What type of anemia is suggested by a patient with a family history of anemia, pale conjunctiva, and a palpable spleen?

Hereditary Hemolytic Anemia with Splenomegaly

This clinical presentation—family history of anemia, pale conjunctiva (indicating anemia), and palpable splenomegaly—most strongly suggests a hereditary hemolytic anemia, with hereditary spherocytosis and pyruvate kinase deficiency being the primary considerations.

Key Differential Considerations

The combination of familial anemia and splenomegaly points to a chronic hereditary hemolytic process. The two most common hereditary hemolytic anemias presenting with prominent splenomegaly are:

Hereditary Spherocytosis

• Most common hereditary hemolytic anemia with characteristic splenomegaly 1, 2
• Results from red blood cell membrane protein defects (spectrin, ankyrin, Band-3, protein 4.1 or 4.2) 3
• Spherocytes visible on peripheral blood smear distinguish this from enzyme deficiencies 3
• Splenectomy achieves clinical cure of anemia in most patients 2

Pyruvate Kinase Deficiency

• Second most common consideration when family history and splenomegaly are present 4
• Splenomegaly occurs in approximately 80% of patients 4
• Critical distinguishing feature: red cell morphology is usually unremarkable (only mild anisocytosis and poikilocytosis), contrasting sharply with the spherocytes seen in hereditary spherocytosis 4
• Patients may tolerate anemia surprisingly well due to increased 2,3-DPG causing rightward shift in oxygen dissociation curve 4

Diagnostic Approach

The key to distinguishing these conditions is the peripheral blood smear:

• If spherocytes are present: Hereditary spherocytosis is most likely 3

  • Confirm with EMA (eosin-5'-maleimide) binding test by flow cytometry, which is the recommended screening test 3
  • Osmotic fragility testing is traditional but has lower sensitivity and specificity 3

• If red cell morphology is normal or near-normal: Consider pyruvate kinase deficiency 4

  • Requires exclusion of immune-mediated hemolysis, other membrane defects, unstable hemoglobin, and paroxysmal nocturnal hemoglobinuria first 4
  • Confirm with PK enzyme activity assay (ICSH standardized method) 4
  • Molecular testing of PKLR gene for definitive diagnosis 4

Essential Laboratory Workup

All patients with suspected hereditary hemolytic anemia require:

• Complete blood count with reticulocyte count 4
• Markers of hemolysis: elevated LDH, reduced haptoglobin, elevated indirect bilirubin 4
• Peripheral blood smear examination (critical for morphology) 4
• Family history documentation 4

Critical Pitfalls to Avoid

• Recent transfusion history must be obtained before enzyme testing, as donor red cells can mask PK deficiency for up to 120 days and cause falsely normal results 4, 5
• High reticulocyte counts can also cause falsely normal PK enzyme activity 4
• Iron overload can occur even without transfusions in both conditions due to ineffective erythropoiesis 4, 5
• Do not perform splenectomy in hereditary stomatocytosis, which can also present similarly but has contraindications to splenectomy due to thrombophilic risk 4

Other Considerations

While less common, other hereditary hemolytic anemias (G6PD deficiency, other red cell enzyme deficiencies, unstable hemoglobins) should remain on the differential, but these typically present with different clinical patterns and less prominent splenomegaly 4.