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Jerry L. Spivak Erythropoiesis, the orderly, continuous process by which primitive erythroid progenitor cells give rise to mature circulating erythrocytes, is regulated by the hormone erythropoietin. While a number of other hematopoietic growth factors, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF), as well as other cytokines such as insulin-like growth factor-I (IGF-I) are also involved in the lineage-specific maturation of erythroid progenitor cells, none are as important as erythropoietin. Erythropoietin serves not only as mitogen, but also as a survival factor for erythroid progenitor cells and appears to facilitate their differentiation as well.(1) In the absence of sufficient erythropoietin production, as in the case of chronic renal failure, profound anemia ensues, which is entirely reversible by replacement therapy with recombinant human erythropoietin. However, erythropoietin is not merely a lineage- and stage-specific hematopoietic growth factor. The principal function of the erythrocyte is to transport oxygen from the lungs to the other tissues, and erythropoietin is the linchpin in the simple but elegant mechanism which ensures that under normal circumstances erythrocyte production is balanced with tissue oxygen requirements. Erythropoietin is a 30,400 M.W. glycoprotein produced primarily in the kidneys in adults and only to a small extent in the liver.(2) The erythropoietin gene is also expressed in the brain and some other tissues, but its physiologic role in these locations has not been established. The gene for erythropoietin is present as a single copy on chromosome 7. The erythropoietin gene is highly conserved on an evolutionary basis with over 90% homology between human and simian genes and an 80% homology between human and rodent erythropoietin genes.(3) The high degree of evolutionary conservation, its production in two different organs and its constant presence in the blood serve to emphasize the importance of erythropoietin in the body’s economy. Indeed, it is probably for this reason that to date, after more than 10 years of clinical experience with recombinant human erythropoietin, no convincing evidence for the production of a neutralizing antibody against this protein has been reported. In the kidney, erythropoietin is produced by peritubular interstitial cells located mainly in the inner renal cortex. There are no preformed stores of erythropoietin and production is constitutive in some interstitial cells while it is inducible by hypoxia in others.(4) Erythropoietin production occurs in an all-or-none fashion in each of these cells. Within the liver, erythropoietin is produced in both hepatocytes and interstitial cells.(5) As in the kidneys, production is both constitutive and inducible, but in contrast to the kidneys, within each hepatocyte synthesis of erythropoietin is directly related to the degree of tissue hypoxia. Furthermore, a much greater degree of hypoxia is required to upregulate erythropoietin production in the liver than in the kidneys. Erythropoietin production is tightly regulated at the level of its gene and is independent of its plasma level. Hypoxia is the physiologic stimulus for upregulation of erythropoietin production, while erythrocytosis and, as a corollary, an elevated plasma viscosity suppress erythropoietin production but never completely. Hypoxia appears to
This expectation has been corroborated in numerous studies where it has been demonstrated that there is a log-linear increase in plasma erythropoietin with increasing degrees of anemia. Importantly.with which it shares ~20% sequenceÑbears little homology to any other circulating protein. erythropoietin mRNA is stabilized by hypoxia. the immunoassay for erythropoietin in the blood can also serve as the surrogate measure of tissue hypoxia. immunoreactive erythropoietin circulating in the blood is equivalent to biologically active erythropoietin. Since hypoxia is the only known physiological stimulus for increasing erythropoietin production. There is an important caveat here. there are no preformed stores of the hormone in any organ. Furthermore. in a particular individual. and erythropoietin production is regulated solely at the level of its gene and is independent of its plasma concentration.(8) The erythropoietin immunoassay has provided substantial insight into the physiology and pharmacology of the protein. it is also the basis for a “normal” plasma erythropoietin level in patients with compensated hypoxic erythrocytosis. There is a small diurnal variation with the highest levels occurring in the morning. Erythropoietin production on a constitutive basis is uninfluenced by either age or gender and for a given individual. If the individual’s basal erythropoietin level was unknown. providing an additional mechanism to enhance synthesis of the protein.(9) Since hypoxia is the only known physiologic stimulus for erythropoietin production. The development of recombinant human erythropoietin led to the establishment of a sensitive. such an increase would. presumably. The erythropoietin immunoassay has proved to be clinically useful because there is only one form of circulating erythropoietin.(4) With alleviation of anemia or hypoxia. plasma erythropoietin levels show no correlation with the hemoglobin level. erythropoietin production is tightly regulated and within the normal range of hemoglobin. Consequently. varying from 4-26 mU/ml. as well as providing the basis for determining which anemic patients might benefit from receiving it. is very slow relative to that of other hematopoietic growth factors and is not at all influenced by the size of the erythroid progenitor cell pool. erythropoietin is biochemically unique and. for both men and women. not be recognized. Similarly.(10) Indeed. hypoxia could induce a doubling or even a tripling of the basal erythropoietin level without causing it to rise outside the normal range. reproducible immunoassay for the protein which has replaced cumbersome and insensitive bioassays. the mean plasma . is the basis for the presence of a “normal” plasma erythropoietin level in patients with a compensated hemolytic anemia.activate erythropoietin gene transcription through the mediation of a rapidly turning over heme protein in erythropoietin-producing cells. This. however.(6) In addition to activation or upregulation of gene transcription. However. the circulating erythropoietin level is constant over time just as that individual’s red cell mass is constant. because the range of normal for circulating erythropoietin is wide. with the exception of TPO . anemia should be associated with an increase in plasma erythropoietin. a behavior reflected by the log-linear increase in plasma erythropoietin that is observed with tissue hypoxia or increasing anemia. erythropoietin production is rapidly down regulated and plasma erythropoietin returns to its baseline level.(7) Recruitment of renal peritubular interstitial cells to produce erythropoietin occurs in an exponential fashion. the plasma clearance of erythropoietin is independent of its plasma concentration. therefore.
As a consequence of this behavior. even though men have a larger red cell mass. plasma erythropoietin levels are highly variable and bear no relationship to the degree of anemia.5 grams%. Patients with inflammatory disorders such as rheumatoid arthritis often become anemic.(12) The increase in blood viscosity. erythropoietin levels will be rapidly down regulated into the normal range as a consequence of other mechanisms for dealing with impaired tissue oxygenation. although a reduction in ambient oxygen tension can cause a rapid increase in plasma erythropoietin. in chronic renal failure.5 mg%. increments in plasma erythropoietin with increasing degrees of anemia or tissue hypoxia are relatively modest and do not elevate plasma erythropoietin outside the normal range until the hemoglobin level falls below 10. restoration of the hemoglobin to normal after induced blood loss. when the hypoxia is corrected. it requires a much more severe degree of tissue hypoxia than for a normal individual and even then. patients with chronic renal disease have profound anemia without an increase in plasma erythropoietin outside the normal range. takes place very slowly since such blood donations are planned not to lower the hemoglobin level below 10. Studies of plasma erythropoietin in this group of patients have demonstrated that . even in the absence of anemia. In keeping with the lack of correlation between plasma erythropoietin hemoglobin within the normal range of hemoglobin values. renal parenchymal disease can have a substantial negative impact on erythropoietin production.erythropoietin level is identical for men and women. the log-linear inverse correlation between plasma erythropoietin and the hemoglobin level is lost completely. by an unknown mechanism. Below this level of hemoglobin. plasma erythropoietin unequivocally rises outside the normal range. It is also important to remember that increased blood viscosity per se. such as may occur with autologous blood donations. Thus. Furthermore. unless the reduction in ambient oxygen is severe. but the threshold for production of the protein is also increased. not only is the ability to produce erythropoietin impaired. These patients are not incapable of increasing plasma erythropoietin under hypoxic conditions. The difference in red cell mass between men and women and the presence of similar plasma erythropoietin levels can be accounted for by gender-based differences in androgen production. the erythropoietin assay will not be useful for distinguishing between hypoxic and non-hypoxic erythrocytosis unless the plasma erythropoietin level is unequivocally outside the normal range. which occurs in patients with polycythemia vera. the plasma erythropoietin level will be within the normal range.(11) For these reasons. erythropoietin production is not sustained even though the patient may still be anemic. it should not be surprising that in many patients with cyanotic congenital heart disease or pulmonary insufficiency and an associated erythrocytosis. as soon as the plasma creatinine level rises above 1.(13) However. thus. Thus. Assay of plasma erythropoietin has provided substantial insight into the impact of various disease states on erythropoietin production. also suppresses erythropoietin production. it is important that the inherent mechanisms the body employs to maintain the erythropoietin level as low as possible always be taken into consideration when the results of a plasma erythropoietin assay are being evaluated. In contrast to normal individuals in whom plasma erythropoietin is tightly regulated. may down regulate erythropoietin production. In general. in patients with chronic renal disease.5 mg%. Indeed. Since erythropoietin is produced primarily in the kidneys in adults.
however. erythropoietin plays an indispensable role in promoting the proliferation of these cells.5 mg%. the plasma erythropoietin assay is not useful if the creatinine is greater than 1. in the presence of anemia. Erythropoietin interacts with its receptors to facilitate their . but also to impaired bone marrow function.(15) However. suggests a hormone deficient state.(18) the first five days of the post-operative period. as a consequence of tissue hypoxia. when the bilirubin is greater than 2 mg%.(20) In certain situations. which indicates that anemia in this circumstance is due not only to impaired erythropoietin production. It should also not be employed unless correctable causes for anemia have been excluded. Thereafter. treatment with antiretroviral agents often improves erythropoietin production remarkably. erythropoietin therapy has a good chance of success assuming that bone marrow function is normal and that there are adequate stores of iron and other essential nutrients. Interestingly. the plasma erythropoietin level can be a useful tool for determining who might benefit from administration of recombinant human erythropoietin. Erythropoietin interacts with its target cells through specific high affinity receptors that are present primarily on erythroid progenitor cells.(17) pregnancy. a simultaneous response of the bone marrow is usually not apparent. If these criteria have been met. However. the development of anemia in such patients implies that there is simultaneously an impairment in bone marrow responsiveness to erythropoietin. cancer patients can increase their plasma erythropoietin level promptly when they become hypoxic. is present but blunted. Both in vivo and in vitro studies of erythropoiesis have indicated that other growth factors such as IL-3. This has been most carefully studied in HIV-infected patients in whom erythropoietin production is severely depressed in the presence of anemia. Other situations in which erythropoietin production is blunted include prematurity. It is also not useful if the hemoglobin level is not less than 10. this response is not sustained after the hypoxia is corrected even though the patient may still be anemic. supporting their survival and facilitating their differentiation.(14) Since the body’s capacity to produce erythropoietin. As mentioned above. In certain patients with liver disease. however.although a response to tissue hypoxia with respect to an elevation in plasma erythropoietin is present.5 mg% or if the bilirubin is greater than 2 mg%.(20) With these caveats in mind. cancer patients behave very much like patients with end stage renal disease in that there is no correlation in these patients between plasma erythropoietin and the hemoglobin level. Patients with cancer constitute another group in whom anemia is not associated with an appropriate increase in endogenous erythropoietin production. GM-CSF. SCF and IGF-I are involved in the proliferation of erythroid progenitor cells during the early stages of commitment. As a corollary. the plasma erythropoietin level may actually be elevated inappropriately. as long as the plasma erythropoietin level is less than 500 mU/ml. Like patients with end stage renal disease. this response for any degree of anemia is lower than it is in comparable anemic patients who do not have an underlying inflammatory disorder. In the same fashion. then a plasma erythropoietin level that has not risen substantially outside the normal range. plasma erythropoietin may also be inappropriately elevated. This occurs transiently with the administration of cancer chemotherapy or the conditioning regimen for bone marrow transplantation.(16) Indeed. patients with a chronic infectious illness also have a blunted erythropoietin response to anemia.(19) and a variable period of time after allogeneic bone marrow transplantation.
and on occasion more effective. In this regard.dimerization which activates the non-receptor. Pharmokinetic studies have indicated that intravenous administration of erythropoietin results in an exponential decline in its plasma level with a half life between 6-9 hours. in some instances the hormone need not be given more than once or twice a week to sustain an adequate elevation of the hemoglobin level. have not been fully characterized. is that erythropoietin is a highly specific growth factor and its administration in vivo results only in elevation of the red cell mass. It is for this reason that it is prudent to start erythropoietin replacement therapy with the lowest dose of erythropoietin that will achieve the desired increment in hemoglobin elevation. but importantly. As a general rule. than intravenously administered erythropoietin. What is clear. that expansion of the erythroid progenitor cell pool is exponential. the mean dose required to maintain that response was approximately 75 U/kg administered three times a week. to date. iron should be administered concomitantly with erythropoietin to patients with end stage renal disease when the serum ferritin is less than 200 ng/ml.(24) Initial clinical trials of recombinant human erythropoietin were conducted in anemic patients with end stage renal disease. and elevation of the platelet count only occurs when elevation of the red cell mass induces tissue iron deficiency. administration of recombinant erythropoietin proved to be remarkably effective in alleviating anemia and eliminating transfusion requirements. erythropoietin administration does not affect the white cell count in any fashion. in a responsive individual not only may expansion of the red cell mass occur rapidly.(23) Subcutaneous administration of similar quantities of the hormone results in a much lower plasma erythropoietin level. With higher doses of the hormone a definite dose response affect was observed. as opposed to prevention of programmed cell death or induction of differentiation.(25) The minimal time to observe a response was 2-4 weeks with these larger doses of erythropoietin. Indeed. These anemic patients with end stage renal disease appeared to be quite sensitive with respect to development of iron deficiency as their red cell mass expanded. membrane-associated tyrosine kinase JAK2. however. Patients with end stage renal disease also proved to be more sensitive to the . but that level is sustained much longer than when the hormone is given intravenously. and subsequent studies using erythropoietin administered subcutaneously have indicated that lower maintenance doses are equally effective and indeed. but blood viscosity will be elevated out of proportion to the expansion of the red cell mass because of the concomitant reduction in plasma volume.(22) Thus. In these patients. a dose of 200 U/kg was not more effective than 100 U/kg.(21) Activation of JAK2 appears necessary for proliferation of erythroid progenitor cells but is not itself sufficient for this. and that elevation of the red cell mass by erythropoietin is associated with a reduction in plasma volume. active at the picomolar level. subcutaneous administration has proved to be as efficacious. The minimal dose of erythropoietin that proved effective within a reasonable period of time was 50 U/kg administered three times weekly. It is also important to be aware that erythropoietin is an extremely potent hormone. Since only a modest elevation in plasma erythropoietin is sufficient to saturate available erythropoietin receptors. Once the desired response was achieved. the erythropoietin receptormediated signal transduction pathways specific for proliferation. These initial studies were conducted using erythropoietin administered intravenously.
HIV-infected patients.(28) This was true for patients receiving chemotherapy. Squamous cell histology was associated with a better response rate than adenocarcinoma. an increase in hemoglobin could be expected between 2-4 weeks after initiation of therapy.(28) The overall response rate in a variety of clinical trials has been approximately 60%. the response rate of patients receiving chemotherapy was similar to patients not undergoing chemotherapy.(27) Erythropoietin therapy was effective in patients receiving Zidovudine. the type of tumor. as well as for those on no retroviral therapy. Importantly. the presence of iron deficiency. the extent of prior chemotherapy. Factors that appeared to influence the efficacy of recombinant human erythropoietin in anemic cancer patients included the patient’s performance status. Recombinant erythropoietin therapy has proven to be remarkably safe in anemic cancer patients. Patients with carcinoma of the lung responded more frequently than those with carcinoma of the breast or ovary and patients with multiple myeloma responded more frequently than those with a lymphoma or Hodgkin disease. Patients with chronic inflammatory or infectious disorders or cancer often develop a nondescript form of normochromic normocytic anemia with impaired iron utilization. the patients most likely to obtain a response to erythropoietin replacement therapy were those whose endogenous plasma erythropoietin level was less than 500 mU/ml. Importantly. In patients with anemia associated with rheumatoid arthritis. and these side effects were prominent during the first eight weeks of therapy. Dose-ranging studies have suggested that a dose of 100150 U/kg administered subcutaneously three times a week should be adequate to correct anemia. including its histology. Erythropoietin has not been demonstrated to stimulate tumor cell proliferation and does not influence the . in Zidovudine-treated patients. occult bleeding or hemolysis. which is associated with an appropriately low plasma erythropoietin level for the degree of anemia.development of de novo hypertension or exacerbation of hypertension when recombinant erythropoietin was administered. the plasma erythropoietin level.(26) Similarly. Depending on the dose. which can be compared with the response rate of anemic HIVinfected patients to erythropoietin of approximately 40%. recombinant erythropoietin given subcutaneously in a dose of 100-200 U/kg three times weekly alleviated anemia and reduced transfusion requirements. however. the presence of splenomegaly and the presence of an infectious process. in anemic. erythropoietin therapy has proved effective in alleviating symptomatic anemia even in the presence of impairment of iron reutilization. Recombinant erythropoietin in a dosedependent fashion can alleviate the anemia associated with cancer and reduce transfusion requirements. erythropoietin did not prevent a response to granulocyte colony-stimulating factor (G-CSF) when this was given simultaneously. but rather a consequence of the change in the red cell mass alone or together with a change in the plasma volume. This was true both in the presence of chemotherapy and its absence. as well as for those who were not on chemotherapy. the type of chemotherapy employed. In one study. The development of hypertension or its exacerbation are not a direct consequence of erythropoietin. The success of erythropoietin in alleviating the anemia and reducing or eliminating transfusion requirements in patients with chronic end stage renal disease led to its use in other disorders in which anemia was associated with impaired erythropoietin production. Over the past several years a substantial experience with the use of erythropoietin in anemic cancer patients has accumulated.
(29) The tight regulation of plasma erythropoietin under normal circumstances and with only modest degrees of anemia suggested that recombinant erythropoietin therapy might have a role in patients providing blood preoperatively for autologous donation. erythropoietin therapy did not result in a more accelerated recovery of the hemoglobin level than in a control group.(29) Similarly. However. A number of studies have evaluated the endogenous production of erythropoietin in bone marrow transplant patients and the effectiveness of recombinant human erythropoietin in alleviating anemia in this situation. Thus.(33) In the ten years since recombinant erythropoietin was introduced into clinical practice it has proven to be a remarkably safe and effective therapeutic agent. The major . In patients receiving allogeneic bone marrow. and impaired erythropoietin production may last as long as 12 months after the transplantation. and also to prevent anemia in bone marrow donors. in patients with a plasma erythropoietin level of greater than 1. it is also worth noting that erythropoietin can be used safely in pregnant women to alleviate anemia and the need for transfusions in the appropriate situations since the hormone does not cross the placenta. while those with more advanced stages of myelodysplasia are least likely to respond. since in this situation it has been demonstrated that the hormone can alleviate anemia and eliminate transfusion requirements. Erythropoietin has proved to be safe in such patients and has had no adverse effects on either neutrophil or platelet production. erythroid recovery was much faster in patients receiving erythropoietin than in those who did not. In patients receiving autologous bone marrow. patients with refractory anemia are most likely to respond to erythropoietin. the extent of red cell transfusion requirements was not different in the two groups. Erythropoietin levels are suppressed following bone marrow transplantation. a response rate as high as 40% has been obtained in patients with refractory sideroblastic anemia. a large number of studies have defined the indications for the use of erythropoietin in autologous blood donors and perioperatively. erythropoietin therapy may have an important role.production of leukocytes or platelets nor interfere with the activity of simultaneously administered myeloid growth factors. when erythropoietin is employed together with G-CSF. In patients whose anemia persists more than several months after bone marrow after bone marrow transplantation.(30) However. and from other anemic patients or patients with small blood volumes who would be unable to donate enough blood to meet their anticipated needs. particularly those with a birth weight of 1. Erythropoietin therapy is appropriate to correct anemia preoperatively in patients who reject blood transfusions because of religious convictions.000 mU/ml. a response to erythropoietin therapy is unlikely.(32) In this regard.000 grams or less. Over the past several years. to obtain blood for autologous donation from anemic. the most important factors with respect to erythropoietin responsiveness are the endogenous plasma erythropoietin level and the type of myelodysplastic syndrome. however.(31) Several recent studies have also established that recombinant erythropoietin is both safe and effective for reducing transfusion requirements in premature infants. In patients with myelodysplasia. The ability of erythropoietin to alleviate anemia or transfusion requirements in patients with myelodysplasia has been less successful than in anemic patients associated with other forms of cancer. alloimmunized patients.
Eckardt KU. The clinical phyiology of erythropoietin. 1988. Bondurant MC. sequencing. 1986. 1991. Development of radioimmunoassays for human erythropoietin using recombinant erythropoietin as tracer and immunogen. Blood 70:822. Relation of serum erythropoietin levels to renal excretory function: evidence for lowered set point for erythropoietin production in chronic renal failure. Barnes DC. Blood 77:1228. Bondurant MC. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. REFERENCES Spivak JL. Bengtsson C. 1988. Arnold CM. Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. McVicar MI. JAMA 261:3104. 1993. Koury MJ. and evolutionary analysis of the mouse erythropoietin gene. Haga P. and serum erythropoietin concentration. Gaines Das RE. Br J Haematol 72:85. 1986. Till JA. Wide L. Koury MJ. 1989. Therapeutically. Semin Hem 30(4):2. Caro J. Mol Cell Biol 6:2731. Shinebourne EA. Cotes. Blood 74: 645. Dunning SP. Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Arth Rheum 31:1318. Circadian rhythm of erythropoietin in human serum. McDonald JD. Erythropoietin is both a mitogen and a survival factor. The hormone can also be used gainfully to expand the red cell mass perioperatively and to facilitate autologous blood and bone marrow donation. Serum immunoreactive erythropoietin in rheumatoid arthritis: impaired response to anaemia. Birgegard G. Serum immunoreactive erythropoietin in children with cyanotic and acyanotic congenital heart disease. Clemons GK. 1989. JL Spivak. Isaacs MA et al. recombinant erythropoietin should be used to eliminate the requirement for blood transfusions and the correction of symptomatic anemia. Cotes PM. 1988. Lane J. J Pediatr 113:1015. Graber SE. Lin FK. PM. Minty BD. Serum immunoreactive erythropoietin in HIVinfected patients. Pham TH. J Clin Invest 91:251. Koury MJ. 1987. Bondurant MC. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit. Gaul CC. Spivak JL. Spivak JL. J Immunol Meth 99:235. 1989. Fuchs E et al. Koury ST. Goldberg MA. Koury ST. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Goldberg MA. Increased plasma viscosity as a reason for inappropriate erythropoietin formation. Bunn HF. Semenza GL. renal erythropoietin mRNA. Mol Cell Biol 842. Bunn HF. 1993. Chandra M. 1987. Cloning. Singh A. Goldwasser E. Egrie JC. Blood 77:2497. . 1991. Hogans BB. Tam RC.contribution of recombinant erythropoietin is that it enables us to obtain many of the benefits of blood transfusion without transfusing blood. Hochberg MC. Zimmermann A et al. 1991. Science 242:1412. Blood 77:271.
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Brown MS. . Stevenson DK. Shannon KM. Recombinant human erythropoietin and its role in transfusion medicine. Abels RI. Simmons CF. Erythropoietin after bone marrow transplantation. Hematol Oncol Clin N Amer 8:975. Brim M. 1995. Pediatrics 95:1. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Ehrenkranz RA. Millard DD. Alverson DC. Bifano EM. Keith JF III. Davis CB. 1994. Mills S. Transfusion 34:1. 1994. Miller CB. Mentzer WC. Widness JA. Phibbs RH.Spivak JL. Gleason CA.
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