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!

References:

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