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Anemias due to increased red blood cell destruction (also known as hemolytic anemias or Group IV anemias) comprise a broad group of disorders characterized by reduced red blood cell survival because hemolysis occurs before the end of the normal erythrocyte life cycle. In these conditions, red blood cell loss exceeds the regenerative capacity of the bone marrow, generally producing an erythropoietic response with reticulocytosis, which may nevertheless be absent or inadequate in the early stages, during aplastic crises or in the presence of bone marrow failure and, in the most severe cases, signs of tissue injury due to hypoxia.

Hemolytic anemias may be divided into acquired forms (predominantly autoimmune, microangiopathic or secondary to external factors) and hereditary forms (structural defects of the red blood cell membrane, hereditary spherocytosis, hereditary elliptocytosis, G6PD deficiency, pyruvate kinase deficiency, other membrane disorders). Among the acquired forms, particularly important conditions include autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria and microangiopathic anemias.

The clinical presentation and prognosis are extremely heterogeneous and depend on the underlying cause, the rate of the hemolytic process and the compensatory capacity of the bone marrow. Manifestations may range from subclinical, well-compensated forms to acute and potentially fatal presentations.

Hemolytic anemias comprise very different conditions that share a premature reduction in red blood cell survival due to causes that are extrinsic or intrinsic to the red blood cell.

Etiology allows the following distinction:

• Acquired forms, which may depend on extrinsic factors or on an acquired defect intrinsic to the erythroid clone. Among these, autoimmune hemolytic anemia is caused by the production of autoantibodies against red blood cell antigens, with activation of macrophage-mediated or complement-mediated destruction. Microangiopathic anemias are instead caused by mechanical injury to red blood cells as they pass through abnormal microcirculation, as in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Paroxysmal nocturnal hemoglobinuria instead arises from an acquired defect of the red blood cell membrane caused by a PIGA gene mutation in hematopoietic stem cells.
• Hereditary forms, related to intrinsic defects of red blood cells. This group includes hereditary spherocytosis and hereditary elliptocytosis (red blood cell membrane abnormalities), enzyme defects such as glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency, hereditary hemoglobinopathies, including thalassemias and hemolytic structural variants, as well as other rare membrane disorders.

The common denominator of these disorders is reduced red blood cell survival due to premature destruction of red blood cells, which may occur within the bloodstream (intravascular hemolysis) or, more frequently, in the spleen and liver (extravascular hemolysis).

The pathogenetic mechanisms vary according to the cause:

• In autoimmune forms, the formation of autoantibodies causes opsonization of red blood cells and their removal by the reticuloendothelial system, or activation of complement-mediated lysis.
• In microangiopathic forms, red blood cell destruction results from mechanical fragmentation in small vessels altered by thrombi or endothelial injury; hemolysis caused by prosthetic valves or circulatory devices is instead macroangiopathic/mechanical.
• In hereditary forms, the structural or enzymatic defect may cause membrane fragility, reduced deformability or metabolic abnormalities that facilitate red blood cell lysis spontaneously or in the presence of specific triggers, depending on the disease.

Regardless of the cause, accelerated red blood cell loss stimulates erythropoiesis, producing reticulocytosis and, in chronic cases, possible expansion of hematopoietic marrow and the development of extramedullary erythropoiesis.

The risk factors vary according to whether the disorder is acquired or hereditary.

In acquired forms, particularly important factors include:

• The presence of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and chronic lymphoproliferative disorders, which increase the likelihood of developing autoimmune hemolytic anemia
• Exposure to hemolytic drugs, including penicillins, quinidine, cephalosporins, methyldopa and dapsone, or to toxic chemicals
• Macroangiopathic mechanical hemolysis: prosthetic valves, circulatory devices or high-shear vascular lesions; this must be distinguished from thrombotic microangiopathy.
• Viral or bacterial infections, such as hepatitis, mononucleosis and atypical pneumonia, which may trigger the production of red blood cell autoantibodies

In hereditary forms, the main risk factor is a family history of membrane defects, enzyme deficiencies or hereditary blood disorders, especially in populations with a high prevalence, such as hereditary spherocytosis in Northern Europe or G6PD deficiency in Mediterranean and African regions.

Prevention of hemolytic anemias is possible only for some acquired forms, whereas in hereditary forms it is limited to genetic counseling and measures to prevent hemolytic crises. Useful strategies include:

• Avoiding exposure to hemolytic drugs and substances in predisposed individuals, for example those with G6PD deficiency
• Careful monitoring of patients with vascular prostheses or autoimmune diseases to identify signs of hemolysis early
• Genetic counseling in families with a history of hereditary hemolytic anemias
• Education to recognize precipitating factors for hemolytic crises, including infections, fava beans, certain foods and oxidative stress

It should be emphasized that hereditary forms caused by genetic mutations cannot currently be prevented, whereas in acquired forms prompt withdrawal of the responsible drug or timely treatment of infections reduces the risk of severe crises.

The clinical manifestations of hemolytic anemias depend on the rate, severity and type of hemolysis. Onset may be acute, subacute or chronic, and symptoms reflect both the anemia and the release of red blood cell degradation products.

During history taking, the most frequent signs and symptoms are progressive fatigue, cutaneous and mucosal pallor, jaundice, which is more evident in acute hemolysis, dark urine, particularly in intravascular forms, tachycardia and reduced exercise tolerance. Splenomegaly may occur; elongation of the facial bones and skeletal deformities from erythroid expansion mainly concern specific severe congenital anemias and not chronic hemolysis in general.

The clinical presentation differs according to the specific form:

• In autoimmune hemolytic anemia, onset may be rapid, with severe anemia, jaundice and splenomegaly. In some chronic forms, progression is more insidious.
• In thrombotic microangiopathies, anemia is often associated with signs of organ damage, particularly neurological and renal, due to microvascular compromise; in other fragmentation anemias, manifestations depend on the cause.
• In hereditary forms, symptoms may remain latent or present with exacerbations related to the specific disease; infections may aggravate hemolysis, whereas oxidative stress is typical mainly of some enzymopathies. Chronic jaundice and splenomegaly are often present.
• G6PD deficiency: crises are triggered by fava beans, oxidant drugs or infections; other enzyme deficiencies have different triggers and courses.

Physical examination reveals pallor, cutaneous and scleral jaundice, splenomegaly, particularly in chronic hereditary variants, and, in acute intravascular hemolysis, signs of hemoglobinuria, with dark urine.

In children, hereditary forms may present with prolonged neonatal jaundice, growth delay, recurrent hemolytic crises or complications of hyperbilirubinemia.

The diagnosis of hemolytic anemia is based on a sequential pathway integrating clinical, laboratory and instrumental findings. Suspicion arises in the presence of anemia with reticulocytosis, jaundice and increased products of red blood cell breakdown, especially when there is no apparent cause of blood loss.

The first step is a complete blood count with reticulocytes, which documents anemia of variable severity associated with reticulocytosis, an increase in young red blood cells, and sometimes mild reactive leukocytosis or thrombocytosis.

The peripheral blood smear shows characteristic morphological findings: spherocytes, in hereditary spherocytosis or autoimmune anemia, red blood cell fragments, or schistocytes, in microangiopathic forms, and Heinz bodies, detectable with supravital staining in G6PD deficiency.

Biochemical tests show increased indirect bilirubin, elevated LDH, reduced haptoglobin, potentially to undetectable levels, and, in intravascular forms, hemoglobinuria.

The diagnostic pathway then proceeds according to the clinical suspicion:

• Direct antiglobulin test: supports the diagnosis of immune hemolysis when positive in the appropriate context, but may be negative in a proportion of AIHA cases and positive without hemolysis.
• Tests for membrane disorders: EMA binding test, ektacytometry or other targeted tests according to the suspicion; osmotic fragility is neither the sole nor the preferred test in every case.
• In microangiopathic anemias, coagulation tests, assessment of kidney function and investigation for signs of microvascular thrombosis are required.
• PNH: high-sensitivity flow cytometry on granulocytes and monocytes with FLAER and at least two GPI-anchored markers; red blood cell analysis is complementary.

The differential diagnosis includes other forms of anemia, particularly those due to impaired production or blood loss, as well as the various immune and nonimmune causes of hemolysis. A rational approach and an appropriate sequence of tests are essential to characterize the specific disorder and select treatment.

The complications of hemolytic anemias result from persistent hemolysis, the severity of anemia, the treatments administered and associated clinical conditions.

The main complications include:

• Heart failure secondary to chronic anemia and tissue hypoxia
• Pigment gallstones: the increased bilirubin load and precipitation of calcium bilirubinate promote pigment gallstone formation.
• Iron overload, especially after repeated transfusions or in specific anemias with increased intestinal absorption; isolated chronic hemolysis does not invariably cause it
• Severe infections, particularly in splenectomized patients, including bacteremia caused by encapsulated organisms
• Aplastic crises, for example those caused by parvovirus B19, which may cause severe acute anemia in patients with stressed erythropoiesis
• Acute kidney injury in massive intravascular hemolysis, due to hemoglobin deposition in the renal tubules
• Adverse reactions to immunosuppressive or chelating drugs

Quality of life may be impaired by the chronic nature of the disorder, the need for periodic treatment and psychological and social consequences, particularly in pediatric and working-age patients.