A 60-Year-Old Woman with Severe Macrocytic Anemia, Thrombocytopenia, and Schistocytes
A 60-year-old woman with a medical history of hypothyroidism presented to our hospital with a hemoglobin of 6.1 g/dL after being referred by her primary care physician for severe anemia. She reported fatigue, dyspnea on exertion, and decreased appetite for several months. One of her friends noticed a yellow discoloration of her eyes which prompted her to come to the hospital. On arrival, she was afebrile, had a regular heart rate of 100/min, respiratory rate of 16, and a normal oxygen saturation on room air. Her physical exam was significant for icteric sclera and generalized jaundice. Her initial laboratory results were as follows.
| Value | Reference Range | |
| White Blood Cell (WBC) | 3.03 K/cmm | 4.00-12.40 K/cmm |
| Hemoglobin | 6.1 g/dL | 11.6-15.2 g/dL |
| Hematocrit | 18.1% | 34.9-44.4% |
| Main Corpuscular Volume (MCV) | 119 fL | 80-100 fL |
| Platelets | 39 K/cmm | 150-450 K/cmm |
Metabolic panel demonstrated creatinine of 1.6 mg/dL, blood urea nitrogen (BUN) of 28 mg/dL, normal electrolytes, aspartate aminotransferase (AST) of 110 U/L, and a total bilirubin of 5.9 mg/dL (indirect bilirubin 5.5 mg/dL). Further lab results demonstrated lactate dehydrogenase (LDH) of 15,910 U/L, haptoglobin of 9 mg/dL, reticulocyte count of 1.9 percent, international normalized ratio (INR) of 1.2, prothrombin time (PT) of 14.4 seconds, partial thromboplastin time (PTT) of 24 seconds, and fibrinogen of 238 mg/dL. A peripheral blood smear revealed rare schistocytes. A direct antiglobulin test (DAT) was negative. A computed tomography (CT) of the abdomen and pelvis demonstrated a normal-sized spleen without evidence of adenopathy. A CT of the chest demonstrated two 4 mm lung nodules with benign characteristics. Two units of red blood cells (RBCs) were administered.
Answer: C
The patient’s vitamin B12 level was very low at 70 pg/mL (normal, 250-950 pg/mL) with a methylmalonic acid level of 2.41 nmol/mL (normal, <0.40 nmol/mL) and a normal folate level. Intrinsic factor antibody testing was positive. As such, the patient was diagnosed with macrocytic anemia and thrombocytopenia due to severe vitamin B12 deficiency in the setting of pernicious anemia.
Differentiating severe vitamin B12 deficiency with pseudo-thrombotic microangiopathy (TMA) from thrombotic thrombocytopenic purpura (TTP) is of the utmost importance to avoid unwarranted plasmapheresis (Table). Severe vitamin B12 deficiency or defective cobalamin metabolism can present similarly to a TMA with microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and end-organ damage from microvascular thrombosis. The pathophysiology of TMA in vitamin B12 deficiency is multifactorial, but is most closely related to hyperhomocysteinemia. Vitamin B12 deficiency results in hyperhomocysteinemia along with decreased plasma methionine levels and methylmalonic aciduria. These products generate reactive oxygen species leading to endothelial dysfunction, platelet activation, and increased tissue factor expression with activation of coagulation cascade. Hyperhomocysteinemia is also associated with increased oxidative stress via the formation of superoxide and hydrogen peroxide radicals, which cause direct endothelial damage, facilitating the formation of atherosclerosis and a platelet plug. The combination of these factors is thought to lead to peripheral hemolysis, causing the formation of 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 compared to vitamin B12 deficiency without MAHA.
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Table. Symptoms and laboratory features to differentiate between TTP and metabolism-mediated TMA.
| TTP | Metabolism-mediated TMA | |
| Cause | Deficiency of ADAMTS13 | Cobalamin deficiency (congenital or acquired), causing hyperhomocysteinemia, methylmalonic aciduria, endothelial dysfunction, platelet activation, and activation of coagulation cascade |
| MAHA | Present | Present |
| Neurologic symptoms | Present | May be present |
| Renal impairment | Less common | May be present |
| Thrombocytopenia | Severe | Less severe |
| Retic count | High | Low |
| LDH | Elevated | Markedly elevated |
| Fever | May be present | Absent |
In this case, the factors that differentiate our patient from classic TTP are macrocytic anemia with low reticulocyte index along with a very low vitamin B12 level. Another helpful feature can be a very high LDH level.
Both a TMA and severe vitamin B12 deficiency can present with a high MCV. In the setting of hemolytic disorders, a high MCV can be due to a high reticulocyte count. Vitamin B12 is required for the synthesis of DNA and cell division, and when it is deficient the cell lines cannot mature and lead to macrocytic anemia and thrombocytopenia. Severe macrocytosis with MCV levels greater than 115 fL is associated almost exclusively with megaloblastic anemias, including severe vitamin B12 deficiency.
Severe vitamin B12 deficiency leads to cellular arrest, which causes intramedullary hemolysis of immature RBCs and the release of LDH. This process leads to extremely high levels of LDH, which can also be helpful in differentiating TTP from severe vitamin B12 deficiency, as most patients with TTP exhibit LDH levels less than 2,500 IU/L, while levels exceeding 2,500 IU/L indicate the possibility of severe vitamin B12 deficiency.
The reticulocyte index can also be a helpful parameter in differentiating pseudo-TMA from TTP. Patients who have a pseudo-TMA have a low reticulocyte count of around 3 percent, compared to those with TTP who have a high reticulocyte count averaging around 18 percent. Our patient’s level of 1.9 percent was more consistent with severe vitamin B12 deficiency due to underproduction of erythrocytes in the marrow.
Occasional schistocytes may be seen in severe vitamin B12 deficiency; however, marked poikilocytosis is often present and can mimic schistocytosis. The concurrent hemolysis is attributed to intramedullary destruction of RBCs. This is different from TTP, in which there is marked schistocytosis on the peripheral smear due to intravascular MAHA. Although we did not measure homocysteine levels in our patient, we believe that high homocysteine levels could have contributed to the patient's hemolysis as mentioned above.
The patient was administered 1,000 μg of vitamin B12 intramuscularly for three days. On the day of discharge, she had improved energy levels, WBC was 3.46 K/cmm, hemoglobin was 8.9 gm/dL, and platelets were 67 K/cmm. The patient was instructed to continue with monthly injections of vitamin B12 1,000 μg.
- 1. Routh JK, Koenig SC. Severe vitamin B12 deficiency mimicking thrombotic thrombocytopenic purpura. Blood. 2014;124:1844.
- 2. Bailey M, Maestas T, Betancourt R, et al. A rare cause of thrombotic thrombocytopenia purpura- (TTP-) like syndrome, vitamin B12 deficiency: Interpretation of significant pathological findings. Case Rep Hematol. 2019;2019:1529306.