B12 deficiency induced hemolytic anemia – 6/27/18

Ernest presented an interesting case of a middle aged man with h/o CVA presenting with symptomatic megaloblastic anemia, found to have vitamin B12 deficiency induced thrombotic microangiopathy!

Clinical Pearls:

  • A “pseudo” TMA can develop in patients with severe vitamin B12 deficiency via red cell destruction in the bone marrow, leading to high LDH but modest rise in total bilirubin.
  • B12 related hemolysis is similar to TTP so the latter must be ruled out!
  • Treatment involves aggressive vitamin B12 replacement and is not responsive to plasmapharesis.

Differential for megaloblastic (MCV >120) anemia:

  • Vitamin B12 deficiency (elevation of both MMA and homocysteine)
  • Folate deficiency (elevation of homocysteine alone)
  • Drug induced (methotrexate, hydroxyurea, zidovudine, azathioprine, 5-FU, acyclovir, capecitabine)
  • Copper deficiency

When schistocytes are on the smear –> non-immune hemolysis.

Primary TMA syndromes:

  • TTP
    • Low levels of ADAMTS13
    • Renal failure, neurologic changes, fever, schistocytes, thrombocytopenia
      • Classic pentad only seen in 1/3 of patients
      • Triad of elevated LDH, schistos, and thrombocytopenia? –> check ADAMTS13
  • Shiga toxin mediated HUS
    • Shigella and certain serotypes of E Coli such as O157:H7 and O104:H4.
    • Classically with renal dysfunction and HTN as predominant findings
    • Bloody diarrhea
    • More common in children
  • Complement mediated
    • Hereditary deficiency of regulatory proteins in the alternative complement pathway
  • Drug mediated
    • Quinine, quetiapine, immunosuppressants, chemotherapy, calcineurin inhibitors
  • Metabolism mediated
    • Cobalamin C deficiency (inborn error of metabolism)
      • Mutations in the MMACHC gene (methylmalonic aciduria and homocystinuria type C)
  • Coagulation mediated
    • Hereditary deficiency of proteins in the coag pathway

Systemic disorder associated with MAHA and thrombocytopenia:

  • Pregnancy complications (HELLP)
  • Severe HTN
  • Systemic infections (bacterial endocarditis, HIV, CMV, RMSF)
  • Malignancies (with or without DIC)
  • Autoimmune diseases: SLE, systemic scleroderma, APLS.
  • DIC
  • Severe vitamin B12 deficiency

Final note on pernicious anemia:

  • Most common in Nothern Europeans
  • Check in people with vitamin B12 deficiency and no other identifiable cause
  • Intrinsic factor antibodies are the test of choice
    • Low sensitivity but high specificity
    • High sensitivity but low specificity (seen in other autoimmune disease as well as healthy individuals without autoimmune disease)
  • What about Schilling test?
    • Not available anymore!


Acharya et al. Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature. J Hematol Oncol. 2008.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s