Discussion
B12 deficiency is the leading cause of megaloblastic anemia and in developed countries is often overlooked. It is more common in the elderly but the estimated prevalence is around 6% in people younger than 60 years in the United Kingdom and United States [2]. Causes of severe of B12 deficiency generally involve disruption of some aspect of the physiologic pathway for B12 absorption comprising intrinsic factor and the cubam receptor in the terminal ileum [3]. In the reported case, there are several factors that could have contributed to B12 deficiency, his history of intestinal resection and his uncontrolled celiac disease. Despite not being frequently reported, B12 deficiency in patients with celiac disease has a prevalence of between 8% and 41% [4, 5].
Hematologic manifestations consist of all blood elements being affected by this ineffective megaloblastic hematopoiesis. Initially, the cell content and size of RBC usually precede the onset of anemia. Nuclear hypersegmentation of neutrophils is another common early manifestation. Neutropenia and thrombocytopenia can infrequently follow as late features with a resulting pancytopenia that can ultimately become severe enough to mimic a severe aplastic anemia.
Hematopoietic precursor cells produced in the bone marrow are defective in B12 deficiency. As a result, they undergo cell death in the marrow and are phagocytosed before they can exit into the blood as reticulocytes. This intramedullary hemolysis manifests itself with increased markers of cell turnover such as LDH and markers of increased hemoglobin breakdown such as indirect hyperbilirubinemia and decreased or absent haptoglobin. As a means of compensating, erythropoietin levels rise and the bone marrow becomes more hypercellular (as shown in Fig. 1), however the reticulocyte count fails to rise [6].
In our case, his pancytopenia and reticulocytopenia were evident and consistent with a megaloblastic picture. However, his LDH seemed to be elevated out of proportion to the degree of hemolysis he experienced. When compared to patients with thrombotic thrombocytopenic purpura (TTP), Noël et al showed that patients who had pseudo-TMA had significantly higher LDH levels, platelet counts and lower reticulocyte counts in the adult population [7]. Hyperhomocysteinemia has also been implicated (not checked in our patient) in increasing the risk of hemolysis in vitamin B12 in vitro in addition to causing endothelial damage leading to intravascular hemolysis and RBC fragmentation [8]. This combination of intramedullary and intravascular hemolysis could potentially account for the degree of LDH elevation seen in this case.
There have been three other cases of reported pediatric pseudo- TMA secondary to B12 in the literature [9-12]. These cases all occurred because of decreased intake and our case highlights the need to follow patients with malabsorptive syndromes. Because many of the cases were initially thought to have thrombotic thrombocytopenic purpura (TTP), they received plasma exchange with gradual improvement of their symptoms. This improvement is thought to be due to B12 contained in the infused plasma during the exchange[13].
The PLASMIC score has served as prediction tool for severe ADAMTS13 deficiency[14] but has not been evaluated in differentiating TTP from a pseudo-TMA. While it is well recognized as a helpful adjunct in the adult population, few studies have looked at its utility in children and adolescents. Linder et al showed retrospectively that the PLASMIC score was able to accurately identify pediatric patients at highest risk for severe ADAMTS13 deficiency with a sensitivity of 100% and a specificity of 78.1% [15]. In evaluating the PLASMIC scores of pediatric cases in the literature; 75% of the patients with B12 induced pseudo-TMA would have been placed in a low risk category (TABLE 1). This may prove to be a helpful adjunct to physicians when faced with this clinical presentation.
The treating team deduced that his initial pancytopenia had been secondary to his B12 deficiency given his history. This case posed a diagnostic challenge and highlights to pediatric hematologists this unusual presentation of B12 induced TMA and that it should be considered in the differential with a patient presenting with a TMA syndrome.
References
1. Kottke-Marchant, K., Diagnostic approach to microangiopathic hemolytic disorders. Int J Lab Hematol, 2017. 39 Suppl 1 : p. 69-75.
2. Hunt, A., D. Harrington, and S. Robinson, Vitamin B12 deficiency. Bmj, 2014. 349 : p. g5226.
3. Green, R., Vitamin B(12) deficiency from the perspective of a practicing hematologist. Blood, 2017. 129 (19): p. 2603-2611.
4. Dahele, A. and S. Ghosh, Vitamin B12 deficiency in untreated celiac disease. Am J Gastroenterol, 2001. 96 (3): p. 745-50.
5. García-Manzanares, A. and A.J. Lucendo, Nutritional and dietary aspects of celiac disease. Nutr Clin Pract, 2011. 26 (2): p. 163-73.
6. Orkin, S.H., D.E. Fisher, and D. Ginsburg, Nathan and Oski’s hematology and oncology of infancy and childhood . 2015, Philadelphia (Pa.): Elsevier Saunders.
7. Noël, N., et al., Hemolysis and schistocytosis in the emergency department: consider pseudothrombotic microangiopathy related to vitamin B12 deficiency. Qjm, 2013. 106 (11): p. 1017-22.
8. Ventura, P., et al., A role for homocysteine increase in haemolysis of megaloblastic anaemias due to vitamin B(12) and folate deficiency: results from an in vitro experience. Biochim Biophys Acta, 2004. 1739 (1): p. 33-42.
9. Asano, T., et al., Neglect-induced pseudo-thrombotic thrombocytopenic purpura due to vitamin B12 deficiency. Pediatr Int, 2015. 57 (5): p. 988-90.
10. Delbet, J.D. and T. Ulinski, Thrombotic microangiopathy and breastfeeding: where is the link? Answers. Pediatr Nephrol, 2018.33 (6): p. 987-989.
11. Delbet, J.D. and T. Ulinski, Thrombotic microangiopathy and breastfeeding: where is the link? Questions. Pediatr Nephrol, 2018.33 (6): p. 985-986.
12. Dimond, A., J.N. George, and C. Hastings, Severe vitamin B-12 deficiency in a child mimicking thrombotic thrombocytopenic purpura.Pediatr Blood Cancer, 2009. 52 (3): p. 420-2.
13. Green, R., Anemias beyond B12 and iron deficiency: the buzz about other B’s, elementary, and nonelementary problems. Hematology, 2012. 2012 (1): p. 492-498.
14. Bendapudi, P.K., et al., Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol, 2017.4 (4): p. e157-e164.
15. Linder, G.E., et al., Assessment of the Plasmic Score Utility for Classification of Pediatric Thrombotic Microangiopathies. Blood, 2019. 134 (Supplement_1): p. 1075-1075.
Figure Legend
Table 1: WBC: white blood cell count, Hb: hemoglobin, MCV: mean corpuscular volume, Plt: platelet count,
ANC: Absolute Neutrophil Count, Retic: reticulocyte count, LDH: lactate dehydrogenase.