INTRODUCTION
Thrombotic microangiopathy (TMA) encompasses severe conditions caused by microvascular
thrombosis including thrombotic thrombocytopenic purpura (TTP) and Shiga toxin-mediated
hemolytic uremic syndrome (HUS).1 These disorders, associated with high morbidity,
share unifying features: microangiopathic hemolytic anemia (MAHA), thrombocytopenia,
and organ disfunction.2 MAHA describes Coombs-negative hemolysis from intravascular
red blood cell fragmentation producing schistocytes on peripheral blood smear.3 TTP
and HUS are not the only forms of TMA. Cases of metabolism mediated TMA from vitamin
B12 deficiency have been reported termed pseudothrombotic microangiopathy (pseudo-TMA).4–6
Differentiating the etiology of TMA, specifically TTP and vitamin B12 deficiency is
critical as the treatments and prognoses are different. Treatment for TTP requires
plasma exchange associated with increased complications and cost as compared to the
treatment for vitamin B12 deficiency, which is simply supplementation.7 Unnecessary
plasma exchange has been reported due to the misdiagnosis of TTP when the actual diagnosis
was vitamin B12 deficiency.8
The incidence of TTP is less than one case per year per million.9 Vitamin B12 deficiency,
on the other hand, is far more common. The most frequent serum vitamin B12 cut-off
level to diagnose vitamin B12 deficiency is 150 pmol/L (203 pg/ml). Using this serum
vitamin B12 cut-off level, the prevalence of vitamin B12 deficiency is 5% to 15%.10
Approximately 2.5% of vitamin B12 deficiency cases present with hemolytic anemia,
thrombocytopenia, and schistocytosis.11 Therefore, even though a small proportion
of vitamin B12 presents with MAHA, the incidence is higher than TTP. We report a case
of a man presenting with profound pancytopenia concerning for TTP that was actually
secondary to vitamin B12 deficiency.
CASE REPORT
A 65-year-old Caucasian male with a history of hepatitis C presented to the emergency
room after laboratory evaluation at his primary care provider’s office revealed pancytopenia.
He endorsed a one-month history of increasing fatigue, interfering with his work as
a security guard. He denied a history of blood or coagulation disorders, autoimmune
disease, cancer, recent trauma, immobilization, or travel. He initially denied any
history of heavy alcohol consumption.
Vital signs were within normal limits. On physical exam, conjunctival pallor was noted.
Cardiovascular exam was significant for a 2/6 systolic murmur. He had bilateral 1+
pitting edema of the lower extremities to the mid-calf with discoloration consistent
with venous stasis. His skin showed diffuse ecchymosis of the forearms bilaterally.
Table 1 shows lab values on admission.
A peripheral blood smear showed 4% schistocytes, 2+ teardrop cells, and hypersegmented
neutrophils. Coomb’s test was negative. His iron studies and folate levels were within
normal limits. Coagulation studies were within normal limits. The patient was transfused
with packed red blood cells. A diagnosis of vitamin B12 deficiency was made and treatment
with intramuscular vitamin B12 initiated. After further questioning, he disclosed
that his diet consisted almost exclusively of tomato soup and meatless sandwiches.
Since the death of his father and brother earlier in the year, he had increased his
alcohol consumption significantly more than he initially indicated, drinking around
8 – 10 beers daily. His ADAMTS13 activity later returned as 100% activity. He was
treated with intramuscular vitamin B12 and follow-up as an outpatient showed complete
resolution of his anemia four months later.
DISCUSSION
Patients showing schistocytosis and thrombocytopenia merit screening for TTP as this
disease can be lethal. The PLASMIC score (Table 2) quantifies the likelihood of TTP.12
Each criterion scores a point. If the score is in the intermediate to high range (5
to 7 points), a presumptive diagnosis in the appropriate clinical context can be made
and is sufficient to initiate treatment. Our patient’s PLASMIC score of 5 fell into
the intermediate risk. However, his clinical presentation was due solely to vitamin
B12 deficiency. Differentiating vitamin B12 deficiency with pseudo-TMA from TTP is
of the utmost importance to avoid unnecessary plasma exchange. As with TTP, vitamin
B12 deficiency also can present with MAHA and thrombocytopenia, as seen in our case.
Vitamin B12 is necessary for the proper synthesis of deoxyribo-nucleic acid (DNA)
and cell division of hematopoietic cells.13 Without adequate stores the nucleated
precursors of hematopoietic cells, lines cannot mature, leading to megaloblastic anemia.
Neutropenia and thrombocytopenia subsequently may develop.14 As the precursor cells
are unable to mature, cellular arrest occurs, leading to intramedullary cell death.
Lactate dehydrogenase (LDH) enzymes are released during the destruction of nucleated
red cells. Therefore, intramedullary hemolysis of immature red blood cells, as seen
in vitamin B12 deficiency, can lead to high LDH levels. In fact, LDH levels may be
useful in differentiating TTP from vitamin B12 deficiency, as most patients with TTP
exhibit LDH levels less than 2500 IU/L, while levels exceeding 2500 IU/L indicate
the possibility of vitamin B12 deficiency.15
As bilirubin elevation results from the catabolism of heme, the hemolysis of erythroid
precursors, which produce little hemoglobin, results in only a minor increase in bilirubin
levels.16 In contrast, peripheral hemolysis of mature erythrocytes, which have a high
amount of hemoglobin, leads to a much higher indirect bilirubin level. Our patient’s
LDH levels were much higher relative to his bilirubin levels, more consistent with
intramedullary hemolysis of immature erythrocytes secondary to vitamin B12 deficiency.
ADAMTS13 cleaves von Willebrand factor multimers that are secreted from vascular endothelial
cells.17 ADAMTS13 deficiency results in unusually large von Willebrand factor multimers,
causing platelet thrombi in small vessels with high shear rates, creating schistocytes.
Vitamin B12 causes hyperhomocysteinemia, decreased plasma methionine levels, and methylmalonic
aciduria. These are associated with platelet activation, generation of reactive oxygen
species, endothelial dysfunction, increased tissue factor expression, and coagulation
activation. The combination of these factors is thought to lead to peripheral hemolysis,
causing schistocytes. Individuals with homozygous or compound heterozygous mutations
in a gene encoding the methylmalonic aciduria and homocystinuria type C protein (MMACHC)
are more predisposed to pseudo-TMA as compared to vitamin B12 deficiency without MAHA.
The most helpful parameter in differentiating pseudo-TMA and TTP may be the reticulocyte
count.15 Those who have pseudo-TMA averaged a 3% reticulocyte count and TTP averaged
18%.18 Our patient’s level of 3.8% was more consistent with vitamin B12 deficiency.
The reticulocyte production index (RPI) makes corrections for both the hematocrit
and the reticulocyte lifespan.19 Making these corrections determines whether the reticulocytosis
truly is increased. In cases of anemia, RPI less than 2 is considered inappropriately
low. Our patient’s RI was 0.50, indicating a hypoproliferative process.
Both TMA and vitamin B12 deficiency can present with a high MCV.20 In the setting
of hemolytic disorders, a high MCV can be due to a high reticulocyte count. Severe
macrocytosis with levels greater than 115 fL is associated almost exclusively with
megaloblastic anemias, including vitamin B12 deficiency. Our patient’s high MCV with
a low RI is more consistent with megaloblastic anemia rather than TTP. Of note, ADAMTS13
activity level typically is decreased in TTP; however, due to time limitations, treatment
decisions often are initiated prior to obtaining it.
CONCLUSION
In summary, vitamin B12 deficiency associated with pseudo-TMA can present similarly
to TTP with hemolytic anemia, schistocytosis, and thrombocytopenia. Obtaining the
correct diagnosis is possible if the clinician understands the clinical differences
and differing mechanisms. Vitamin B12 deficiency typically presents with an elevated
MCV and relatively low reticulocyte count, whereas TTP may or may not present with
an elevated MCV and elevated reticulocyte count.18,20 MCV greater than 115 fL is consistent
with megaloblastic anemias. Vitamin B12 deficiency typically presents with relatively
higher levels of LDH and lower levels of bilirubin compared with TMA.15,16 MAHA is
a feature of both TMA and pseudo-TTP, however, the etiologies of the two differ.17