Physiologic Response to Anemia

Anemia

• Anemia is defined by a reduction in hemoglobin concentration, hematocrit, and/or red blood cell (RBC) count.1 Multiple factors impact hemoglobin concentration, including age, sex, smoking, hypoxemia, pregnancy status, altitude, and medications.
• Anemia is defined by the World Health Organization as a hemoglobin concentration of less than 12.0 g/dL in nonpregnant females, less than 11.0 g/dL in pregnant patients, and less than 13.0 g/dL in males.1 While patients with hemoglobin concentrations less than 7.0 g/dL are almost certainly symptomatic, patients with other comorbidities may be symptomatic at higher hemoglobin levels.^1,2
• Common signs and symptoms of anemia include weakness, lethargy, restless legs, dyspnea, pallor, and tachycardia.^1,2 While clinical presentation can vary depending on the underlying cause of the anemia, most of the presenting symptoms of anemia are manifestations of impaired oxygen delivery.^1,2
• Anemia has a broad differential diagnosis, with some of the most common underlying etiologies being iron deficiency/other nutritional deficiencies, hemolysis, blood loss (chronic vs. acute), renal disease, liver disease, and genetic hemoglobinopathies.^1,2

Compensation in Anemia: Systemic Mechanisms

• Several complex physiologic changes occur in the body to compensate and optimize tissue oxygen delivery in anemia (Figure 1). In anemia, a reduced hematocrit leads to a decrease in blood viscosity, which in turn causes a reduction in systemic vascular resistance (SVR) and afterload.³ Recruitment of microvessels, increased nitric oxide (NO) activity, and stimulation of angiogenesis (in chronic anemia) can increase vasodilation, reducing SVR and afterload.³
• Conversely, the sympathetic nervous system activation observed in anemic patients counteracts some of the vasodilatory and hemodilutional effects on SVR, helping to maintain adequate preload while increasing heart rate (chronotropy) and enhancing left ventricular contractility (inotropy), ultimately resulting in a net increase in cardiac output.³
• Euvolemia is critical for the maintenance of these compensatory mechanisms, and anemic patients who become hypovolemic decompensate rapidly.
• The reduced oxygen delivery to the myocardium in anemia, combined with abnormal coronary perfusion, results in an impaired compensatory response in patients with underlying cardiovascular disorders, such as coronary artery disease. This increases their risk of developing severe clinical symptoms in the presence of anemia.³
• Another important compensatory mechanism is the redistribution of blood flow in anemic patients, prioritizing oxygen delivery to critical organs such as the heart, lungs, and brain.⁴ This results in reduced perfusion to skin, muscle, liver, and kidneys.

Compensation in Anemia: Cellular Adaptations

• At a cellular level, chronic anemia also results in an increase in 2,3-DPG levels, which causes a decrease in affinity between oxygen and hemoglobin and shifts the hemoglobin-oxygen dissociation curve to the right.³ This shift allows for more oxygen to be unloaded from red blood cells and delivered to tissues at any given partial pressure of oxygen (PO₂), thereby optimizing tissue oxygen delivery in the setting of decreased oxygen-carrying capacity secondary to anemia.³
• Decreased tissue PO₂ also leads to the upregulation of hypoxic molecules, such as HIF-1α and NOS.³ HIF-1ɑ expression activates HIF dependent genes and stimulates erythropoiesis, angiogenesis, and changes in metabolism.4 NOS-derived NO is thought to mediate cardiovascular responses to anemia by regulating vascular reactivity and tissue perfusion.⁴