes less hemolytic and more pancytopenic and ultimately has the clinical picture of AA. Since AA is probably an organ-specific autoimmune disease in which T cells cause damage to hematopoietic stem cells, the same may be true of PNH, with the specific proviso that the damage spares PNH stem cells. Skewing of the T cell repertoire in patients with PNH supports this notion. In addition, in mouse models, PNH stem cells do not expand when the rest of the bone marrow is normal, and by high-sensitivity flow cytometry technology, very rare PNH cells harboring PIG-A mutations can be demonstrated in normal people. In view of these facts, it seems that an element of bone marrow failure (BMF) in PNH is the rule rather than the exception. An extreme view is that PNH is a form of AA in
which BMF is masked by the massive expansion of the PNH clone that populates the patient's bone marrow. The mechanism whereby PNH stem cells escape the damage suffered by non-PNH stem cells is not yet known. Paroxysmal Nocturnal Hemoglobinuria: Treatment Unlike other acquired HAs, PNH may be lifelong and most patients receive supportive treatment only, including transfusion of filtered red cells 2 whenever necessary. Folic acid supplements (at least 3 mg/d) are mandatory; the serum iron should be checked periodically and iron supplements administered as appropriate. Long-term glucocorticoids are not indicated because there is no evidence that they have any effect on chronic hemolysis, and their side effects are considerable and potentially dangerous. The only form of treatment that can provide a cure for PNH is allogeneic bone marrow transplantation (BMT); when an HLA-identical sibling is available, BMT should be offered to any young patient with severe PNH. 2 Now that filters with excellent removal of white cells are routinely used, the traditional washing of red cells, which aimed to avoid white cell reactions triggering hemolysis, is no longer necessary and considered wasteful. A major advance in the management of PNH has been the development of a humanized monoclonal antibody, eculizumab, directed against the complement
protein C5 (Fig. 101-9). By blocking the complement cascade downstream of C5, this antibody provides a medical intervention capable of controlling complement- dependent hemolysis in PNH. In an international multicenter placebo-controlled randomized trial on 87 patients who had been selected on grounds of having severe transfusion-dependent hemolysis, eculizumab completely abolished the need for blood transfusion in about one-half of the patients. Eculizumab administered intravenously at q2wk intervals also ameliorated the anemia in most patients and dramatically improved their quality of life. Figure 101-9
Therapeutic efficacy of an anti-C5 antibody on the anemia of paroxysmal nocturnal hemoglobinuria. (From P Hillmen et al: N Engl J Med 355:1233, 2006; with permission.) For patients with PNH-AA syndrome, immunosuppressive treatment with antilymphocyte globulin (ALG or ATG) and cyclosporine A may be indicated. Although no formal trial has ever been conducted, this approach has helped particularly to relieve severe thrombocytopenia and/or neutropenia in patients in whom these were the main problem(s). By contrast, there is often little immediate effect on hemolysis. Thrombolytic therapy with tissue plasminogen activator may
be indicated after severe thrombosis. Any patient who has had deep vein thrombosis at any site in the abdomen or in a limb should be on regular anticoagulant prophylaxis.