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Pernicious Anemia With Spuriously Normal Vitamin B12 Level Might Be Misdiagnosed As Myelodysplastic Syndrome
Case Report
Pernicious Anemia With Spuriously Normal Vitamin B12 Level Might Be Misdiagnosed As Myelodysplastic Syndrome Dhaval R. Shah,1 Naval Daver,2 Gautam Borthakur,2 Cheryl Hirsch-Ginsberg,2 Thein H. Oo2 Clinical Practice Points Vitamin B12 deficiency can present with cytopenias,
dysplastic features, and can mimic myelodysplastic syndromes. Patients with pernicious anemia might have spuriously normal or increased vitamin B12 levels due to the
presence of anti-intrinsic factor antibodies that might interfere with new automated assays. Hematologic manifestations of pernicious anemia include megaloblastic anemia, pancytopenia, pseudothrombotic microangiopathy, and venous thromboembolism related to homocysteinemia.
Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Anti-intrinsic factor antibodies, Homocystinemia, Myelodysplastic syndrome, Pernicious anemia, Vitamin B12 deficiency
Introduction
Case
Patients with pernicious anemia (PA) can present with cytopenias, dysplastic features, and symptoms that can mimic myelodysplastic syndrome (MDS). Diagnosis of vitamin B12 deficiency in PA can be difficult because of the presence of anti-intrinsic antibodies that might interfere with automated assays leading to spuriously normal or increased vitamin B12 levels. Vitamin B12 deficiency is classically associated with bone marrow (BM) failure and demyelinating neuropathy. BM failure is characterized by ineffective erythropoiesis leading to megaloblastic anemia and hypersegmented neutrophils.1 Life-threatening manifestations can include pseudothrombotic microangiopathy, severe pancytopenia, and intramedullary hemolysis.2 BM examination in patients with cobalamin deficiency can occasionally reveal dysplastic features and/or transient cytogenetic abnormalities that might result in a misdiagnosis of MDS or acute leukemia.3,4 Herein, we report a case of PA that was misdiagnosed as MDS. Our patient had concurrent hyperhomocysteinemia resulting in pulmonary embolism (PE).
A 53-year-old man presented to an outside hospital in June 2013 with shortness of breath, dizziness, and fatigue. He had a history of hypertension, type 2 diabetes mellitus, diastolic cardiac dysfunction, and a remote history of anemia of unclear etiology. Complete blood count (CBC) on admission revealed white blood cell (WBC) count of 6.36 (range, 4.8-10.8) K/mL, hemoglobin (Hb) 7.4 (range, 14.0-18.0) g/dL, hematocrit 21.4% (range, 42.0%-52.0%), mean corpuscular volume (MCV) 105.4 (range, 80-100.0) fL, mean corpuscular Hb (MCH) 36.5 (range, 25.434.6) pg/cell, mean corpuscular hemoglobin concentration 34.6 (range, 33.0-37.0) g/dL, red cell distribution width 19.2 (range, 11.5%-14.5%), platelet (PLT) 189 (range, 130-400) K/mL, mean platelet volume 11.5 (range, 7.2-11.1) fL, nucleated RBC 0.8%, segments 50%, bands 3%, and lymphocytes 47%. Blood film report revealed mild hypochromia, few schistocytes, and few target cells. He received 4 U of red blood cells within a 1-week period. BM biopsy revealed markedly hypercellular marrow with marked erythroid hyperplasia and moderate to marked megaloblastic changes, moderate dysplastic changes, and left-shifted maturation. Granulocytic maturation also showed megaloblastic features. BM karyotyping revealed 46, XY in all 20 metaphases. Serum vitamin B12 and folate were normal. A diagnosis of refractory cytopenia with multilineage dysplasia/MDS was made. In July 2013, he came to our institution for a second opinion. He revealed a history of anemia 10 years ago, for which he was
1
Baylor College of Medicine, Houston, TX The University of Texas M.D. Anderson Cancer Center, Houston, TX
2
Submitted: Jan 20, 2014; Revised: Feb 8, 2014; Accepted: Feb 11, 2014 Address for correspondence: Thein H. Oo, MD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1464, Houston, TX 77030 Fax: 713-563-4443; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.02.002
Clinical Lymphoma, Myeloma & Leukemia Month 2014
-1
Pernicious Anemia, Vitamin B12, and Myelodysplastic Syndrome hospitalized for a month with frequent blood transfusions. He received treatment with intravenous immune globulin (IVIG) for a possible hemolytic process. However, he developed an allergic reaction to IVIG and it was discontinued prematurely. His counts ultimately recovered and he was doing well until the recent admission. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. He was taking amlodipine, carvedilol, glipizide, hydralazine, lisinopril, metformin, and linagliptin at the time of admission. Laboratory studies showed WBC 5.9 (range, 4-11) K/mL, Hb 8.9 (range, 12-16.0) g/dL, MCV 93 (range, 80-100) fL, PLT 153 (range, 140-450) K/mL, reticulocyte 0.5% (range 0.5%-1.5%). Biochemistry results were significant for an lactate dehydrogenase of 16,351 (range, 313-618) U/L, a total bilirubin of 1.9 (range, 0-1.0) mg/dL, an indirect bilirubin of 1.4 mg/dL, haptoglobin 4 (range, 32-197) mg/dL, and serum erythropoeitin of 74 (range, 5.2-25.3) mIU/mL. The vitamin B12 (measured using electrochemiluminescence immunoassay) was 659 (range, 211-946) pg/mL, folate was 9.6 (range, 7.3-26.1) ng/mL, and ferritin was 959 (range, 30-400) ng/mL. Urinalysis revealed moderate hemoglobinuria. Peripheral blood smear revealed anisopoikilocytosis, macroovalocytes, basophilic stippling, rare schistocytes, teardrop forms, burr cells, microspherocytes, target cells, and hypersegmented neutrophils (Fig. 1). No blasts or immature cells were present. Repeat BM aspirate and biopsy showed myeloid:erythroid ratio 1.1:1.0, cellularity 100%, megaloblastic left-shifted erythropoiesis with cytoplasmic vacuolation and nuclear budding and mildly dyspoietic megakaryocytes. The marrow differential showed 1% blasts with predominance of erythroid precursors including normoblasts and pronormoblasts (1% blast, 1% promyelocytes, 10% myelocytes, 17% metamyelocytes, 19% granulocytes, 1% eosinophils, 6% lymphocytes, 2% monocytes, 2% pronormoblasts, and 40% normoblasts); 2% ring sideroblasts were also seen. Serum copper, lead, zinc, and vitamin B6 levels were within the normal range. The direct antiglobulin test was negative, however, super-Coombs test was weakly positive for immunoglobulin (Ig) G. Work-up for paroxysmal nocturnal hemoglobinuria was negative. Despite normal serum vitamin B12 level, vitamin B12
Figure 1 Blood Smear Showing Hypersegmented Neutrophil
2
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Clinical Lymphoma, Myeloma & Leukemia Month 2014
deficiency remained a suspicion based on the presence of hypersegmented neutrophils and megaloblastic erythropoiesis. Fasting serum homocysteine level was increased at 120 (range, < 13) mmol/L, methylmalonic acid (MMA) was increased at 7.89 (normal < 0.40) nmol/mL. Antiparietal cell antibody assay was negative but anti-intrinsic factor antibody was detectable. The clinical constellation of hemolysis (low serum haptoglobin, high serum lactate dehydrogenase, hemoglobinuria), low reticulocyte count, and high MMA and homocysteine levels, suggest a diagnosis of PA with severe intramedullary hemolysis (ineffective erythropoiesis). The patient was prescribed subcutaneous vitamin B12 of 1000 mcg weekly for 4 weeks followed by 1000 mcg monthly thereafter. Unfortunately, on his way back home, he experienced chest pain at the airport. He returned to our emergency room and computed tomogram pulmonary angiogram showed the presence of PE. Rivaroxaban was prescribed for 3 months. The most likely cause for his PE was the transient risk attributed by the presence of homocysteinemia. His homocysteine level normalized with B12 therapy. In October 2013, CBC revealed a Hb of 14.0 g/dL, WBC of 6.8, and PLT count of 184.
Discussion Pernicious anemia is the most common cause of vitamin B12 deficiency worldwide. It is an autoimmune disorder characterized by destruction of gastric parietal cells and associated with the presence of an antiparietal cell antibody and/or anti-intrinsic factor antibody.1 The first step in diagnosis of vitamin B12 deficiency is usually measurement of serum B12 levels. However, the use of newer automated analyzers might be associated with falsely normal or even falsely increased vitamin B12 levels, especially in the presence of anti-intrinsic factor antibodies.5,6 Our patient had a normal serum B12 level; however the abnormal peripheral smear prompted us to check serum MMA and serum homocysteine levels. Elevated MMA and homocysteine levels with detectable anti-intrinsic factor antibodies confirmed the diagnosis of PA in our patient. Hyperhomocysteinemia associated with vitamin B12 deficiency has been associated with increased risk of arterial and venous thrombosis.7-9 Thrombosis in this setting usually occurs in the presence of markedly increased homocysteine levels as seen in our patient. With vitamin B12 supplementation, homocysteine levels usually normalize resulting in reduced risk for thrombosis. However, the optimal duration of anticoagulation in cases remains uncertain. In our patient, the homocysteine levels normalized after initiating vitamin B12 injections. Therefore, we decided to treat the patient for a total duration 3 months as recommended for patients with thrombosis in the presence of a transient risk factor. Our case highlights several important teaching points. First, the diagnosis of vitamin B12 deficiency can be enigmatic and physicians need to be aware of the wide range of hematological manifestations associated with vitamin B12 deficiency. Vitamin B12 deficiency can be a MDS-mimic.10 Misdiagnosing vitamin B12 deficiency as MDS could result in devastating consequences. Second, schistocytes can occasionally be seen in severe vitamin B12 deficiency. Rarely, the schistocytes can be profound enough to resemble thrombotic thrombocytopenic purpura.11,12 Third, the presence of microspherocytes and weakly positive IgG using the super-Coombs test suggests coexistent subclinical warm autoimmune hemolysis (Hb returns to normal
Dhaval R. Shah et al without the use of steroids) because autoimmune hemolytic anemias might occur in association with PA.13,14 Fourth, normal vitamin B12 levels do not rule out vitamin B12 deficiency, especially with newer assays which might be confounded by anti-intrinsic factor antibodies resulting in falsely normal or falsely increased B12 values.5,6,15 Finally, hyperhomocysteinemia associated with vitamin B12 deficiency is a risk factor for arterial and venous thrombosis.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013; 368:149-60. 2. Andrès E, Affenberger S, Zimmer J, et al. Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency. Clin Lab Haematol 2006; 28:50-6. 3. Heath C, Fliegelman L. Cytogenetic observations in vitamin B12 and folate deficiency. Blood 1966; 27:800-15. 4. Parmentier S, Meinel J, Oelschlaegel U, et al. Severe pernicious anemia with distinct cytogenetic and flow cytometric aberrations mimicking myelodysplastic syndrome. Ann Hematol 2012; 91:1979-81.
5. Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. N Engl J Med 2012; 367:385-6. 6. Yang DT, Cook RJ. Spurious elevations of vitamin B12 with pernicious anemia. N Engl J Med 2012; 366:1742-3. 7. Remacha AF, Souto JC, Piñana JL, et al. Vitamin B12 deficiency, hyperhomocysteinemia and thrombosis: a case and control study. Int J Hematol 2011; 93:458-64. 8. Remacha AF, Souto JC, Rámila E, Perea G, Sarda MP, Fontcuberta J. Enhanced risk of thrombotic disease in patients with acquired vitamin B12 and/or folate deficiency: role of hyperhomocysteinemia. Ann Hematol 2002; 81:616-21. 9. Limal N, Scheuermaier K, Tazi Z, Sene D, Piette JC, Cacoub P. Hyperhomocysteinaemia, thrombosis and pernicious anaemia. Thromb Haemost 2006; 96:233-5. 10. Steensma DP. Dysplasia has a differential diagnosis: distinguishing genuine myelodysplastic syndromes (MDS) from mimics, imitators, copycats and impostors. Curr Hematol Malig Rep 2002; 7:310-20. 11. Tadakamalla AK, Talluri SK, Besur S. Pseudo-thrombotic thrombocytopenic purpura: a rare presentation of pernicious anemia. N Am J Med Sci 2011; 3:472-4. 12. Dimond A, George JN, Hastings C. Severe vitamin B12 deficiency in a child mimicking thrombotic thrombocytopenic purpura. Pediatr Blood Cancer 2009; 52: 420-2. 13. Zafad S, Madani A, Harif M, et al. Pernicious anemia associated with autoimmune hemolytic anemia and alopecia areata. Pediatr Blood Cancer 2007; 49: 1017-8. 14. Salvidio E, Venzano C, Boccaccio P, et al. Pernicious anemia followed by autoimmune hemolytic anemia. Proc R Soc Med 1975; 68:421-2. 15. Hamilton MS, Blackmore S, Lee A. Possible cause of false normal B-12 assays. BMJ 2006; 333:654-5.
Clinical Lymphoma, Myeloma & Leukemia Month 2014
-3
Pernicious Anemia With Spuriously Normal Vitamin B12 Level Might Be Misdiagnosed As Myelodysplastic Syndrome Dhaval R. Shah,1 Naval Daver,2 Gautam Borthakur,2 Cheryl Hirsch-Ginsberg,2 Thein H. Oo2 Clinical Practice Points Vitamin B12 deficiency can present with cytopenias,
dysplastic features, and can mimic myelodysplastic syndromes. Patients with pernicious anemia might have spuriously normal or increased vitamin B12 levels due to the
presence of anti-intrinsic factor antibodies that might interfere with new automated assays. Hematologic manifestations of pernicious anemia include megaloblastic anemia, pancytopenia, pseudothrombotic microangiopathy, and venous thromboembolism related to homocysteinemia.
Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Anti-intrinsic factor antibodies, Homocystinemia, Myelodysplastic syndrome, Pernicious anemia, Vitamin B12 deficiency
Introduction
Case
Patients with pernicious anemia (PA) can present with cytopenias, dysplastic features, and symptoms that can mimic myelodysplastic syndrome (MDS). Diagnosis of vitamin B12 deficiency in PA can be difficult because of the presence of anti-intrinsic antibodies that might interfere with automated assays leading to spuriously normal or increased vitamin B12 levels. Vitamin B12 deficiency is classically associated with bone marrow (BM) failure and demyelinating neuropathy. BM failure is characterized by ineffective erythropoiesis leading to megaloblastic anemia and hypersegmented neutrophils.1 Life-threatening manifestations can include pseudothrombotic microangiopathy, severe pancytopenia, and intramedullary hemolysis.2 BM examination in patients with cobalamin deficiency can occasionally reveal dysplastic features and/or transient cytogenetic abnormalities that might result in a misdiagnosis of MDS or acute leukemia.3,4 Herein, we report a case of PA that was misdiagnosed as MDS. Our patient had concurrent hyperhomocysteinemia resulting in pulmonary embolism (PE).
A 53-year-old man presented to an outside hospital in June 2013 with shortness of breath, dizziness, and fatigue. He had a history of hypertension, type 2 diabetes mellitus, diastolic cardiac dysfunction, and a remote history of anemia of unclear etiology. Complete blood count (CBC) on admission revealed white blood cell (WBC) count of 6.36 (range, 4.8-10.8) K/mL, hemoglobin (Hb) 7.4 (range, 14.0-18.0) g/dL, hematocrit 21.4% (range, 42.0%-52.0%), mean corpuscular volume (MCV) 105.4 (range, 80-100.0) fL, mean corpuscular Hb (MCH) 36.5 (range, 25.434.6) pg/cell, mean corpuscular hemoglobin concentration 34.6 (range, 33.0-37.0) g/dL, red cell distribution width 19.2 (range, 11.5%-14.5%), platelet (PLT) 189 (range, 130-400) K/mL, mean platelet volume 11.5 (range, 7.2-11.1) fL, nucleated RBC 0.8%, segments 50%, bands 3%, and lymphocytes 47%. Blood film report revealed mild hypochromia, few schistocytes, and few target cells. He received 4 U of red blood cells within a 1-week period. BM biopsy revealed markedly hypercellular marrow with marked erythroid hyperplasia and moderate to marked megaloblastic changes, moderate dysplastic changes, and left-shifted maturation. Granulocytic maturation also showed megaloblastic features. BM karyotyping revealed 46, XY in all 20 metaphases. Serum vitamin B12 and folate were normal. A diagnosis of refractory cytopenia with multilineage dysplasia/MDS was made. In July 2013, he came to our institution for a second opinion. He revealed a history of anemia 10 years ago, for which he was
1
Baylor College of Medicine, Houston, TX The University of Texas M.D. Anderson Cancer Center, Houston, TX
2
Submitted: Jan 20, 2014; Revised: Feb 8, 2014; Accepted: Feb 11, 2014 Address for correspondence: Thein H. Oo, MD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1464, Houston, TX 77030 Fax: 713-563-4443; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.02.002
Clinical Lymphoma, Myeloma & Leukemia Month 2014
-1
Pernicious Anemia, Vitamin B12, and Myelodysplastic Syndrome hospitalized for a month with frequent blood transfusions. He received treatment with intravenous immune globulin (IVIG) for a possible hemolytic process. However, he developed an allergic reaction to IVIG and it was discontinued prematurely. His counts ultimately recovered and he was doing well until the recent admission. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. He was taking amlodipine, carvedilol, glipizide, hydralazine, lisinopril, metformin, and linagliptin at the time of admission. Laboratory studies showed WBC 5.9 (range, 4-11) K/mL, Hb 8.9 (range, 12-16.0) g/dL, MCV 93 (range, 80-100) fL, PLT 153 (range, 140-450) K/mL, reticulocyte 0.5% (range 0.5%-1.5%). Biochemistry results were significant for an lactate dehydrogenase of 16,351 (range, 313-618) U/L, a total bilirubin of 1.9 (range, 0-1.0) mg/dL, an indirect bilirubin of 1.4 mg/dL, haptoglobin 4 (range, 32-197) mg/dL, and serum erythropoeitin of 74 (range, 5.2-25.3) mIU/mL. The vitamin B12 (measured using electrochemiluminescence immunoassay) was 659 (range, 211-946) pg/mL, folate was 9.6 (range, 7.3-26.1) ng/mL, and ferritin was 959 (range, 30-400) ng/mL. Urinalysis revealed moderate hemoglobinuria. Peripheral blood smear revealed anisopoikilocytosis, macroovalocytes, basophilic stippling, rare schistocytes, teardrop forms, burr cells, microspherocytes, target cells, and hypersegmented neutrophils (Fig. 1). No blasts or immature cells were present. Repeat BM aspirate and biopsy showed myeloid:erythroid ratio 1.1:1.0, cellularity 100%, megaloblastic left-shifted erythropoiesis with cytoplasmic vacuolation and nuclear budding and mildly dyspoietic megakaryocytes. The marrow differential showed 1% blasts with predominance of erythroid precursors including normoblasts and pronormoblasts (1% blast, 1% promyelocytes, 10% myelocytes, 17% metamyelocytes, 19% granulocytes, 1% eosinophils, 6% lymphocytes, 2% monocytes, 2% pronormoblasts, and 40% normoblasts); 2% ring sideroblasts were also seen. Serum copper, lead, zinc, and vitamin B6 levels were within the normal range. The direct antiglobulin test was negative, however, super-Coombs test was weakly positive for immunoglobulin (Ig) G. Work-up for paroxysmal nocturnal hemoglobinuria was negative. Despite normal serum vitamin B12 level, vitamin B12
Figure 1 Blood Smear Showing Hypersegmented Neutrophil
2
-
Clinical Lymphoma, Myeloma & Leukemia Month 2014
deficiency remained a suspicion based on the presence of hypersegmented neutrophils and megaloblastic erythropoiesis. Fasting serum homocysteine level was increased at 120 (range, < 13) mmol/L, methylmalonic acid (MMA) was increased at 7.89 (normal < 0.40) nmol/mL. Antiparietal cell antibody assay was negative but anti-intrinsic factor antibody was detectable. The clinical constellation of hemolysis (low serum haptoglobin, high serum lactate dehydrogenase, hemoglobinuria), low reticulocyte count, and high MMA and homocysteine levels, suggest a diagnosis of PA with severe intramedullary hemolysis (ineffective erythropoiesis). The patient was prescribed subcutaneous vitamin B12 of 1000 mcg weekly for 4 weeks followed by 1000 mcg monthly thereafter. Unfortunately, on his way back home, he experienced chest pain at the airport. He returned to our emergency room and computed tomogram pulmonary angiogram showed the presence of PE. Rivaroxaban was prescribed for 3 months. The most likely cause for his PE was the transient risk attributed by the presence of homocysteinemia. His homocysteine level normalized with B12 therapy. In October 2013, CBC revealed a Hb of 14.0 g/dL, WBC of 6.8, and PLT count of 184.
Discussion Pernicious anemia is the most common cause of vitamin B12 deficiency worldwide. It is an autoimmune disorder characterized by destruction of gastric parietal cells and associated with the presence of an antiparietal cell antibody and/or anti-intrinsic factor antibody.1 The first step in diagnosis of vitamin B12 deficiency is usually measurement of serum B12 levels. However, the use of newer automated analyzers might be associated with falsely normal or even falsely increased vitamin B12 levels, especially in the presence of anti-intrinsic factor antibodies.5,6 Our patient had a normal serum B12 level; however the abnormal peripheral smear prompted us to check serum MMA and serum homocysteine levels. Elevated MMA and homocysteine levels with detectable anti-intrinsic factor antibodies confirmed the diagnosis of PA in our patient. Hyperhomocysteinemia associated with vitamin B12 deficiency has been associated with increased risk of arterial and venous thrombosis.7-9 Thrombosis in this setting usually occurs in the presence of markedly increased homocysteine levels as seen in our patient. With vitamin B12 supplementation, homocysteine levels usually normalize resulting in reduced risk for thrombosis. However, the optimal duration of anticoagulation in cases remains uncertain. In our patient, the homocysteine levels normalized after initiating vitamin B12 injections. Therefore, we decided to treat the patient for a total duration 3 months as recommended for patients with thrombosis in the presence of a transient risk factor. Our case highlights several important teaching points. First, the diagnosis of vitamin B12 deficiency can be enigmatic and physicians need to be aware of the wide range of hematological manifestations associated with vitamin B12 deficiency. Vitamin B12 deficiency can be a MDS-mimic.10 Misdiagnosing vitamin B12 deficiency as MDS could result in devastating consequences. Second, schistocytes can occasionally be seen in severe vitamin B12 deficiency. Rarely, the schistocytes can be profound enough to resemble thrombotic thrombocytopenic purpura.11,12 Third, the presence of microspherocytes and weakly positive IgG using the super-Coombs test suggests coexistent subclinical warm autoimmune hemolysis (Hb returns to normal
Dhaval R. Shah et al without the use of steroids) because autoimmune hemolytic anemias might occur in association with PA.13,14 Fourth, normal vitamin B12 levels do not rule out vitamin B12 deficiency, especially with newer assays which might be confounded by anti-intrinsic factor antibodies resulting in falsely normal or falsely increased B12 values.5,6,15 Finally, hyperhomocysteinemia associated with vitamin B12 deficiency is a risk factor for arterial and venous thrombosis.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013; 368:149-60. 2. Andrès E, Affenberger S, Zimmer J, et al. Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency. Clin Lab Haematol 2006; 28:50-6. 3. Heath C, Fliegelman L. Cytogenetic observations in vitamin B12 and folate deficiency. Blood 1966; 27:800-15. 4. Parmentier S, Meinel J, Oelschlaegel U, et al. Severe pernicious anemia with distinct cytogenetic and flow cytometric aberrations mimicking myelodysplastic syndrome. Ann Hematol 2012; 91:1979-81.
5. Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. N Engl J Med 2012; 367:385-6. 6. Yang DT, Cook RJ. Spurious elevations of vitamin B12 with pernicious anemia. N Engl J Med 2012; 366:1742-3. 7. Remacha AF, Souto JC, Piñana JL, et al. Vitamin B12 deficiency, hyperhomocysteinemia and thrombosis: a case and control study. Int J Hematol 2011; 93:458-64. 8. Remacha AF, Souto JC, Rámila E, Perea G, Sarda MP, Fontcuberta J. Enhanced risk of thrombotic disease in patients with acquired vitamin B12 and/or folate deficiency: role of hyperhomocysteinemia. Ann Hematol 2002; 81:616-21. 9. Limal N, Scheuermaier K, Tazi Z, Sene D, Piette JC, Cacoub P. Hyperhomocysteinaemia, thrombosis and pernicious anaemia. Thromb Haemost 2006; 96:233-5. 10. Steensma DP. Dysplasia has a differential diagnosis: distinguishing genuine myelodysplastic syndromes (MDS) from mimics, imitators, copycats and impostors. Curr Hematol Malig Rep 2002; 7:310-20. 11. Tadakamalla AK, Talluri SK, Besur S. Pseudo-thrombotic thrombocytopenic purpura: a rare presentation of pernicious anemia. N Am J Med Sci 2011; 3:472-4. 12. Dimond A, George JN, Hastings C. Severe vitamin B12 deficiency in a child mimicking thrombotic thrombocytopenic purpura. Pediatr Blood Cancer 2009; 52: 420-2. 13. Zafad S, Madani A, Harif M, et al. Pernicious anemia associated with autoimmune hemolytic anemia and alopecia areata. Pediatr Blood Cancer 2007; 49: 1017-8. 14. Salvidio E, Venzano C, Boccaccio P, et al. Pernicious anemia followed by autoimmune hemolytic anemia. Proc R Soc Med 1975; 68:421-2. 15. Hamilton MS, Blackmore S, Lee A. Possible cause of false normal B-12 assays. BMJ 2006; 333:654-5.
Clinical Lymphoma, Myeloma & Leukemia Month 2014
-3