Patients with heart failure (HF) often experience anemia as a comorbidity. Although anemia is typically diagnosed by measuring hemoglobin (Hb) levels, anemia can also be diagnosed using red cell deficit or hemodilution with plasma volume expansion. Nearly half of patients with advanced HF and low ejection fractions (HFLEF) have anemia based on hemodilution with normal red cell volumes. However, it is unclear whether this relationship also exists in patients with HF and preserved ejections (HFPEF). Thus, a study by Abramov et al examined whether (1) patients with anemia and HFPEF have a similar prevalence of dilutional anemia as patients with HFLEF, and whether (2) a correlation exists between Hb values and red cell volume in patients with anemia and HF.

In the study, 46 patients – aged 21 years or older – with HF were divided into an HFLEF group (22) and an HFPEF group (24). Anemia was defined by the World Health Organization criteria of Hb level <13 g/dL in men and <12 g/dL in women. Blood volume and red blood cell volume were compared to normal values after being calculated by plasma volume, measured hematocrit for trapped plasma, and mean body hematocrit in the study patients. Although Hb levels were similar, excess plasma volume was more frequent in HFLEF patients (100%) than in HFPEF patients (71%). Also, HFLEF patients experienced less red blood cell deficit compared to HFPEF patients, but the incidence of dilutional anemia was greater (41% versus 12%, respectively). Finally, in all HF patients, no significant association was found between Hb levels and the percentage of red cell volume deviation from baseline values. The poor correlation of Hb levels and red cell volume was likely observed because of the confounding effects of alterations in plasma volume, secondary to the underlying disease or diuretic therapy.

This study's results point to some important implications in the treatment of anemic patients with HF. Two popular treatments – intravenous iron and erythropoietic stimulators – have shown mixed results, and few studies have considered dilutional anemia as a reason for these ambiguous outcomes. Specifically, treatment with erythropoietic stimulators has often resulted in reductions in plasma volume. Therefore, the authors contend diuresis may be a safer approach in the treatment of anemic patients with HF. Further study is needed to determine if these results are generalizable to the overall HF population, as this trial was restricted to only patients with severe HF at tertiary care centers.

Abramov D, Cohen RS, Katz SD, Mancini D, Maurer MS. Comparison of blood volume characteristics in anemic patients with low versus preserved left ventricular ejection fractions. Am J Cardiol. 2008 Oct 15;102(8):1069-72.

NAAC Expert Commentary:
This article relied on the indirect assessment of red blood cell (RBC) volume by the I-131 labeled albumin method in heart failure patients with preserved and low ejection fraction. The authors found plasma volume excess in 41% of low EF patients and 12% in preserved EF patients. The authors purport that the anemia in heart failure patients may be due to dilutional anemia and should be treated with diuretics.

There are numerous assumptions made when estimating blood volume indirectly from an estimate of plasma volume rather than estimating blood volume by directly measuring the blood volume via labeling the red blood cells with a chromium marker. These assumptions include using a nomogram for estimating plasma volume, assuming the ratio of total body hematocrit to venous hematocrit is constant (i.e. the f ratio), and assuming the translocation of plasma volume across the arteriolar capillaries is similar in patients with and without heart failure. It is known that the actual plasma volume is dependent on the amount of lean muscle mass in an individual. We do not know if these relationships are valid in patients with heart failure.

In individual patients, the f ratio has a coefficient of variation of ±5%, which can translate into a ±10% change in blood volume estimates.¹ The correct f ratio in patients with heart failure remains unknown as this has not been evaluated. In heart failure patients the permeability diffusion is increased, leading to an increase in extracellular fluid, but no increase in plasma volume.² Since the authors did not correct for this increased capillary permeability, it is uncertain if the estimated plasma volume also included some extracellular volume. Direct measurement of blood volume using the chromium labeled standard had a R² of 0.83 relative to the indirect method of estimating blood volume with iodine labeled albumin.³ It is important to note that none of the comparison studies were performed in anemic heart failure patients where all of the assumptions may be invalid.

The authors have previously reported that although the patients were clinically euvolemic, the mean pulmonary capillary wedge pressure (PCWP) was markedly elevated at 26 mm Hg in the patients with hemodilutional anemia.⁴ Treatment with erythropoiesis-stimulating agents (ESAs) in the patients with hemodilutional anemia increased the RBC mass and reduced the plasma volume.⁵ The increase in hemoglobin and peak oxygen consumption was similar in patients with hemodilutional and true anemia.

The validity of the indirect measurement used to determine blood volume in this study remains unknown for heart failure patients who may have leaky capillaries. In such patients, leaky capillaries can lead to a loss of albumin to the interstitial space, causing an overestimation of the plasma volume and subsequently, an overestimation of the red cell volume. If this occurred, there may be problem with the indirect method used to estimate RBC mass. The results of this analysis would be more compelling if the authors had used a direct measurement of red cell volume or if the indirect method had been validated in heart failure patients.

We know that Hb levels correlate with oxygen delivery, increased cardiac output, cytokine activation, and mortality in heart failure patients with both preserved and low EF. We do not have any data to suggest that any of these measurements vary in patients with a true blood deficit versus dilutional anemia. Other authors have noted that anemia can resolve over time in heart failure patients. It is certainly reasonable to diurese patients with low EF to achieve a euvolemic state. However, if the anemia persists, appropriate treatment of these patients remains uncertain. The results of trials using intravenous iron or ESAs are ongoing and we await the results.

References

1. Retzlaff JA, Tauxe WN, Kiely JM, Stroebel CF. Erythrocyte volume, plasma volume, and lean body mass in adult men and women. Blood. 1969 May;33(5):649-61. Link.
2. Galatius S, Bent-Hansen L, Wroblewski H, Kastrup J. Plasma clearance of polyfructosan and extracellular body fluid distribution in idiopathic dilated cardiomyopathy and after heart transplantation. Am J Cardiol. 2000 Apr 1;85(7):843-48. Link.
3. Balga I, Solenthaler M, Furlan M. Should whole-body red cell mass be measured or calculated? Blood Cells Mol Dis. 2000 Feb;26(1):25-31. Link.
4. Androne AS, Katz SD, Lund L, LaManca J, Hudaihed A, Hryniewicz K, Mancini DM. Hemodilution is common in patients with advanced heart failure. Circulation. 2003 Jan 21;107(2):226-29. Link.
5. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003 Jan 21;107(2):294-99 Link.

Last Updated: December 3, 2008