of Erythropoiesis Following Trauma
by By Alicia M. Mohr, MD
In research conducted in the Division of Trauma at UMDNJUniversity Hospital’s trauma center, I have pursued a separate line of investigation on erythropoietic dysfunction following severe injury. Erythropoiesis and the formation of red blood cells is a complex process involving bone marrow stem cells, progenitor cells, and stromal cells. Severe traumatic injury is a stress state, commonly associated with a “fight or flight response.” During this time, the stress hormones epinephrine and norepinephrine are released and bind to adrenergic receptors. It is the impact of this stress or “adrenergic state” on erythropoiesis and its subsequent dysfunction that is the focus of my research.
Persistent anemia is a common occurrence in critically injured patients and multiple transfusions are frequently needed. Anemia has associated adverse effects and the safety of transfusions is uncertain. An understanding of the pathophysiology of anemia in the intensive care unit (ICU) patient facilitates selection of an optimal treatment strategy. Adrenergic modulation of erythropoiesis is known to occur under normal conditions and typically red blood cell growth is enhanced. Yet, following traumatic injury, red blood cell growth is suppressed and the presence of anemia is persistent. Adrenergic stimulation is known to accompany traumatic injury but there is no information on its effects on bone marrow during trauma. We hypothesize that since adrenergic stimulation occurs with trauma, the anemia associated with injury may be related to the cells’ altered ability to proliferate and differentiate into red blood cells. This response is due to either the magnitude or the persistence of adrenergic stimulation that occurs with injury. If true, an investigation of the contributions of bone marrow stroma and the mediators involved in altered erythropoiesis after injury, as well as the use of adrenergic antagonists, may produce important advances in trauma care by suggesting a clinical approach to anemia that could diminish its current morbidity.
My work regarding the adrenergic modulation of erythropoiesis following trauma is an extension of the research that I began in the laboratory of David Livingston, MD. That research provided the groundwork and background for my current studies. Knowing that persistent anemia follows severe injury, and that the defect lies in the bone marrow rather than in peripheral blood, allows us to analyze the specific impact of the stress state on bone marrow erythropoiesis. My initial studies have focused on hormonally replicating in vitro the stress state using normal bone marrow. We are also expanding our study to include trauma patients admitted to the Surgical Trauma ICU at UMDNJ-University Hospital.
In one of our studies, we have demonstrated that urine norepinephrine levels from critically injured patients are significantly elevated as compared to a control group (Figure 1). The initial elevation of norepinephrine immediately following injury is six times that of normal levels. This super-stimulated state lasts for seven to 10 days following severe injury. Epinephrine levels are also elevated but return to baseline levels more quickly.
Figure 1. Mean urine norepinephrine levels (ug/day) are significantly increased in critically ill patients compared to normal controls from the date of admission up to day 10 post injury.
Adrenergic agonists, epinephrine, norepinephrine and isoproterenol, were added to bone marrow cultures in vitro to assess their effect on erythropoietic progenitors, specifically erythroid burst forming units (BFU-E) and erythroid colony forming units (CFU-E). These adrenegic agonists induced proliferation of BFU-E and CFU-E, which were grown in the presence of bone marrow stroma. All three adrenergic agents exerted their highest stimulatory effect at lower doses. At the highest concentration, most colony numbers dropped considerably, suggesting that the adrenergic effect is dose-related. In our studies, BFU-E colonies had a significantly higher response than did CFU-E to adrenergic agonists. This differential effect to catecholamine stimulation may be a hierarchical response resulting from the adrenergic effect on the terminal maturation at the BFU-E stage, which precedes CFU-E in the erythropoietic maturation scheme. To determine if the bone marrow stroma is essential for this proliferative process associated with adrenergic stimulation, bone marrow stroma was depleted. When these same adrenergic agonists are added to bone marrow cultures of BFU-E and CFU-E lacking bone marrow stroma, the proliferative effect is abrogated (Figure 2).
Figure 2. BFU-E colonies grown with the addition of norepinephrine, epinephrine, isoproterenol in cultures with the presence of stroma (+ stroma) vs. stroma-depleted bone marrow (- stroma).
Thus far, we have shown that there is a significant and persistent hypercatecholamine state after severe injury. Our in vitro analyses support the notion that erythropoiesis is also modulated by the adrenergic system. Our research discovered a dichotomy. On one hand there is a hypercatecholamine period after severe injury that is characterized by overt bone marrow dysfunction, seen as anemia and leucopenia. Yet, on the other hand, our data shows that the addition of adrenergic agents to erythroid precursors in vitro leads to an overwhelming pro-erythropoietic stimulus. Future studies will focus on the mechanisms that account for the paradox of adrenergic stimulation observed in trauma patients as opposed to the in vitro effects on bone marrow cultures.
There may be a direct correlation between the magnitude and duration of the stress response seen following injury and resultant erythropoietic dysfunction. Perhaps with the use of adrenergic antagonists, the adrenergic modulation of erythropoiesis may be altered.
Alicia M. Mohr, MD, is a volunteer faculty member in the Department of Surgery at UMDNJ-New Jersey Medical School (NJMS). Dr. Mohr graduated from NJMS and completed her surgical residency training at UMDNJ-University Hospital. After completing a fellowship in trauma/critical care surgery at the University of North Carolina, she returned to join the faculty of the medical school in 2000. Dr. Mohr recently received the Wyeth Research Scholarship from the Eastern Association for the Surgery of Trauma for her research entitled Adrenergic Modulation Of Erythropoiesis Following Severe Injury