Stress Erythropoiesis - Pathogenesis, Clinical Manifestations, and Management

Introduction

Erythropoiesis is the production of new red blood cells (erythrocytes) from tissues that produce blood components. It is a constant physiological process that starts during fetal life. The site of production varies by different developmental stages. Erythropoiesis occurs in the yolk sac in the first few weeks of fetal life, followed by the fetal liver and spleen in the next few months. By the time of birth, the entire erythropoiesis shifts to bone marrow. Erythropoiesis that occurs normally in the bone marrow is termed steady-state erythropoiesis, which is a well-balanced and homeostatic mechanism. When this balance is disturbed or becomes inadequate, stress erythropoiesis is activated. This article discusses the various aspects of stress erythropoiesis and its clinical significance.

What Happens When Steady-State Erythropoiesis Is Disturbed?

Steady-state erythropoiesis has an increased capacity to generate new erythrocytes from the multipotent hematopoietic stem cells present in the medulla of bone marrow (medullary erythropoiesis). The average erythrocyte production in an adult human is 2.5 x 10^6 erythrocytes per second and the mean lifespan of a single red blood cell is 120 days. This production is balanced with the degradation of functionally old erythrocytes in the spleen and liver. Oxygen demand and supply to the tissues control normal erythropoietic homeostasis. Dysregulation of steady-state erythropoiesis leads to,

• Anemic Condition - Due to decreased production of red blood cells oxygen carrying capacity is reduced in the blood leading to fatigue and weakness.

• Erythrocytosis - Overproduction of red blood cells results in increased viscosity of blood, altering blood flow rate and resulting in thrombogenic (formation of blood clot) complications.

What Are the Factors That Activate Stress Erythropoiesis?

Stress erythropoiesis is a complex pathway that is triggered when the production of red blood cells is decreased or insufficient to meet the oxygen requirement of the body. Failure in steady-state erythropoiesis due to injury of erythroid lineage (precursors of red blood cells) and disruption in the homeostatic balance due to excessive destruction of erythrocytes in the spleen and liver also favor stress erythropoiesis. The various factors that activate stress erythropoiesis are

• Acute anemic stress.

• Hypoxic conditions.

• Hemorrhage.

• Hemolysis.

• Nutrient deficiency.

• Secondary response to sickle cell anemia and thalassemia.

• Erythropoietic injury (bone marrow disorders like leukemia).

• Inflammatory stimuli due to underlying disease (myelodysplastic syndrome).

• Bone marrow ablative chemotherapies.

• Hematopoietic stem cell exhaustion.

• Bone marrow transplantation.

• Drug-induced (Phenylhydrazine-induced).

• Pregnancy.

How Does Stress Erythropoiesis Take Place?

There are considerable differences between stress and steady-state erythropoiesis which include progenitors (cells from erythroid lineage), initiating signals and pathways, and organ systems. Unlike steady-state erythropoiesis, stress erythropoiesis occurs in sites outside the bone marrow like the spleen and liver (extra-medullary erythropoiesis). In vitro and in vivo experimental models are studied to explore human stress erythropoiesis and to enhance novel clinical studies to focus on the therapeutic management of stress erythropoiesis.

The concept of stress erythropoiesis is a recently evolving hypothesis in red blood cell physiology research and still, there are enormous gaps in its scientific understanding that creates potent space for more research and clinical data. Also, there exist differences in mechanisms due to evolutionary variations between species. Recent studies have proved that some stress erythropoiesis pathways are closely related and highly conserved between mouse species and humans. Therefore much of the stress erythropoiesis models have been documented in the analysis of murine models. Some of the well-established pathways include,

• Infection and inflammation are the common switch-on stimuli for stress erythropoiesis. Pro-inflammatory cytokines (released during infection) that stimulate hematopoietic production to increase myeloid effector cells (cells that produce immunity) needed to fight infection also trigger erythrocyte production.

• Bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis pathway is activated as an inflammatory response (due to hypoxic or hematopoietic injury) and generates new erythrocytes to maintain homeostasis till steady-state erythropoiesis resumes back to normal functioning.

• Phagocytosis (cell destruction) of red blood cells by macrophages in the spleen stimulate inflammation which induces stress erythropoiesis mediated by toll-like receptors (TLRs).

• TLR signaling (increased in phagocytosis of infectious agents) enhances the production of cytokines that increase the number of stress erythroid progenitors in the spleen. This mechanism compensates for the inhibition of steady-state erythropoiesis by proinflammatory cytokines.

• Production of erythropoietin (an enzyme produced by kidneys that help in normal erythropoiesis) is increased in hypoxic stress and causes increased production of the transcription factor SPI-C that favors enhanced stimulation of erythroid progenitor cells.

What Are the Clinical Manifestations of Stress Erythropoiesis?

Stress erythropoiesis by itself is not a disease or disorder caused by a single identity. It is a physiological response to maintain erythropoietic homeostasis which gets inhibited when steady-state erythropoiesis takes over. But when homeostasis does not occur due to certain pathological or inflammatory conditions stress erythropoiesis is exaggerated without control and sometimes leads to clinical complications. Although the number of red blood cells is more, oxygen transport is greatly affected since the newly formed red blood cells are not mature enough to carry hemoglobin molecules resulting in anemic symptoms. The clinical signs and symptoms usually mimic underlying disorders. Some of them are,

• Fatigue.

• Breathlessness.

• Weakness.

• Polycythemia vera (a type of blood cancer characterized excessive production of red blood cells).

• Disseminated blood clots.

• Erythropoietic porphyria (unmetabolized heme products accumulated in the liver).

• Bilirubinemia (due to increased destruction of red blood cells).

How to Detect Stress Erythropoiesis Clinically?

Diagnosis of stress erythropoiesis is often masked by the disorders that activate it. Being a complex mechanism the specificity and accuracy of its detection are confounded by other parameters. Recent studies are carried out to identify stress erythropoiesis, thereby, effectively managing its etiological perspective. The following parameters help in identifying stress erythropoiesis.

• Red cell distribution width (RDW) is increased due to the increased number of red blood cells.

• Presence of anisocytosis (unequal size of red blood cell).

• Polycythemia vera (due to increased hemoglobin concentration).

• Iron overload detected by serum iron (ferritin) levels.

• Precursors of erythrocytes are identified in the peripheral blood (due to dysregulation of erythropoiesis).

How to Manage Stress Erythropoiesis?

Since stress erythropoiesis is a compensatory mechanism, the management of the causative dysfunction or abnormality plays a foremost role in managing stress erythropoiesis. Without treating the underlying disorder, stress erythropoiesis cannot be stopped and would continue to activate. However, symptomatic intervention would help in avoiding further complications.

• Management of anemia.

• Regulation of chemotherapy.

• Chelating therapy in iron overload and porphyria.

• Micronutrient supplementation like selenium (Se) is identified as a regulator of erythropoiesis.

Conclusion

Stress erythropoiesis is an intrinsic homeostatic mechanism that includes various signals and activators of erythropoiesis. Studies suggest that it is triggered as an inflammatory response to infection and tissue damage. Stress erythropoiesis is beneficial in life-threatening situations such as sudden loss of blood or immediate oxygen requirement thereby maintaining continuous oxygen supply to the tissues and proper functioning of the vital organs.