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.