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Pernicious Anemia Associated Cobalamin Deficiency and Thrombotic Microangiopathy: Case Report and Review of the Literature.

1. Introduction

Microangiopathic hemolytic anemia (MAHA) refers to any hemolytic anemia associated with fragmented red blood cells (schistocytes) and small vessel pathology. Thrombotic microangiopathy (TMA) includes heterogeneous disorders characterized by MAHA, thrombocytopenia, and organ damage due to microvascular occlusion [1].

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two types of TMAs which may be fatal without prompt recognition and treatment. Thrombotic thrombocytopenic purpura (TTP), first described in 1924 [2], is a rapidly progressive and life-threatening condition which, in the past, was characterized by a classic pentad of MAHA, thrombocytopenia, fever, renal dysfunction, and neurologic abnormalities. The incidence of TTP in the United States is on the rise and is estimated to be about 4 cases per 1000000 [3]. It can be a familial or acquired idiopathic TTP and it may be an isolated episode or a recurring event. Chronic relapsing type-TTP is most often seen in infants and children, while two-thirds of patients with idiopathic single-episode TTP are adults [4-6].

TTP results from immunoglobulin G (IgG) and autoantibodies to von Willebrand factor-cleaving protease (ADAMTS-13). ADAMTS-13 is required for degradation of the highly adhesive and reactive forms of large von Willebrand factor multimers which can be up to approximately 20000 kDa in size [7, 8]. The current standard of care in the management of acquired TTP is daily therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) replacement until the resolution of neurological symptoms (if applicable), return of platelet count greater than 150 k/uL, and LDH near normal range for 2 to 3 consecutive days [9]. TPE works by removing ADAMTS-13 antibodies and cytokines and infusing FFP containing functional ADAMTS13 [10]. Its role is unclear and some reports suggest that it may be harmful in the management of infection associated HUS which results from toxin-mediated endothelial injury [9]. On the other hand, noninfectious HUS, which results from excessive alternative complement activation, may benefit from plasma infusion or TPE, while Eculizumab is the preferred therapeutic strategy for controlling atypical HUS and limiting renal damage [11,12].

TTP and other hemolytic microangiopathies are often severe with significant morbidity and mortality rates remaining as high as 10-20% in spite of TPE [13, 14]. The hematological features of TTP, such as thrombocytopenia, hemolytic anemia, and schistocytosis, suggest a wide differential diagnosis, including, but not limited to, disseminated intravascular coagulation, HUS, and autoimmune hemolysis. The diagnosis of TTP maybe challenging since certain conditions can mimic the signs and symptoms of TTP [15].

TMA has been reported in association with pregnancy [16-19], human immunodeficiency virus (HIV) [20], malignancy and chemotherapeutic agents [21, 22], malignant hypertension [23], systemic lupus erythematosus (SLE) [24], bone marrow transplantation [25,26], and drugs [27] including antiplatelets [28,29], antimalarials [30], and immunosuppressants [31, 32].

Cobalamin (vitamin B12) deficiency induced TMA is a rare condition which closely resembles the clinical features of TTP such as thrombocytopenia, hemolytic anemia, and schistocytosis. This report presents a case of cobalamin deficiency induced TMA in a patient initially suspected of having TTP, with important implications for the work-up and treatment of patients with suspected TTP.

2. Case Description

A 43-year-old Hispanic male with no past significant medical history presented to the emergency department (ED) with syncope, progressive fatigue, decreased appetite, weight loss of 40 lbs over the past six months, and one-month history of jaundice. The patient denied any chest pain, dyspnea, fever, cough, tingling, numbness, headache, visual changes, focal weakness, abdominal pain, bleeding, leg swelling, rash, changes in urinary or bowel habits, or sick contacts or any history of anemia. Upon initial physical examination, the patient was afebrile with a blood pressure of 135/69 mmHg and tachycardia. The patient had pallor and diffuse jaundice without hepatosplenomegaly, skin rash, or palpable purpura. On neurological exam, the patient was alert and oriented to person, place, and time with normal sensation and muscle strength in all extremities. Examination of the remaining systems was unremarkable.

Initial laboratory (Table 1) investigations revealed anemia, reticulocytosis, increased mean corpuscular volume of the red blood cells, thrombocytopenia, leukopenia, and a markedly elevated lactate dehydrogenase (LDH) level. Schistocytes, anisocytes, macrocytes, microcytes, ovalocytes, helmet, and tear drop cells were present on the peripheral blood smear. Bilirubin, aspartate aminotransferase (AST), and D-dimers were elevated, while haptoglobin was decreased. Iron indices were consistent with hemolytic anemia. Renal function was preserved. Hepatitis panel was positive for hepatitis B surface antigen and core antibody, confirming a diagnosis of active hepatitis B infection. An abdominal ultrasound revealed cholelithiasis, splenomegaly, hepatic steatosis, and a nonobstructive renal calculus. The presence of hemolytic anemia, schistocytosis, thrombocytopenia, and elevated LDH in this patient were suggestive of TTP or atypical HUS, possibly related to hepatitis B.

On days 1 and 3 of admission, the patient was transfused with two and one units of packed red blood cells, respectively. On day 2, the patient was transfused with one unit of platelets. The combination of a peripheral blood smear suggestive of MAHA and thrombocytopenia serves as an acceptable indication for the initiation of TPE [9, 33] and, therefore, the patient underwent two sessions of TPE with fresh frozen plasma replacement on days 2 and 3. The platelet patterns following TPE in TTP/HUS can vary [34] and therefore alternative etiologies were dismissed until TTP could be ruled out. Steroids and antihistamines were added to the TPE regimen because the patient developed a skin reaction presumed to be secondary to the blood products.

Cobalamin deficiency was noted at admission laboratory evaluation but was not accepted as the underlying cause of patient's clinical condition. However, one dose of 1000 mcg of cyanocobalamin was administered intramuscularly on day 3. Additional TPE sessions were continued until day 5, while ADAMTS-13 report was pending. The platelet count remained in a range of 18-37 K/uL despite daily TPE. On day 6, a normal ADAMTS-13 report was reported and TTP was ruled out. Platelet count improved to 90 and 138 K/uL on days 8 and 9, respectively.

Further investigations were also positive for intrinsic factor-blocking antibodies and an elevated gastrin level consistent with a diagnosis of pernicious anemia. The patient's condition improved markedly and the patient was discharged on day 9 with outpatient follow-up for vitamin B12 supplementation.

3. Discussion

Cobalamin deficiency induced TMA poses a diagnostic hurdle for clinicians encountering patients presenting with thrombocytopenia, hemolytic anemia, and schistocytosis. Although the differential diagnosis should always seek ruling out the most life-threatening conditions first, measurement of cobalamin and methylmalonic acid level to the current diagnostic panel for the evaluation of TTP can direct physicians to proper diagnosis and management [9]. Moreover, our case report emphasizes the limited awareness among physicians regarding cobalamin deficiency induced TMA, since TPE was continued in spite of the evidence of severe cobalamin deficiency. A lack of awareness of this entity is also illustrated by the absence of a recommendation for cobalamin measurement in suspected TTP in the 2012 British Journal of Hematology Guidelines [35]. TTP carries a mortality rate of 90% without TPE [35] and a delay in the initiation of TPE serves as an independent risk factor for short-term mortality [36]. However, a mortality rate of 2.3% and a major complications rate of 24% have been attributed to TPE [37]. Our patient had evidence of active hepatitis B infection with mild liver dysfunction which complicated the diagnosis because hepatitis can be associated with thrombocytopenia and aplastic anemia [38, 39]. Moreover, TMA has been reported in association with hepatitis C related heat insoluble cryoglobulinemia [40]. Therefore, the continuation of TPE until TTP could be excluded was considered to outweigh potential risks in our patient. The exclusion of TTP in the presence of cobalamin deficiency may be further complicated by a pre-TPE low ADAMTS-13 activity level [41, 42].

Cobalamin is vital for DNA synthesis and hematopoietic cell division. Its ingestion occurs in the protein-bound state and, thus, requires release by gastric acid and pancreatic protease. Cobalamin is most efficiently absorbed in the distal ileum bound to intrinsic factor, a protein produced by the gastric parietal cells. Passive diffusion alone contributes to absorption of only 1-5% of the daily intake of cobalamin [43]. Cobalamin circulates in the plasma bound to either holotranscobalamin (6-20%) or holohaptocorrin (80%). Holotranscobalamin delivers cobalamin to all DNA-synthesizing cells and serves as the earliest marker of cobalamin deficiency [44].

Cobalamin derivatives serve as cofactors in two major cellular reactions. The generation of methionine from homocysteine requires cytoplasmic methylcobalamin and the conversion of methyl-malonyl-coenzyme A to succinyl-coenzyme A requires mitochondrial 5-deoxyadenosylcobalamin [45]. Hence, cobalamin depletion often leads to the accumulation of homocysteine and methylmalonic acid, which serve as surrogate markers of cobalamin deficiency. There is a lack of consensus regarding the gold standard assay for the determination of cobalamin levels [46]. Patients with pernicious anemia may exhibit falsely elevated serum cobalamin levels due to intrinsic factor antibody interference [47-49]. Homocysteine levels demonstrate poorer specificity than methylmalonic acid levels but increased levels of methylmalonic acid may not correlate with clinical cobalamin deficiency as was seen in a Danish study which reported a lack of significant difference in the prevalence of cobalamin deficiency related symptoms in individuals with methylmalonic acid [greater than or equal to] 0.4 [micro]mol/L versus <0.4 [micro]mol/L [50]. In renal insufficiency, a normal to high cobalamin level cannot rule out functional deficiency [51,52]. The evaluation of methylmalonic acid and holotranscobalamin levels can distinguish between functional cobalamin deficiency and cobalamin storage depletion but both of these markers may be falsely elevated in renal impairment [5355]. Therefore, the interpretation of the markers of cobalamin deficiency warrants an assessment of renal function. In addition, holotranscobalamin, methylmalonic acid, and homocysteine levels are poorer predictors of the hematological response to vitamin B12 therapy compared to a low total cobalamin level [56]. Moreover, a total cobalamin level of 156-450 pmol/L cannot rule out cobalamin deficiency [57]. The presence of megaloblastic anemia is a nonspecific and insensitive reflection of vitamin B12 status [58, 59].

Cobalamin deficiency was traditionally thought to be a disease of elderly Caucasians but is now known to be common in multiple ethnic groups and ages [60]. The causes of cobalamin deficiency include pernicious anemia, dietary deficiency associated with vegetarian and vegan diets, postsurgical malabsorption, and malabsorption secondary to gastrointestinal pathology [61]. The daily requirement of cobalamin is 6-9 micrograms. Because the body stores between 2 and 5 milligrams of cobalamin, its deficiency usually develops slowly and manifests after multiple years of inadequate dietary intake or malabsorption [62].

The prevalence of cobalamin deficiency is 3-40% depending on the definition and biochemical markers used as well as the population explored [63-66]. Pernicious anemia is a common cause of cobalamin deficiency and results from autoimmune destruction of parietal cells and intrinsic factor deficiency related cobalamin malabsorption. The development of hypochlorhydria due to the loss of parietal cells leads to an increase in gastrin levels. The prevalence of pernicious anemia is 0.1% in the general population which increases to 1.9% in patients aged older than 60 years [67, 68] and it contributes to 20-50% of cobalamin deficiency cases [69]. Both parenteral and oral doses of cyanocobalamin, hydroxocobalamin, or methylcobalamin may be used in pernicious anemia related cobalamin deficiency [70, 71], although hydroxocobalamin administration is associated with better uptake and storage compared to other forms [72]. Oral cobalamin doses of 1000 mcg per day lead to more than adequate absorption via passive diffusion to meet daily requirements in intrinsic factor deficient patients [43]. Nonetheless, parenteral cobalamin replacement is preferred in patients with cobalamin deficiency related neurological deficits. The typical vitamin B12 replacement approach usually consists of a monthly cobalamin dose of 100-1000 mcg [72].

TMA develops in about 2.5% of cobalamin deficiency cases [73, 74]. The pathogenesis of cobalamin deficiency induced TMA is poorly understood but may involve homocysteine and/or its derivatives initiating endothelial injury and dysfunction [75]. Mild-to-moderate hyperhomocysteinemia has been shown to trigger the activation of coagulation cascade, alter endothelial adhesive properties, and impair the vascular response to L-arginine [76]. The activation of the coagulation pathway may increase D-dimer levels as was seen in our patient as well as in another case report in which D-dimer levels correlated with the degree of schistocytosis [77]. In addition, macrocytic erythrocytes resulting from cobalamin deficiency have reduced deformability which predisposes to entrapment in the microcirculation [78]. Furthermore, ineffective erythropoiesis secondary to cobalamin deficiency leads to intramedullary hemolysis, indirect hyperbilirubinemia, elevated LDH, low haptoglobin, and microangiopathic features on peripheral blood smear. Taken together, these events consequently result in fragmentation of erythrocytes and manifest as TMA. Immune dysfunction is suspected to be involved in the development of TMA, since the majority of cobalamin deficiency induced TMA cases have been reported in patients with pernicious anemia [74,77,79-88]. However, a key role of immune dysfunction in cobalamin deficiency induced TMA seems less likely because patients with autosomal recessive disorders of cobalamin activation [89, 90] and food-cobalamin malabsorption have also presented with TMA [41, 88].

Noel et al. compared clinical and biochemical parameters in seven patients with cobalamin deficiency induced TMA and seven patients with TTP [88]. First, none of the seven patients with cobalamin deficiency induced TMA exhibited acute renal failure, while all of the patients with TTP did. Second, none of the seven patients with cobalamin deficiency induced TMA presented with severe neurological symptoms, such as drowsiness or coma, as is common in TTP. Third, LDH levels were much higher and bilirubin levels were much lower than expected in the cobalamin deficiency induced TMA group compared to the TTP group. Fourth, the TTP group exhibited an elevated reticulocyte count, which was absent in the cobalamin deficiency induced TMA group.

TTP is associated with significant mortality and demands early diagnosis and prompt initiation of TPE. The diagnosis of TTP can be supported by a deficient ADAMTS-13 activity level but the long turnaround times of ADAMTS-13 testing limit its utility and TTP largely remains a clinical diagnosis. Although fluorescence resonance energy transfer (FRETS) method for determining ADAMTS-13 activity is a rapid technique, it is not widely available. Alternative underlying causes, especially cobalamin deficiency, should be explored at presentation in all cases of suspected TTP. The 2012 British Journal of Hematology Guidelines recommends that serological testing for HIV, hepatitis B and hepatitis C, autoantibody screen, and pregnancy test, when appropriate, be performed at presentation for patients with suspected TTP, given the reported correlation between HIV infection, viral hepatitis, and thrombocytopenia [35]. Given the emergence of multiple case reports of cobalamin deficiency induced TMA, we strongly recommend the addition of cobalamin and methylmalonic acid testing to the diagnostic panel. Aggressive interventions [86,91] such as TPE, Rituximab, and steroids may be avoided by increasing physician awareness regarding cobalamin deficiency induced TMA and routine screening for cobalamin deficiency. Furthermore, empirical oral cobalamin supplementation in TTP suspected cases may be considered in light of the limited specificity of screening for cobalamin deficiency and the lack of evidence of cobalamin toxicity.

4. Conclusion

Cobalamin deficiency induced TMA is a rare condition but should be considered in all patients presenting with clinical and laboratory features of TTP. The presence of leukopenia, macrocytes, and a slightly elevated reticulocyte count are initial clues that raise suspicion for cobalamin deficiency induced TMA. The emergence of multiple case reports of cobalamin deficiency induced TMA warrants the addition of cobalamin and methylmalonic acid testing in all cases of suspected TTP. By adding cobalamin and methylmalonic acid testing to all TMA screens, the diagnostic delays in detecting and treating cobalamin deficiency as well as the potential TPE related iatrogenic harm may be prevented.

http://dx.doi.org/10.1155/2017/9410727

Competing Interests

The authors declare that they have no competing interests and that the results presented have not been published previously in whole or part, except in abstract format.

Authors' Contributions

Farhanah Yousaf collected data, analyzed and interpreted data, and prepared the manuscript; Bruce Spinowitz analyzed and interpreted data and edited the manuscript draft; Chaim Charytan analyzed and interpreted data and edited the manuscript draft; Marilyn Galler analyzed and interpreted data and finalized the manuscript.

References

[1] J. N. George and C. M. Nester, "Syndromes of thrombotic microangiopathy," New England Journal of Medicine, vol. 371, no. 7, pp. 654-666, 2014.

[2] E. Moschcowitz, "An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries. An undescribed disease," The American Journal of Medicine, vol. 13, no. 5, pp. 567-569,1952.

[3] T. J. Torok, R. C. Holman, and T. L. Chorba, "Increasing mortality from thrombotic thrombocytopenic purpura in the United States--analysis of national mortality data, 1968-1991," American Journal of Hematology, vol. 50, no. 2, pp. 84-90,1995.

[4] J. L. Moake, C. K. Rudy, J. H. Troll et al., "Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura," New England Journal of Medicine, vol. 307, no. 23, pp. 1432-1435,1982.

[5] J. Moake, M. Chintagumpala, N. Turner et al., "Solvent/detergent-treated plasma suppresses shear-induced platelet aggregation and prevents episodes of thrombotic thrombocytopenic purpura," Blood, vol. 84, no. 2, pp. 490-497,1994.

[6] M. Furlan, R. Robles, M. Solenthaler, M. Wassmer, P. Sandoz, and B. Lammle, "Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura," Blood, vol. 89, no. 9, pp. 3097-3103,1997.

[7] H.-M. Tsai, R. L. Nagel, V. B. Hatcher, and I. I. Sussman, "Endothelial cell-derived high molecular weight von Willebrand factor is converted into the plasma multimer pattern by granulocyte proteases," Biochemical and Biophysical Research Communications, vol. 158, no. 3, pp. 980-985,1989.

[8] Z. M. Ruggeri and T. S. Zimmerman, "The complex multimeric composition of factor VIII/von Willebrand factor," Blood, vol. 57, no. 6, pp. 1140-1143,1981.

[9] J. Schwartz, J. L. Winters, A. Padmanabhan et al., "Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the writing committee of the american society for apheresis: the sixth special issue," Journal of Clinical Apheresis, vol. 28, no. 3, pp. 145-284, 2013.

[10] H. M. Reeves and J. L. Winters, "The mechanisms of action of plasma exchange," British Journal of Haematology, vol. 164, no. 3, pp. 342-351, 2014.

[11] J.-C. Davin and N. C. van de Kar, "Advances and challenges in the management of complement-mediated thrombotic microangiopathies," Therapeutic Advances in Hematology, vol. 6, no. 4, pp. 171-185, 2015.

[12] S. R. Cataland and H. M. Wu, "How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome," Blood, vol. 123, no. 16, pp. 2478-2484, 2014.

[13] Y. Benhamou, C. Assie, P.-Y. Boelle et al., "Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience," Haematologica, vol. 97, no. 8, pp. 1181-1186, 2012.

[14] G. A. Rock, K. H. Shumak, N. A. Buskard et al., "Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura," New England Journal of Medicine, vol. 325, no. 6, pp. 393-397,1991.

[15] J. L. Moake, "Journey in reverse: TTP from bedside to blood bank to bench," Journal of Clinical Apheresis, vol. 22, no. 1, pp. 37-49, 2007.

[16] W. E. Fuchs, J. N. George, L. N. Dotin, and D. A. Sears, "Thrombotic thrombocytopenic purpura: occurrence two years apart during late pregnancy in two sisters," The Journal of the American Medical Association, vol. 235, no. 19, pp. 2126-2127, 1976.

[17] F. Fakhouri, "Pregnancy-related thrombotic microangiopathies: clues from complement biology," Transfusion and Apheresis Science, vol. 54, no. 2, pp. 199-202, 2016.

[18] J. N. George, C. M. Nester, and J. J. Mcintosh, "Syndromes of thrombotic microangiopathy associated with pregnancy," Hematology, vol. 2015, no. 1, pp. 644-648, 2015.

[19] M. Yan, A. K. Malinowski, and N. Shehata, "Thrombocytopenic syndromes in pregnancy," Obstetric Medicine, vol. 9, no. 1, pp. 15-20, 2016.

[20] M. U. Rarick, B. Espina, R. Mocharnuk, Y. Trilling, and A. M. Levine, "Thrombotic thrombocytopenic purpura in patients with human immunodeficiency virus infection: a report of three cases and review of the literature," American Journal of Hematology, vol. 40, no. 2, pp. 103-109,1992.

[21] M. A. Elliott, L. Letendre, D. A. Gastineau, J. L. Winters, R. K. Pruthi, and J. A. Heit, "Cancer-associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration," European Journal of Haematology, vol. 85, no. 1, pp. 43-50, 2010.

[22] G. Garcia and J. P. Atallah, "Antineoplastic agents and thrombotic microangiopathy," Journal of Oncology Pharmacy Practice, 2016.

[23] N. Khanal, S. Dahal, S. Upadhyay, V. R. Bhatt, and P. J. Bierman, "Differentiating malignant hypertension-induced thrombotic microangiopathy from thrombotic thrombocytopenic purpura," Therapeutic Advances in Hematology, vol. 6, no. 3, pp. 97-102, 2015.

[24] P. Caramaschi, M. M. Riccetti, A. F. Pasini, T. Savarin, D. Biasi, and G. Todeschini, "Systemic lupus erythematosus and thrombotic thrombocytopenic purpura. Report of three cases and review of the literature," Lupus, vol. 7, no. 1, pp. 37-41,1998.

[25] V. Roy, M. A. Rizvi, S. K. Vesely, and J. N. George, "Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes," Bone Marrow Transplantation, vol. 27, no. 6, pp. 641-646, 2001.

[26] J. L. Moake and J. J. Byrnes, "Thrombotic microangiopathies associated with drugs and bone marrow transplantation," Hematology/Oncology Clinics of North America, vol. 10, no. 2, pp. 485-497, 1996.

[27] Z. L. Al-Nouri, J. A. Reese, D. R. Terrell, S. K. Vesely, and J. N. George, "Drug-induced thrombotic microangiopathy: a systematic review of published reports," Blood, vol. 125, no. 4, pp. 616-618, 2015.

[28] H.-M. Tsai, L. Rice, R. Sarode, T. W. Chow, and J. L. Moake, "Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura," Annals of Internal Medicine, vol. 132, no. 10, pp. 794-799, 2000.

[29] C. L. Bennett, J. M. Connors, J. M. Carwile et al., "Thrombotic thrombocytopenic purpura associated with clopidogrel," New England Journal of Medicine, vol. 342, no. 24, pp. 1773-1777, 2000.

[30] Y. A. Park, S. N. Hay, K. E. King et al., "Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy," Journal of Clinical Apheresis, vol. 24, no. 3, pp. 115-119, 2009.

[31] N. L. Boyer, A. Niven, and J. Edelman, "Tacrolimus-associated thrombotic microangiopathy in a lung transplant recipient," BMJ Case Reports, vol. 2013, article 8, 2013.

[32] C. Odek, T. Kendirli, A. Yaman, T. Ileri, Z. Kuloglu, and E. Ince, "Cyclosporine-associated thrombotic microangiopathy and thrombocytopenia- associated multiple organ failure: a case successfully treated with therapeutic plasma exchange," Journal of Pediatric Hematology/Oncology, vol. 36, no. 2, pp. e88-e90, 2014.

[33] R. Sarode, N. Bandarenko, M. E. Brecher et al., "Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research," Journal of Clinical Apheresis, vol. 29, no. 3, pp. 148-167, 2014.

[34] S. N. Hay, J. A. Egan, P. A. Miilward, N. Bandarenko, and M. E. Brecher, "Patterns of platelet response in idiopathic TTP/HUS: frequency of declining platelet counts with plasma exchange and the recognition and significance of a pseudo refractory state," Therapeutic Apheresis and Dialysis, vol. 10, no. 3, pp. 237-241, 2006.

[35] M. Scully, B. J. Hunt, S. Benjamin et al., "Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies," British Journal of Haematology, vol. 158, no. 3, pp. 323-335, 2012.

[36] V. Peigne, P. Perez, M. Resche Rigon et al., "Causes and risk factors of death in patients with thrombotic microangiopathies," Intensive Care Medicine, vol. 38, no. 11, pp. 1810-1817, 2012.

[37] S. Som, C. C. Deford, M. L. Kaiser et al., "Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011 (CME)," Transfusion, vol. 52, no. 12, pp. 2525-2532, 2012.

[38] X. Wang, W. Jiang, F. Li et al., "Abnormal platelet kinetics are detected before the occurrence of thrombocytopaenia in HBV-related liver disease," Liver International, vol. 34, no. 4, pp. 535-543, 2014.

[39] B. Rauff, M. Idrees, S. A. R. Shah et al., "Hepatitis associated aplastic anemia: a review," Virology Journal, vol. 8, article 87, 2011.

[40] H. Wu, H.-B. Zou, Y. Xu et al., "Hepatitis C virus-related heatinsoluble cryoglobulinemia and thrombotic microangiopathy," TheAmerican Journal of the Medical Sciences, vol. 346, no. 4, pp. 345-348, 2013.

[41] T. Asano, H. Narazaki, K. Kaizu et al., "Neglect-induced pseudothrombotic thrombocytopenic purpura due to vitamin B12 deficiency," Pediatrics International, vol. 57, no. 5, pp. 988-990, 2015.

[42] A. Dimond, J. N. George, and C. Hastings, "Severe vitamin B-12 deficiency in a child mimicking thrombotic thrombocytopenic purpura," Pediatric Blood and Cancer, vol. 52, no. 3, pp. 420-422, 2009.

[43] H. Berlin, R. Berlin, and G. Brante, "Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor," Acta Medica Scandinavica, vol. 184, no. 1-6, pp. 247-258, 1968.

[44] E. Nexo and E. Hoffmann-Lucke, "Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility," American Journal of Clinical Nutrition, vol. 94, no. 1, pp. 359S-365S, 2011.

[45] I. Mellman, H. F. Willard, and L. E. Rosenberg, "Cobalamin binding and cobalamin-dependent enzyme activity in normal and mutant human fibroblasts," The Journal of Clinical Investigation, vol. 62, no. 5, pp. 952-960,1978.

[46] R. Carmel, "Diagnosis and management of clinical and subclinical cobalamin deficiencies: why controversies persist in the age of sensitive metabolic testing," Biochimie, vol. 95, no. 5, pp. 1047-1055, 2013.

[47] M. S. Hamilton, S. Blackmore, and A. Lee, "Possible cause of false normal B-12 assays," British Medical Journal, vol. 333, no. 7569, pp. 654-656, 2006.

[48] L. T. Vlasveld, J. W. van't Wout, P. Meeuwissen, and A. Castel, "High measured cobalamin (vitamin B12) concentration attributable to an analytical problem in testing serum from a patient with pernicious anemia," Clinical Chemistry, vol. 52, no. 1, pp. 157-159, 2006, Erratum in: Clinical Chemistry, vol. 52, no. 2, no. 342, 2006.

[49] A. P. Van Rossum, L. T. Vlasveld, and A. Castel, "Falsely elevated cobalamin concentration in multiple assays in a patient with pernicious anemia: a case study," Clinical Chemistry and Laboratory Medicine, vol. 51, no. 9, pp. e217-e219, 2013.

[50] A.-M. Hvas, J. Ellegaard, and E. Nexo, "Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency," Archives of Internal Medicine, vol. 161, no. 12, pp. 1534-1541, 2001.

[51] W. Herrmann, R. Obeid, H. Schorr, and J. Geisel, "Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk," Clinical Chemistry and Laboratory Medicine, vol. 41, no. 11, pp. 1478-1488, 2003.

[52] W. Herrmann, H. Schorr, R. Obeid, and J. Geisel, "Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians," The American Journal of Clinical Nutrition, vol. 78, no. 1, pp. 131-136, 2003.

[53] W. Herrmann, H. Schorr, R. Obeid, J. Makowski, B. Fowler, and M. K. Kuhlmann, "Disturbed homocysteine and methionine cycle intermediates S-adenosylhomocysteine and Sadenosylmethionine are related to degree of renal insufficiency in type 2 diabetes," Clinical Chemistry, vol. 51, no. 5, pp. 891-897, 2005.

[54] R. Obeid, M. Kuhlmann, C.-M. Kirsch, and W. Herrmann, "Cellular uptake of vitamin B12 in patients with chronic renal failure," Nephron Clinical Practice, vol. 99, no. 2, pp. c42-c48, 2005.

[55] R. Obeid, H. Schorr, R. Eckert, and W. Herrmann, "Vitamin B12 status in the elderly as judged by available biochemical markers," Clinical Chemistry, vol. 50, no. 1, pp. 238-241, 2004.

[56] A. Goringe, R. Ellis, I. McDowell et al., "The limited value of methylmalonic acid, homocysteine and holotranscobalamin in the diagnosis of early B12 deficiency," Haematologica, vol. 91, no. 2, pp. 231-234, 2006.

[57] R. Obeid and W. Herrmann, "Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid," Clinical Chemistry and Laboratory Medicine, vol. 45, no. 12, pp. 1746-1750, 2007.

[58] W. P. Oosterhuis, R. W. L. M. Niessen, P. M. M. Bossuyt, G. T. B. Sanders, and A. Sturk, "Diagnostic value of the mean corpuscular volume in the detection of vitamin B12 deficiency," Scandinavian Journal of Clinical and Laboratory Investigation, vol. 60, no. 1, pp. 9-18, 2000.

[59] J. Lindenbaum, E. B. Healton, D. G. Savage et al., "Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis," New England Journal of Medicine, vol. 318, no. 26, pp. 1720-1728, 1988.

[60] K. Willoughby, C. Greenberg, and B. Keith, "Masked pernicious anemia: a literature review and case presentation," Journal of the South Carolina Medical Association, vol. 109, no. 1, pp. 12-15, 2013.

[61] S. P. Stabler, "Vitamin B12 deficiency," New England Journal of Medicine, vol. 368, no. 2, pp. 149-160, 2013.

[62] R. Carmel, "Current concepts in cobalamin deficiency," Annual Review of Medicine, vol. 51, pp. 357-375, 2000.

[63] P. Sipponen, F. Laxen, K. Huotari, and M. Harkonen, "Prevalence of low vitamin B12 and high homocysteine in serum in an elderly male population: association with atrophic gastritis and helicobacter pylori infection," Scandinavian Journal of Gastroenterology, vol. 38, no. 12, pp. 1209-1216, 2003.

[64] E. Andres, N. H. Loukili, E. Noel et al., "Vitamin B12 (cobalamin) deficiency in elderly patients," CMAJ, vol. 171, no. 3, pp. 251-259, 2004.

[65] J. Lindenbaum, I. H. Rosenberg, P. W. F. Wilson, S. P. Stabler, and R. H. Allen, "Prevalence of cobalamin deficiency in the Framingham elderly population," The American Journal of Clinical Nutrition, vol. 60, no. 1, pp. 2-11,1994.

[66] M. S. Morris, P. F. Jacques, I. H. Rosenberg, and J. Selhub, "Elevated serum methylmalonic acid concentrations are common among elderly Americans," Journal of Nutrition, vol. 132, no. 9, pp. 2799-2803, 2002.

[67] B.-H. Toh, I. R. Van Driel, and P. A. Gleeson, "Pernicious anemia," New England Journal of Medicine, vol. 337, no. 20, pp. 1441-1448,1997.

[68] R. Carmel, "Pernicious anemia," in Encyclopedia of Gastroenterology, L. R. Johnson, Ed., pp. 170-171, Academic Press, Waltham, Mass, USA, 2004.

[69] N. H. Loukili, E. Noel, G. Blaison et al., "Update of pernicious anemia. A retrospective study of 49 cases," La Revue de Medecine Interne, vol. 25, no. 8, pp. 556-561, 2004.

[70] E. Andres, N. H. Loukili, E. Noel et al., "Effects of oral crystalline cyanocobalamin 1000 [micro]g/d in the treatment of pernicious anemia: an open-label, prospective study in ten patients," Current Therapeutic Research--Clinical and Experimental, vol. 66, no. 1, pp. 13-22, 2005.

[71] A. M. Kuzminski, E. J. Del Giacco, R. H. Allen, S. P. Stabler, and J. Lindenbaum, "Effective treatment of cobalamin deficiency with oral cobalamin," Blood, vol. 92, no. 4, pp. 1191-1198,1998.

[72] E. Andres, H. Fothergill, and M. Mecili, "Efficacy of oral cobalamin (vitamin B12) therapy," Expert Opinion on Pharmacotherapy, vol. 11, no. 2, pp. 249-256, 2010.

[73] E. Andres, S. Affenberger, J. Zimmer et al., "Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency," Clinical and Laboratory Haematology, vol. 28, no. 1, pp. 50-56, 2006.

[74] E. Andres, S. Affenberger, L. Federici, and A. S. Korganow, "Pseudo-thrombotic microangiopathy related to cobalamin deficiency," The American Journal of Medicine, vol. 119, no. 12, article e3, 2006.

[75] K. S. McCully, "Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis," American Journal of Pathology, vol. 56, no. 1, pp. 111-128,1969.

[76] F. Nappo, N. De Rosa, R. Marfella et al., "Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins," The Journal of the American Medical Association, vol. 281, no. 22, pp. 2113-2118,1999.

[77] A. Malek and R. Nasnas, "An unusual presentation of pseudothrombotic microangiopathy in a patient with autoimmune atrophic gastritis," Case Reports in Hematology, vol. 2016, Article ID 1087831, 4 pages, 2016.

[78] S. K. Ballas, P. Saidi, and M. Constantino, "Reduced erythrocytic deformability in megaloblastic anemia," American Journal of Clinical Pathology, vol. 66, no. 6, pp. 953-957,1976.

[79] L. Garderet, E. Maury, M. Lagrange, A. Najman, G. Offenstadt, and B. Guidet, "Schizocytosis in pernicious anemia mimicking thrombotic thrombocytopenic purpura," The American Journal of Medicine, vol. 114, no. 5, pp. 423-425, 2003.

[80] J. K. Routh and S. C. Koenig, "Severe vitamin B12 deficiency mimicking thrombotic thrombocytopenic purpura," Blood, vol. 124, no. 11, p. 1844, 2014.

[81] S. Podder, J. Cervates, and B. R. Dey, "Association of acquired thrombotic thrombocytopaenic purpura in a patient with pernicious anaemia," BMJ Case Reports, 2015.

[82] A. K. Tadakamalla, S. K. Talluri, and S. Besur, "Pseudo-thrombotic thrombocytopenic purpura: a rare presentation of pernicious anemia," North American Journal of Medical Sciences, vol. 3, no. 10, pp. 472-474, 2011.

[83] T. M. Chapuis, B. Favrat, and P. Bodenmann, "Cobalamin deficiency resulting in a rare haematological disorder: a case report," Journal of Medical Case Reports, vol. 3, article 80, 2009.

[84] C. J. Dalsania, V. Khemka, M. Shum, L. Devereux, and N. A. Lachant, "A sheep in wolf's clothing," The American Journal of Medicine, vol. 121, no. 2, pp. 107-109,2008.

[85] D. Zamir, I. Polychuck, T. Reitblat, I. Leibovitz, and G. Lugassy, "An unusual coincidence of thrombotic thrombocytopenic purpura and pernicious anemia," Harefuah, vol. 141, no. 8, article 762, pp. 692-694, 2002.

[86] P. L. Blanc, E. Legrand, and J. M. Marc, "False Moskowitz disease, true Biermer disease," La Revue de Medecine Interne, vol. 20, no. 11, pp. 1046-1047, 1999.

[87] M. Malla and M. Seetharam, "To treat or not to treat: a rare case of pseudo-thrombotic thrombocytopenic purpura in a Jehovah's Witness," Transfusion, vol. 56, no. 1, pp. 160-163,2016.

[88] N. Noel, G. Maigne, G. Tertian et al., "Hemolysis and schistocytosis in the emergency department: consider pseudothrombotic microangiopathy related to vitamin B12 deficiency," Quarterly Journal of Medicine, vol. 106, no. 11, pp. 1017-1022, 2013.

[89] M. T. Geraghty, E. J. Perlman, L. S. Martin et al., "Cobalamin C defect associated with hemolytic-uremic syndrome," The Journal of Pediatrics, vol. 120, no. 6, pp. 934-937,1992.

[90] P. Russo, J. Doyon, E. Sonsino, H. Ogier, and J.-M. Saudubray, "A congenital anomaly of vitamin B12 metabolism: a study of three cases," Human Pathology, vol. 23, no. 5, pp. 504-512,1992.

[91] V. Jubault, I. De Lacroix-Szmania, J. Zittoun et al., "Hemolysis and schizocytosis, malabsorption and the 'folate trap': unusual semiological peculiarities associated with vitamin B12 deficiency," La Revue de Medecine Interne, vol. 19, no. 12, pp. 921923, 1998.

Farhanah Yousaf, Bruce Spinowitz, Chaim Charytan, and Marilyn Galler

New York-Presbyterian/Queens, Flushing, NY, USA

Correspondence should be addressed to Farhanah Yousaf; fay9005@nyp.org

Received 24 October 2016; Revised 22 December 2016; Accepted 26 December 2016; Published 6 February 2017

Academic Editor: Rolando Cimaz
TABLE 1: Laboratory investigations.

Investigation                          At admission        During
                                                      hospitalization

                                              Hematology studies
Hemoglobin (g/dL)                          5.0
Reticulocyte count (%)                     2.6
Mean corpuscular volume (fL)               111
Platelets (K/uL)                            24
White cell count (K/uL)                    2.77
vWF protease activity/ADAMTS-13 (%)         88
BUN (mg/dL)                                 21
Creatinine (mg/dL)                         0.69
BUN/creatinine ratio                        30
GFR                                        125
                                            Coagulation studies
Prothrombin time                           12.4
APTT                                       24.2
D-Dimer (ng/mL)                            668
                                               Chemistry studies
LDH (U/L)                                  3906
Bilirubin [indirect] (mg/dL)               4.1
AST (U/L)                                   69
ALT (U/L)                                   40
Alkaline phosphatase (U/L)                  65
Cyanocobalamin (pg/mL)                      38
Folate (ng/mL)                              14
Gastrin (pg/mL)
Methylmalonic acid (nmol/L)
Haptoglobin (mg/dL)                        <10
                                              Flow cytometry
PNH w/FLAER                                               Negative
                                             Serology studies
Intrinsic factor blocking Ab                              Positive
Hepatitis B surface antigen              Positive
HBV core Ab                              Reactive
HIV                                    Nonreactive
Parvovirus B19 (IgG/IgM)                 Negative
EBV
CMV
Tissue transglutaminase Ab (IgA/IgG)
                                               Urine studies
Urinalysis                                              Unremarkable
Urine culture
                                              Other
Stool guaiac
Peripheral blood smear *                    Schistocytes, anisocytes,
                                            macrocytes, microcytes,
                                         ovalocytes, helmet, and tear
                                                   drop cells
Abdominal ultrasound *                  Cholelithiasis, splenomegaly,
                                           hepatic steatosis, and
                                          nonobstructive renal calculus

Investigation                          At discharge    Reference
                                                         range

                                              Hematology studies
Hemoglobin (g/dL)                          9.3         13.5-17.5
Reticulocyte count (%)                                  0.2-2.0
Mean corpuscular volume (fL)               107          80-100
Platelets (K/uL)                           138          150-400
White cell count (K/uL)                    7.96        4.8-10.8
vWF protease activity/ADAMTS-13 (%)                     68-163
BUN (mg/dL)                                              6-20
Creatinine (mg/dL)                                      0.7-1.2
BUN/creatinine ratio                                     10-20
GFR
                                            Coagulation studies
Prothrombin time
APTT
D-Dimer (ng/mL)                                          <209
                                               Chemistry studies
LDH (U/L)                                               135-225
Bilirubin [indirect] (mg/dL)                             0-0.9
AST (U/L)                                                5-40
ALT (U/L)                                                5-41
Alkaline phosphatase (U/L)                              40-130
Cyanocobalamin (pg/mL)                                  211-946
Folate (ng/mL)                                          7.3-20
Gastrin (pg/mL)                            1077          <100
Methylmalonic acid (nmol/L)                1491         87-318
Haptoglobin (mg/dL)                                     30-200
                                              Flow cytometry
PNH w/FLAER
                                             Serology studies
Intrinsic factor blocking Ab                           Negative
Hepatitis B surface antigen                            Negative
HBV core Ab                                           Nonreactive
HIV                                                   Nonreactive
Parvovirus B19 (IgG/IgM)                               Negative
EBV                                      Negative
CMV                                      Negative
Tissue transglutaminase Ab (IgA/IgG)     Negative
                                               Urine studies
Urinalysis                             Unremarkable
Urine culture                           No growth
                                              Other
Stool guaiac                             Negative
Peripheral blood smear *                    Schistocytes, anisocytes,
                                            macrocytes, microcytes,
                                         ovalocytes, helmet, and tear
                                                   drop cells
Abdominal ultrasound *                  Cholelithiasis, splenomegaly,
                                           hepatic steatosis, and
                                          nonobstructive renal calculus

* Peripheral blood smear and abdominal ultrasound findings at
admission; LDH: lactate dehydrogenase; EBV: Epstein-Barr virus;
CMV: cytomegalovirus; HIV: human immunodeficiency virus; HBV:
hepatitis B virus; PNH: paroxysmal nocturnal hemoglobinuria
[antibodies were directed against CD33, CD45, and glycophorin A
(for gating) and CD14, CD16, CD24, CD55, and CD59 as well as FLAER
for flow cytometric assessment of glycophosphatidylinositol- (GPI-)
linked molecules].
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Title Annotation:Case Report
Author:Yousaf, Farhanah; Spinowitz, Bruce; Charytan, Chaim; Galler, Marilyn
Publication:Case Reports in Medicine
Article Type:Case study
Date:Jan 1, 2017
Words:6158
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