**Vena Cava Malformations as an Emerging Etiologic Factor for Deep Vein Thrombosis in Young Patients**

Massimiliano Bianchi1, Lorenzo Faggioni1, Virna Zampa1, Gina D'Errico1, Paolo Marraccini2 and Carlo Bartolozzi1 *1Azienda Ospedaliero-Universitaria Pisana, 2Istituto di Fisiologia Clinica del CNR 1,2Italia* 

## **1. Introduction**

42 Deep Vein Thrombosis

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Deep venous thrombosis (DVT) is an illness of clinical interest, due to the associated morbidity and mortality and its social and health care consequences. The etiology in young patients has shown it frequently associated with congenital coagulation abnormalities and acquired/inherited risk factors (table I) (a,b).

#### **Inherited**

Common G169A mutation in the factor V gene (factor V Leiden) G20219A mutation in the protrombin (factor II) gene Homozygous C677T mutation in the methylenetetrahydrofolate reductase gene Rare Antitrombin deficiency Protein C deficiency Protein S deficiency Very rare Dysfibrinogenemia Homozygous homocystinuria Probably inherited Increased levels of factor VII, IX, XI or fibrinogen **Acquired** Surgery and trauma Prolonged immobilization Older age Cancer Myeloproliferative disorders Previous thrombosis Pregnancy and the puerperium Use of contraceptives or hormone-replacement therapy

Vena Cava Malformations as an

the aorta, and caudal to the superior mesenteric artery.

Emerging Etiologic Factor for Deep Vein Thrombosis in Young Patients 45

Fig 1) develop ventromedial to the posterior cardinal veins and ventrolateral to the aorta. The intersubcardinal anastomosis forms between the paired subcardinal veins, anterior to

Fig. 1. Conceptual framework for development of the IVC. Composite schematic shows the

contribute to development of the IVC. The pictured veins are not all present simultaneously.

Anastomosis between the posterior cardinal and subcardinal veins (light violet in Fig 1) develop on each side at approximately the level of the intersubcardinal anastomosis. At the same time, union occurs between the right subcardinal vein and the hepatic segment of the IVC, which forms from the vitelline vein. As the cranial portions of the posterior cardinal veins begin to atrophy, blood return from the lower extremities is shunted through the postsubcardinal anastomosis, then through the subcardinal-hepatic anastomosis to the hepatic segment of the IVC. This process establishes the pre-renal division of the IVC. The next major development is the appearance of the paired supra-cardinal veins (goldenrod in Fig 1), which lie dorso-medial to the posterior cardinal veins and dorso-lateral to the aorta. Initially, multiple anastomosis form between the posterior and supracardinal veins. On each side, a suprasubcardinal anastomosis (yellow in Fig 1) develops from union of the postsupracardinal and the postsubcardinal anastomosis. In addition, intersupracardinal anastomosis develop dorsal to the aorta. The supracardinal veins then separate into cranial (azygos) and caudal (lumbar) ends. Meanwhile, inferiorly, anastomosis develop between the two posterior cardinal veins and between the posterior and lumbar supracardinal veins. With further atrophy of the posterior cardinal veins, blood return from the lower extremities is shunted through the supracardinal system to the suprasubcardinal anastomosis, then to the pre-renal division of the IVC. In addition, blood return from the left side of the body is shunted to the right across the intersupracardinal and interpostcardinal anastomosis.

relative positions and interrelationships of the three paired embryonic vessels that

card= cardinal, post= posterior, SMA= superior mesenteric artery, v= vein, 1=

intersubcardinal anastomosis, 2 = intersupracardinal anastomosis.

Resistence to activated protein C (not due alterations in the factor V gene Antiphospholipid antibodies) Mild to moderate hyperomocysteinemia

Table 1. inherited and acquired risk factors for DVT.

However, recent radiological advances derived from multislice computerized tomography (CT) and magnetic resonance imaging (MRI) have identified vena cava malformations as a new etiologic factor to be considered.(c-g)

The objectives of the present chapter are to describe the embryogenesis and the spectrum of congenital anomalies of the inferior vena cava (IVC) as a risk factor in DVT in young patients. Anomalies of the inferior vena cava (IVC) and its tributaries have been known to anatomists since 1793, when Abernethy(h) described a congenital meso-caval shunt and azygos continuation of the IVC in a 10-month-old infant with polysplenia and dextrocardia. Since the development of cross-sectional imaging, congenital anomalies of the IVC and its tributaries have become more frequently encountered in asymptomatic patients(c). The imaging study with CT and MRI of the abdominal vein structures require a specific thecnique of acquisition in relation with contrast medium injection. During the usual vascular study, that are acquired in arterial phase, the visualization of veins is not adequate for the recognition of the vein system. This may are usually readily identified on CT and magnetic resonance (MR) imaging scans of the abdomen and pelvis obtained with intravenously administered contrast medium. In addition, with helical acquisition, the venous structures may be imaged during the arterial phase, when little or no contrast material is present in the veins. Therefore, in these cases the diagnostic request is essential for correct interpretation of vein vasculature and to avoid erroneous diagnosis (retroperitoneal and mediastinal masses or adenopathy) and to alert the surgeon and angiographer about the characteristics of vascular anatomy.

### **1.1 The embryogenesis of the IVC**

The embryogenesis and the anatomic variations of the IVC become more clear with the development of the CT and magnetic resonance (MR) imaging in clinical practice. In the past Phillips(i) has published a comprehensive review of the embryogenesis of the IVC. In brief, the infrahepatic IVC develops between the 6th and 8th weeks of embryonic life as a composite structure formed from the continuous appearance and regression of three paired embryonic veins. In order of appearance, they are the posterior cardinal, the subcardinal, and the supracardinal veins (Fig 1).

Under ordinary circumstances, the prerenal division is formed from union of the hepatic segment (green area), a vitelline vein derivative, and the right subcardinal vein (magenta area). The renal segment is formed from the suprasubcardinal anastomosis (yellow area) and the postsubcardinal anastomosis (light violet area). The infrarenal segment derives from the right supracardinal vein (goldenrod area). The posterior cardinal veins (dark violet area) form the iliac veins (Adapted and reprinted, with permission, from reference d). Initially, all blood return from the body wall caudal to the heart proceeds through the posterior cardinal veins (dark violet in Fig 1). Blood return from the viscera is conveyed by the vitelline veins (green in Fig 1), which drain the yolk sac. Subsequently, the subcardinal veins (magenta in

However, recent radiological advances derived from multislice computerized tomography (CT) and magnetic resonance imaging (MRI) have identified vena cava malformations as a

The objectives of the present chapter are to describe the embryogenesis and the spectrum of congenital anomalies of the inferior vena cava (IVC) as a risk factor in DVT in young patients. Anomalies of the inferior vena cava (IVC) and its tributaries have been known to anatomists since 1793, when Abernethy(h) described a congenital meso-caval shunt and azygos continuation of the IVC in a 10-month-old infant with polysplenia and dextrocardia. Since the development of cross-sectional imaging, congenital anomalies of the IVC and its tributaries have become more frequently encountered in asymptomatic patients(c). The imaging study with CT and MRI of the abdominal vein structures require a specific thecnique of acquisition in relation with contrast medium injection. During the usual vascular study, that are acquired in arterial phase, the visualization of veins is not adequate for the recognition of the vein system. This may are usually readily identified on CT and magnetic resonance (MR) imaging scans of the abdomen and pelvis obtained with intravenously administered contrast medium. In addition, with helical acquisition, the venous structures may be imaged during the arterial phase, when little or no contrast material is present in the veins. Therefore, in these cases the diagnostic request is essential for correct interpretation of vein vasculature and to avoid erroneous diagnosis (retroperitoneal and mediastinal masses or adenopathy) and to alert the surgeon and

The embryogenesis and the anatomic variations of the IVC become more clear with the development of the CT and magnetic resonance (MR) imaging in clinical practice. In the past Phillips(i) has published a comprehensive review of the embryogenesis of the IVC. In brief, the infrahepatic IVC develops between the 6th and 8th weeks of embryonic life as a composite structure formed from the continuous appearance and regression of three paired embryonic veins. In order of appearance, they are the posterior cardinal, the subcardinal,

Under ordinary circumstances, the prerenal division is formed from union of the hepatic segment (green area), a vitelline vein derivative, and the right subcardinal vein (magenta area). The renal segment is formed from the suprasubcardinal anastomosis (yellow area) and the postsubcardinal anastomosis (light violet area). The infrarenal segment derives from the right supracardinal vein (goldenrod area). The posterior cardinal veins (dark violet area) form the iliac veins (Adapted and reprinted, with permission, from reference d). Initially, all blood return from the body wall caudal to the heart proceeds through the posterior cardinal veins (dark violet in Fig 1). Blood return from the viscera is conveyed by the vitelline veins (green in Fig 1), which drain the yolk sac. Subsequently, the subcardinal veins (magenta in

Resistence to activated protein C (not due alterations in the factor V gene

Antiphospholipid antibodies)

Mild to moderate hyperomocysteinemia

new etiologic factor to be considered.(c-g)

Table 1. inherited and acquired risk factors for DVT.

angiographer about the characteristics of vascular anatomy.

**1.1 The embryogenesis of the IVC** 

and the supracardinal veins (Fig 1).

Fig 1) develop ventromedial to the posterior cardinal veins and ventrolateral to the aorta. The intersubcardinal anastomosis forms between the paired subcardinal veins, anterior to the aorta, and caudal to the superior mesenteric artery.

Fig. 1. Conceptual framework for development of the IVC. Composite schematic shows the relative positions and interrelationships of the three paired embryonic vessels that contribute to development of the IVC. The pictured veins are not all present simultaneously. card= cardinal, post= posterior, SMA= superior mesenteric artery, v= vein, 1= intersubcardinal anastomosis, 2 = intersupracardinal anastomosis.

Anastomosis between the posterior cardinal and subcardinal veins (light violet in Fig 1) develop on each side at approximately the level of the intersubcardinal anastomosis. At the same time, union occurs between the right subcardinal vein and the hepatic segment of the IVC, which forms from the vitelline vein. As the cranial portions of the posterior cardinal veins begin to atrophy, blood return from the lower extremities is shunted through the postsubcardinal anastomosis, then through the subcardinal-hepatic anastomosis to the hepatic segment of the IVC. This process establishes the pre-renal division of the IVC. The next major development is the appearance of the paired supra-cardinal veins (goldenrod in Fig 1), which lie dorso-medial to the posterior cardinal veins and dorso-lateral to the aorta. Initially, multiple anastomosis form between the posterior and supracardinal veins. On each side, a suprasubcardinal anastomosis (yellow in Fig 1) develops from union of the postsupracardinal and the postsubcardinal anastomosis. In addition, intersupracardinal anastomosis develop dorsal to the aorta. The supracardinal veins then separate into cranial (azygos) and caudal (lumbar) ends. Meanwhile, inferiorly, anastomosis develop between the two posterior cardinal veins and between the posterior and lumbar supracardinal veins. With further atrophy of the posterior cardinal veins, blood return from the lower extremities is shunted through the supracardinal system to the suprasubcardinal anastomosis, then to the pre-renal division of the IVC. In addition, blood return from the left side of the body is shunted to the right across the intersupracardinal and interpostcardinal anastomosis.

Vena Cava Malformations as an

Emerging Etiologic Factor for Deep Vein Thrombosis in Young Patients 47

(a)

Fig. 2. Partial malrotation and left IVC in a 49-year-old man. (a) Schematic shows a left IVC terminating at the left renal vein. (b-e) CT scans presented from caudal to cranial show the anomaly. (b) Note the left IVC (arrow) inferior to the renal veins. (c) The left IVC joins the left renal vein (arrow). (d) The left renal vein (arrow) crosses anterior to the aorta in the normal fashion. (e) A normal right-sided prerenal IVC is formed from the confluence of the left (straight arrow) and right (curved arrow) renal veins. Note the increased attenuation of the right renal vein relative to that of the left due to absence of dilution from relatively unenhanced lower-extremity venous return. The major clinical significance of this anomaly

is the potential for misdiagnosis as left-sided paraaortic adenopathy(k).

Finally, the left supracardinal vein is one of the last veins to disappear, although Huntington and McLure(j) state that the vessel does not so much atrophy as become incorporated into the right supracardinal vein by coalescence of the multiple anastomosis. In summary, the normal IVC is composed of four segments: hepatic, suprarenal, renal, and infrarenal. The hepatic segment is derived from the vitelline vein. The right subcardinal vein develops into the suprarenal segment by formation of the subcardinal-hepatic anastomosis. The renal segment develops from the right suprasubcardinal and postsubcardinal anastomosis. It is generally accepted that the infra-renal segment derives from the right supracardinal vein, although this idea is somewhat controversial(i). In the thoracic region, the supracardinal veins give rise to the azygos and hemiazygos veins. In the abdomen, the postcardinal veins are progressively replaced by the subcardinal and supracardinal veins but persist in the pelvis as the common iliac veins.
