Vitamin B12 Deficiency-Related Pseudo-Thrombotic Microangiopathy Might be Misdiagnosed and Treated with Plasma Product Therapy: Review of the Literature and Analysis of the Reported Cases

Introduction: Pseudo-thrombotic microangiopathy (pseudo-TMA) is a recognized clinical manifestation of vitamin B12 deficiency, manifested as microangiopathic hemolytic anemia, schistocytosis, high serum lactate dehydrogenase (LDH), and low plasma haptoglobin. Such cases have been misdiagnosed as thrombotic thrombocytopenic purpura and patients were subjected to treatment with plasma product therapy. We conducted literature search and analysis of cobalamin deficiency-pseudo thrombotic microangiopathy (pseudo-TMA) cases from published literature.

Material & Methods: We performed comprehensive literature search in PUBMED, EMBASE, SCOPUS and GOOGLE SCHOLAR databases using the terms "B12 AND microangiopathy", "cobalamin AND microangiopathy", "B12 AND thrombotic thrombocytopenic purpura", "cobalamin AND thrombotic thrombocytopenic purpura", "pernicious anemia AND microangiopathy", "pernicious anemia AND thrombotic thrombocytopenic purpura", "B12 AND schistocytes", "cobalamin AND schistocytes", "pernicious anemia AND schistocytes". We extracted data from eligible cases and analyzed them. The primary endpoint was to determine the frequency of use of plasma product therapy (plasma transfusion and/or plasma exchange). The secondary endpoint was to identify the clinical and laboratory differences between the cases treated with plasma products and cobalamin therapy versus those treated with cobalamin therapy only. The distribution of each categorical variable was be summarized in terms of its frequencies and percentages. Continuous variables were compared between groups (plasma product therapy versus no-plasma therapy) by non-parametric methods. Chi-square test or Fisher exact test was used to assess differences between categorical variables.

Results: Total of 8116 citations were identified from the literature search and 4880 duplicates were identified and removed. In addition, 3200 ineligible citations were excluded. A total of 36 patients were available for analysis. Patient characteristics were described in Table 1. After comparison of clinical and laboratory variables between plasma therapy group and non-plasma therapy group, we found that patients who were treated with plasma therapy had much lower platelet count of 41 x 10⁹/L whereas 100 x 10⁹/L in non-plasma therapy group with p-value of <0.000. No other differences were identified between both groups.

Conclusions: 38.8% of reported cases of cobalamin deficiency-related pseudo-TMA were treated with plasma product therapy. Median duration of symptom was 2 weeks before the correct diagnosis was made. Seemingly, low platelet count appeared to be the basis on deciding the use of plasma product therapy. However, we could not confirm if thrombocytopenia was the main clinical factor to consider "true" TMA. Moreover, schistocytes were present in 30 out of 36 cases; thus the presence of schistocytes was not the main clinical aspect leading to the decision to use plasma product therapy. No other clinical or laboratory aspects were different between the two groups. Improved awareness of this condition in the hematology community and reaching the precise diagnosis is critical to avoid unnecessary and expensive plasma product therapy.

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