Deep Venous Thrombosis Caused by Congenital Absence of Inferior Vena Cava, Combined with Hyperhomocysteinemia

Deep Venous Thrombosis Caused by Congenital Absence of Inferior Vena Cava, Combined with Hyperhomocysteinemia

Deep Venous Thrombosis Caused by Congenital Absence of Inferior Vena Cava, Combined with Hyperhomocysteinemia Sang Seob Yun, MD, Ji Il Kim, MD, Kee Hw...

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Deep Venous Thrombosis Caused by Congenital Absence of Inferior Vena Cava, Combined with Hyperhomocysteinemia Sang Seob Yun, MD, Ji Il Kim, MD, Kee Hwan Kim, MD, Gi Young Sung, MD, Do Sang Lee, MD, Jeong Soo Kim, MD, In Sung Moon, MD, Keun Woo Lim, MD, and Young Bok Koh, MD, Seoul, Korea

We present a case of suprarenal and infrarenal absence of the inferior vena cava, combined with hyperhomocysteinemia in a 39-year-old woman who presented with symptoms of deep venous thrombosis. The patient also had a homozygous mutation of C677T methylenetetrahydrofolate reductase. Deep vein thrombosis has a multifactorial etiology involving both genetic and acquired factors. Absence of the inferior vena cava is a rare congenital anomaly, but recently it was confirmed as an important risk factor for the development of deep vein thrombosis, especially in young persons. Hypercoagulability due to hyperhomocysteinemia with a tendency toward venous stasis, mediated by congenital absence of the inferior vena cava is thought to have caused deep vein thrombosis in our patient. To our knowledge, this association has not yet been reported. The clinical features and prognosis of this entity are discussed.

Congenital absence of the inferior vena cava (AIVC) presenting as atresia or a total absence is a rare vascular defect. Particularly, combined absence of the suprarenal and infrarenal IVC has been reported in only eight cases.1-8 AIVC is usually discovered incidentally because patients are typically asymptomatic of the condition itself but are symptomatic of associated conditions such as congenital heart disease, polysplenia, asplenia, and inversion of bowel viscera.9 Deep vein thrombosis (DVT) has been described in patients with AIVC,10,11 and recent reports suggest that there may be an association between the two conditions.12,13 Hyperhoniocysteinemia (HCY) is an established risk factor for DVT. In this report, we describe a 39-year-old patient with DVT caused by congenital absence of the supra- and infrarenal IVC, combined with HCY. Clinical features of the

Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea. Correspondence to: Ji Il Kim, MD, Department of Surgery, Catholic University Medical College, Uijonbu St. Mary’s Hospital, 65-1, Kumo-dong, Uijongbu-Shi, Kyunggi-Do, 480-130 Republic of Korea, E-mail: [email protected] Ann Vasc Surg 2004; 18: 124-129 DOI: 10.1007/s10016-003-0087-x Ó Annals of Vascular Surgery Inc. Published online: 20 January 2004 124

case as well as the diagnostic and therapeutic options taken are discussed.

CASE REPORT A 39-year-old woman was admitted to our hospital with painful swelling of both legs. There was no history of immobilization, trauma, surgery, oral contraceptive use, or venous thromboembolism in the family. The results of the physical examination were essentially within normal limits except for an edematous swelling of both lower extremities that was brightly colored and sensitive to pressure. In addition, prominent, dilated, tortuous superficial vessels on the lower abdominal wall and pelvis were noted. The routine laboratory values were normal. Coagulation studies showed hyperhomocysteinemia (29 lmol/ L, reference value; 5–15 lmol/L), a positive D-dimer test, and a homozygous mutation of C677T methylenetetrahydrofolate reductase (MTHER). Other parameters, including antithrombin III, protein C, protein S, plasminogen, fibrinogen, factor V Leiden mutation, antinuclear antibody, anticardiolipin antibody, activated protein C resistance, and prothrombin gene mutation, did not show a defect predisposing to thrombophilia. A venous duplex scan was performed, which showed bilateral thrombotic occlusion of the femoral veins. However, the proximal extent was not seen. A computed tomography (CT) scan demonstrated low-density changes in both proximal femoral veins, a finding consistent with DVT. The patent IVC was seen from the right atrium to the level of the hepatic vein confluence. Below the hepatic

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veins, the IVC was not observed. A prominent azygous vein, hemiazygous vein, paravertebral venous plexus, and lumbar vein were seen. A magnetic resonance angiogram (MRA) revealed a normal-caliber vena cava between the hepatic veins and right atrium, agenesis of the suprarenal segment of the IVC associated with azygous continuation, and absence of the infrarenal segment of the IVC (Fig. 1). From these findings, congenital agenesis of the IVC in combination with hyperhomocysteinemia was diagnosed and interaction of the defects was suggested as the cause of DVT. After the diagnosis was made, the patient was treated with subcutaneous low-molecular-weight heparin (LMWH) injection for 5 days. Afterward, oral warfarin and folic acid were administered, and swelling in both legs subsided gradually. The patient was discharged with a recommendation to continue lifelong therapy within a therapeutic international normalized ratio (INR) of 2-3. In addition, we advised the patient to avoid overexertion, prolonged immobilization, and oral contraceptive use. We rechecked the homocystein level at 4 and 8 weeks after folic acid supplementation. After 4 weeks, the homocystein level fell to 21 lmol/L and by 8 weeks it fell to within normal range (13 lmol/L). Currently, the patient is well with no recurrence of DVT after 10-month follow-up.

DISCUSSION The embryology of the IVC has been well described.5,14-18 The embryologic derivation of the IVC is complex, involving development and regression of segments of the paired postcardinal, subcardinal, and supracardinal veins and the hepatic veins at approximately the sixth week after conception. The intrahepatic IVC derives from hepatic sinusoids. Whereas the infrarenal IVC and the azygous/hemiazygous systems derive from supracardinal veins, the suprarenal, extrahepatic cava forms from the subcardinal vein. (Both subcardinal and supracardinal remnants contribute to the renal collar.) The iliac veins, like the superior vena cava, derive from the posterior cardinal vein. Failure of formation of these anastomoses with persistence rather than regression of the supracardinal segments presumably leads to the clinical finding of a dilated azygous/hemiazygous ‘‘continuation’’ with congenital absence of the IVC. Absence or agenesis of the IVC is often used to describe two distinct entities. First, failure of the hepatic-subcardinal anastomosis results in the suprarenal interruption of the IVC with an azygous continuation. Approximately 90% of previously reported cases involved absence of the suprarenal portion of the IVC.19 This occurs in

Fig. 1. Gadolinium-enhanced MRA. Below the hepatic vein (HV), the inferior vena cava (IVC) is completely absent. Renal venous collaterals collect the venous blood from both patent renal veins (RV) and drain into azygous vein (AV), which is enlarged to compensate the anomaly. Enlarged paravertebral veins are shown. AA, abdominal aorta; PV, portal vein.

approximately 0.6 to 2% of patients with other congenital cardiovascular defects, 0.3 to 0.5% in otherwise healthy individuals.9,20-22 Common cardiac defects include dextrocardia, atrial septal defect, atrioventricular canal, and pulmonary arterial stenosis. There is a frequent association with transposed abdominal viscera, dysgenesis of the lungs, polysplenia or asplenia, and renal hypoplasia or agenesis.23 Second, absence of the infrarenal segment of the IVC is an extremely rare anomaly. Past studies report that only 6% of IVC anomalies involved the renal or infrarenal segments.19 Since 1957, 21 cases proven by imaging have been reported in the English-language literatures.1,24,25 In addition to

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our patient, at least nine reports have been published pertaining to absence of the infrarenal IVC along with suprarenal segment.1-8 Among them, only one case had associated congenital anomaly. Six cases had symptoms of DVT, the other three cases presented as a prominent left paraspinous mass, urinary retention, or prominent superficial varicosity. The reasons for developmental failure are unclear. Most researchers believe that the cause lies in embryonic dysgenesis affecting separate segments or the entire IVC.5,9,16-18 Others suggest that the infrarenal absence of the IVC is not embryonic in origin, rather the result of intrauterine or perinatal thrombosis.3,7,26 In the literature, AIVC was commonly asymptomatic. Patients who have a deep venous collateral system that drains blood from the lower extremities to the heart via azygous and hemiazygous veins, without other combined anomalies, usually remain asymptomatic. Most cases, were detected incidentally upon routine radiologic screening or abdominal surgery. In patients at risk for thrombogenic events, however inadequate blood return through collaterals may increase the venous blood pressure in the veins of the leg, favoring venous stasis and subsequent DVT, and chronic venous insufficiency.5-7,23,27,28 The incidence of DVT in the Western population is estimated at 1 in 1000 individuals per annum.29 This figure varies with age, and in adults between 20 and 40 years of age the incidence is 10 times lower.30 The percentage of AIVC in DVT is estimated to be around 5–6.7%,1,12,13 a rate greater than expected (5% observed 0.5% expected). Through a computerized MEDLINE search of English-language reports published up to 2002, we found 26 cases of DVT in patients with congenital anomalies of the IVC.1,6-8,10-13,19,23-25,28,31-33 We reviewed the reported cases along with the case presented above (Table I). Three notable features of IVC malformation with DVT were found. First, patients with these anomalies were significantly younger. In the literature, the mean age (± standard deviation) of DVT in the general population is 53 ± 19 years,1 but that of the group having AIVC with DVT is 27 ± 9.7 years. Second, an excess of bilateral thrombosis was observed. Previous papers report that DVT is bilateral in 11-44% of general cases.34,35 Combining the data of previously reported cases with our own, bilateral DVT (including 6 cases of controlateral DVT history) was seen in 16 out of 26 (54%) cases associated with an IVC anomaly. Third, 18 of 26 patients (69%) had no other precipitating factors or clotting defects. This review suggests that the presence of AIVC

Annals of Vascular Surgery

should be considered in young patients with idiopathic, recurrent, or bilateral DVT. The absence of precipitating factors or clotting factor defects predisposing to hypercoagulability also suggests that AIVC may be a sufficient cause for the development of DVT. Venous thrombosis is now believed to be a multifactorial disease. Since HCY is a common abnormality, it is likely to interact with other inherited or acquired prothrombotic factors to increase the overall risk of venous thrombosis.36,37 More recently, an association between HCY and a heightened risk of venous thromboembolism has been documented, suggesting that HCY might be involved not only in atherogenesis but also in thrombogenesis.38 The mechanisms by which HCY might contribute are incompletely understood. We did not find any other causes of hyperhomocysteinemia in our patient. (The patient’s thyroid function, renal function, and fasting blood glucose level were normal). But we did not check for vitamin deficiency and cystathionine b-synthase. Therefore, it is difficult to say whether homozyous mutation of C677T methylenetetrahydrofolate reductase is the cause of hyperhomocysteinemia. We were able to make the correct diagnosis by means of a CT scan and MRA. Both techniques make AIVC readily discernible.21,39 MRA, however, has the advantage of providing a simple, noninvasive method for revealing vascular structures in anatomical detail without exposing the patient to ionized radiation. For AIVC, surgical intervention is seldom indicated. In most cases, lifelong oral anticoagulation therapy is sufficient. In the literature only one patient did not respond sufficiently to conservative management.6 The patient underwent bypass surgery from the right common iliac vein to azygous vein with 13-mm ringed polytetrafluoroethylene (PTFE) graft material. Thrombolysis is another treatment option in iliofemoaral DVT. But in cases of DVT caused by AIVC, thrombolytic therapy was given in only three cases, and two cases failed.1,2,24 We did not use this treatment for two reasons. First, immediately after treating the patient with anticoagulation, leg elevation, and elastic stocking support, swelling and discomfort in both legs gradually subsided. Second, the patient and her family refused thrombolysis. The mainstay of treatment of HCY is folic acid, alone or in combination with vitamin B12 and vitamin B6. Our patient was treated with anticoagulation therapy, vitamin supplementation, stocking support, leg elevation, and exercise for the lower extremities. The patient was also advised to avoid additional thrombogenic risk factors,


23 28 37 30 23 18 40 26 12 20 22 15 19 21

Awartani and McComb (1999)33 Klessen et al. (1999)8 Timmers et al. (1999)23

Hamoud et al. (2000)11 Chee et al. (2001)12


20 35 44 39

Schneider et al. (2002)32

Present case (2003)


()) ()) ())

()) ()) ()) ()) ()) ()) ()) Hypoplasis of right kidney ()) ()) ())

NR ()) ()) ()) Hypoplasis of right kidney ()) ()) Absence of right kidney ()) ()) ())


Combined anomalies


Unilateral Botha Unilateral

Botha Both Unilateral

Both Both Botha Unilateral Both Unilateral Both Both

Botha Unilateral Both

Unilateral Both Unilateral

NR Unilateral Unilateral Botha Botha


Site of DVTa

HCY, hyperhomocysteinemia; NR, not recorded. a Patient had history of controlateral DVT. b Predisposing factors include immobilization, surgery, oral contraceptive pills, trauma, and malignancy.





25 24 22

Obernosterer et al.(2002)1

Tsuji et al. (2001)24

Ramanathan et al. (2001)25 Ruggeri et al. (2001)13


18 19 41 30 49

Glerup and Therkildsen (1994)31 Salto et al. (1995)10 Dougherty et al. (1996)6 Shah et al. (1996)19 Ordonez et al. (1998)7



Milner and Marchan (1993)2


Age (years)


Table I. Summary of published cases of DVT caused by congenital IVC malformation


No Yes Yea

Yes No No

No No Yes No No No No No

Yes No No

Yes No No

NR No Yes Yes Yes


Recurrence of DVT

()) ()) Protein S deficiency ()) ()) Factor V mutation HCY

()) ()) Factor V mutation ()) ()) ()) ()) ()) ()) ()) ())

()) ()) ())

Factor XII deficiency NR ()) ()) ()) ())

Underlying coagulopathy


Yes No No

No Yes Yes

No No No No No No No No

No No Yes

Yes No No

NR No No No No


Precipitating factorsb


Anticoagulation Anticoagulation Anticoagulation

Anticoagulation Anticoagulation Anticoagulation

Anticoagulation Anticoagulation Anticoagulation Anticoagulation Anticoagulation Anticoagulation Anticoagulation Thrombolysis

Anticoagulation Anticoagulation Anticoagulation

Anticoagulation Anticoagulation Anticoagulation

Anticoagulation Anticoagulation Bypass surgery Anticoagulation Anticoagulation



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such as unusual physical activity, prolonged immobilization, and oral contraceptive use. Our case report and the literature suggest that a more thorough investigation should be carried out in young patients with recurrent and bilateral DVT to exclude IVC anomalies. Hypercoagulability induced by HCY with a tendency toward venous stasis mediated by AIVC was the causae of DVT in our patient. To our knowledge, this is the first reported case of DVT due to AIVS, combined with hyperhomocysteinemia. REFERENCES 1. Obernosterer A, Aschauer M, Schnedl W, et al. Anomalies of the inferior vena cava in patients with iliac venous thrombosis. Ann Intern Med 2002;136:37-41. 2. Milner LB, Marchan R. Complate absence of inferior vena cava presenting as paraspinous mass. Thorax 1980;35:798800. 3. Mosli HA, Papoff WJ, Moors DE. Unusual clinical presentation of a patient with absent inferior vena cava. J Urol 1985;134:969-971. 4. Knudtzon J, Gudmundson TE, Svane S. Congenital absence of the entire inferior vena cava. Acta Chir Scand 1986; 152:541-546. 5. Debing E, Tielemans Y, Jolie E, et al. Congenital absence of inferior vena cava. Eur J Vasc Surg 1993;7:201-203. 6. Dougherty MJ, Calligaro KD, de Laurentis DA. Congenitally absent inferior vena cava presenting in adulthood with venous stasis and ulceration: a surgically treated case. J Vasc Surg 1996;23:141-146. 7. Ordonez FS, Carrasco JCG, Recio FJB, et al. Absence of the inferior vena cava causing repeated venous thrombosis in an adult. Angiology 1998;49:951-956. 8. Klessen C, Deutsch HJ, Karasch T, et al. Thrombosis of the deep leg and pelvic veins in congenital agenesis of the vena cava inferior. Dtsch Med Wochenschr 1999;124:523-526. 9. Anderson RC, Adams P, Burke B. Anomalous inferior vena cava with azygos continuation (infrahepatic interruption of the inferior vena cava). J Pediatr 1961;59:370-383. 10. Saito H, Sano N, Kaneda I, et al. Multisegmental anomaly of the inferior vena cava with thrombosis of the left inferior vena cava. Cardiovasc Intervent Radiol 1995;18:410-413. 11. Hamoud S, Nitecky S, Engel A, et al. Hypoplasia of the inferior vena cava with azygos continuation presenting as recurrent leg deep vein thrombosis. Am J Med Sci 2000; 319:414-416. 12. Chee YL, Culligan DJ, Watson HG. Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young. Br J Haematol 2001;114:878-880. 13. Ruggeri M, Tosetto A, Castaman G, et al. Congenital absence of the inferior vena cava: a rare risk factor for idiopathic deep vein thrombosis. Lancet 2001;357:441. 14. Embryology. In: Williams, PL, Warwick, R, Bannister, LH, Eds. Gray’s Anatomy, 37th ed. Edinburgh: Churchill Livingstone, 1989, pp 219-226. 15. Philips E. Embryology, normal anatomy and anomalies. In: Ferris, EJ, Hipona, FA, Kahn, PC, Shapiro, JH, Eds. Venography of the Inferior Vena Cava and Its Branches. Baltimore: Williams and Wilkins, 1969, pp 1-32.

Annals of Vascular Surgery

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