Recombinant human erythropoietin to assist autologous blood donation by patients with anemia

Abbreviations: AABB = A m e r i c a n Associat ion o f Blood Banks; Epo = ery thropoiet in ; Hb = hemog lob in ; Hct = hematocr i t ; rHuEpo = r e c o m b i n a n t h u m a n ery thropo ie t in

D espite all of our technical and scientific achievements, allogeneic transfusion is still considered a procedure to be avoided if pos-

sible, because it cannot be made entirely risk free. In candidates for elective surgery, the safest alternative to allogeneic blood is the use of the patient's own blood, obtained by using various autotransfusion techniques. ~-3 Among these, preoperative blood do- nation likely represents the best approach, both be- cause of its simplicity and because of its efficacy. Autologous blood is believed to be more costly than allogeneic blood, and a study based on decision- analysis techniques has concluded that, given the improved safety of allogeneic transfusions nowa- days, the increased protection afforded by donating autologous blood is limited and may not justify the increased cost. 4 Despite the apparent financial dis- advantage, many in the scientific community believe that reduction of allogeneic blood use via autolo- gous blood donation should be recommended. 5 In addition, the high cost of preoperative autologous blood donation mainly reflects the cost of collecting and discarding units that are not used. 6 It can there- fore be minimized by applying these programs only to patients who really need and can benefit from them.

Irrespective of their cost effectiveness, autotrans- fusion programs are not invariably medically effec- tive, as discussed in detail elsewhere] The main reason for this is that many patients, during the relatively short time for which the collected units can be stored, are unable to predeposit sufficient blood to meet their transfusion needs, s In a retro- spective study on 2500 cases, only two thirds of patients were found to be able to predeposit the optimal amount of autologous blood9; the major cause for failure was a fall in Hct below the thresh- old of 33%, which often occurred after the first or second donation. Two major factors determine the amount of blood that the individual patient can

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predeposit: the patient's red cell mass and the pa- tient's ability to rapidly reconstitute the volume of red cells withdrawn during the predonation pro- gram. Clearly, patients of small size or with low baseline Hct (i.e., with a small red cell mass) do not generally succeed in predepositing the quantity of blood required to cover their transfusion require- ments.

The other crucial variable for a successful autol- ogous donation program is the patient's ability to rapidly reconstitute his/her red cell mass. Under the stimulus of anemia, the erythroid marrow is able to increase its level of production severalfold. 1° The full proliferative response, however, requires several days, and its magnitude is affected by the endoge- nous Epo response to anemia and by the level of iron supply. 1° Even if the iron supply to the erythron is adequate, the proliferative capacity of the ery- throid marrow may be limited by endogenous Epo production .11 Epo production, in fact, increases sig- nificantly only for Hct values of <30% (or Hb <10 gm/dl). 12 According to AABB standards, however, donation should not take place when Hct is <33% and Hb <11 gm/dl. This means that the degree of anemia induced by autologous blood donations is never sufficient to increase endogenous Epo levels as much as it would be required for an optimal expansion of erythropoiesis.

Goodnough et al. 13 were the first to clearly show that rHuEpo is effective in stimulating erythropoie- sis and increasing both new red cell production and autologous blood donation in candidates for elective surgery. For more information on the use of rHuEpo for facilitating the procurement of autolo- gous blood, the reader is referred to the recent, very comprehensive review by Goodnough et al. 14

In our guidelines for the use of rHuEpo outside the setting of uremia, 7 we concluded that, as far as autologous blood donation programs are concerned, rHuEpo should be used in a carefully targeted ap- proach for conditions likely to yield significant re- ductions in the transfusion of allogeneic blood, such as in anemic patients, in individuals with a calcu- lated blood volume <5 L, or with alloimmunization.

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At least two studies have already clearly shown that rHuEpo is safe and effective in stimulating erythro- poiesis and allowing preoperative donation of blood for autologous use in patients who are unable to deposit blood preoperatively because of anemia. 15'a6 In this issue a report by Goodnough and Marcus ~7 confirms and extends previous observations a:~ in pa- tients with anemia caused by rheumatoid arthritis. These individuals generally have lower serum Epo levels than do patients with comparable anemia caused by iron deficiency, and inflammatory cyto- kines are responsible for this defective endogenous Epo production. 7 These cytokines also inhibit ery- throid progenitor cell proliferation and impair iron supply to the erythron, as thus playing a major role in the pathogenesis of the so-called anemia of chronic disease. 7 Interestingly, Goodnough and Marcus 17 show that patients with rheumatoid arthritis respond to rHuEpo and, by doing so, benefit from aggressive blood conservation programs to the same extent as other anemic patients.

It has been clearly shown that anemia caused by rheumatoid arthritis can be corrected by rHuEpo treatment outside the setting of preoperative dona- tionJ 9 Only occasionally, however, do patients with rheumatoid arthritis have Hb levels lower than 9 gm/dl, and practically none of these subjects is de- pendent on transfusion. In addition, the most ane- mic patients are likely to have coexistent iron defi- ciency and may benefit from intravenous iron administration, z° In our opinion, therefore, there is little room for widespread rHuEpo treatment of anemia caused by rheumatoid arthritis] Nonethe- less, the use of rHuEpo in a preoperative donation program, as suggested both by Mercuriali et al) 5 and by Goodnough and Marcus, 17 is fully justified. More generally, we favor a patient-oriented ap- proach to the use of rHuEpo that allows adminis- tration of this expensive drug only to indMduals who are very likely to respond and benefit from this treatment. 7 This approach is also intended to max- imize the potential cost-effectiveness of rttuEpo therapy.

In my opinion, the treatment protocol adopted by Goodnough and Marcus 17 could be further improved. There is no question that autologous blood donors require iron supplementation during rHuEpo treat- merit. 7 However, although iron absorption can in- crease severalfold when rHuEpo is used, 21 oral iron supplementation may still be insufficient to match iron demands by the stimulated erythroid marrow. A recent study in patients with kidney disease indicates that those supplemented with intravenous iron have an enhanced Hb response to rHuEpo with lower dosage

Editorial 355

requirements when compared with patients receiving oral iron. 2z Some American physicians appear to be reluctant to use intravenous iron dextran (preparation available in the United States) be- cause of a certain risk of anaphylaxis (I cannot comment on this because I have no experience with the use of iron dextran). With over 1000 intravenous administrations of iron saccharate (available in Europe), no anaphylactic reaction nor any other life-threatening complication has been observed by us. 7'15'23 It is worth noting that equivalent results have been obtained in anemic patients with rheumatoid arthritis by Goodnough and Marcus, 17 who administered 600 U/kg of rHuEpo (iv; 6 times over 3 weeks) plus oral iron, and by Mercuriali et al., as who administered half the rHuEpo dose (300 U/kg, iv, 6 times over 3 weeks) plus intravenous iron. The other point concerns the optimum route for rHuEpo admin- istration. We have shown that subcutaneous ad- ministration of rHuEpo combined with intrave- nous iron is highly effective in autologous blood donors and, compared with intravenous adminis- tration, allows a marked reduction (approximately 50%) in the total rHuEpo dose. 7

In conclusion, the available evidence indicates that in autologous blood donors, rHuEpo should routinely be given subcutaneously (250 to 300 U/kg 6 times over 3 weeks) and that it should be com- bined with intravenous iron saccharate (200 mg by intravenous infusion at each donation visit). Anemic patients with rheumatoid arthritis are particularly likely to benefit from this treatment.

M A R I O C A Z Z O L A , M D Department of Internal Medicine and Medical Therapy

Internal Medicine and Medical Oncology University of Pavia Medical School

IRCCS Policlinico S. Matteo 27100 Pavia, Italy

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