Epidemiology and Etiology
Epidemiology
- 5% of all cases of anemia
- Hereditary causes present early in life.
- Autoimmune hemolytic anemia (AIHA) is more common in middle-aged and older adults.
- Males are predominantly affected by X-linked hereditary spherocytosis.
Causes
Intravascular hemolysis
- Mechanical (mechanical prosthetic valves, hemodialysis)
- Transfusion reaction
- Paroxysmal nocturnal hemoglobinuria
- Infection (sepsis)
- Microangiopathic (hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation)
Extravascular hemolysis
- Intrinsic hemolytic anemia (abnormal membrane structure or shape of the RBCs)
- Membrane defect:
- Hereditary spherocytosis
- Enzyme deficiency:
- G6PD deficiency
- Pyruvate kinase deficiency
- Hemoglobinopathy:
- Sickle cell anemia
- Thalassemia
- Membrane defect:
- Extrinsic hemolytic anemia (coated RBCs)
- AIHA
- Cold agglutinin anemia
- Warm agglutinin anemia
- ABO incompatibility, Rhesus incompatibility
- Drugs (e.g., rifampin, nonsteroidal anti-inflammatory drugs, penicillin)
- Infections (malaria), gas gangrene
- Hypersplenism
- AIHA
Pathophysiology
Hemolytic anemia is a normocytic anemia.
- Extravascular hemolysis
- Normal breakdown of RBCs occurs in the spleen every 120 days.
- An increased splenic clearance occurs in:
- IgG/IgM tagging of RBCs in auto-immune conditions
- Intrinsically defective RBCs: sickle cell, spherocytosis, G6PD deficiency
- Increased breakdown results in increased heme which is converted into bilirubin.
- Excessive bilirubin → unconjugated bilirubinemia and jaundice
- Iron from the breakdown also begins to accumulate in the spleen.
- Excessive functioning and clearance results in splenomegaly.
- Intravascular hemolysis
- RBCs become fragmented when passing through narrowed vessel lumen (microangiopathic) or prosthetic valves (macroangiopathic).
- Splitting of the RBCs results in schistocytes in the smear.
- Hemoglobin in the bloodstream binds to haptoglobin.
- Excessive heme also presents in the urine as hematuria/hemoglobinuria.
Normal erythrocyte life cycle
Image by Lecturio.Clinical Manifestations
- Jaundice
- Splenomegaly (mainly in extravascular causes)
- Cholelithiasis
- Hematuria/hemoglobinuria
- Symptoms of anemia:
- Shortness of breath
- Fatigue
- Syncope
- Tachycardia
- Sickle cell patients present with acute pain syndromes.
- Patients with G6PD deficiency and patients with paroxysmal nocturnal hemoglobinuria present with episodic hematuria.
- AIHA (cold) patients present with cold sensitivity.
Diagnostics
General
- ↓ Hb, N-MCV, N-MCH
- Reticulocytosis (≤ 3%)
- Decreased hematocrit
- Increased lactate dehydrogenase
- Decreased haptoglobin
- Increased unconjugated bilirubin
Intravascular hemolysis
- Hemoglobinuria/hemosiderinuria: hemoglobin that exceeds haptoglobin binding (most sensitive)
- Schistocytes on blood film
- Indirect Coombs test (positive for complements)
Extravascular hemolysis
- Direct Coombs test (positive for IgM/IgG)
- Blood film: spherocytes, sickle cell anemia, agglutination (in IgM AIHA)
Schistocytes (fragmented RBCs) seen in intravascular hemolysis
Image: “Schistocytes” by Prof. Osaro Erhabor. License: Public Domain
Hemosiderinuria in intravascular hemolysis
Image: “Hemosiderinuria. Perls’ reaction weakly positive in the urine.” by Salido, Eduardo & Cabañas, Valentín & Berenguer, Mercedes & Macizo, María & Candel, Faustino & Pérez-López, Raúl & Moraleda, Jose. (2014). Serological Findings in a Child with Paroxysmal Cold Haemoglobinuria. Case reports in medicine. 2014. Edited by Lecturio.
Patient with CLL presents with warm AIHA. Blood film shows spherocytes.
Image: “CLL with Autoimmune Hemolytic Anemia” by Ed Uthman from Houston, TX, USA. License: CC BY 2.0
Treatment
- Manage underlying cause.
- Supplement with folic acid to boost compensatory erythrocytosis.
- Manage hyperkalemia due to increased cell breakdown.
- Splenectomy for extravascular hemolytic diseases
Differential Diagnoses
- Sickle cell anemia: a hereditary hemoglobinopathy due to a deficiency is the beta-globin chain. It is an autosomal recessive disease and presents with symptoms of hemolysis in hypoxic conditions.
- Thalassemia: a hereditary hemoglobinopathy due to a deficiency of either alpha or beta-globin chain. Results in an array of symptoms based on which and how many gene deletions have occurred. Patients have chronic hemolysis and present with symptoms of hemolytic anemia, rendering them transfusion-dependent.
- G6PD deficiency: an enzyme deficiency linked to a deficiency of glucose-6-phosphate dehydrogenase activity. Patients present with episodic hemolysis due to exposure to an oxidative stress agent.
- Hereditary spherocytosis: an inherited deficiency in cytoskeletal and membrane proteins that stabilize an RBC. The deficiency results in loss of biconcave shape to a spherical shape.
- Hemolytic uremic syndrome: a triad of hemolysis, renal failure, and low platelets usually secondary to Escherichia coli (O157:H7) infection. Microangiopathic hemolysis is due to platelet adherence to vascular walls.
- Disseminated intravascular coagulopathy: an imbalance of plasmin and thrombin leads to intravascular coagulation. There is an excessive consumption of platelets, coagulation factors, and fibrinogen due to thrombus formation. Thrombosis results in the fragmentation of RBCs.
- Splenomegaly: Enlargement of the spleen due to increased workload is seen in hemolytic anemias. There are many other causes of splenomegaly: infiltration, abnormal blood flow, and immunological disorders.
