The primary finding of this study was that initial macrocytosis was associated with 30-day mortality in elderly patients with major trauma, along with factors such as transfusions within 4 hours of admission, hypotension, and anemia.
The prevalence of macrocytosis in the general population is about 3% (10, 11), and the etiologic factors for macrocytosis range from vitamin B12 and folate deficiency and the use of chemotherapeutic and anticonvulsant agents to alcoholism, chronic obstructive pulmonary disease, and bone marrow disorder (10, 12, 13). Although the number of studies is limited, recent studies have shown that a high MCV is associated with poor outcomes in several diseases (5–9). In our cohort, the prevalence of macrocytosis was 16.3%, and it was associated with increased 30-day mortality compared to that in the normocytosis group. This finding may be explained by hypoperfusion due to major trauma in patients with macrocytosis. The relationship between MCV and Hb was established almost a century ago (14), which was validated in a more recent study where MCV was shown to vary in a strict linear relationship with the average Hb content of RBCs (15). Accordingly, larger erythrocytes (macrocytes) accommodate a greater amount of Hb compared to smaller erythrocytes (16). In our study, no statistical differences were found in the mean MCV values between the anemic and non-anemic groups (Additional file 1); however, between the hypotension and non-hypotension groups, the mean MCV value and proportion of macrocytosis showed significant differences (Additional file 2).
Multiple major traumas can cause systemic inflammatory response syndrome (SIRS) via hormonal, metabolic, and immunological mediators (17, 18). This response occurs immediately after major trauma and aggravates the initial damage caused by hypoperfusion and reperfusion (19). This metabolic response is associated with increased oxygen demand in the tissues (17). Consequently, to compensate for the increased oxygen consumption, the body reacts with tachycardia, increased cardiac output, increased respiratory rate, and vasodilatation (17, 20). As mentioned previously, anemia due to acute blood loss, hemolysis, or malignancy is known as normocytic anemia (1). In most cases, the etiology of macrocytosis may involve abnormal RBC development, abnormal RBC membrane composition, increased reticulocyte count, or a combination of these factors (21). Although the results of the high proportion of macrocytosis in our study are not explained by any particular etiologies, it seems reasonable that erythrocytes are enlarged to respond to the increased oxygen demand; however, biological studies are required to confirm this.
Erythrocytes transport oxygen and carbon dioxide, and their membranes have systemic antioxidant properties since they are potentially exposed to oxidative stress (22). Macrocytosis is a structural and functional abnormality of the erythrocyte membrane (8, 21). Oxidative stress resulting from the overproduction of reactive oxygen species is considered to contribute to the development and progression of cardiovascular disease (23). Therefore, MCV is not only an indicator of anemia but also a marker of inflammation and endothelial function (5). Studies investigating the underlying pathophysiology of macrocytosis in patients with trauma are required in the future.
Our study had several limitations. First, it was a retrospective, observational, single-center study. Second, we could not account for confounding factors such as chronic hepatitis, chronic renal disease, or alcohol abuse on MCV changes, and the influence of these factors should be addressed in future studies. Third, we could not always distinguish between patients admitted through the emergency room and those transferred from other hospitals, which could have altered the MCV values. Finally, macrocytosis is indicated by a high MCV on the CBC test and is confirmed by peripheral blood smear analysis. Thus, further study by peripheral blood smear is required.