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Pseudo-thrombotic thrombocytopenic purpura due to severe vitamin [B.sub.12] deficiency.

INTRODUCTION

Microangiopathic hemolytic anemia denotes an anemia due to fragmentation of erythrocytes in the setting of their traversing partial vascular occlusion or abnormal vascular surfaces under increased shear stress within small vessels. (1) Examples of syndromes and clinical presentations in which microangiopathic hemolytic anemia is known to occur include the relatively common disseminated intravascular coagulation and associated malignancies, vasculitis as in systemic lupus erythematosus, other autoimmune conditions including systemic sclerosis and antiphospholipid syndrome, hematopoietic stem-cell or organ transplantation, severe preeclampsia, eclampsia and hemolysis, elevated liver-enzyme levels, and low platelet (HELLP) syndrome, and malignant hypertension. Moreover, a more recent grouping of disorders encompassing microangiopathic hemolytic anemia has been proposed known as the primary thrombotic microangiopathy syndromes. These are a diverse set of disorders with the following unifying features: microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction; the thrombotic microangiopathies are defined by evidence supporting a defined cause. (2) The primary thrombotic microangiopathy syndromes include nine subcategories and both hereditary and acquired etiologies. These syndromes comprise entities such as thrombotic thrombocytopenic purpura (in hereditary and acquired forms), hemolytic uremic syndrome, and complement-mediated, metabolismmediated, coagulation-mediated, drug-mediated (as both immune phenomenon and toxic dose-related reaction), and complement-mediated thrombotic microangiopathies.

Within the category of metabolism-related primary thrombotic microangiopathy, abnormal [B.sub.12] metabolism has been suggested as an underlying etiology. Furthermore, reports of [B.sub.12] deficiency through a variety of mechanisms have surfaced in the setting of clinical syndromes of microangiopathic hemolytic anemia and thrombotic microangiopathy. Overall, however, there have been relatively few case reports and series in the medical literature concerning the development of microangiopathic hemolytic anemia or thrombotic microangiopathy attributable to abnormal [B.sub.12] metabolism (3,5) or [B.sub.12] deficiency. (2,6,8) In addition, there are fewer reports highlighting the use of cobalamin rather than plasmapheresis for presumptive microangiopathic anemia related to [B.sub.12] deficiency. (7,9) Presented herein is a case of [B.sub.12] deficiency due to pernicious anemia leading to microangiopathic hemolytic anemia

and concurrent thrombosis accompanied by a brief review of the pertinent literature.

CASE REPORT

A 41-year-old African American woman with hypothyroidism presented reporting two months of fatigue and left lower leg pain. Her pain had worsened in intensity, and she reported associated episodes of calf tenderness and swelling exacerbated upon exertion were reported. She denied recent trauma, immobilization, or travel. The patient also denied confusion, dizziness, or fever, but did endorse shortness of breath upon exertion and recent heavy menstrual periods.

Vital signs were within normal limits. Mild edema, calf tenderness and ecchymosis of the left lower leg and pale conjunctiva were noted. Laboratory analysis revealed hemoglobin 5.6 g/dL, hematocrit 16.9%, platelet count 92 x 109/L, white blood cell count 6.4 x 109/L, reticulocyte count 3.3%, mean corpuscular volume 113.2 fL, lactate dehydrogenase 3137 IU/L, homocysteine 69.5 [micro]mol/L, and normal creatinine. Marked schistocytosis (2+) was revealed upon peripheral blood smear. Non-occlusive thrombus in the left popliteal vein was discovered on lower extremity ultrasound. A diagnosis of presumed pernicious anemia was made. The patient was transfused two units of packed red blood cells and responded appropriately. Further laboratory investigation revealed a vitamin [B.sub.12] level <50 pg/mL with unremarkable iron studies. ADAMTS13 activity was measured at 67%, excluding the diagnosis of thrombotic thrombocytopenic purpura. Treatment with intramuscular vitamin [B.sub.12] over 10 days resulted in significant improvement of anemia and thrombocytopenia (Table 1). Additional workup was positive for anti-parietal cell and anti-intrinsic factor antibodies, confirming the diagnosis of pernicious anemia.

DISCUSSION

Although the clinical presentation and thrombocytopenia in the case described may be concerning upon initial consideration for thrombotic thrombocytopenic purpura, further inspection of peripheral blood and other laboratory values can disclose alternative diagnoses and etiologies for microangiopathic hemolytic anemia and thrombocytopenia. While the pentad traditionally associated with TTP includes microangiopathic hemolytic anemia, thrombocytopenia, neurological symptoms, fever, and renal dysfunction, it is often not present in its entirety as patients present to medical attention. Patients presenting to the emergency department with the triad of hemolytic anemia, schistocytosis, and thrombocytopenia certainly merit screening for TTP, as this can be a lethal disease. Some estimates of overall mortality in the absence of proper treatment have been placed as high as 90%. Treatment with plasma infusion affords repletion of ADAMTS13 in deficient individuals in the case of hereditary TTP. (10) In the setting of acquired TTP, a controlled trial has suggested a 78% survival rate when plasma exchange is utilized. (11) Another mainstay of therapy of TTP--whether hereditary or acquired--is the administration of glucocorticoids, while immunomodulatory molecules such as rituximab may be indicated in refractory cases. Rarely is the use of dialysis necessary. Given the high mortality in the absence of treatment, even patients without true TTP are often treated with these therapies. (12)

There exists an impressive diversity of syndromes, both acquired and hereditary, that may account for such a clinical picture of microangiopathy and thrombocytopenia. Not only have genetic or acquired derangements in ADAMTS13-mediated cleavage of von Willebrand Factor been described as the underpinnings of thrombotic microangiopathy (as in TTP), but also complement-, toxic-, drug-, coagulation-, and metabolicmediated pathophysiologies. (2) Metabolic causes for thrombotic microangiopathy identified thus far appear to involve specifically vitamin [B.sub.12] metabolism. (2) In children, for example, mutations in the gene encoding the methylmalonic aciduria and homocystinuria type C (MMACHC) have been identified that result in abnormal cobalamin C metabolism, termed cobalamin C disease, which in turn has been associated with endothelial dysfunction, platelet activation, coagulation cascade activation, and increased expression of tissue factor. (13) This disorder is treated with infusion of hydroxycobalamin.

More recently, there have been rare reports of [B.sub.12] deficiency causing a thrombotic microangiopathy with thrombocytopenia and a "pseudo-TTP" syndrome. A review from 2015, compared the 13 published cases of such pseudo-TTP that presented with extreme hematologic abnormalities resulting from deficiency of vitamin [B.sub.12,] while also presenting a fourteenth recorded case of this rare syndrome. (8) It has previously been reported that elevated lactate dehydrogenase levels, high mean corpuscular volume, and low reticulocyte counts together suggest a thrombotic microangiopathy related to [B.sub.12] deficiency and should prompt further investigation. (6) A similar conclusion was found in reviewing cases of pseudo-TTP and TTP, which noted that the most helpful parameter in differentiating pseudo-TTP from TTP is the absolute reticulocyte count, as patients with pseudo-TTP attributable to [B.sub.12] deficiency tend to remain reticulocytopenic. (8) Interestingly, our patient exhibited similar reticulocytopenia when compared to patients with TTP (Table 2). LDH levels may also be useful in differentiating these clinical entities, as the majority of patients with true TTP exhibit LDH levels < 2500 IU/L, while levels exceeding 2500 IU/L may alert the provider to the possibility of pseudo-TTP with [B.sub.12] deficiency. (8) In a small retrospective study comparing 7 patients with pseudo-thrombotic microangiopathy (pseudo-TMA) due to [B.sub.12] deficiency with 6 patients with true TTP, pseudo- TMA patients demonstrated higher mean levels of lactate dehydrogenase, higher platelet count, and lower reticulocyte count when compared with their counterparts afflicted with TTP. When compared to patients with [B.sub.12] deficiency without evidence of a microangiopathic hemolytic anemia, pseudo-TMA patients demonstrated lower vitamin [B.sub.12] levels and were more likely to have pernicious anemia. (6) These laboratory findings may provide insight into the initial differentiation between TTP and a pseudo-TMA syndrome (Table 2).

As early as 1998 and 1999, two French investigators published separate reports of individuals exhibiting the phenomenon of [B.sub.12] deficiency mimicking TTP. (14,15) These patients exhibited LDH levels well above the aforementioned 2500 IU/L, at 5700 IU/L and 7900 IU/L in the respective reports. One of these patients received plasma exchange initially. Following this study, a case of schistocytosis with [B.sub.12] deficiency was again initially treated with plasma exchange. (16) In 2006, a case series highlighted 6 patients with [B.sub.12] deficiency that presented with a clinical picture of pseudo-thrombotic microangiopathy; the frequency of this clinical presentation was 2.4% in a cohort of more than 250 patients with documented [B.sub.12] deficiency. (17) This same group of investigators has also described pseudo-TTP in 2 patients with food- cobalamin malabsorption. (18) A subsequent case review describes initiation of plasma exchange for a syndrome consistent with TTP, however, the patient was found to be without clinical or laboratory response after the fifth session exchange. Further workup was pursued, and a bone marrow aspirate and biopsy demonstrated hypercellular marrow with erythroid hyperplasia and atypia without evidence of blast cells or chromosomal abnormalities. [B.sub.12] level was within normal limits in this case; however, methylmalonic acid level was found to be several orders of magnitude greater than the upper limit of normal, prompting testing for anti-intrinsic factor antibodies, which were identified. (9) The patient was subsequently diagnosed with pernicious anemia and treated with intramuscular cyanocobalamin rather than plasma exchange, with notable clinical and hematologic improvement. Most recently, a similar clinical picture was initially identified by the authors as TTP given the triad of schistocytosis, thrombocytopenia, and elevated lactate dehydrogenase in a Jehovah's Witness; interestingly, while plasma exchange was primarily offered given the clinical suspicion for TTP, the patient declined the intervention on the basis of her religious beliefs--a component of the case acknowledged by the authors as helpful in pursuing the correct diagnosis. Further testing revealed normal ADAMTS13 activity, while [B.sub.12] was significantly low; anti-intrinsic factor and antiparietal cell antibody positivity confirmed the diagnosis of pernicious anemia, and remarkable clinical and hematologic improvement were noted in this patient as well after initiation of intramuscular cyanocobalamin. (7)

The essential point of distinguishing between the various underlying causes of microangiopathy lies in the ultimate identification of correct management decisions for patients. As demonstrated in our case above and the similar cases referenced herein, the choice of therapy directed towards [B.sub.12] deficiency rather than towards immediate management of thrombotic thrombocytopenic purpura resulted in clinical and hematologic improvement while limiting exposure to adverse effects of plasma exchange. Such adverse effects, although relatively rare, might include complications from catheter insertion (hemorrhage, pneumothorax, infection) or reaction to infused plasma. Further data elucidating the risk associated with plasma exchange were reported in a recent study, which revealed a 24% rate of major complications and 2.3% overall mortality. (19) Several authors have noted previously that it is fairly common for patients to undergo plasma exchange before the diagnosis of [B.sub.12] deficiency is made in such cases. The identification and treatment of [B.sub.12] deficiency is important also because cobalamin replacement is relatively safe and cost-effective. Correction of depleted [B.sub.12] level has been associated with reversal of all hematologic abnormalities attributable to the deficiency in the absence of a concomitant hematologic disorder as well as some of the neuropsychiatric effects it may provoke. (20)

It is well known that vitamin [B.sub.12] is required for the synthesis of DNA and for division and differentiation of erythrocyte precursors. [B.sub.12] is a necessary cofactor for the methylation of homocysteine to methionine, and in patients with pernicious anemia, this pathway becomes disrupted, leading to the buildup of homocysteine in the blood (Figure 1). Hemolytic anemia may result from [B.sub.12] deficiency as erythrocyte precursor maturation is arrested, resulting in cellular lysis in the intramedullary compartment. Elevation in homocysteine is responsible for marked hemolysis in the peripheral blood as well, since homocysteine in vitamin [B.sub.12] deficiency can cause endothelial dysfunction. (16) Such endothelial dysfunction engenders the formation of microvascular thrombi and the shearing of erythrocytes peripherally are characteristic of the microangiopathic clinical picture. To differentiate between intramedullary and peripheral hemolysis, it may be helpful to measure the reticulocyte count and lactate dehydrogenase, as a lack of elevation in reticulocyte count and high LDH is more consistent with intramedullary hemolysis. In the present study, endothelial dysfunction may also have accounted for the unprovoked deep vein thrombosis discovered in our patient.

[B.sub.12] deficiency--whether resulting from genetic disorders of metabolism, autoimmune-mediated impairment of absorption, or other causes of dietary deficiency such as bariatric surgery may masquerade as TTP or another syndrome in the family of thrombotic microangiopathies given the degree to which these entities express overlapping clinical features. Extreme elevations in LDH in such clinical scenarios along with inappropriate reticulocytopenia may be more suggestive of underlying [B.sub.12] deficiency. Early diagnosis of pernicious anemia and treatment with vitamin [B.sub.12] in a patient presenting with microangiopathic hemolytic anemia are associated with fewer complications and significant clinical improvement compared to plasma exchange for presumed thrombotic thrombocytopenic purpura. It is thus of critical importance to recognize that [B.sub.12] deficiency may lead to the development of a clinical syndrome of microangiopathic hemolytic anemia so that the most efficacious intervention can be provided as soon as possible and that adverse effects from exposure to inappropriate therapy are avoided.

REFERENCES

(1.) Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U. Williams Hematology. New York: The McGraw-Hill Companies, Inc; 2010.

(2.) George JN, Nester CM. Syndromes of thrombotic microangiopathy. The New Engl J Med. Nov 6 2014;371(19):1847-1848.

(3.) Russo P, Doyon J, Sonsino E, Ogier H, Saudubray JM. A congenital anomaly of vitamin B12 metabolism: a study of three cases. Human Pathology. May 1992;23(5):504-512.

(4.) Geraghty MT, Perlman EJ, Martin LS, et al. Cobalamin C defect associated with hemolytic-uremic syndrome. The J Pediatr. Jun 1992;120(6):934-937.

(5.) Cornec-Le Gall E, Delmas Y, De Parscau L, et al. Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency. American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. Jan 2014;63(1):119-123.

(6.) Noel N, Maigne G, Tertian G, et al. Hemolysis and schistocytosis in the emergency department: consider pseudothrombotic microangiopathy related to vitamin B12 deficiency. QJM: Monthly Journal of the Association of Physicians. Nov 2013;106(11):10171022.

(7.) Malla M, Seetharam M. To treat or not to treat: a rare case of pseudo-thrombotic thrombocytopenic purpura in a Jehovah's Witness. Transfusion. Jan 2016;56(1):160- 163.

(8.) Walter K, Vaughn J, Martin D. Therapeutic dilemma in the management of a patient with the clinical picture of TTP and severe B12 deficiency. BMC hematology. 2015;15:16.

(9.) Dalsania CJ, Khemka V, Shum M, Devereux L, Lachant NA. A sheep in wolf's clothing. Am J Med. Feb 2008;121(2):107-109.

(10.) Furlan M, Robles R, Morselli B, Sandoz P, Lammle B. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura. Thrombosis and Haemostasis. Jan 1999;81(1):8-13.

(11.) Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. The New Engl J Med. Aug 8 1991;325(6):393-397.

(12.) George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. Nov 18 2010;116(20):4060-4069.

(13.) Coppola A, Davi G, De Stefano V, Mancini FP, Cerbone AM, Di Minno G. Homocysteine, coagulation, platelet function, and thrombosis. Seminars in Thrombosis and Hemostasis. 2000;26(3):243-254.

(14.) Jubault V, De Lacroix-Szmania I, Zittoun J, et al. [Hemolysis and schizocytosis, malabsorption and the "folate trap": unusual semiological peculiarities associated with vitamin B12 deficiency]. La Revue de medecine interne / fondee ... par la Societe nationale francaise de medecine interne. Dec 1998;19(12):921-923.

(15.) Blanc PL, Legrand E, Marc JM. [False Moskowitz disease, true Biermer disease]. La Revue de medecine interne / fondee ... par la Societe nationale francaise de medecine interne. Nov 1999;20(11):10461047.

(16.) Garderet L, Maury E, Lagrange M, Najman A, Offenstadt G, Guidet B. Schizocytosis in pernicious anemia mimicking thrombotic thrombocytopenic purpura. Am J Med. Apr 1 2003;114(5):423-425.

(17.) Andres E, Affenberger S, Federici L, Korganow AS. Pseudothrombotic microangiopathy related to cobalamin deficiency. The Am J Med. Dec 2006;119(12):e3.

(18.) Andres E, Affenberger S, Vinzio S, et al. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am J Med. Oct 2005;118(10):1154-1159.

(19.) Som S, Deford CC, Kaiser ML, et al. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. Transfusion. Dec 2012;52(12):2525-2532; quiz 2524.

(20.) Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. Sep 1 1990;76(5):871-881.

Paul A. Trubin, MD; Justin A. Edward, MS; Monica Dhand, MD

Drs. Trubin, Edward, and Dhand are all associated with the Tulane University Health Sciences Center, department of internal medicine--New Orleans, LA.

Caption: FIGURE 1--HOMOCYSTEINE-METHIONINE PATHWAY: Severe vitamin B12 deficiency can lead to increased serum levels of homocysteine, which causes endothelial damage and the formation of microvascular thrombi.
TABLE 1: Improvement following 10-day treatment with IM B12 (1000 mcg)

                 Day 0            Day 7             Day 10

WBC              6.4 x            4.6 x             7.0 x
                 [10.sup.9]/L     [10.sup.9]/L      [10.sup.9]/L
Hemoglobin       5.6 g/dL         8.8 g/dL          9.8 g/dL
Platelets        92 x             139 x             271 x
                 [10.sup.9]/L     [10.sup.9]/L      [10.sup.9]/L
MCV              113.2 fL         98.5 fL           95.8 fL

TABLE 2: Lab value distinctions between TTP and thrombotic
microangiopathy related to vitamin B12 deficiency

                 TTP              Pseudo-TMA        Our Patient
                 ([n=6.sup.)6]    ([n=7.sup.)6]

LDH              1460 IU/L        7310 IU/L         3137 IU/L
Platelets        12.5 x           73 x              92 x
                 [10.sup.9]/L     [10.sup.9]/L      [10.sup.9]/L
Reticulocyte     18%              3%                3.3%
Count
MCV              92 fL            110.6 fL          113.2 fL
Hemoglobin       6.9 g/dL         4.2 g/dL          5.6 g/dL

(6) Average values from Noel et al. with p<0.05
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Author:Trubin, Paul A.; Edward, Justin A.; Dhand, Monica
Publication:The Journal of the Louisiana State Medical Society
Article Type:Report
Date:Nov 1, 2016
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