Abstract
We report a case of a 39-year-old man with inferior vena cava (IVC) thrombus after withdrawal of IVC filter. He complained of 1-week history of swelling in his right leg, and computed tomography (CT) demonstrated occlusive thrombus in right femoral and popliteal veins. Venous thrombectomy was attempted after IVC filter placement. The filter was withdrawn without IVC filter-associated thrombus and the patient was discharged on warfarin. On day 21 after discharge, he complained of progressive swelling and CT revealed a significant amount of thrombus in IVC where the filter had been placed. Despite adequate anticoagulant therapy, CT showed increased thrombus extending from infra-renal IVC to common iliac vein. Systemic work-up for the risk factors of venous thromboembolism revealed the presence of hyperhomocysteinemia (total homocysteine 83.1 μmol/L; normal range 5–15 μmol/L) due to unbalanced diet with deficiency of folic acid and vitamin B12. Four weeks after administration of folic acid, vitamin B6/B12 as the treatment of hyperhomocysteinemia in addition to warfarin, swelling of his leg improved with significant resolution of thrombus by CT. CT also demonstrated a severe stenosis of the IVC just below the renal veins. At 6 months, he complained of mild post-thrombotic sequelae with no evidence of recurrent IVC thrombus.
<Learning objective: Hyperhomocysteinemia is associated with higher risk for venous thromboembolism as well as atherosclerotic diseases. Serum homocysteine level is partly explained by genetic background as well as dietary deficiency of folic acid or vitamin B6/B12. Hyperhomocysteinemia is related with low intake of vegetables and seafood. We should be aware of hyperhomocysteinemia when the thrombus increased despite optimal anticoagulant therapy. B vitamins and folic acid therapy might be effective in patients with severe hyperhomocysteinemia.>
Keywords: Inferior vena cava thrombus, Inferior vena cava filter, Hyperhomocysteinemia, B vitamins, Folic acid
Introduction
Hyperhomocysteinemia is a risk factor for venous thromboembolism as well as atherosclerotic diseases through endothelial dysfunction due to an increased generation of reactive oxygen species and a decreased nitric oxide bioavailability. Serum homocysteine level is partly explained by genetic background as well as dietary deficiency of folic acid or vitamin B6/B12. Inferior vena cava (IVC) thrombus associated with filters is not uncommon in clinical practice. However, IVC thrombus after withdrawal of filter is rare, particularly in the absence of hepatic or renal tumors. Furthermore, IVC stenosis after resolution of thrombus associated with hyperhomocysteinemia is also rare. We report a case of extensive IVC thrombus after withdrawal of IVC filter in a patient with hyperhomocysteinemia because of dietary deficiency of folic acid or vitamin B6/B12.
Case report
A 39-year-old man presented with a 1-week history of swelling in his right leg. He had no past medical or surgical history. Duplex ultrasound and computed tomography (CT) demonstrated occlusive thrombus in the right superficial femoral and popliteal veins. His protein S and protein C levels were normal (protein S: 110.7%, protein C: 86.0%). Unfractionated heparin and warfarin were initiated, with adjustment of the dose to maintain the international normalized ratio (INR) between 2.0 and 3.0. On day 10 after hospitalization, venous thrombectomy was attempted by a Fogarty catheter from his right femoral vein, because the thrombus increased despite optimal anticoagulant therapy. A retrievable OptEase IVC filter (Cordis, Milpitas, CA, USA) was temporarily placed in the infra-renal IVC because of a concern that parts of the clot might break loose during the procedure (Fig. 1). Little thrombus was removed by the procedure. On day 22 after hospitalization, the filter was withdrawn without any evidence of IVC filter-associated thrombus, and the patient was discharged from the hospital on warfarin with adjustment of the dose to maintain the INR between 2.0 and 3.0.
Fig. 1.
A retrievable OptEase inferior vena cava (IVC) filter (Cordis, Milpitas, CA, USA) in the infra-renal IVC (coronal section, axial section).
On day 21 after discharge, the patient returned to the hospital, complaining of progressive swelling in his right leg. His INR was 1.72. CT revealed a significant amount of thrombus in IVC where the filter had been placed. Adequate anticoagulant therapies such as unfractionated heparin (for 3 weeks), urokinase (for 3 days), and rivaroxaban (15 mg/day) (for 3 weeks) were administered. However, CT showed increased thrombus extending from infra-renal IVC to common iliac vein (Fig. 2). He was subsequently referred to our hospital. Systemic work-up for the risk factors of venous thromboembolism revealed the presence of hyperhomocysteinemia (total homocysteine 83.1 μmol/L: normal range 5–15 μmol/L) due to unbalanced diet with deficiency of folic acid (2.4 ng/mL: normal range 3.6–12.9 ng/mL) and vitamin B12 (227 pg/mL: normal range 233–914 pg/mL). Antinuclear antibody (fluorescent antibody technique) was negative at 1:40 dilution of blood, and immunoglobulin G anticardiolipin antibodies (IgG ACA) were 1.0 IgG phospholipid (GPL) U/mL. Lupus anticoagulant (diluted Russell’s viper venom time rate) was 1.05 ng/mL: normal range less than 1.3 ng/mL. Tumor marker elevation was not observed; carcinoembryonic antigen (CEA) (1.6 ng/mL: normal range less than 5.0 ng/mL), carbohydrate antigen 19-9 (CA19-9) (5.4 U/mL: normal range less than 37.0 ng/mL), and α-fetoprotein (AFP) (2.4 ng/mL: normal range less than 15.0 ng/mL).
Fig. 2.
A significant amount of thrombus in inferior vena cava where the filter had been placed (coronal section, axial section).
Four weeks after administration of folic acid (15 mg/day), vitamin B6 (100 mg/day), and vitamin B12 (100 μg/day) as the treatment for hyperhomocysteinemia in addition to warfarin, serum homocysteine level decreased (total homocysteine: 12.4 μmol/L), and swelling of his leg improved with significant resolution of thrombus by CT. CT also demonstrated a severe stenosis of the IVC just below the renal veins (Fig. 3). At 6 months, he complained of mild post-thrombotic sequelae with no evidence of recurrent IVC thrombus.
Fig. 3.
Significant resolution of thrombus and a severe stenosis of the inferior vena cava (coronal section, axial section).
Discussion
Homocysteine is an intermediate metabolite of methionine or cysteine. Hyperhomocysteinemia is regarded as a risk factor for atherosclerotic diseases such as cerebrovascular disease and coronary artery disease.Vascular endothelial cells are impaired due to an increased generation of reactive oxygen species and a decreased nitric oxide bioavailability. In addition to vascular endothelial cell disorder, vascular smooth muscle cell proliferation, platelet and factor V activation, and tissue factor induction cause hypercoagulable state. IVC filter placement would be a viable option during transvenous thrombectomy because of a concern that parts of the clot might break loose during the procedure, although a recent clinical trial did not support the use of retrievable IVC filter plus anticoagulation in patients who can be treated with anticoagulation [1], [2]. In this case, hyperhomocysteinemia might be related with extensive IVC thrombosis secondary to injured vessel wall by IVC filter because a significant amount of thrombus was present in IVC where the filter had been placed.
Serum homocysteine level is partly explained by genetic background as well as dietary deficiency of folic acid or vitamin B6/B12 with impaired metabolism of homocysteine to methionine or cysteine. Green and yellow vegetables include folic acid and seafood includes vitamin B6/B12. Hyperhomocysteinemia in this case might be related with several factors such as low intake of vegetables and seafood, smoking habit, and being male. Genetic screening tests including methylenetetrahydrofolate reductase were not performed because the patient and his family refused genetic screening. Previous randomized controlled trials demonstrated that hyperhomocysteinemia was associated with higher risk for venous thromboembolism as well as atherosclerotic diseases [3], [4]. Although B vitamins and folic acid have been reported to reduce blood homocysteine levels, it is controversial whether the intake of B vitamins and folic acid attributes to reducing thrombus in patients with hyperhomocysteinemia. Some previous studies did not support the use of B vitamins as secondary prevention in patients with venous thromboembolism [5], [6]. However, these studies included patients with no or mild homocysteinemia (11.5 ± 1.4 μmol/L in the Heart and Outcomes Prevention Evaluation 2 [HOPE-2] study [7]; 15.1 [95% confidence interval: 14.3–16.0] μmol/L in the Vitamins and Thrombosis [VITRO] study [6]). The effect of lowering homocysteine levels in patients with intermediate (total homocysteine 30–100 μmol/L) or severe hyperhomocysteinemia (total homocysteine >100 μmol/L) remains unknown. In the present case, serum homocysteine level was very high (83.1 μmol/L: normal range 5–15 μmol/L), and the thrombus did not resolve despite adequate anticoagulant therapy until the initiation of additional folic acid and B vitamins. There was no apparent risk factor for venous thromboembolism other than hyperhomocysteinemia, suggesting that high levels of homocysteine and vessel wall injury might be causally related with venous thrombus despite the optimal anticoagulation with warfarin. Therefore, B vitamins and folic acid therapy might be effective in reducing venous thromboembolism in patients with intermediate or severe hyperhomocysteinemia. Venous wall elastic recoil or residual luminal stenosis after resolution of thrombus were often observed in patients with deep vein thrombosis. This is the first case that represents severe stenosis of IVC after resolution of IVC thrombus.
References
- 1.Mismetti P., Laporte S., Pellerin O., Ennezat P.V., Couturaud F., Elias A. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015;313:1627–1635. doi: 10.1001/jama.2015.3780. [DOI] [PubMed] [Google Scholar]
- 2.Gogalniceanu P., Johnston C.J., Khalid U., Holt P.J., Hincliffe R., Loftus I.M. Indications for thrombolysis in deep venous thrombosis. Eur J Vasc Endovasc Surg. 2009;38:192–198. doi: 10.1016/j.ejvs.2009.03.023. [DOI] [PubMed] [Google Scholar]
- 3.Ray J.G. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med. 1998;158:2101–2106. doi: 10.1001/archinte.158.19.2101. [DOI] [PubMed] [Google Scholar]
- 4.Nygard O., Nordrehaug J.E., Refsum H., Ueland P.M., Farstad M., Vollset S.E. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230–236. doi: 10.1056/NEJM199707243370403. [DOI] [PubMed] [Google Scholar]
- 5.Ray J.G., Kearon C., Yi Q., Sheridan P., Lonn E. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Ann Intern Med. 2007;146:761–767. doi: 10.7326/0003-4819-146-11-200706050-00157. [DOI] [PubMed] [Google Scholar]
- 6.den Heijer M., Willems H.P., Blom H.J., Gerrits W.B., Cattaneo M., Eichinger S. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood. 2007;109:139–144. doi: 10.1182/blood-2006-04-014654. [DOI] [PubMed] [Google Scholar]
- 7.Lonn E., Yusuf S., Arnold M.J., Sheridan P., Pogue J., Micks M. Heart Outcomes Prevention Evaluation (HOPE) 2 investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567–1577. doi: 10.1056/NEJMoa060900. [DOI] [PubMed] [Google Scholar]