ReviewVitamin B12 deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA)
Introduction
Thrombotic microangiopathy (TMA) syndromes share in common many clinical and pathological features. The triad of microangiopathic hemolytic anemia, thrombocytopenia and organ damage represent their cornerstone clinical features whereas the main pathological hallmarks are endothelial damage and platelet activation resulting in arteriolar and capillary thrombosis [[1], [2], [3]].
The etiologic spectrum of TMA ranges from abnormalities in the ADAMTS13, with the accumulation of ultra-large von Willebrand factor multimers in the life-threatening thrombotic thrombocytopenic purpura [TTP], to a long list of complementopathies including atypical hemolytic uremic syndrome [aHUS]. It also includes mechanical etiologies.
Severe vitamin B12 (Cobalamin - Cbl) deficiency or defective metabolism of cobalamin may lead to a TMA-like picture. The later has been termed metabolism- mediated TMA (MM- TMA) [4].
Eliciting the exact cause of TMA is therefore crucial for the choice of a successful therapeutic option. However, in view of the life-threatening nature of the disorder, empiric treatment is often initiated pending the results of complicated and advanced laboratory testing. In contrast, cobalamin-mediated TMA could be treated by simple replacement of vitamin B12. It is therefore of primordial importance to identify these cases promptly.
Section snippets
Defective cobalamin metabolism and MM-TMA
At least 21 genes may affect the absorption, transport, storage, and intracellular processing of Cbl [5]. Thus, deficiency of Cbl and/or its metabolites can result from either genetic mutations or other conditions affecting the intake, absorption and storage. Under normal circumstances, the human liver stores of Cbl are sufficient to meet the body needs for several years, even with reduced intake or impaired absorption.
Cbl deficiency, or a defect in its metabolism, result in
Acquired vitamin B12 deficiency and Pseudo-TMA
If congenital deficiencies of vitamin B12 metabolism are rare, acquired vitamin B12 deficiency, on the other hand, is very common as the mechanisms of its absorption are quite complex. Vitamin B12 deficiency is therefore a very common finding in the elderly population and in the context of other immune disorders. Acquired vitamin B12 deficiency can present with signs of mechanical hemolysis, thrombocytopenia, elevated lactate dehydrogenase (LDH) and is usually coupled with a low reticulocyte
Diagnosis and treatment of MM-TMA and B12 deficiency-induced Pseudo-TMA
The diagnosis of such conditions therefore rests on a high index of suspicion. Since Cbl C occurs mostly in the pediatric population, pediatricians and neonatologists usually incorporate MM-TMA in their diagnostic algorithm for TMA. The increased awareness about the disorder helped therefore to identify and treat cases correctly in a timely manner. Pseudo-TMA secondary to severe B12 deficiency, on the other hand, can mimic TTP and is often associated with an elevated D-dimer. The results of
Conclusions
Vitamin B12 deficiency or abnormalities of cobalamin metabolism can result in a picture that mimics TMA. The congenital forms can usually be discerned as they occur mostly in the pediatric population in whom the diagnostic algorithms include testing for the various cobalamin parameters. In the adult population, however, where cobalamin deficiency is common, pseudo-TMA can pass un-noticed with empiric treatment often initiated based on clinical suspicion. It seems appropriate therefore to use
References (43)
- et al.
Cobalamin C defect associated with hemolytic-uremic syndrome
J Pediatr
(1992) - et al.
Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type
Mol Genet Metab
(2008) - et al.
A derangement in B 12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria
Biochem Biophys Res Commun
(1969) - et al.
Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation
Am J Kidney Dis
(2005) - et al.
Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency
Lancet
(2015) - et al.
Management of hemolytic uremic syndrome
Presse Med.
(2012) - et al.
Kidney disease in cobalamine C deficiency
Nephrol Ther
(2019) Cobalamin C deficiency-associated thrombotic microangiopathy: uncommon or unrecognized?
Lancet
(2015)- et al.
Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency
Am J Kidney Dis
(2014) - et al.
B12 deficiency leading to marked poikilocytosis versus true schistocytosis, a pernicious problem
Transfus Apher Sci
(2017)
Cobalamin deficiency presenting with thrombotic microangiopathy(TMA) features: a systematic review
Transfus Apher Sci
Pseudo-thrombotic microangiopathy related to cobalamin deficiency
Am J Med
Vitamin B12 deficiency–A 21 st century perspective
Clin Med
Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study
Lancet Haematol
The PLASMIC score for thrombotic thrombocytopenic purpura
Lancet Haematol
Validation of the PLASMIC score at a university medical center
Transfus Apher Sci
Thrombotic microangiopathies
N Engl J Med
Hemolytic uremic syndrome, thrombotic thrombocytopenia purpura, and other thrombotic microangiopathies and coagulopathies
Syndromes of thrombotic microangiopathy
N Engl J Med
Genetic disorders of vitamin B(12) metabolism: eight complementation groups—eight genes
Expert Rev Mol Med
Homocysteine, coagulation, platelet function, and thrombosis
Semin Thromb Hemost
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2021, Thrombosis UpdateCitation Excerpt :Additionally, hyperhomocysteinemia has been implicated in increasing the risk of hemolysis in vitamin B12 deficiency as a result of endothelial dysfunction and subsequent fragmentation of red blood cells [9]. This has also been evidenced by the TMA like picture that occurs with defective vitamin B12 metabolism (metabolism mediated TMA) which results in endothelial dysfunction, platelet activation and propagation of the clotting cascade [10]. This combination of intramedullary and intravascular hemolysis because of endothelial dysfunction could potentially account for the degree of LDH elevation seen in our case.