March 2024 Case

Thrombotic microangiopathies (TMAs) are a heterogenous group of rare disorders characterized by the clinical findings of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and possible organ damage or dysfunction. MAHA is a form of anemia caused by direct antiglobulin test (DAT) negative red blood cell hemolysis with increased schistocytes on a peripheral blood smear. The primary TMA syndromes include thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and complement-mediated TMA (CM-TMA).

Pseudo-thrombotic microangiopathy (pseudo-TMA) is a rare, yet recognized, clinical presentation of vitamin B12 deficiency. Patients with pseudo-TMA present like other TMA syndromes including MAHA, thrombocytopenia, and schistocytosis. As a result, these can be misdiagnosed as other TMA syndromes and patients can have a delay in the correct treatment or receive unnecessary therapies.

In the case detailed below, we describe a case of pseudo-TMA in a patient with vitamin B12 deficiency secondary to pernicious anemia.

A 61-year-old male with a history of stroke, gastrointestinal reflux disease, and hyperlipidemia presented to the emergency department with worsening fatigue and shortness of breath on exertion for one month. He also stated he had 40-pound unintentional weight loss over the last 3 to 4 months. Complete blood count showed a profound macrocytic anemia and thrombocytopenia. Hemoglobin (Hgb) was 3.2 g/dL (reference range: 13–17 g/dL), mean corpuscular volume (MCV) was 124.4 FL (reference range: 80–100 FL), and platelet count was 43,000/UL (reference range: 150,000–450,000/UL). The white blood cell count was within normal limits at 4,180/UL (reference range: 4,000–11,000/UL). Coagulation studies showed an elevated prothrombin time (PT) of 17.5 seconds and an international normalized ratio (INR) of 1.5 (reference range: PT: 11.9-14.4 sec/INR: 0.8-1.3). Peripheral blood smear showed increased schistocytes (2 to 4/HPF). Anemia work-up was remarkable for a DAT negative hemolysis with elevated lactate dehydrogenase (LDH), undetectable haptoglobin, and elevated indirect bilirubin. Reticulocyte count and percentage were not elevated. Labs also showed both a folate and vitamin B12 deficiency. The patient was afebrile and his kidney function was normal. Moreover, there were no neurologic symptoms present.

Given the presence of hemolysis, thrombocytopenia, and the increased schistocytes, the differential diagnosis included primary TMA syndromes as well as secondary TMA in the setting of a possible occult malignancy. Transfusion Medicine was consulted to perform plasmapheresis for possible TTP. However, given the low PLASMIC score (score: 4) and absence of neurologic involvement, the decision was made to hold off on plasmapheresis. A Disintegrin and Metalloproteinase with Thrombospondin type-1 motif, member 13 (ADAMTS13) activity and intrinsic factor blocking antibody (IFBA) labs were drawn and sent out to outside laboratories.  

The patient was admitted to the hospital and started on vitamin B12 1000 mcg IM and folic acid 5 mg. Given the profound anemia, the patient was transfused several units of red blood cells (pRBCs). To rule out an occult malignancy, computed tomography (CT) imaging of the chest, abdomen, and pelvis were performed which were all unremarkable. A bone marrow biopsy showed mildly hypercellular marrow with increased megakaryocytes and no evidence of lymphoma or other marrow-based disorders. Over the next 2 weeks, the patient’s Hgb and platelet counts improved to 8.1 g/dL and 366,000/UL, respectively. Hemolysis labs also showed gradual improvement. Three days into his hospital admission, ADAMTS13 activity was resulted as mildly decreased at 47% (reference range: ≥ 67%). This was not consistent with a diagnosis of TTP which typically has an ADAMTS13 activity level of < 10%. The IFBA assay was positive consistent with a diagnosis of pernicious anemia. The patient was discharged on weekly vitamin B12 injections for the next two months with outpatient follow-up with a hematologist.

As demonstrated in our patient, a vitamin B12 deficiency can rarely present as a pseudo-TMA that mimics primary TMA syndromes with similar features of hemolytic anemia, thrombocytopenia, and increased schistocytes. The early recognition of these signs and symptoms that are not classically associated with vitamin B12 deficiency can help to avoid inappropriate treatment and invasive procedures. Patients who present with multiple risk factors for vitamin B12 deficiency such as macrocytic anemia, a social history significant for alcohol use disorder, an abnormal dietary history, or a personal and/or family history of autoimmune diseases should raise clinical concern. In this patient population, vitamin B12 supplementation should be considered at the onset of presentation as it can result in rapid improvement in bone marrow production and normalization of blood cell parameters.

1. Fahmawi, Yazan et al. "Vitamin B12 deficiency presenting as pseudo-thrombotic microangiopathy: a case report and literature review." Clinical pharmacology: advances and applications vol. 11 127-131. 27 Aug. 2019, doi:10.2147/CPAA.S207258
2. Hassouneh, Ramzi et al. "Severe Vitamin B12 Deficiency Mimicking Microangiopathic Hemolytic Anemia." Journal of hematology vol. 10,4 (2021): 202-205. doi:10.14740/jh889
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