Definition and severity classification
Anemia is a decrease in hemoglobin levels relative to the norm. The norm is determined either by professional associations in their guidelines or by laboratories based on their own population reference ranges. In clinical practice, it is convenient to use WHO thresholds. Grading anemia by severity has practical implications: in severe anemia, the question of a blood transfusion is considered. Hemoglobin norms differ for men, women, and pregnant individuals: women experience chronic physiological blood loss (menstruation), while pregnant individuals develop physiological hemodilution.
Clinical manifestations
Regardless of their etiology, all anemias share general symptoms associated with hypoxia: fatigue, dyspnea, and worsened angina pectoris. The blood becomes less saturated with hemoglobin—manifesting as pallor—and less viscous, causing it to flow faster through vessels. This accounts for an aortic systolic murmur, a split second heart sound, and a pulsating tinnitus.
Certain types of anemias present with specific symptoms:
- Iron deficiency anemia — pica (perverted appetite) and restless legs syndrome
- Vitamin B12 deficiency — paresthesia, ataxia, oral ulcers
- Hemolytic anemias — jaundice
Etiology and physiology of erythropoiesis
By mechanism, anemias are divided into acute blood loss, impaired red blood cell production, and hemolysis (destruction of red blood cells). Impaired production may be due to a deficiency of substances required for hemoglobin synthesis or for bone marrow cell proliferation and differentiation, chronic diseases, toxins, liver and kidney diseases, endocrine disorders, or direct bone marrow damage.
For cell differentiation in the bone marrow, renal erythropoietin is required, as well as vitamin B12 and folic acid, which are obtained exclusively via the gastrointestinal tract. Absorption of B12 requires Castle's intrinsic factor produced in the stomach. Hemoglobin consists of heme, protein, and iron—a defect in any component impairs the hemoglobin saturation of the erythrocyte. Iron is absorbed via the protein ferroportin and transported by transferrin to the bone marrow; during the breakdown of old erythrocytes in the spleen, iron is stored as ferritin and reused. The liver can block iron uptake by increasing the production of hepcidin in response to inflammation.
Laboratory diagnostics
Key erythrocyte indices are MCV (mean corpuscular volume) and the reticulocyte index; other parameters (MCH, MCHC, RDW) are auxiliary. A complete blood count also evaluates ESR as a marker of inflammation, while smear microscopy reveals red blood cell morphology and neutrophil segmentation.
Biochemical blood tests assess vitamin B12 and folic acid metabolism, markers of hemolysis (haptoglobin, lactate dehydrogenase, indirect bilirubin, Coombs test), and iron metabolism parameters: ferritin, transferrin, serum iron, and transferrin saturation. Modern diagnostic classification is based on MCV: anemias are divided into microcytic, normocytic, and macrocytic. It is important to remember that both microcytic and macrocytic anemias can present initially as normocytic, with the exception of most hereditary forms.
Microcytic anemias
Microcytic anemia is associated with impaired hemoglobin synthesis at the level of protein chains (hemoglobinopathies, notably thalassemia), heme (sideroblastic anemia, lead poisoning), or iron (malabsorption, chronic blood loss, anemia of chronic disease).
The diagnostic algorithm begins by determining ferritin (target norm is 30 ng/mL, which significantly increases sensitivity compared to the laboratory reference of 10–14 ng/mL). If ferritin is reduced, iron deficiency anemia is diagnosed. If ferritin is elevated, the Mentzer index (MCV / red blood cell count) is calculated: a value below 13 indicates probable thalassemia, which is confirmed by hemoglobin electrophoresis. When acute-phase reactants are elevated, anemia of chronic disease is diagnosed.
Criteria for iron deficiency anemia: ferritin below 30 ng/mL, transferrin saturation less than 20%, elevated soluble transferrin receptors above 1.52 mg/L. Causes other than blood loss include hypochlorhydria, celiac disease, Helicobacter pylori infection, and proton pump inhibitor use. Treatment begins with oral iron (preferably Fe2+, or Fe3+ if poorly tolerated); if ineffective or severe, intravenous administration is initiated with the dose calculated based on body weight and target hemoglobin. The underlying cause of iron deficiency must be identified: in menstruating women without red flags, treatment alone may suffice, whereas in men and non-menstruating women, upper endoscopy (EGD) and colonoscopy are performed to locate the source of blood loss.
Normocytic and macrocytic anemias
Normocytic anemia is typical for acute blood loss, chronic kidney disease (reduced erythropoietin), bone marrow damage from toxins or tumors, hemolysis, and hypothyroidism. Diagnostic algorithm: exclusion of hemolysis via reticulocytes, followed by screening for anemia of chronic disease and deficiency anemias, and evaluation of liver, kidney, and thyroid function.
Macrocytic anemia (MCV greater than 100 fL) is divided into megaloblastic (B12 deficiency, folic acid deficiency, drug toxicity, hereditary DNA synthesis disorders) and non-megaloblastic (liver disease, alcohol use, hypothyroidism, reticulocytosis). Vitamin B12 deficiency causes not only anemia but also neurological symptoms — ataxia, peripheral neuropathy, cognitive impairment; a frequent cause is autoimmune gastritis with antibodies against intrinsic factor (pernicious anemia), as well as metformin use. Folic acid deficiency does not cause neurological manifestations. Diagnosis in cases of borderline B12 levels involves homocysteine and methylmalonic acid.
Hemolytic anemias
Hemolysis is classified as extrinsic (antibodies, infections, toxins, mechanical trauma) and intrinsic (defect in the erythrocyte membrane, enzymes, or hemoglobin), as well as intravascular and extravascular. In intravascular hemolysis, free hemoglobin enters the bloodstream with a risk of acute kidney injury, accompanied by a more marked decrease in haptoglobin. Specific symptoms of hemolysis include back pain, hematuria, hypotension, jaundice, splenomegaly, and gallstones.
Main forms:
- Autoimmune hemolytic anemia — warm (IgG) and cold (IgM), diagnosed via the Coombs test
- Microangiopathic hemolytic anemia — TTP, HUS, DIC, severe preeclampsia, and HELLP syndrome, diagnosed via schistocytes with a negative Coombs test
- Glucose-6-phosphate dehydrogenase deficiency — oxidative hemolysis triggered by infections and certain medications
- Hereditary spherocytosis and sickle cell anemia — hereditary membrane and hemoglobin disorders with characteristic complications (aplastic crisis, vaso-occlusive crises, acute chest syndrome)
Laboratory signs of hemolysis: elevated lactate dehydrogenase, decreased haptoglobin, reticulocytosis above 2%, elevated indirect bilirubin. Before splenectomy, which is used in several hemolytic anemias, vaccination against pneumococcus, meningococcus, and Haemophilus influenzae is required due to the increased risk of encapsulated organism infections.
Key points
- Anemia is diagnosed relative to the hemoglobin reference range, which varies by sex and physiological status.
- The primary diagnostic criterion for classifying anemias in modern practice is mean corpuscular volume (MCV).
- In microcytic anemia, the first step is to measure ferritin with a target threshold of 30 ng/mL.
- Anemia of chronic disease is accompanied by elevated ferritin as an acute-phase reactant against the background of functional iron deficiency.
- Vitamin B12 deficiency presents with neurological symptoms, unlike folic acid deficiency.
- In hemolysis, key markers are elevated LDH and reticulocytes, alongside decreased haptoglobin.
- A negative Coombs test in the presence of schistocytes indicates mechanical rather than immune hemolysis.
- Vaccination against encapsulated microorganisms is mandatory prior to splenectomy.