What is the relationship between vitamin B12 deficiency and thrombocytopenia?

Vitamin B12 Deficiency and Thrombocytopenia Relationship

Vitamin B12 deficiency can cause thrombocytopenia and in severe cases can present as pseudo-thrombotic microangiopathy that mimics thrombotic thrombocytopenic purpura (TTP), requiring immediate B12 supplementation rather than plasmapheresis. 1, 2

Pathophysiological Relationship

Vitamin B12 deficiency affects platelet production and function through several mechanisms:

1. Ineffective Hematopoiesis: B12 is essential for DNA synthesis in all rapidly dividing cells, including megakaryocytes (platelet precursors)

2. Pseudo-TMA Presentation: In severe cases (occurs in approximately 2.5% of B12 deficiency cases), patients can develop:

   • Hemolytic anemia
   • Thrombocytopenia
   • Schistocytosis (fragmented red blood cells)
   • This constellation mimics thrombotic microangiopathy 2

3. Hyperhomocysteinemia: B12 deficiency leads to elevated homocysteine levels, which:

   • Contributes to endothelial dysfunction
   • Creates a paradoxical prothrombotic state despite thrombocytopenia 3
   • Increases risk of venous thromboembolism

Clinical Presentations

• Isolated Thrombocytopenia: Can occur without the classic macrocytic anemia or other hematologic abnormalities 4

• Pseudo-TTP Syndrome: Presents with:

  • Microangiopathic hemolytic anemia
  • Low platelet count
  • Schistocytes on peripheral blood smear
  • Normal ADAMTS13 activity (differentiating it from true TTP) 5, 6

• Combined Thrombocytopenia and Thrombosis: In severe cases with hyperhomocysteinemia, patients can paradoxically develop:

  • Low platelet count
  • Venous thromboembolism (including pulmonary embolism)
  • Life-threatening complications 3

Diagnostic Approach

When thrombocytopenia is present:

1. Check B12 levels: Total B12 <180 ng/L or active B12 <25 pmol/L confirms deficiency 1

2. Additional testing:

   • Complete blood count with peripheral smear (look for schistocytes, hypersegmented neutrophils)
   • Methylmalonic acid and homocysteine levels (elevated in B12 deficiency)
   • ADAMTS13 activity (normal in pseudo-TMA, low in true TTP) 1, 6

3. Investigate underlying cause:

   • Pernicious anemia (check intrinsic factor antibodies)
   • Ileal disease or resection
   • Inflammatory bowel disease
   • Metformin use
   • Vegan/vegetarian diet 1

Treatment Approach

1. Immediate B12 supplementation:

   • 1000-2000 μg daily (oral, sublingual, or intramuscular)
   • For severe cases with neurological symptoms or pseudo-TMA: intramuscular route preferred initially 1, 6

2. Avoid unnecessary plasmapheresis:

   • Approximately 40% of pseudo-TMA cases are misdiagnosed as TTP 2
   • Plasmapheresis provides limited benefit in B12-deficiency thrombocytopenia
   • Prompt diagnosis and B12 supplementation is the appropriate treatment 5, 6

3. Monitor response:

   • Platelet count should normalize with B12 supplementation
   • Continue monitoring until normalization 1

Common Pitfalls and Caveats

• Misdiagnosis as TTP: Leading to unnecessary plasmapheresis and delayed appropriate treatment 2, 6

• Overlooking B12 deficiency in isolated thrombocytopenia: Always consider nutritional deficiencies in the differential diagnosis 4

• Failure to recognize thrombotic risk: Despite thrombocytopenia, hyperhomocysteinemia from B12 deficiency creates a prothrombotic state 3

• Incomplete workup: Failure to identify the underlying cause of B12 deficiency can lead to recurrence 1

• Delayed treatment: B12 deficiency left untreated for more than 3 months may cause permanent neurological damage 1