We report the case of a 60-year-old woman with a history of ataxia who sought evaluation after a syncopal episode. A diagnostic workup revealed pulmonary emboli, pernicious anemia (PA), hyperhomocysteinemia, and a G20210A prothrombin gene mutation. She was successfully treated with homocysteine-lowering therapy, including high doses of oral cobalamin. She also received oral anticoagulation for 6 months. At 1 year of follow-up, no further thrombotic episodes had occurred. Our report highlights the thrombotic risk of hyperhomocysteinemia secondary to PA in a patient with the G20210A prothrombin gene mutation.
Key words: cobalamin; hyperhomocysteinemia; pernicious anemia; prothrombin gene variant: pulmonary embolism; thrombophilia
Abbreviations: IF = intrinsic factor: MMA = methylmalonic acid; PA = pernicious anemia
Pernicious anemia (PA) is commonly associated with hyperhomocysteinemia. (1) The purpose of this report was to highlight the thrombotic risk of hyperhomocysteinemia secondary to PA. Additionally, our patient was found to be a carrier of the prothrombin gene mutation. To the best of our knowledge, this is the first report of pulmonary thromboembolic disease that possibly was triggered by hyperhomocysteinemia secondary to PA.
A 60-year-old African-American woman sought evaluation after a syncopal episode. She complained of an unsteady gait for 3 weeks prior to hospital admission but denied dyspnea, chest pain, or dizziness. Her medical history was remarkable for well-controlled hypertension. There was no history of thrombosis, miscarriages, recent physical trauma, or prolonged air travel. The initial assessment revealed an ill-appearing woman with a BP of 110/75 mm Hg, heart rate of 130 beats/min, and respiratory rate of 25 breaths/min. Pulse oximetry was 94% on room air. A showed an increased mean corpuscular volume and a normal hemoglobin level. Biochemical and clotting profiles were normal. The ECG showed sinus tachycardia without right heart strain. Chest radiograph findings were normal. Arterial blood gas levels measured with the patients breathing room air revealed the following: pH, 7.46; PaC[O.sub.2], 25 mm Hg; and P[O.sub.2], 73 mm Hg. Lower extremity Doppler scans were negative for deep venous thrombosis. The results of a ventilation/perfusion lung scan were abnormal (Fig 1, middle, A). The patient received a diagnosis of pulmonary embolism and began therapy with IV heparin. Further extensive laboratory data are presented in Table 1. She was discharged from the hospital while receiving therapy with homocysteine-lowering agents, including folate (1 mg/d), pyridoxine (100 mg/d), and high-dose oral cobalamin (1,500 mg/d). She continued to receive oral anticoagulation therapy for 6 months. Serum methylmalonic acid (MMA), homocysteine, and cobalamin levels normalized after 3 months of therapy (Table 1). A repeat ventilation/perfusion lung scan 6 months later demonstrated significant improvement (Fig 1, bottom, B). She recovered completely from her ataxia. After 1 year of follow-up, the results of the patient's age-appropriate cancer screening examination has been negative. There have been no further episodes of thrombosis.
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PA is the most common cause of cobalamin deficiency. Intrinsic factor (IF), a glycoprotein that is produced by the gastric parietal cells, is essential in facilitating cobalamin absorption. An autoimmune insult against these cells causing decreased IF production is the usual basis for this disorder. (2) Since cobalamin is required in the folate-dependent remethylation of homocysteine to methionine and in the folate-independent conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A, serum levels of homocysteine and MMA are increased in 95% of patients with cobalamin deficiency. (1) Hyperhomocysteinemia is a well-recognized risk factor for thrombosis and atherosclerotic vascular disease. (3)
Currently, PA can be diagnosed in the early stages based on the presence of anti-IF/anti-parietal cell antibodies even before alteration of hematologic parameters. In a series of 100 patients with PA, 70% had hemoglobin levels of > 12 g/dL, and 36% have a mean corpuscular volume of < 100 fL, at the time of diagnosis. (4) Peripheral polyneuropathy (ie, paresthesias and sensory ataxia) along with subacute combined spinal cord degeneration are well-recognized neurologic manifestations of the disease. If the initiation of cobalamin replacement therapy is delayed, the neurologic deficits may not revert. (2) Given that about 2% of cobalamin intake is passively absorbed through an IF-independent pathway, (5) we treated our patient with high doses of oral cobalamin, avoiding the parenteral route in the setting of anticoagulation. Her clinical recovery, evidenced by the reversal of neurologic symptoms, was likely due to the early diagnosis and successful treatment of the cobalamin deficiency.
Our patient also was found to be a carrier of the G20210A prothrombin gene mutation. This genetic defect has been described in 2.5% of healthy individuals (6) and is also recognized as a prothrombotic condition. We believe that the hyperhomocysteinemia associated with the PA may have decreased her threshold for thrombosis and triggered her massive pulmonary embolism. Given that vitamin supplementation was effective in correcting her hyperhomocysteinemia and considering the low risk for recurrent thromboembolic events in heterozygous carriers of the prothrombin gene mutation, (6) the initiation of lifelong secondary thromboprophylaxis was not justified. Therefore, we discontinued oral anticoagulation therapy after 6 months.
The prothrombotic potential of hyperhomocysteinemia associated with PA may be unrecognized. Indeed, hyperhomocysteinemia may decrease the threshold for thrombosis, especially in the face of coexistent prothrombotic conditions. Our report emphasizes the successful correction of cobalamin deficiency by using high doses of oral cobalamin in a patient with PA. Our study also confirms that hyperhomocysteinemia is an easily correctable risk factor, the presence of which should be considered in patients presenting with venous thrombotic disease and/or pulmonary embolisms.
(1) Savage D, Lindenbaum J, Allen R. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiency. Am J Med 1994; 96:239-246
(2) Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med 1997; 337:1441-1448
(3) Alpert MA. Homocyst(e)ine, atherosclerosis, and thrombosis. South Med J 1999; 92:858-865
(4) Pruth R, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc 1994; 69:144-150
(5) Kuzminski AM, Del Giacco EJ, Allen RH, et al. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92:1192-1198.
(6) Eichinger S, Minar E, Hirschl M, et al. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost 1999; 81:14-18
* From the Department of Medicine (Drs. Caldera and Moral and the Divisions of Cardiology (Dr. Kotler) and Pulmonary and Critical Care Medicine (Dr, Eiger), Albert Einstein Medical Center, Philadelphia, PA.
Received April 1, 2002; revision accepted May 1, 2002.
Correspondence to: Angel Caldera, MD, Department of Medicine, Albert Einstein Medical Center, 5401 Old York Rd, Philadelphia. PA 19141; e-mail: firstname.lastname@example.org
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