Why does vitamin B12 deficiency cause low levels of white blood cells (WBC), platelets, and anemia?

Why Vitamin B12 Deficiency Causes Pancytopenia

Core Mechanism: Impaired DNA Synthesis Leading to Apoptosis

Vitamin B12 deficiency causes low WBC, platelets, and anemia because it impairs DNA synthesis in rapidly dividing cells, leading to maturation arrest and apoptotic cell death of blood cell precursors in the bone marrow. 1

The Fundamental Pathophysiology

Vitamin B12 is essential for DNA synthesis in all rapidly dividing cells, particularly hematopoietic precursors in the bone marrow. 2 When B12 is deficient, the following cascade occurs:

• Erythroblasts (red cell precursors) undergo rapid cell division during early erythropoiesis but cannot complete DNA synthesis properly, causing them to succumb to programmed cell death (apoptosis). 1

• This disordered DNA synthesis creates maturation arrest, where cells cannot progress through normal developmental stages, resulting in ineffective erythropoiesis. 1

• The same mechanism affects all three cell lines—myeloid (WBC), megakaryocytic (platelets), and erythroid (RBC)—because all require rapid DNA synthesis for proliferation. 3

Why All Three Cell Lines Are Affected

The bone marrow produces approximately 200 billion red cells, 100 billion white cells, and 100 billion platelets daily, all requiring intact DNA synthesis. 2

• Vitamin B12 deficiency creates a hypoproliferative state where the bone marrow cannot maintain adequate production across all cell lines. 1

• The reticulocyte count (immature RBCs) is characteristically low or inappropriately normal despite anemia, confirming inadequate bone marrow response. 4, 5

• Peripheral blood smear shows macroovalocytes and hypersegmented neutrophils (neutrophils with >5 nuclear lobes), pathognomonic features of megaloblastic changes. 6, 3

The Hemolytic Component

Beyond impaired production, B12 deficiency causes a secondary hemolytic process:

• Ineffective erythropoiesis leads to intramedullary hemolysis (destruction of abnormal RBCs within the bone marrow before release). 7

• This manifests as elevated lactate dehydrogenase (LDH), indirect hyperbilirubinemia, and occasionally schistocytes on peripheral smear, mimicking thrombotic microangiopathy. 7, 3

• This "pseudothrombotic microangiopathy" presentation can be mistaken for serious conditions requiring plasmapheresis, making correct diagnosis critical. 7

Clinical Implications and Diagnostic Approach

Laboratory Findings That Confirm the Mechanism

• Macrocytic anemia (MCV >100 fL) with pancytopenia (low RBC, WBC, and platelets). 6, 3

• Low or inappropriately normal reticulocyte count despite anemia, indicating bone marrow production failure. 4, 5

• Elevated LDH and indirect bilirubin from intramedullary hemolysis. 7, 3

• Serum B12 level <250 pg/mL, though methylmalonic acid and homocysteine should be measured if clinical suspicion remains high with borderline B12 levels. 8

Critical Pitfall to Avoid

Never initiate folic acid supplementation before excluding or treating B12 deficiency, as folate can mask B12 deficiency and precipitate subacute combined degeneration of the spinal cord. 1 This occurs because:

• Folate can partially correct the hematologic abnormalities while neurologic damage progresses. 1
• The neurological complications of B12 deficiency (demyelination of posterior and lateral spinal columns) are irreversible if not treated promptly. 1

Treatment Response Confirms the Mechanism

Intramuscular hydroxocobalamin 1 mg three times weekly for 2 weeks (or alternate days if neurological involvement) reverses the pancytopenia by restoring DNA synthesis capacity. 1

• Reticulocyte count rises within 3-5 days (reticulocyte crisis), confirming bone marrow recovery. 6

• Hemoglobin increases by approximately 1 g/dL per week, MCV normalizes over 6-8 weeks, and WBC/platelet counts normalize within 1-2 weeks. 6

• This dramatic response to B12 supplementation proves the deficiency was causing production failure, not peripheral destruction. 6, 3

Why Oral Therapy May Be Insufficient Initially

Intramuscular administration bypasses absorption issues and achieves rapid tissue saturation, which is critical in severe deficiency with pancytopenia. 2, 8

• Gastrointestinal absorption requires intrinsic factor and is unreliable in pernicious anemia or malabsorptive states. 2
• Only 1% of oral B12 is absorbed by passive diffusion, requiring very high doses (1-2 mg daily) to be effective. 2, 8
• Severe deficiency with neurological symptoms mandates intramuscular therapy for rapid correction. 1