Erythropoiesis in multiple myeloma: defective red cell production due to inappropriate erythropoietin production

We investigated the pathophysiology of erythropoiesis in 62 patients with multiple myeloma and examined whether it would establish a rational basis for the treatment of their anaemia with recombinant human erythropoietin. Erythropoietin (Epo) production was evaluated by serum levels and erythropoiesis was quantitated by serum transferrin receptor (TfR) levels, both assessed relative to the degree of anaemia. Instead of the expected stimulation of erythropoiesis in response to anaemia, haematocrit correlated positively with marrow erythropoietic activity, indicating that the mechanism of anaemia was primarily defective red cell production. Erythropoiesis decreased and anaemia worsened significantly with advancing clinical stage. 25% of the patients had inadequate Epo production and this proportion increased to 50% in stage 3. Inappropriate Epo production was seen in 60% of patients with renal impairment but was also observed in a number of patients with normal renal function. Erythropoiesis correlated strongly with the adequacy of Epo production, particularly in advanced disease. We conclude that most myeloma patients have defective red cell production even in the absence of massive marrow infiltration and that inappropriate Epo production contributes to their anaemia.     

Erythropoietin deficiency in the anaemia of chronic disorders

Defective iron metabolism, mild haemolysis and impaired erythropoiesis contribute to the anaemia of chronic disorders (ACD), but evidence for a deficiency of circulating erythropoietin (Epo) is equivocal. We have examined serum Epo in moderately anaemic patients with Hb less than 10 g/dl--41 patients with ACD (23 associated with rheumatoid disease and 18 with malignancy), 17 with uncomplicated iron-deficiency anaemia and 33 with chronic renal failure (CRF). In ACD the serum Epo (mean (confidence limits] results of 41 (31, 54) mU/ml for the rheumatoid group and 63 (49, 80) mU/ml for the malignancy group, were significantly lower than the Epo of 104 (78, 136) mU/ml for the iron-deficiency group. The CRF group with more severe anaemia had serum Epo of 27 (19, 35) mU/ml. Thus, recombinant human erythropoietin (rHu Epo) should be considered for the treatment of ACD associated with rheumatoid disease and malignancy.     

Impaired erythropoietin responsiveness to the anaemia in rheumatoid arthritis. A possible inverse relationship with iron stores and effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one

We investigated the serum erythropoietin (Epo) response in 11 rheumatoid arthritis (RA) patients without anaemia, 7 with RA and iron deficiency (ID) and 12 with RA and anaemia of chronic disease (ACD). In all patients the serum Epo was higher than in healthy subjects. Apparently this increase was insufficient to prevent anaemia in ID and ACD. Serum Epo correlated negatively with serum ferritin. Ten RA patients with ACD were treated with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). No obvious toxicity signs occurred after one week of treatment. It effectively released iron from iron stores. The Hb rise (in 70% of the patients) was correlated positively with an Epo increase and negatively with a serum ferritin decrease. We conclude that a serum Epo increase does not overcome ACD. Epo response might correlate inversely with iron stores. L1 treatment effectively chelates iron from iron stores. The effects of L1 on erythropoiesis and serum Epo and its safety need further substantiation after prolonged treatment in more RA patients.     

Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production

Epoetin beta, three-times weekly (t.i.w.), is effective in reversing anaemia in lymphoproliferative disorders. The current study investigated whether an epoetin beta dose of 30,000 IU given subcutaneously once weekly (q.w.) was at least as effective as 10,000 t.i.w. administration in anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin (Epo) production. Overall, 241 anaemic patients with multiple myeloma, low-grade non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, all with serum Epo values 相似文献   

Decreased erythropoietin response in Plasmodium falciparum malaria-associated anaemia

Abstract: One of the most serious manifestations of Plasmodium falciparum malaria is anaemia. Its established causes are increased red cell destruction and ineffective erythropoiesis. Since proinflammatory cytokines have been shown to suppress the in vitro synthesis of erythropoietin (Epo), we measured serum immunoreactive Epo in 90 Sudanese patients suffering from malaria. Even in severe cases of anaemia (blood haemoglobin <80 g/l), serum Epo levels rarely exceeded 300 U/l. For comparison, serum Epo was increased up to 12,000 U/l in a reference group of Caucasian patients with anaemia not associated with infection. Moreover, the slope of the log Epo/haemoglobin regression line was less steep in malarial anaemia. Thus, as documented for other chronic inflammatory disorders, there is a relative lack of Epo in malaria-associated anaemia. Treatment with the antimalarial drug chloroquine may aggravate the defect in Epo production, because chloroquine inhibited Epo synthesis when tested in cell culture.     

The role of erythropoietin in the anaemia of chronic disease in rheumatoid arthritis

Summary We reviewed studies on the role of erythropoietin (Epo) in the anaemia of chronic disease (ACD) in rheumatoid arthritis (RA). A relatively impaired Epo response to the anaemia was found in a number of studies although in others serum Epo level was the same as in other types of anaemia. Some arguments are found in favour of a reduced bone marrow-Epo sensitivity although these reflect results mainly from in vitro experiments. It is not yet established whether bone marrow macrophage Epo production is impaired in ACD. In two cases Epo administration to RA patients resulted in increased erythropoiesis. It was concluded that impaired Epo production or reduced bone marrow Epo sensitivity might be associated with ACD but it is not certain whether these factors are causally linked with ACD or side phenomena of RA disease activity. Future Epo treatment in RA and ACD will possibly solve this question.     

Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis

Systemic-onset juvenile chronic arthritis (SoJCA) is associated with high levels of circulating interleukin-6 (IL-6) and is frequently complicated by severe microcytic anemia whose pathogenesis is unclear. Therefore, we studied 20 consecutive SoJCA patients with hemoglobin (Hb) levels <12 g/dL, evaluating erythroid progenitor proliferation, endogenous erythropoietin production, body iron status, and iron supply for erythropoiesis. Hb concentrations ranged from 6.5 to 11.9 g/dL. Hb level was directly related to mean corpuscular volume (r = .82, P < .001) and inversely related to circulating transferrin receptor (r = - .81, P < .001) suggesting that the severity of anemia was directly proportional to the degree of iron-deficient erythropoiesis. Serum ferritin ranged from 18 to 1,660 microgram/L and was unrelated to Hb level. Bone marrow iron stores wore markedly reduced in the three children investigated, and they also showed increased serum transferrin receptor and normal-to-high serum ferritin. All 20 patients had elevated IL-6 levels and normal in vitro growth of erythroid progenitors. Endogenous erythropoietin (epo) production was appropriate for the degree of anemia as judged by both the observed to predicted log (serum epo) ratio 10.95 +/- 0.12) and a comparison of the serum epo- Hb regression found in these subjects with that of thalassemia patients. Multiple regression analysis showed that serum transferrin receptor was the parameter most closely related to hemoglobin concentration: variation in circulating transferrin receptor explained 61% of the variation in Hb level (P < .001). In 10 severely anemic patients, amelioration of anemia following intravenous iron administration resulted in normalization of serum transferrin receptor. Defective iron supply to the erythron rather than blunted epo production is the major cause of the microcytic anemia associated with SoJCA. A true body-iron deficiency caused by decreased iron absorption likely complicates long-lasting inflammation in the most anemic children, and this can be recognized by high serum transferrin receptor levels. Although oral iron is of no benefit, intravenous iron saccharate is a safe and effective means for improving iron availability for erythropoiesis and correcting this anemia. Thus, while chronically high endogenous IL-6 levels do not appear to blunt epo production, they are probably responsible for the observed abnormalities in iron metabolism. Anemia of chronic disease encompasses a variety of anemic conditions whose peculiar features may specifically correlate with the type of cytokine(s) predominantly released.     

The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET.

AIMS: Anaemia is a common comorbidity in chronic heart failure (CHF). The predictors of new onset anaemia (NOA) and its long-term prognostic value, particularly in patients treated with beta-blockers, are not known. METHODS AND RESULTS: In COMET, 3029 patients with CHF in NYHA II-IV and EF <35% were randomized to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Plasma haemoglobin (Hb) concentrations were measured at a central laboratory at randomization, at four monthly intervals for the first year and annually thereafter. According to WHO criteria, anaemia was defined when Hb measured <13 g/dL for men and <12 g/dL for women. We considered anaemia to be severe when Hb <11.5 g/dL for men and <10.5 g/dL for women. The baseline mean Hb was 14.2 +/- 1.5 g/dL (n = 2996) and 15.9% of patients had anaemia (males, 16.0%; females, 15.2%). At baseline, severe anaemia was found in 3.3% of patients (males, 3.6%; females, 2.0%). During the study, all-cause mortality (RR 1.47) death or hospitalization (RR 1.28), and heart failure hospitalization (RR 1.43, all P < 0.0001) were higher in anaemic when compared with non-anaemic patients. In patients without anaemia at baseline, at the end of the study, the cumulative frequency of NOA was 28.1% in males and 27.0% in females. NOA increased over time from 14.2% at year 1 to 27.5% at year 5. Predictors of NOA were: higher age, diuretic dose, creatinine (all P < 0.0001), higher serum potassium, lower serum sodium, body mass index, and use of aldosterone antagonists, carvedilol, and digitalis (all P < 0.03). Treatment with carvedilol (vs. metoprolol tartrate) was associated with a 24% increased risk to develop NOA (P = 0.0047), but not severe anaemia (P = 0.18). Patients with a Hb decrease of >3 g/dL (RR 3.37, P < 0.0001) or of 2.0-3.0 g/dL (RR 1.47, P = 0.011) from baseline had an increased subsequent mortality when compared with patients having Hb increases of 0-1.0 g/dL. CONCLUSION: In stable ambulatory CHF patients, development of NOA is frequent and can be predicted by a set of clinical variables. Decreases in Hb over time relate to future increased morbidity and mortality.     

The investigation and treatment of secondary anaemia

Secondary anaemia or the anaemia of chronic disease (ACD) is the commonest form of anaemia in hospitalised patients and the second most prevalent anaemia worldwide after iron deficiency. It is characterised by defective iron incorporation in erythropoiesis, an impaired response to erythropoietin, a decrease in erythropoietin production and cytokine induced shortening of red cell survival. For many patients with ACD the cause is apparent but for many others the underlying disease needs to be determined and such patients are often referred to haematologists for investigation. The search for the cause can be a fascinating exercise in good history taking, examination skills and performing and interpreting appropriate investigations. This review covers the pathogenesis and causes of ACD and then discusses the clinical and laboratory investigation of a patient with suspected ACD. Finally, the management of a patient with ACD is discussed including erythropoiesis stimulating agents (ESAs), intravenous iron and future therapies.     

Ferrokinetics and Erythropoiesis in Man: Red-Cell Production and Destruction in Normal and Anaemic Subjects

Recent advances in the analysis of plasma ⁵⁹Fe clearance have produced a unified method for measuring effective and ineffective erythropoiesis (Ricketts et al , 1975). We have used this method to investigate the balance between red-cell production and destruction in normal subjects and in patients with megaloblastic anaemia, iron deficiency anaemia and refractory hypoplastic anaemia. The results show that the normal marrow can maintain an appropriate red-cell mass by altering red-cell production to match destruction. In the anaemias we have studied there is an increased rate of either intra- or extra-medullary red-cell destruction. The response of the marrow may be limited by iron supply, by defective nuclear maturation or by some intrinsic marrow defect.     

Iron deficiency and anaemia in heart failure: understanding the FAIR‐HF trial

Treatment of anaemia in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction has traditionally focused on erythropoietin‐stimulating agents. However, recent studies have shown that treatment with intravenous (IV) iron can improve the symptoms and quality of life in patients with CHF and iron deficiency (ID), with or without anaemia. The management of ID is becoming an important therapeutic target in patients with CHF, and in this article, we will review iron metabolism in the context of anaemia and heart failure. We will also focus on the importance of diagnosing and treating ID, preferably with IV iron preparations, in patients with CHF.     

Erythropoietin production and erythropoiesis in compensated and anaemic states of hereditary spherocytosis

A compensated haemolytic state is defined by decreased red cell life-span without anaemia, i.e. by increased erythropoiesis in the absence of the physiological stimulus for erythropoietin (Epo) production. We evaluated s-Epo levels and the expansion of erythropoiesis (as measured by circulating transferrin receptor, s-TfR) in 32 patients with hereditary spherocytosis (HS) with the aim of verifying whether the enhanced erythropoiesis of compensated haemolysis was Epo-dependent. 20 of the patients (62.5%) had normal Hb values (> 12 g/dl in females and > 13 g/dl in males). Their compensated haemolytic state was the result of up to 8.2 times normal s-Epo and up to 3.9 times normal s-TfR levels, which were maintained by physiological regulation of erythropoiesis, as documented by the inverse dependence of Hb on s-Epo levels. Considering that patients with iron-deficiency anaemia represented the predicted physiological Epo response to anaemia, the observed/predicted ln s-Epo ratio (O/P ratio) was calculated in HS patients with anaemia and was used as an index of the adequateness of Epo production. All the anaemic HS patients had an O/P ratio > 1, documenting inappropriately high s-Epo levels. This work demonstrates that the compensated haemolytic state of HS patients is produced by an inappropriately high s-Epo level, and that the pattern of Epo overproduction is a biological characteristic of the disease.     

Erythropoietin production and erythropoiesis in compensated and anaemic states of hereditary spherocytosis

A compensated haemolytic state is defined by decreased red cell life-span without anaemia, i.e. by increased erythropoiesis in the absence of the physiological stimulus for erythropoietin (Epo) production. We evaluated s-Epo levels and the expansion of erythropoiesis (as measured by circulating transferrin receptor, s-TfR) in 32 patients with hereditary spherocytosis (HS) with the aim of verifying whether the enhanced erythropoiesis of compensated haemolysis was Epo-dependent. 20 of the patients (62.5%) had normal Hb values (> 12 g/dl in females and > 13 g/dl in males). Their compensated haemolytic state was the result of up to 8.2 times normal s-Epo and up to 3.9 times normal s-TfR levels, which were maintained by physiological regulation of erythropoiesis, as documented by the inverse dependence of Hb on s-Epo levels. Considering that patients with iron-deficiency anaemia represented the predicted physiological Epo response to anaemia, the observed/predicted ln s-Epo ratio (O/P ratio) was calculated in HS patients with anaemia and was used as an index of the adequateness of Epo production. All the anaemic HS patients had an O/P ratio > 1, documenting inappropriately high s-Epo levels. This work demonstrates that the compensated haemolytic state of HS patients is produced by an inappropriately high s-Epo level, and that the pattern of Epo overproduction is a biological characteristic of the disease.     

The pathological consequences of anaemia

Many patients with chronic diseases such as chronic renal failure, chronic inflammatory bowel disease and rheumatoid arthritis are anaemic. Recently congestive heart failure (CHF) has also been found to be associated with anaemia. In all these diseases this anaemia or chronic disease is at least partially due to excessive production of cytokines and leukotrines that interfere both with the effect of erythropoietin (EPO) at the bone marrow and the release of stored iron in the reticuloendothelial system. Treating this anaemia with subcutaneous EPO and IV iron improves the weakness, fatigue, cachexia, nutritional state, mood, cognitive function and quality of life. In the case of CHF it also improves cardiac function and patient functional class, prevents deterioration of renal function and markedly reduces hospitalization. Very few agents in medicine improve so many aspects of the patient so well and so quickly. Unfortunately (for the suffering patient) this anaemia is often ignored and goes untreated.     

The pathological consequences of anaemia.

Many patients with chronic diseases such as chronic renal failure, chronic inflammatory bowel disease and rheumatoid arthritis are anaemic. Recently congestive heart failure (CHF) has also been found to be associated with anaemia. In all these diseases this anaemia or chronic disease is at least partially due to excessive production of cytokines and leukotrines that interfere both with the effect of erythropoietin (EPO) at the bone marrow and the release of stored iron in the reticuloendothelial system. Treating this anaemia with subcutaneous EPO and IV iron improves the weakness, fatigue, cachexia, nutritional state, mood, cognitive function and quality of life. In the case of CHF it also improves cardiac function and patient functional class, prevents deterioration of renal function and markedly reduces hospitalization. Very few agents in medicine improve so many aspects of the patient so well and so quickly. Unfortunately (for the suffering patient) this anaemia is often ignored and goes untreated.     

Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well.

AIMS: Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients. METHODS AND RESULTS: We studied 97 patients with CHF, of which 15 had anaemia (Hb<13.0 g/dL in men and Hb<12.0 g/dL in women), without haematinic deficiencies. Glomerular filtration rate (GFR) and extracellular volume (ECV) were measured as the clearance and the distribution volume of constantly infused 125I-iothalamate, respectively. Effective renal plasma flow (ERPF) was determined as the clearance of 131I-hippuran. Anaemic CHF patients displayed significantly reduced GFR (P=0.002), ERPF (P=0.005) and EPO production (P=0.001), and an elevated ECV (P=0.015). Multivariable analysis demonstrated that lower GFR (P=0.003), lower ERPF (P=0.004), lower EPO production (P=0.006), and a higher ECV (P=0.001) were significant independent predictors of lower haemoglobin levels. CONCLUSION: Anaemia in CHF is not only independently associated with impaired renal perfusion and blunted EPO production, but to fluid retention as well.     

Erythropoiesis in the anaemia of chronic disease.

The amount and effectiveness of erythropoiesis was measured using 59Fe in 10 patients with the anaemia of chronic disease and in 10 iron deficient patients with a comparable degree of anaemia. In both conditions the anaemia was the result of the failure of the marrow to compensate for a modest degree of peripheral haemolysis but ineffective erythropoiesis was significantly greater in iron deficiency than in chronic disease. The results suggest that although the peripheral blood picture is similar in both conditions the anaemia of chronic disease cannot be attributed simply to iron deficient erythropoiesis.     

Erythropoiesis in the Anaemia of Chronic Disease

The amount and effectiveness of erythropoiesis was measured using ⁵⁹Fe in 10 patients with the anaemia of chronic disease and in 10 iron deficient patients with a comparable degree of anaemia. In both conditions the anaemia was the result of the failure of the marrow to compensate for a modest degree of peripheral haemolysis but ineffective erythropoiesis was significantly greater in iron deficiency than in chronic disease. The results suggest that although the peripheral blood picture is similar in both conditions the anaemia of chronic disease cannot be attributed simply to iron deficient erythropoiesis.     

Serum erythropoietin in chronic lymphocytic leukaemia

Anaemia is a frequent complication of advanced chronic lymphocytic leukaemia (CLL) and several cytokines known to inhibit erythropoietin (Epo) formation are produced by CLL B cells. Therefore we measured serum Epo levels in 47 CLL patients to determine whether Epo was a significant factor in the development of their anaemia. Epo levels were increased compared to normal individuals and this elevation appeared adequate for the degree of anaemia. The slope of the regression of Epo versus haemoglobin (Hb) was similar to that of a reference group. Serum transferrin receptor (sTfR) levels were also appropriately elevated for the degree of anaemia and correlated with serum Epo. Advanced stage was not associated with reduction of Epo production but diminished erythropoietic activity was observed in several patients. The results indicate that anaemia in CLL is not characterized by inadequate Epo production.     

The non-haematopoietic biological effects of erythropoietin

In the haematopoietic system, the principal function of erythropoietin (Epo) is the regulation of red blood cell production, mediated by its specific cell surface receptor (EpoR). Following the cloning of the Epo gene ( EPO ) and characterization of the selective haematopoietic action of Epo in erythroid lineage cells, recombinant Epo forms (epoetin-alfa, epoetin-beta and the long-acting analogue darbepoetin-alfa) have been widely used for treatment of anaemia in chronic kidney disease and chemotherapy-induced anaemia in cancer patients. Ubiquitous EpoR expression in non-erythroid cells has been associated with the discovery of diverse biological functions for Epo in non-haematopoietic tissues. During development, Epo–EpoR signalling is required not only for fetal liver erythropoiesis, but also for embryonic angiogenesis and brain development. A series of recent studies suggest that endogenous Epo–EpoR signalling contributes to wound healing responses, physiological and pathological angiogenesis, and the body's innate response to injury in the brain and heart. Epo and its novel derivatives have emerged as major tissue-protective cytokines that are being investigated in the first human studies involving neurological and cardiovascular diseases. This review focuses on the scientific evidence documenting the biological effects of Epo in non-haematopoietic tissues and discusses potential future applications of Epo and its derivatives in the clinic.