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...
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Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 17) 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 previoushistory of well-documented AA. On the other hand, sometimes a patient with PNHbecomes less hemolytic and more pancytopenic and ultimately has the clinicalpicture of AA. Since AA is probably an organ-specific autoimmune disease inwhich T cells cause damage to hematopoietic stem cells, the same may be true ofPNH, with the specific proviso that the damage spares PNH stem cells. Skewingof the T cell repertoire in patients with PNH supports this notion. In addition, inmouse models, PNH stem cells do not expand when the rest of the bone marrow isnormal, and by high-sensitivity flow cytometry technology, very rare PNH cellsharboring PIG-A mutations can be demonstrated in normal people. In view ofthese facts, it seems that an element of bone marrow failure (BMF) in PNH is therule rather than the exception. An extreme view is that PNH is a form of AA inwhich BMF is masked by the massive expansion of the PNH clone that populatesthe patients bone marrow. The mechanism whereby PNH stem cells escape thedamage 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 receivesupportive treatment only, including transfusion of filtered red cells 2 whenevernecessary. Folic acid supplements (at least 3 mg/d) are mandatory; the serum ironshould be checked periodically and iron supplements administered as appropriate.Long-term glucocorticoids are not indicated because there is no evidence that theyhave any effect on chronic hemolysis, and their side effects are considerable andpotentially dangerous. The only form of treatment that can provide a cure for PNHis allogeneic bone marrow transplantation (BMT); when an HLA-identical siblingis 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 reactionstriggering hemolysis, is no longer necessary and considered wasteful. A major advance in the management of PNH has been the development of ahumanized monoclonal antibody, eculizumab, directed against the complementprotein 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-controlledrandomized trial on 87 patients who had been selected on grounds of havingsevere transfusion-dependent hemolysis, eculizumab completely abolished theneed for blood transfusion in about one-half of the patients. Eculizumabadministered intravenously at q2wk intervals also ameliorated the anemia in mostpatients and dramatically improved their quality of life. Figure 101-9 Therapeutic efficacy of an anti-C5 antibody on the anemia ofparoxysmal nocturnal hemoglobinuria. (From P Hillmen et al: N Engl J Med355:1233, 2006; with permission.) For patients with PNH-AA syndrome, immunosuppressive treatment withantilymphocyte globulin (ALG or ATG) and cyclosporine A may be indicated.Although no formal trial has ever been conducted, this approach has helpedparticularly to relieve severe thrombocytopenia and/or neutropenia in patients inwhom these were the main problem(s). By contrast, there is often little immediateeffect on hemolysis. Thrombolytic therapy with tissue plasminogen activator maybe indicated after severe thrombosis. Any patient who has had deep veinthrombosis at any site in the abdomen or in a limb should be on regularanticoagulant prophylaxis.