Vitamin B12 deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA)

doi:10.1016/j.transci.2019.102717

Transfusion and Apheresis Science

Volume 59, Issue 1, February 2020, 102717

https://doi.org/10.1016/j.transci.2019.102717 Get rights and content

Abstract

Thrombotic microangiopathies (TMA) are characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ damage resulting from mechanical factors, accumulation of the ultra-large von Willebrand factor multimers or complement-mediated abnormalities. Severe acquired vitamin B12 (Cobalamin - Cbl) deficiency or congenital defective Cbl metabolism could lead to a picture that mimics TMA. The later has been termed metabolism-mediated TMA (MM- TMA). This confusing picture is mediated partly by the large red cell fragmentation coupled with reduced platelet production in the absence of vitamin B12 and partly by the accumulated byproducts and metabolites that induce endothelial injury and hence organ damage. Expensive and complicated treatment for TMA is often initiated on an empiric basis, pending the results of confirmatory tests. In contrast, vitamin B12 Pseudo-TMA and MM-TMA could be treated with proper vitamin B12 supplementation. It is therefore important to identify these disorders promptly. The recent availability of a validated scoring system such as the PLASMIC score uses simple clinical and laboratory parameters. As it incorporates the mean corpuscular volume in its laboratory parameters, this helps in the identification of pseudo and MM-TMA. Perhaps some minor modification of this scoring system by changing the parameters of hemolysis to include reticulocytosis and rather than and/or other hemolytic parameters could even help refine this identification.

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

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Thrombotic microangiopathies (TMAs) are a group of life-threatening conditions requiring urgent management and characterized by a clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic tissue injury. Severe vitamin B12 (Cobalamin—Cbl) deficiency or defective cobalamin metabolism, particularly defects in intracellular B12 metabolism, may lead to a TMA-like picture. The latter has been termed metabolism-mediated TMA (MM-TMA). This confusing picture is mediated partly by ineffective erythropoiesis with significant red cell fragmentation resulting in a hemolytic pattern, coupled with reduced platelet production and endothelial injury with organ damage resulting from accumulated toxic byproducts of B12 dysmetabolism. However, unlike in classic thrombotic thrombocytopenic purpura, where therapeutic plasma exchange has to be initiated promptly, cases of MM-TMA can be treated, if diagnosed properly, with adequate B12 replacement.
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Thrombotic microangiopathies (TMAs) are a group of rare disorders that can be considered life threatening. The hallmark of this disease is a microangiopathic hemolytic anemia associated with thrombocytopenia which could be congenital or acquired. Acquired vitamin B12 deficiency is overlooked in developed countries but if severe, can mimic a TMA. We report the case of 17-year-old male with celiac disease who presented with a week of fatigue and jaundice. Initial evaluation revealed pancytopenia and hemolysis with a preliminary differential concerning for a myelodysplastic process or a thrombotic microangiopathy. There was no evidence of renal failure, or neurological changes and his hemoglobin stabilized with transfusion therapy. Subsequent bone marrow testing confirmed absence of malignancy or infiltrative processes. B12 levels were found to be undetectable and once replaced his signs and symptoms resolved. Replacement supported the diagnosis of a Vitamin B12 deficiency induced pseudo-thrombotic microangiopathy. When faced with a clinical presentation of a TMA in a child or an adolescent patient, physicians must be aware of the possibility of vitamin B12 deficiency especially in patients at risk for malabsorption.

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ReviewVitamin B12 deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA)

Abstract

Introduction

Section snippets

Defective cobalamin metabolism and MM-TMA

Acquired vitamin B12 deficiency and Pseudo-TMA

Diagnosis and treatment of MM-TMA and B12 deficiency-induced Pseudo-TMA

Conclusions

J Pediatr

Mol Genet Metab

Biochem Biophys Res Commun

Am J Kidney Dis

Lancet

Presse Med.

Nephrol Ther

Lancet

Am J Kidney Dis

Transfus Apher Sci

Transfus Apher Sci

Am J Med

Clin Med

Lancet Haematol

Lancet Haematol

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

Review
Vitamin B12 deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA)