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Letters to the Editor
Anemia and hemodilution: analysis of a single center
cohort based on 2,858 red cell mass measurements
Anemia is the most frequent hematologic disorder worldwide. It was biologically defined many years ago by the World Health Organization (WHO) as a decrease in circulating hemoglobin concentration [Hb] to <120 g/L in women and <130 g/L in men.1 In severe anemia (i.e., anemia causing symptoms or when [Hb] <70-80 g/L), curative treatments (e.g., iron, folates, vitamin B12 sup- plementation or erythropoiesis stimulating agents [ESA]) or transfusions are typically used. Approximately 85 mil- lion red blood cell (RBC) units are transfused per year worldwide.2
In a recent study, Otto et al.3 reported that in approxi- mately half the cases anemia can be explained as a result of hemodilution (increased plasma volume [PV]) rather than by a reduction in red cell mass (RCM), especially in chronic heart and liver diseases. These results, obtained by using total hemoglobin mass measurement with car- bon monoxide rebreathing method and PV indirect calcu- lation, suggest that treatment of anemias could be over- prescribed for hemodiluted patients.
In order to determine whether anemia-related treat- ment could be over-prescribed for “anemic” patients in our institution, we retrospectively analyzed RCM and PV from normal, anemic and polycythemic patients using direct measurements of red cell and plasma volumes (Cr51-labeled RBC and I125-labeled albumin). Briefly, 2,858 RCM and PV performed concomitantly in our depart- ment between 2010 and 2017 (mostly for suspected myeloproliferative diseases) were retrospectively ana- lyzed in addition to [Hb] and hematocrit (Hct) determina- tion. These measurements were performed in different situations: i) looking for real RCM decrease in case of low [Hb] in presence of possible cause of hemodilution or in absence of other obvious causes of [Hb] decrease; ii) looking for “masked” RCM increase in presence of known myeloproliferative neoplasm in case of low or normal [Hb]; or iii) confirming polycythemia in case of elevated [Hb]. We then selected a group of “anemic” patients with low [Hb] (<120 g/L in women and <130 g/L in men) and classified them according to the severity of the anemia (WHO classification of anemia4): mild ane- mia (110-119 g/L for women and 110-129 g/L for men, n=27), moderate anemia (80-109 g/L, n=27) and severe anemia (< 80 g/L, n=9). We also selected a control group (n=97) defined as follow: [Hb] 120-160 g/L in women and 130-165 g/L in men, Hct ≤48% in women and ≤49% in men, mean corpuscular volume 80-100 fL, RCM ≤ +25% of normal value, absence of JAK2V617F mutation,
no splenomegaly, white blood cell (WBC) count 4- 10x109/L and platelet count 150-450x109/L, and a group of “polycythemic” patients with increased [Hb] (>160 g/L in women and >165 g/L in men) (n=1,815). Patients' characteristics are summarized in Table 1 and a flow chart of the study is shown in Online Supplementary Figure S1.
PV categories had previously been defined according to Otto et al.3: plasmatic contraction if PV < -8% of the expected theoretical value, normal if ≥ -8% and ≤ +8%, moderate expansion if > +8% and ≤ +25%, and severe expansion if > +25%. RCM was considered as normal when varying between -25% and +25% of the theoreti- cal value, increased (polycythemia) when RCM > +25% of the theoretical normal RCM, and reduced when RCM < -25% of the theoretical normal RCM according to Pearson et al.5
We first focused on anemic and control subjects. Anemic patients had a significantly higher PV than the control group (mean PV +41% vs. -5%; P<0.0001) (Figure 1A), 94% of them had PV > +8% (vs. 9% in the control group) and 73% PV > +25% (vs. 0% in the control group) (Table 2), confirming with direct measurement previous findings from Otto et al.3 about the high frequency of hemodilution in anemic patients. There was also a statis- tical difference in RCM between the control group and the anemic group (mean RCM -12.7% vs. +8.8% for ane- mic and control groups, respectively; P<0.0001) (Figure 1B). Only 24% (n=15) of anemic patients had RCM < -25% of the expected theoretical value (Table 2 and Figure 1C), confirming that, in our cohort, a decrease in [Hb] may be due more often to an increase in PV rather than related to a decrease in RCM in clinical practice. Among anemic patients, no patient with mild anemia had RCM < -25%, while patients with moderate anemia presented a 25.9% risk of RCM < -25% and those with severe anemia a risk of 88.9% (Table 2), suggesting that even in severe anemic patients, patients may have hemodilution rather than an important reduction in the RCM. Moreover, 77.8% (n=7) of the severe anemic patients with RCM < -25% also have increased PV > +25%. This suggests that, in the vast majority of cases, severe anemia is related to both reduced RCM and increased PV.
We then focused on the correlations between [Hb], PV and RCM. Studying the whole cohort according to the [Hb] revealed a direct correlation between [Hb] level and PV (P=0.0006). This was also observed when focusing on anemic (P<0.0001) and control patients (P=0.0006) (data not shown). A direct correlation between [Hb] and RCM was found in the whole cohort: the lower the [Hb] level, the lower the RCM (P<0.0001). This correlation between
Table 1. Characteristics of anemic patients, control subjects, and of patients with increased hemoglobin concentration.
“Anemic” Control “Polycythemic”
N
Age (years) M/F
WBC (x109/L) [Hb] (g/L) Hct (%)
Platelets (x109/L)
All Mild Moderate Severe
63 27 27 9 97 1,815
61.0±19.4 1.4 8.7±8.3 103±20 31.7±5.9
322±329
61.0±17.2 1.7 8.5±4.6 120±6 36.9±2.0
490±430
63.9±21.1 1.1 9.2±11.3 97±8 29.8±3.2
207±116
52.5±19.8
2.0
7.6±7.1
67±6
21.6±3.4
152±117
52.4±16.8
2.7
6.7±1.5
158±7
46.1±2.0
247±69
56.7±15.2
5.8
8.0±4.3
177±9
51.4±3.1
256±153
M/F: sex ratio male/female; WBC: white blood cell count; [Hb]: hemoglobin concentration; Hct: hematocrit. Polycythemic patients in this table are all patients with increased [Hb] whatever the cause: red cell mass increase (real polycythemia) or plasma volume decrease (hemoconcentration).
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