Hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia

Abstract

In practice, clinicians generally consider anemia (circulating hemoglobin concentration < 120 g.l^-1 in non-pregnant females and < 130 g.l^-1 in males) as due to impaired hemoglobin synthesis or increased erythrocyte loss or destruction. Rarely is a rise in plasma volume relative to circulating total hemoglobin mass considered as a cause. But does this matter? We explored this issue in patients, measuring hemoglobin concentration, total hemoglobin mass (optimized carbon monoxide rebreathing method) and thereby calculating plasma volume in healthy volunteers, surgical patients, and those with inflammatory bowel disease, chronic liver disease or heart failure. We studied 109 participants. Hemoglobin mass correlated well with its concentration in the healthy, surgical and inflammatory bowel disease groups (r=0.687-0.871, P<0.001). However, they were poorly related in liver disease (r=0.410, P=0.11) and heart failure patients (r=0.312, P=0.16). Here, hemoglobin mass explained little of the variance in its concentration (adjusted R²=0.109 and 0.052; P=0.11 and 0.16), whilst plasma volume did (R² change 0.724 and 0.805 in heart and liver disease respectively, P<0.0001). Exemplar patients with identical (normal or raised) total hemoglobin masses were diagnosed as profoundly anemic (or not) depending on differences in plasma volume that had not been measured or even considered as a cause. The traditional inference that anemia generally reflects hemoglobin deficiency may be misleading, potentially resulting in inappropriate tests and therapeutic interventions to address 'hemoglobin deficiency' not 'plasma volume excess'. Measurement of total hemoglobin mass and plasma volume is now simple, cheap and safe, and its more routine use is advocated.

Figure 1.

Hematological variables in healthy volunteers and patient sub-groups. Hct (%), hematocrit percentage (A); [Hb], hemoglobin concentration (B); tHb-mass, total hemoglobin mass (g & g.kg⁻¹) (C & D). *P<0.0001 for Hct and [Hb] in LD patients compared to all other groups. No differences in tHb-mass (g or g.kg⁻¹) between groups. Data expressed as mean (± standard deviation error bars). HV: healthy volunteers; IBD: inflammatory bowel disease; HF: heart failure; LD: liver disease.

Figure 2.

Plasma volume in healthy volunteers and patient sub-groups. Plasma volume (ml & ml.kg⁻¹) (A & B). (A) PV (ml) between LD and HV, *P=0.006, PV (ml) between LD and IBD, **P=0.002 and PV (ml) between LD and surgical patients, ^†P=0.003; (B) PV (ml kg⁻¹) between LD and IBD, *P=0.008, PV between LD and surgical patients, **P=0.004. Data expressed as mean (± standard deviation error bars). HV: healthy volunteers; IBD: inflammatory bowel disease; HF: heart failure; LD: liver disease; PV: plasma volume.

Figure 3.

Hemoglobin concentration and hematocrit in all patients categorized by plasma volume status. Plasma volume contraction (n=3) was classified as > minus 8% from expected norms. Normal PV (n=24) was classified as derived PV within ± 8% of the expected normal volume on an individual level. Mild to moderate volume expansion (n=36) was considered >8% to <25% deviation from expected norms, and severe PV expansion (n= 46) as >25% of the expected normal volume. *P=0.005 for [Hb] in severe PV expansion vs. mild to moderate, ^†P<0.0001 for [Hb] in severe PV expansion vs. normal PV. Data expressed as mean (± standard deviation error bars). PV: plasma volume; [Hb]: hemoglobin concentration (g.l⁻¹); Hct (%): hematocrit percentage.

Figure 4.

Unadjusted relationship between hemoglobin concentration and total hemoglobin mass. Healthy controls (A, n=21), patients with IBD (B, n=22), surgical patients (C, n=28), liver disease (D, n=16) and HF (E, n=22). tHb-mass (g): total hemoglobin mass; [Hb] (g.l⁻¹): hemoglobin concentration.

Figure 5.

Individual participant data for total hemoglobin mass, plasma volume and hemoglobin concentration. Participants ranked by tHb-mass (g.kg⁻¹) (dark gray bars) from smallest to largest with corresponding PV (ml.kg⁻¹) (light gray bars) and [Hb] (g.l⁻¹) (black circles) in healthy volunteers (A), inflammatory bowel disease (B), surgical (C), chronic heart failure (D), and chronic liver disease (E). PV: plasma volume; [Hb]: hemoglobin concentration.