Pancytopenia: Common Things Occur Commonly
Authors: Krule Alexander , Murga Zamalloa Carlos A. , Khan Irum , Quigley John G 
Published: December 2024

In older patients (pts), bone marrow (BM) disease such as myelodysplastic syndrome (MDS) is a common cause of pancytopenia. However, the dysplastic marrow findings of MDS may be seen with infections, nutritional deficiencies, or drug-related side effects. Detection of genetic alterations helps confirm clonal myeloid neoplasms, but ~10% of MDS pts have no genetic abnormalities.

A 67 yo woman with a PMHx of DM type II presented to clinic with an 8-month history of cytopenias describing severe fatigue, easy bruising, and chest pain without neurologic or B symptoms. Physical exam was unremarkable apart from ecchymoses.

Laboratory results: WBC 2.6 x 109/L, ANC 0.9 K/µL, Hgb 7.6 g/dL (MCV 100.9 fL), platelets 115 x 109/L, with evidence of marked hemolysis (unconj. bilirubin 2.6 mg/dL [ULN 0.2], LDH 5500 U/L [ULN 180], haptoglobin &lt;10 mg/dL), reticulocyte index 0.57% and negative Coombs' test.

Iron studies and folate levels were normal, vitamin B12 (B12) was 410 pg/mL (ref. range 181-914).

Smear revealed macrocytic, normochromic red cells with polychromasia, occasional target cells and megaloblastic forms, red cell agglutination; no schistocytes or spherocytes.

BM was hypercellular with increased erythroid elements (M:E=0.5), and trilineage dysplasia. Cytogenetics, myeloid FISH, and NGS studies (Neogenomics myeloid panel) were negative for MDS-related genetic alterations. Serum erythropoeitin at 194 mU/mL was low for hematocrit of 20%. Serum protein electrophoresis, extensive viral testing, Hgb electrophoresis, red cell osmotic fragility testing and enzymopathy studies were normal. Highly sensitive DAT (“Super Coombs' test”; Versiti), cryoglobulins and B- and T-cell clonality assays were all negative.

Prednisone and darbopoietin were prescribed for an assumed MDS-related DAT-negative immune-mediated hemolytic process, with complete resolution of cytopenias by 4 months. Pancytopenia/hemolysis recurred 3 months after steroid taper, and weekly rituximab 375 mg/m2 x 4 weeks and a 2nd steroid burst were initiated with resolution. Four months later, cytopenias recurred.

CT scans were negative for organomegaly or lymphadenopathy. Highly sensitive flow assays of RBCs and WBCs for PNH were normal.

Repeat BM was hypercellular with increased erythroid elements, megaloblastic maturation, 11% ringed sideroblasts and 20% dysplasia in the myeloid and megakaryocytic lineages. BM failure syndromes gene panel (Invitae) was negative for mutations.

Rituximab was resumed for 8 monthly doses, but she subsequently relapsed with Hgb 6.3, LDH 10,433, ANC 0.6 K/uL and platelets of 74 x 109/L that responded to PRBCs and reinstitution of immunosuppression. Given the poorly sustained BM responses and the increased rate of erythropoiesis (‘use‘), nutritional studies were repeated. B12 levels were 101 pg/mL with an elevated methylmalonic acid of 29.0 μmol/L (ULN 0.40). Intrinsic factor (IF) antibody was positive, confirming a diagnosis of pernicious anemia (PA). Vitamin B12 and folate supplementation led to rapid and sustained (1 yr) resolution of cytopenias.

This typical PA presentation of pancytopenia and hemolysis was confounded by 1), initial workup revealing a normal serum B12, 2), a ‘dysplastic‘-appearing BM, and 3), the recurrent significant, short-lived BM responses to immunosuppression.

Patients with PA may have falsely normal B12 levels due to anti-IF antibodies in the patient's serum interfering with exogenous labelled IF, the vitamin B12-binding protein used in competitive binding luminescence assays of B12 levels in most reference laboratories (Stabler, N Engl J Med. 2013; 368:149). Thus, high titer anti-IF antibodies at presentation likely masked a true B12 deficiency.

The appearance of BM dysplasia in PA is not uncommon, but the presence of ring sideroblasts is relatively rare (e.g., Bharath & Hsia, Blood 2015, 126:2255).

Notably, as PA is an autoimmune disorder of intestinal B12 absorption, the use of rituximab and steroids may have temporarily ameliorated her disease with recovery of normal gastric mucosa, as shown with steroid use over 60 yrs ago (Doig et al., Lancet.1957;270(7003):966, Ardeman, N Engl J Med 1965;273:1352)

In conclusion, if clinical suspicion of PA, measurement of methylmalonic acid should be considered even when B12 levels are normal or low-normal. As occurred here, a false diagnosis of MDS may confer substantial emotional trauma and potentially unnecessary treatment.