Allan J. Erslev

Plasma erythropoietin in polycythemia

Erythropoietin titers of plasma cannot be used to differentiate polycythemia vera from secondary polycythemia since the limit of sensitivity of our current bioassay technics is 50 mU, considerably higher than levels found in normal subjects and in patients with polycythemia. However, erythropoietin is relatively heat stable, and since abundant plasma is available from therapeutic phlebotomies it is possible to prepare and assay highly concentrated, erythropoietin-containing extracts. In 35 normal subjects, erythropoietin levels ranged from less than 5 mU/ml (the limit of sensitivity) to 18 mU/ml with a mean of 7.8 mU/ml. In 21 patients with proved polycythemia vera, the levels were less than 5 mU/ml in all. In 41 patients with suspected secondary polycythemia or polycythemia of unknown origin, the levels ranged from less than 5 to 3,000 mU/ml. Three of the 11 patients with levels less than 5mU/ml were subsequently shown to have polycythemia vera. These results suggest that this refinement of the routine bioassay for erythropoietin may be of clinical importance in the differential diagnosis of polycythemia.

Are the native kidneys responsible for erythrocytosis in renal allorecipients

The development of erythrocytosis following renal transplantation has been reported to be caused by a number of factors. These include acute and chronic rejection, hydronephrosis and renal artery stenosis. In this study, seven patients were noted to have erythrocytosis with hematocrits ranging between 53.5 and 66%. Serum erythropoietin levels were elevated and ranged between 11 and 60 mU/ml with a mean of 31.9 mU/ml in six of seven patients. Selective catheterization of veins of native and transplanted kidneys in three patients revealed mean serum levels of 40.9 and 13.0 mU/ml, respectively. This suggests that excess erythropoietin is being produced from the diseased native kidneys. Bilateral nephrectomy in one patient cured erythrocytosis and dropped systemic levels of erythropoietin (EP) to 6.1 mU/ml. In four of the remaining five patients, hematocrits came down spontaneously to within normal over a 1− to 3-year period. Consequently, it appears that in a number of transplant patients the retained diseased kidneys, having lost all excretory and concentrating function, may remain capable of functioning as endocrine erythropoietin-producing organs.

Erythropoietin Coming of Age

Since 1957, when Jacobson and associates1 demonstrated the renal origin of erythropoietin, it has been assumed that the anemia of chronic renal disease is caused at least in part by a deficiency of...

Pure erythrocytosis classified according to erythropoietin titers

Erythropoietin titers, measured by bioassay of plasma extracts in hypertransfused mice, were determined in 162 patients with absolute erythrocytosis, and the results were correlated with the clinical diagnosis. Fifty-two patients met the diagnostic criteria for polycythemia vera, and all had low or nonmeasurable erythropoietin titers. Of the remaining 110 patients, 62 were suspected clinically as having secondary polycythemia. However, 15 had low erythropoietin titers, casting doubt on the accuracy of the clinical diagnosis. The pathogenesis of the erythrocytosis in the last 48 patients was unknown, and they were designated clinically as having pure erythrocytosis. However, in 20, the erythropoietin titers were increased, and in 28, the titers were low, suggesting that they belonged to at least two different groups. Using erythropoietin titers in the classification of absolute erythrocytosis, the first group should be added to the category of patients with secondary polycythemia as a subgroup with disease due to idiopathic overproduction of erythropoietin (hypererythropoietinemia or essential erythrocytosis). The second group should be added as a subgroup of patients with primary polycythemia under the term erythremia.

Spontaneous increase in erythropoietin and hematocrit value associated with transient liver enzyme abnormalities in an anephric patient undergoing hemodialysis

An anephric patient undergoing hemodialysis experienced an increase in his hematocrit value (19 +/- 1 per cent to 31 +/- 1 per cent) as a result of increased erythropoiesis (reticulocyte count 1.8 per cent to 7.4 per cent). This increase occurred in concert with an elevation of the patients liver enzyme levels and was maintained for four months. The hematocrit value returned to its base line only after the liver function tests showed improvement. During the period when the hematocrit value was increasing, the circulating level of erythropoietin was elavated to 71.0 mU/ml--a level higher than that seen in either anephric or nephric patients undergoing dialysis. When the hematocrit value and liver enzyme levels had returned to their base line values, the erythropoietin level was 4.3 mU/ml--a level in the range seen in anephric patients undergoing dialysis. The observations in this patient suggest that under certain circumstances, the liver can produce erythropoietin in the anephric patient; and, more importantly, that the bone marrow of at least some uremic patients is capable of responding to the endogenous erythropoietin.

Acquired Hemoglobin H Disease

Abstract Although hemoglobin H disease is usually inherited, similar syndromes may be acquired. In a 73-year-old woman of British descent with a myeloproliferative syndrome characterized by striking megakaryocytic hyperplasia and thrombocytosis, we also found hemolytic anemia with hypochromia, microcytosis, marked poikilocytosis and 20 per cent hemoglobin H (beta4). Incubation with brilliant cresyl blue produced inclusions in 60 per cent of the red cells. Hematologic studies before the onset of this illness gave normal results. In vitro studies of globinchain synthesis revealed a marked decrease of alpha-chain production similar to that found in hereditary hemoglobin H disease. The alpha/beta ratio of radioactivities was 0.13, demonstrating a severe imbalance of globin synthesis. Studies of the patients two children gave normal results. Hematologic and globin synthesis in this acquired disorder is similar to those of its hereditary counterpart.

Recent Developments in the Anemia of Chronic Renal Failure

Anemia has remained one of the most characteristic and visible manifestations of chronic renal failure (CRF) for over 150 years. Richard Bright ( 1) first commented on the pallor of patients with renal disease in 1836. Numerous observers have attempted to characterize and explain the underlying anemia since then. Although the degree of anemia appears to be roughly proportional to the degree of azotemia (2) (Fig. l), a close correlation between the hematocrit and the GFR (as estimated by the BUN) (3) does not exist. This observation is not unexpected since any of a number of changes in the rates of red blood cell production and destruction may occur which are not closely related to those factors responsible for or a consequence of decreased glomerular filtration. As Figure 1 illustrates, however, at creatinine clearances below 20 ml min-’ the hematocrit is usually below 35 vol%. Experimental and clinical observations on the effect of intensive dialysis, bilateral nephrectomy, and therapeutic recombinant erythropoietin have clarified some of the pathophysiologic mechanisms responsible for the anemia. It is caused both by failure of renal excretory function leading to hemolysis, blood loss, and marrow suppression and by failure of renal endocrine function leading to impaired erythropoietin production. The latter is the ratelimiting process since the exogenous administration of erythropoietin corrects the anemia, in most if not all patients (4, 5) . With the imminent availability of recombinant erythropoietin for therapeutic use, significant anemia should cease to be a major manifestation of chronic renal failure. The unresolved issues with respect to erythropoietin usage are a determination of the best route(s) and frequency of administration, the optimal level of hematocrit to be attained, and the effect of increases in hematocrit on systemic hemodynamics and the “dialysis prescription.” Although inadequate production of erythropoietin is probably the most important factor in the pathogenesis of anemia in end stage renal disease (ESRD),

Anemia of Cancer and Its Cardiovascular Effects

The principal obligation of blood, heart, and vessels is to maintain a steady and optimal oxygen supply to the tissues. These three organs are controlled by closely integrated feedback circuits, and a change in the function in any one will cause compensatory adjustment in the function of the others. In the case of blood, acute reduction in the oxygen-carrying capacity will result in tissue hypoxia, vascular dilatation, and decreased peripheral vascular resistance, which, abetted by lower blood viscosity, will cause an increase in cardiac output and, in turn, restoration to normal of oxygen supply to the tissues. However, such a primary response by the heart to anemia is metabolically and functionally expensive and is saved for conditions of acute and severe life-threatening anemia. In patients with cancer the associated anemia is usually chronic and of moderate severity, and here the compensatory adjustments in oxygen flow rarely demand an increase in cardiac work, but are accomplished by other means, such as changes in oxygen affinity and redistribution of blood among the tissues.