Hemolytic anemia is a heterogeneous group of disorders characterized by premature destruction of red blood cells (RBCs), resulting in anemia when bone marrow compensation is insufficient to maintain normal hemoglobin levels.

Hemolysis may occur:

• Intravascularly (within blood vessels)

• Extravascularly (within the reticuloendothelial system, especially spleen and liver)

The hallmark of hemolytic anemia is shortened RBC survival (<120 days) with compensatory reticulocytosis.

Pathophysiology

Hemolysis leads to:

• Increased unconjugated (indirect) bilirubin

• Elevated lactate dehydrogenase (LDH)

• Reduced haptoglobin

• Reticulocytosis (marrow response)

• Hemoglobinuria (in intravascular hemolysis)

Chronic hemolysis may cause:

• Pigment gallstones

• Splenomegaly

• Iron overload (in transfusion-dependent cases)

Classification of Hemolytic Anemia

I. Acquired Hemolytic Anemias

A. Immune-Mediated

1. Autoimmune Hemolytic Anemia (AIHA)

• Warm antibody type (IgG-mediated; most common)

• Cold agglutinin disease (IgM-mediated)

2. Alloimmune Hemolysis

• Hemolytic transfusion reactions

• Hemolytic disease of the newborn

• Post-allogeneic transplantation (e.g., marrow transplant)

B. Red Cell Fragmentation Syndromes

• Mechanical destruction (prosthetic cardiac valves, arterial grafts)

• Microangiopathic hemolytic anemia (MAHA)

  • Thrombotic thrombocytopenic purpura (TTP)

  • Hemolytic uremic syndrome (HUS)

  • Disseminated intravascular coagulation (DIC)

C. Other Acquired Causes

• March hemoglobinuria

• Severe infections (e.g., malaria, clostridial sepsis)

• Drugs and toxins

• Burns

• Paroxysmal nocturnal hemoglobinuria (PNH)

II. Hereditary Hemolytic Anemia

A. Membrane Disorders

• Hereditary spherocytosis

• Hereditary elliptocytosis

B. Enzyme (Metabolic) Disorders

• G6PD deficiency

• Pyruvate kinase deficiency

C. Hemoglobin Disorders

• Sickle cell disease (HbS)

• HbC disease

• Unstable hemoglobins

• Thalassemias

Risk Factors

• Family history of hemolytic disorders

• Autoimmune diseases

• Recent blood transfusion

• Infections

• Exposure to oxidative drugs

• Prosthetic heart valves

• Pregnancy (immune-mediated cases)

Signs and Symptoms

Core Features

• Pallor

• Jaundice

• Fatigue

• Dark urine (intravascular hemolysis)

• Splenomegaly

• Reticulocytosis

• Indirect hyperbilirubinemia

Other Clinical Features

• Can occur at any age

• May be acute or chronic

• Symptoms of anemia (dyspnea, tachycardia)

• Gallstones (chronic cases)

• Leg ulcers (chronic hemolysis)

• Bone changes in congenital forms

Rapidly progressive anemia may lead to cardiovascular compromise.

Diagnostic Criteria

Diagnosis is based on:

1. Evidence of anemia

2. Laboratory evidence of hemolysis

3. Identification of underlying cause

Essential laboratory indicators:

• Reticulocytosis

• Elevated LDH

• Low haptoglobin

• Elevated indirect bilirubin

• Positive Direct Antiglobulin Test (DAT) in immune causes

Investigations

Hematological Tests

• Complete blood count (CBC)

• Reticulocyte count

• Peripheral blood smear:

  • Spherocytes (AIHA, hereditary spherocytosis)

  • Schistocytes (MAHA)

  • Bite cells (G6PD deficiency)

• Direct Coombs test (DAT)

• Indirect Coombs test

Biochemical Tests

• Total and indirect bilirubin

• LDH

• Haptoglobin

• Liver function tests

Specific Tests (As Indicated)

• G6PD assay

• Hemoglobin electrophoresis

• Osmotic fragility test

• Flow cytometry for PNH (CD55/CD59 deficiency)

• Malaria parasite test (if endemic area)

Treatment

Management depends on etiology.

Non-Pharmacological Management

• Treat underlying cause

• Avoid triggering agents

• Adequate hydration

• Nutritional support

• Referral to higher center when indicated

General Medical Treatment

i. Remove precipitating factorii. Blood transfusion (if severe symptomatic anemia)iii. Plasmapheresis (in severe immune-mediated cases)

Pharmacological Management

1. Autoimmune Hemolytic Anemia (First-Line)

Prednisolone

• 1–1.5 mg/kg/day (PO)

• Continue 1–3 weeks until Hb >10 g/dL

• Gradual taper over weeks to months

2. Second-Line / Steroid-Refractory Cases

• Cyclophosphamide (dose individualized)

• Azathioprine 100–150 mg/day (PO)

• Cyclosporine 2–5 mg/kg/day

• Rituximab (anti-CD20 monoclonal antibody)

• High-dose IV Immunoglobulin (IVIG)

  • 400 mg/kg/day for 5 days

3. Supportive Therapy

• Folic acid 5 mg PO daily (in severe or chronic cases)

• Iron therapy only if deficiency confirmed

• Thromboprophylaxis in high-risk patients

Surgical Management

Splenectomy

Considered in:

• Steroid-dependent AIHA

• Steroid-refractory cases

• Hereditary spherocytosis (moderate–severe)

Pre-splenectomy vaccination is mandatory (pneumococcal, meningococcal, Hib).

Complications

• Severe anemia

• Thromboembolism

• Gallstones

• Heart failure

• Iron overload (chronic transfusions)

• Post-splenectomy sepsis

Prevention

• Genetic counseling (hereditary forms)

• Avoid oxidative drugs (G6PD deficiency)

• Careful blood crossmatching

• Vaccination (post-splenectomy)

• Early treatment of infections

• Regular monitoring in chronic hemolytic disorders

Prognosis

Prognosis depends on underlying cause:

• Hereditary forms: often chronic but manageable

• Autoimmune forms: variable; many respond to steroids

• Microangiopathic forms: potentially life-threatening if untreated

Early recognition and cause-specific treatment significantly improve outcomes.