Thrombosis Update 2 (2021) 100032

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Thrombosis Update
journal homepage: www.journals.elsevier.com/thrombosis-update

Vitamin B12 malabsorption and pseudo- thrombotic microangiopathy in

an adolescent
Simone M. Chang a, *, Mercia Gondim b, Michael Huang a
a
Department of Pediatric Hematology-Oncology and Stem Cell Transplant, University of Louisville. Louisville, KY, USA
b
Department of Pathology, Norton Children’s Hospital. Louisville, KY, USA

A B S T R A C T

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.

1. Introduction
Thrombotic microangiopathies (TMAs) are a group of rare disorders that
are characterized by microangiopathic hemolytic anemia and thrombocy-
topenia with thrombosis of the microvasculature. The incidence in the pe-
diatric population is around 3 cases/106 population per year [1] and is often
associated with organ dysfunction and encompass congenital and acquired
etiologies [2]. Distinguishing between these disorders is important, as many
TMAs are life-threatening and require emergent intervention.
Acquired B12 deficiency is overlooked because of its rarity in devel-
oped countries [3]. B12 deficiency has been associated with a wide range
of hematologic findings and can include pancytopenia because of inef-
fective hematopoiesis. Vitamin B12 deficiency induced TMA also known
as a pseudo-TMA is also an uncommon manifestation and it mimics the
features of thrombotic thrombocytopenic purpura but requires a drasti-
cally different treatment.
We describe the case of a 17- year-old male who had a history celiac
disease which lead to a vitamin B12 deficiency induced pseudo-TMA
through malabsorption.
1.1. Case description
A 17-year-old male with history of celiac disease was referred to the
emergency room for shortness of breath, fatigue, and lightheadedness for
a week. His history was also significant for iron and vitamin B12 defi-
ciency with symptomatic anemia in the past requiring transfusions. It had
been at least a year since he had taken his last supplements and he had
not adhered to a gluten-free diet. He denied constitutional symptoms,
fevers, bleeding, or recurrent illnesses. On presentation, he was noted to
be tachycardic with a heart rate of 112 beats per minute. His physical
examination was significant for weight below the third percentile, pallor,
mildly icteric sclerae and hepatosplenomegaly. He was alert and oriented
with no neurological deficits.
His complete blood count (CBC) was significant for pancytopenia
with a WBC: 2.42 x 10^3/μL, Hb: 5.9 g/dL, MCV: 95.4 fL, Plt: 111 x 10^3/
μL and a reticulocytopenia of 0.6%. Review of his peripheral smear was
significant for anisocytosis, macrocytosis, poikilocytosis and schistocytes.
Routine chemistries were suggestive of hemolysis with an elevated LDH
of >50 000 U/L, an unconjugated hyperbilirubinemia of 3.7 mg/dL and
an undetectable haptoglobin. His synthetic liver function was unre-
markable with normal coagulation studies despite a notable trans-
aminitis. He had a negative direct coombs, iron studies were
unremarkable and a B12 < 109 pg/mL. His renal function showed a
creatinine of 0.4mg/dL which was unchanged from a year prior to pre-
sentation. A liver ultrasound showed diffuse echogenicity with likely
fatty infiltration but no evidence of thrombosis or portal hypertension.
He was transfused two units of packed red blood cells, which allowed for
stabilization of his hemoglobin.

* Corresponding author. Department of Pediatric Hematology-Oncology and Stem Cell Transplant, 571 South Floyd Street, Ste 445, Louisville, KY, 40202 USA.
E-mail address: simone.chang@louisville.edu (S.M. Chang).

https://doi.org/10.1016/j.tru.2021.100032
Received 17 November 2020; Received in revised form 28 December 2020; Accepted 4 January 2021
2666-5727/Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
S.M. Chang et al.
A wide range of differentials were considered given his unique pre-
sentation and included malignancy, myelodysplasia, bone marrow fail-
ure processes, infection, nutritional deficiencies, and rheumatologic
conditions. Myelodysplasia can present with pancytopenia along with an
associated hemolytic anemia and was one of the more concerning dif-
ferentials. Lyme disease is also associated with hemolysis and thrombo-
cytopenia mimicking a thrombotic microangiopathic picture, but there
was no history of recent exposures, rashes, or fevers, making this un-
likely. Thrombotic microangiopathies were considered, especially
thrombotic thrombocytopenic purpura (TTP) as it is a life-threatening
condition that requires emergent plasma exchange. However, there
was no evidence of end organ damage such as renal failure or neuro-
logical symptoms and his reticulocytopenia could not be accounted for
with this possibility. In addition, the degree of his thrombocytopenia and
the presence of leukopenia did not appear consistent with TTP. Finally,
severe B12 deficiency can result in a myriad of hematologic abnormal-
ities and was also considered.
A bone marrow biopsy and aspirate displayed no changes consistent
with myelodysplasia, malignancy, or bone marrow failure. There was
evidence of erythroid hyperplasia and megaloblastic maturation along
with hypersegmented neutrophils consistent with his B12 deficiency as
shown in Fig. 1. His liver biopsy showed non-alcoholic steatohepatitis
attributed to his uncontrolled celiac disease and the decision was made to
start him on weekly intramuscular vitamin B12 (1000mcg).
Within days, his hematologic parameters stabilized. He followed up
in the clinic one month later and repeat B12 and LDH levels were 525 pg/
mL and 503 U/L respectively with resolution of his symptoms. In the
following six months he has done well with no relapsed disease. The
diagnosis of a vitamin B12 deficiency induced pseudo- TMA was made in
the absence of any other positive findings.
2. 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 [3]. Causes of severe of
B12 deficiency generally involve disruption of some aspect of the phys-
iologic pathway for B12 absorption comprising intrinsic factor and the
cubam receptor in the terminal ileum [4]. In the reported case, his history
of uncontrolled celiac disease was likely the major culprit for vitamin B12
Fig. 1. Bone marrow biopsy with evidence of erythroid hyperplasia.
2
Thrombosis Update 2 (2021) 100032
deficiency. Despite not being frequently reported, B12 deficiency in pa-
tients with celiac disease has a prevalence of between 8% and 41% [5,6].
Ineffective megaloblastic hematopoiesis drives the hematologic
findings found in patients with vitamin B12 deficiency. Initially, changes
in the cell content and size of red blood cells usually precede the onset of
anemia. Nuclear hypersegmentation of neutrophils is another common
early manifestation which can be followed by neutropenia and throm-
bocytopenia. These are generally late features which result pancytopenia
that can ultimately become severe enough to mimic an aplastic anemia.
Hematopoietic precursor cells produced in the bone marrow are also
defective in B12 deficiency. They undergo cell death in the marrow and are
phagocytosed before they can exit into the peripheral 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 because of this
increased intramedullary destruction, reticulocyte counts fail to rise [7].
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. In
the literature, higher levels of LDH, higher platelet counts and lower
reticulocyte counts were all more likely in patients with a pseudo-TMA
when compared to patients with TTP [8]. Additionally, hyper-
homocysteinemia 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 evi-
denced 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.
There have been three other cases of reported pediatric pseudo- TMA
secondary to vitamin B12 deficiency in the literature [11–14]. 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 TTP, they received plasma ex-
change with gradual improvement of their symptoms. Improvement in
hematologic parameters was attributed to B12 contained in the infused
plasma during the exchange [15].
S.M. Chang et al. Thrombosis Update 2 (2021) 100032

Table 1
Table showing characteristics of pediatric cases with B12 deficiency induced thrombotic microangiopathies.
Case Demographics (Age/sex) WBC (/uL) Hb (g/dL) MCV (fL) Plt (/uL) Retic (%) LDH (U/L) B12 (pg/mL) PLASMIC score (risk)

Dimond (2008) 14 yo F 2200 6.5 100 62000 2.7 3454 75 4 (low risk)
Asano (2015) 15 yo F 11600 2.5 128.8 53000 8.7 1903 104 4 (low risk)
Delbet (2018) 7 mo M 440 3.0 90 26000 n/a 8950 n/a 5 (intermediate risk)
Chang (20211) 17 yo M 2420 5.9 95.4 111000 0.6 >50 000 <109 4 (low risk)

WBC: white blood cell count, Hb: hemoglobin, MCV: mean corpuscular volume, Plt: platelet count.
ANC: Absolute Neutrophil Count, Retic: reticulocyte count, LDH: lactate dehydrogenase.

An ADAMTS13 level is essential in ruling out acquired/congenital References

TTP and absence of a level in our case is a noted limitation. The decision
to initiate emergent plasmapheresis is dependent on the clinical pre-
sentation and not the activity level because of its prolonged turnaround
time as it is usually sent to a specialized laboratory. This highlights the
need to be able to differentiate between TTP and other causes of similar
hematologic abnormalities. The PLASMIC score has been developed as a
prediction tool for severe ADAMTS13 deficiency [16]. It consists of seven
elements: platelet count, hemolysis, absence of active neoplasia, absence
of an organ or stem-cell transplant, mean corpuscular value, international
normalized ratio; and serum creatinine. It has been validated as a helpful
adjunct in the adult population with few studies looking at its utility in
children and adolescents. Linder et al. showed 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% [17]. 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 aide 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 un-
usual presentation of vitamin B12 deficiency induced pseudo-TMA and
that it should be considered in the differential in a patient presenting
with a TMA syndrome.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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