Bone marrow failure following severe injury in humans

Abstract

Background: Hematopoietic failure has been observed in experimental animals following shock and injury. In humans, bone marrow dysfunction has been observed in the red cell component and characterized by a persistent anemia, low reticulocyte counts, and the need for repeated transfusions despite adequate iron stores. While a quantitative defect in white blood cell count has not been noted, an alteration in white blood cell function manifesting as an increased susceptibility to infection is well established. Since the etiology of this anemia remains unknown and the bone marrow has been rarely studied following injury, we measured various parameters of hematopoiesis directly using bone marrow from trauma patients and tested the hypothesis that trauma results in profound bone marrow dysfunction, which could explain both the persistent anemia and the alteration in white blood cell function.

Methods: Bone marrow aspirates and peripheral blood were obtained between day 1 and 7 following injury from 45 multiple trauma patients. Normal volunteers served as controls. Peripheral blood was assayed for hemoglobin concentration, reticulocyte count, erythropoietin levels, white blood cell count, and differential. Peripheral blood and bone marrow were cultured for hematopoietic progenitors (CFU-GM, BFU-E, and CFU-E colonies).

Results: Bone marrow CFU-GM, BFU-E, and CFU-E colony formation was significantly reduced while peripheral blood CFU-GM, BFU-E, and CFU-E was increased in the trauma patients compared with normal volunteers. Bone marrow stroma failed to grow to confluence by day 14 in >90% of trauma patients. In contrast, bone marrow stroma from volunteers always reached confluence between days 10 and 14 in culture. The mean hemoglobin concentration and reticulocyte counts of the trauma patients were 8.6 +/- 1.0 g/dL and 2.75 +/- 0.7% respectively, while their plasma erythropoietin levels were 2 to 10 times greater than control values.

Conclusions: Release of immature white blood cells into the circulation may also contribute to a failure to clear infection and an increased propensity to organ failure. Concomitantly, profound changes occur within the bone marrow, which include the increased release of erythroid and myeloid progenitors into the circulation, a decrease in progenitor cell growth within the bone marrow, and an impaired growth of the bone marrow stroma. Erythropoietin levels are preserved following trauma, implying that the persistent anemia of injury is related to the failure of the bone marrow to respond to erythropoietin.

FIGURE 1. Bone marrow myeloid to erythroid (M:E) ratio plotted against the day after injury (n = 22). There is a marked increase from control values (between 1 and 2) as the time progresses after injury. *M:E ratio of 45 for an additional patient.

FIGURE 2. Bone marrow and peripheral blood BFU-E and CFU-GM colony formation from trauma patients (n = 45) and normal volunteers (n = 12). All trauma patients were admitted to the SICU and the mean ISS was 29. The mean and median day of sampling was 4 days and 2 days, respectively. Volunteers were matched to age and gender. *P < 0.05 versus control values.

FIGURE 3. Plasma erythropoietin levels plotted against the hemoglobin concentrations. The circles (•) represent values from individual trauma patients and the squares (▪) represents the values from normal volunteers (n = 6).