E Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia

Abstract

Oral contraceptive use and hyperhomocysteinemia are considered to be relatively weak risk factors for venous thromboembolism. We report a case of acute renal vein thrombosis, a rare and aggressive form of thromboembolism, that occurred in a 21-year-old woman taking oral contraceptives, who was subsequently found to have marked hyperhomocysteinemia. This case suggests that the oral contraceptive and hyperhomocysteinemia may interact in a synergistic manner in the pathogenesis of thrombosis. In oral contraceptive users who develop venous thrombosis in the absence of other risk factors, clinicians should consider investigations for an underlying prothrombotic biochemical disorder. Oral contraceptive use and hyperhomocysteinemia are considered to be relatively weak risk factors for venous thromboembolism. We report a case of acute renal vein thrombosis, a rare and aggressive form of thromboembolism, that occurred in a 21-year-old woman taking oral contraceptives, who was subsequently found to have marked hyperhomocysteinemia. This case suggests that the oral contraceptive and hyperhomocysteinemia may interact in a synergistic manner in the pathogenesis of thrombosis. In oral contraceptive users who develop venous thrombosis in the absence of other risk factors, clinicians should consider investigations for an underlying prothrombotic biochemical disorder. Renal vein thrombosis usually presents as an insidious, chronic disease in patients with the nephrotic syndrome or renal cell carcinoma.1Zucchelli P Renal vein thrombosis.Nephrol Dial Transplant. 1992; 7: 105-108PubMed Google Scholar Acute renal vein thrombosis is rare in adults and usually occurs after blunt abdominal trauma or renal transplantation.2du Buf-Vereijken PW Hilbrands LB Wetzels JF Partial renal vein thrombosis in a kidney transplant: management by streptokinase and heparin.Nephrol Dial Transplant. 1998; 13: 499-502Crossref PubMed Scopus (10) Google Scholar Oral contraceptive (OC) use and hyperhomocysteinemia are associated with an increased risk of venous thromboembolism (VTE) but are considered relatively weak risk factors for VTE.3Stein JH McBride PE Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment.Arch Intern Med. 1998; 158: 1301-1306Crossref PubMed Scopus (140) Google Scholar, 4Douketis JD Ginsberg JS Holbrook A Crowther M Duku EK Burrows RF A reevaluation of the risk for venous thromboembolism with the use of oral contraceptives and hormone replacement therapy.Arch Intern Med. 1997; 157: 1522-1530Crossref PubMed Google Scholar Hyperhomocysteinemia is caused by inherited deficiencies of enzymes involved in homocysteine metabolism (5-methylenetetrahydrofolate reductase [MTHFR], cystathionine β-synthase, methionine synthase), vitamin deficiencies (folate, vitamin B6, vitamin B12), medication use (eg, methotrexate, phenytoin), and chronic diseases (eg, renal insufficiency, malignancy).3Stein JH McBride PE Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment.Arch Intern Med. 1998; 158: 1301-1306Crossref PubMed Scopus (140) Google Scholar We describe a case of acute renal vein thrombosis occurring in a 21-year-old woman who had recently started taking an OC and was found subsequently to have marked hyperhomocysteinemia. Because acute renal vein thrombosis is a rare and aggressive form of VTE, its occurrence in an OC user with hyperhomocysteinemia suggests a synergistic interaction between these risk factors. A 21-year-old woman presented with acute onset of right-sided flank pain of 24 hours’ duration associated with gross hematuria. The patient had no fever or other urinary symptoms. She was previously healthy except for an iron deficiency anemia related to heavy menstrual periods and inadequate dietary intake. The only medication she was taking was the OC, which was started 6 months before presentation. She had no family history of VTE. On examination, she appeared acutely ill and pale with a temperature of 36.8°C, blood pressure of 110/70 mm Hg, and heart rate of 110 beats/min. There was tenderness over the right costovertebral angle and right lower quadrant of the abdomen. The initial laboratory findings were as follows: the urinalysis showed 3+ erythrocytes, 3+ protein, and 1+ leukocytes; hemoglobin, 9.8 g/dL; leukocytes, 12.5 × 109/ L; platelets, 270 × 109/L; and serum electrolyte, albumin, total protein, urea, and creatinine levels were within normal limits. An ultrasonogram of the right kidney revealed an edematous medullary region and disorganization of the renal parenchyma; an inferior venocavagram showed a filling defect at the level of right renal vein, consistent with renal vein thrombosis. After renal vein thrombosis was diagnosed, subsequent laboratory findings were as follows: fasting plasma homocysteine, 134.0 µmol/L (reference, 4.3-13.3 µmol/L); serum folate, 1.68 µg/L (reference, 1.5-10.0 µg/L); red blood cell folate, 654 ng/L (reference, 352-1190 ng/L); serum vitamin B12, 140 ng/L (reference, 180-500 ng/L); and findings on testing for activated protein C resistance (APCR), the prothrombin gene mutation, antiphospholipid antibodies, and deficiencies of protein C, protein S, and antithrombin were negative. The plasma homocysteine, defined as the sum of free homocysteine, cysteine-homocysteine mixed disulfide, and protein-bound homocysteine, was measured (after blood was collected on ice) by cleavage and reduction reactions with use of sodium borohydride, followed by iodoacetic acid treatment by high-pressure liquid chromatography as previously described.5Kluijtmans LA van den Heuvel LP Boers GH et al.Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.Am J Hum Genet. 1996; 58: 35-41PubMed Google Scholar With use of methods previously described,6Uhlendorf BW Mudd SH Cystathionine synthase in tissue culture derived from human skin: enzyme defect in homocystinuria.Science. 1968; 160: 1007-1009Crossref PubMed Scopus (73) Google Scholar, 7Byck S Rosenblatt DS Metabolic cooperation among cell lines from patients with inborn errors of vitamin B12 metabolism: differential response of cblC and cblD.Clin Invest Med. 1991; 14: 153-159PubMed Google Scholar testing was done to investigate the cause of the hyperhomocysteinemia. Cystathionine β-synthase enzyme activity in the patient's cultured skin fibroblasts and MTHRF enzyme activity were normal; the uptake of 14Gerstman BB Piper JM Tomita DK Ferguson WJ Stadel BV Lundin FE Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease.Am J Epidemiol. 1991; 133: 32-37PubMed Google ScholarC-propionate, 14Gerstman BB Piper JM Tomita DK Ferguson WJ Stadel BV Lundin FE Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease.Am J Epidemiol. 1991; 133: 32-37PubMed Google ScholarCMTHFR, and 57Co-CN-cobalamine was normal; and the synthesis of Ado-cobalamine and Me-cobalamine was within normal limits. Urine amino acid quantification was normal with no evidence of homocystinuria; urine methionine was 7 mmol/g of creatinine, and urine cystine was 46 mmol/g of creatinine. Thus, there was no identifiable inborn error of vitamin B or folate metabolism in this patient. Molecular DNA analysis showed that the patient was homozygous for the MTHFR polymorphism A223V (677C?T), which results in a thermolabile form of MTHFR that is associated with elevations of plasma homocysteine.8Frosst P Blom HJ Milos R et al.A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nat Genet. 1995; 10: 111-113Crossref PubMed Scopus (5105) Google Scholar In addition to stopping the OC, the patient received 7 days of intravenous heparin overlapping with warfarin. The latter was administered to achieve an international normalized ratio (INR) of 2.0 to 3.0. She also received folic acid, 5 mg, vitamin B6, 10 mg, and subcutaneous vitamin B12,1 mg, daily for 5 days, followed by a once-daily vitamin preparation, containing folic acid, 0.6 mg, vitamin B6, 8 mg, and vitamin B, 25 µg. During a 2-year follow-up period, the patient has remained on warfarin, with a target INR of 2.0 to 3.0, and vitamin therapy with no episodes of recurrent VTE. After 6 months of treatment, the serum folate and vitamin B levels were 3.0 ng/L and 255 µg/L, respectively; the serum albumin, total protein, urea, and creatinine levels remained within normal limits; a renal scan revealed minimal flow in the right renal vein. Fasting plasma homocysteine levels performed 3, 6, 12, and 24 months after the start of treatment were 77.6, 61.4, 24.7, and 22.5 µmol/L, respectively. This patient had typical clinical and radiologic features of acute renal vein thrombosis. Although acute renal vein thrombosis has been reported in patients with prothrombotic biochemical disorders, including APCR, the antiphospholipid antibody syndrome, and deficiencies of protein C or antithrombin,9Pohl M Zimmerhackl LB Heinen F Sutor AH Schneppenheim R Brandis M Bilateral renal vein thrombosis and venous sinus thrombosis in a neonate with factor V mutation (FV Leiden).J Pediatr. 1998; 132: 159-161Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 10Cosgriff TM Bishop DT Hershgold EJ et al.Familial antithrombin III deficiency: its natural history, genetics, diagnosis and treatment.Medicine (Baltimore). 1983; 62: 209-220PubMed Google Scholar, 11Ko WS Lim PS Sung YP Renal vein thrombosis as first clinical manifestation of the primary antiphospholipid syndrome.Nephrol Dial Transplant. 1995; 10: 1929-1931PubMed Google Scholar, 12Rogers PC Silva MP Carter JE Wadsworth LD Renal vein thrombosis and response to therapy in a newborn with protein C deficiency.Eur J Pediatr. 1989; 149: 124-125Crossref PubMed Scopus (14) Google Scholar this is the first report, to our knowledge, of renal vein thrombosis occurring in the presence of either hyperhomocysteinemia or OC use. In terms of the pathogenesis of the renal vein thrombosis, the patient had 2 relatively weak risk factors for VTE, OC use and hyperhomocysteinemia. Oral contraceptive use is associated with a 2- to 4-fold increased risk of VTE.4Douketis JD Ginsberg JS Holbrook A Crowther M Duku EK Burrows RF A reevaluation of the risk for venous thromboembolism with the use of oral contraceptives and hormone replacement therapy.Arch Intern Med. 1997; 157: 1522-1530Crossref PubMed Google Scholar However, the absolute risk of VTE with OC use is low, with an incidence of about 0.1% per year.13Farmer RDT Preston TD The risk of venous thromboembolism associated with low oestrogen oral contraceptives.J Obstet Gynaecol. 1995; 15: 195-200Crossref Scopus (108) Google Scholar, 14Gerstman BB Piper JM Tomita DK Ferguson WJ Stadel BV Lundin FE Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease.Am J Epidemiol. 1991; 133: 32-37PubMed Google Scholar By comparison, lower limb orthopedic surgery, even with VTE prophylaxis, is associated with a 40-fold higher risk of symptomatic VTE (ie, 4% within 3 months).15Leclerc JR Gent M Hirsh J Geerts WH Ginsberg JS Canadian Collaborative Group The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin: a multi-institutional cohort study of patients who underwent hip or knee arthroplasty.Arch Intern Med. 1998; 158: 873-878Crossref PubMed Scopus (186) Google Scholar Hyperhomocysteinemia is associated with a 2- to 3-fold increased risk of VTE,16den Heijer M Koster T Blom HJ et al.Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.N Engl J Med. 1996; 334: 759-762Crossref PubMed Scopus (1050) Google Scholar, 17Fermo I Vigano D'Angelo S Paroni R Mazzola G Calori G D'Angelo A Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease.Ann Intern Med. 1995; 123: 747-753Crossref PubMed Scopus (244) Google Scholar and the risk may increase in direct proportion to the homocysteine level.18den Heijer M Blom HJ Gerrits WB et al.Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?.Lancet. 1995; 345: 882-885Abstract PubMed Google Scholar In our patient, it is possible that OC exposure, which occurred during the 6 months prior to the thrombotic episode, was the only pathogenic factor. However, a more likely pathogenic mechanism in this patient is that, in the presence of marked hyperhomocysteinemia, exposure to a weak thrombogenic stimulus (ie, the OC) tipped the hemostatic-thrombotic balance, resulting in clinical thrombosis. Several studies suggest that OC users who develop VTE have an increased likelihood of an underlying prothrombotic disorder. In 1 case-control study, OC users with APCR had a 35-fold increased risk of developing VTE, whereas OC nonusers with APCR had an 8-fold increased risk of VTE.19Vandenbroucke JP Koster T Briet E Reitsma PH Bertina RM Rosendaal FR Increased risk of venous thrombosis in oralcontraceptive users who are carriers of factor V Leiden mutation.Lancet. 1994; 344: 1453-1457Abstract PubMed Scopus (861) Google Scholar In another case-control study, OC users with the prothrombin gene mutation had a 20-fold increased risk of cerebral vein thrombosis, and the risk was halved in OC users without this mutation.20Martinelli I Sacchi E Landi G Taioli E Duca F Mannucci PM High risk of cerebral-vein thrombosis in carriers of a prothrombingene mutation and in users of oral contraceptives.N Engl J Med. 1998; 338: 1793-1797Crossref PubMed Scopus (567) Google Scholar In 1 retrospective cohort study of 17 women with VTE who were homozygous for factor V Leiden, 12 (80%) had used the OC prior to the VTE episode.21Rintelen C Mannhalter C Ireland H et al.Oral contraceptives enhance the risk of clinical manifestations of venous thrombosis at a young age in females homozygous for factor V Leiden.Br J Haematol. 1996; 93: 487-490Crossref PubMed Scopus (74) Google Scholar Further, 1 prospective cohort study found that in OC users who developed VTE, the prevalence of deficiencies of protein C, protein S, and antithrombin was 9.2% (10/109),22Bloemenkamp KW Rosendaal FR Helmerhorst FM Vandenbroucke JP Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects.Arch Intern Med. 2000; 160: 49-52Crossref PubMed Scopus (181) Google Scholar which is 3-fold higher than the prevalence of these disorders in OC nonusers with VTE.23Pabinger I Schneider B Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on Natural Inhibitors Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency: a cooperative, retrospective study.Arterioscler Thromb Vasc Biol. 1996; 16: 742-748Crossref PubMed Scopus (241) Google Scholar, 24Tabernero MD Tomas JF Alberca I Orfao A Lopez Borrasca A Vincente V Incidence and clinical characteristics of hereditary disorders associated with venous thrombosis.Am J Hematol. 1991; 36: 249-254Crossref PubMed Scopus (128) Google Scholar In terms of the cause of the hyperhomocysteinemia, this patient was homozygous for the common MTHFR polymorphism that usually results in mild to moderate increases of plasma homocysteine.8Frosst P Blom HJ Milos R et al.A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nat Genet. 1995; 10: 111-113Crossref PubMed Scopus (5105) Google Scholar However, this patient's original plasma homocysteine level was much higher than previously reported in patients with this genotype. Additional tests revealed no deficiencies in the activities of MTHFR and cystathionine β-synthase or abnormalities of cobalamin metabolism. Although vitamin therapy resulted in a marked decrease in homocysteine levels, the patient's plasma homocysteine level did not normalize, possibly as a result of noncompliance with folic acid supplementation; in patients with the MTHFR polymorphism, folic acid supplementation results in normalization of the plasma homocysteine levels.25Guttormsen AB Ueland PM Nesthus I et al.Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (≥40 micromol/liter): the Hordaland Homocysteine Study.J Clin Invest. 1996; 98: 2174-2183Crossref PubMed Scopus (277) Google Scholar It is possible that the OC contributed to the initial elevated homocysteine level, when renal vein thrombosis was diagnosed, as long-term OC use can reduce levels of vitamin B6, folate, and vitamin B12.26Smith JL Goldsmith GA Lawrence JD Effects of oral contraceptive steroids on vitamin and lipid levels in serum.Am J Clin Nutr. 1975; 28: 371-376PubMed Google Scholar, 27Hjelt K Brynskov J Hippe E Lundstrom P Munck O Oral contraceptives and the cobalamin (vitamin B12) metabolism.Acta Obstet Gynecol Scand. 1985; 64: 59-63Crossref PubMed Scopus (23) Google Scholar However, the patient's homocysteine levels remained elevated for months after the OC was stopped, and recent prospective cohort studies have found that exogenous estrogen use does not influence homocysteine levels.28van der Mooren MJ Demacker PN Blom HJ de Rijke YB Rolland R The effect of sequential three-monthly hormone replacement therapy on several cardiovascular risk estimators in postmenopausal women.Fertil Steril. 1997; 67: 67-73Abstract Full Text PDF PubMed Scopus (60) Google Scholar, 29Berger PB Herrmann RR Dumesic DA The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women.Mayo Clin Proc. 2000; 75: 18-23Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In summary, this case suggests that the OC and hyperhomocysteinemia may interact in a synergistic manner in the pathogenesis of venous thrombosis. In OC users who develop VTE in the absence of other risk factors, clinicians should consider investigations for an underlying prothrombotic biochemical disorder. We thank Drs Deborah Renaud and David E. C. Cole for their helpful reviews of the manuscript and Timothy W. Heshka, MSc, MSc, for coordinating the laboratory investigations.