Enoxaparin sodium

This report illustrates how newer imaging techniques are identifying vasculopathies as risk factors for deep venous thrombosis (DVT). In this case, a healthy young man presented with a straightforward DVT but without traditional risk factors. Doppler ultrasonography confirmed a proximal clot, and contrast-enhanced computed tomography identified a hypoplastic inferior vena cava (IVC). DVTs cause considerable morbidity and death each year, including ~200,000 fatal pulmonary embolisms. Specific treatment of DVTs and long-term management and prevention strategies are contingent on the etiology, which can be determined in ~85% of cases. A hypoplastic IVC was discovered during efforts to find the cause of thrombosis, and a Medline search suggests that this anomaly should be considered for young persons with DVTs. DVTs are common and their underlying etiology should be identified to help guide long-term management. Evidence is emerging that an anomalous FVC should be ruled out as a cause of DVT among young patients.

Introduction

Arterial and venous thromboses are a major cause of morbidity and death. Each year in the United States, deep venous thromboses (DVTs) alone are responsible for up to 600.000 pulmonary embolisms (PEs), including 150,000 to 200,000 that are fatal. DVTs and PEs are part of the same disease process and are collectively known as venous thromboembolisms (VTEs). The risk of VTE is greatly increased when components of Virchow's triad, i.e., venous stasis, venous injury, and hypercoagulability, are present. They can occur after trauma or surgery, particularly among nonambulatory patients. Some medications, cancers, and chronic diseases of the cardiovascular or respiratory systems also increase the likelihood of VTEs. The cause of a DVT should be determined whenever possible, to guide specific treatment and to tailor long-term management strategies to prevent recurrence.

This is a case of lower-extremity DVT in a healthy young man who presented with no clinical or historical risk factors for VTE and who did not have a coagulopathy identified by laboratory studies. Contrast-enhanced computed tomography (CT) uncovered a hypoplastic inferior vena cava (IVC), which is increasingly being identified as a cause of lower-extremity DVTs among young patients.

Illustrative case

The patient was a 38-year-old man who presented with a straightforward case of DVT without an immediately apparent proximate cause. He denied trauma or previous history of pain or swelling of the lower extremities and also denied recent travel or sedentary periods. He had no significant medical history or previous operations and took no medications. He neither used tobacco products nor consumed alcoholic beverages, and his family history and review of systems were unremarkable.

The patient was afebrile at presentation and in no distress but walked with a limp, favoring the left leg. His pulse was 85 beats per minute, respiration rate 16 breaths per minute, and blood pressure 117/68 mm Hg. The room air oxygen saturation was 100%. Examination results for the head, neck, chest, back, and abdomen were normal. The heart rate was regular, the lungs completely clear to auscultation, and the electrocardiogram normal. The left groin was tender to palpation over the inguinal nerve-artery-vein bundle, but there was no swelling, discoloration, or bruit. The left leg circumference measured 60 cm and 44 cm at mid-thigh and mid-calf levels, respectively, compared with 56 cm and 41 cm on the right. Pain was elicited from the back of the left knee and calf when the ankle was dorsiflexed (Homans' sign). DVT was suspected, and its presence was confirmed with Doppler ultrasonography, which showed a large clot extending from above the femoral triangle to the popliteal fossa of the left leg.

The patient was admitted to the hospital for therapy, which consisted of left leg elevation, warm compresses, and anticoagulation with enoxaparin, a low-molecular weight heparin (LMWH), administered subcutaneously every 12 hours at a dose of 1 mg/kg. He also received an oral loading dose of 5 mg of warfarin sodium (Coumadin), with a target international normalized ratio (INR) of 2.5 (desired range, 2.0-3.0). Chest radiographs and initial laboratory studies, including complete blood cell count, erythrocyte sedimentation rate. Chem7 panel, liver function tests, prothrombin time/partial thromboplastin time, and urinalysis, yielded normal results. Serum coagulation studies were also performed, and the results were normal; these included protein S, protein C, antithrombin III, antiphospholipid antibody, and factor V Leiden assays. Contrast-enhanced CT scans of the abdomen and pelvis showed a hypoplastic IVC measuring

The swelling was markedly improved in 1 year, with subsequent imaging studies showing complete resolution of the thrombosis.

Discussion

Blood clots, arterial and venous thromboses, are a leading cause of morbidity and death in the United States and are responsible for ~2 million deaths each year.1 Proximal (above the knee) DVTs of the lower extremity are periodically seen in primary care clinics and account for 300,000 to 600,000 PEs annually,1-3 including 150,000 to 200,000 that result in death.4 As noted by Hyers et al.,2 "Treatment regimens for DVT and PE are similar because the two conditions are manifestations of the same disease process. When patients with VTE are carefully studied, the majority of those with proximal DVT also have PE (symptomatic or asymptomatic) and vice versa."

As shown in Table I, the signs and symptoms of DVT are nonspecific, and physical examination alone is unreliable for making the diagnosis.5 Doppler ultrasonography is the principal diagnostic test for DVT,6 and it has a sensitivity as high as 97% among symptomatic patients.7,8 Laboratory markers, magnetic resonance imaging, and CT have also been used to diagnose DVT, but their role remains unclear, although the published sensitivity of magnetic resonance imaging exceeds that of ultrasonography in some reports, particularly for pelvic dots. When ultrasonography or other noninvasive tests are inconclusive and DVT is still suspected, contrast venography remains the diagnostic standard, despite its invasiveness, its potential for complications, and its high cost.2,6,7

Thromboses are usually caused by one or more components of Virchow's triad and, because long-term treatment and prevention strategies are tied to etiology, the responsible component or components should be identified whenever the diagnosis of DVT is made. ' Table II indicates that each leg of Virchow's triad is commonly associated with several possible causes.3 With current methods, the cause is found in 80% to 90% of cases, and >50% of patients with DVT have a congenital or acquired defect of a coagulation protein or of platelets.1 Bick and Kaplan1 published a comprehensive review of the specific therapies for congenital and acquired syndromes of thrombosis and hypercoagulability, and many detailed evidence- and consensus-based recommendations for the management of VTEs attributable to other causes have been published elsewhere.2,3,4,7,9-11 In the reviewed guidelines, therapy is divided into two phases, i.e., initial and long-term treatment. The goals of the initial treatment phase are to stop propagation of the clot, to limit progressive swelling of the leg, and to prevent embolization. The goals of the long-term phase are to expedite resorption of the thrombus and to prevent recurrences.10

Heparin is the initial anticoagulant of choice for most VTEs, and LMWH has replaced unfractionated heparin in most settings, because it has better efficacy and safety.2,9 A straightforward, commonly used, clinical practice guideline for the general use of LMWH is shown in Table III.2 Adjunctive treatments include warm compresses over the thrombosis and elevation of the affected limb.

The best duration of long-term warfarin therapy is uncertain, and recommended courses range from 6 weeks to 3 months after an initial VTE with a reversible, time-limited cause.2,3,8 A 6-month course is usually recommended for idiopathic DVTs, and therapy should be continued for longer periods, possibly for life, for patients with the inherited coagulation protein deficienties noted in Table II.10 The American Heart Association recommends that treatment be continued indefinitely for recurrent thromboses and for an initial VTE among patients with active cancer.2,8,10

The IVC is formed during the sixth to eighth week of gestation, through a process of fusion and regression of three bilaterally paired vessels to a unilateral right-sided system. The intrahepatic segment of the IVC is formed through anastomoses between the inferior cardinal veins and the embryonic vitelline vessels from the omphalomesenteric system. The sacrocardinal veins eventually give rise to the infrarenal segment. IVC anomalies occur when the paired structures do not unite. The posterior cardinal veins, which drain the dorsal wall of the embryo, give rise to the azygous and hemiazygous venous systems.l2 The three most common malformations of the FVC include interruption of the IVC with azygous and hemiazygous continuation, transposition or duplication of the IVC, and circumaortic venous rings. Azygous continuation occurs because of atresia of the retrohepatic segment of the IVC. When the right inferior cardinal vein joins the right superior cardinal vein (instead of the IVC), blood flows to a compensating azygous system and then to the superior vena cava.12,13

A Medline search (with major headings of vena cava. inferior, and venous thrombosis) of English-language journals identified just over 1 dozen published reports concerning VTEs associated with malformations of the IVC.5,12-23 Because of advances in imaging technology, none of the reports was published before 1996, and no studies were found addressing the duration of therapy. The cumulative evidence from the reports suggests, however, that these patients are at increased risk for recurrent WEs and should therefore receive anticoagulation therapy indefinitely after an initial clot. This point is highlighted by the fact that our patient had a second DVT of the left leg within 2 months after electing to discontinue warfarin anticoagulation.

Malformations of the IVC are relatively uncommon in the general population, with a reported prevalence of 0.07% to 8.7%.5,15 In the setting of lower-extremity DVT. however, the incidence of these anomalies appears to be substantially greater. Obernosterer et al.5 published a prospective case series of 97 consecutive patients with confirmed DVTs. Using magnetic resonance angiography, those authors identified an FVC abnormality for 5 (16%) of the 31 patients who had DVTs involving at least one iliac vein. They described absent IVCs, hypoplastic hepatic segments, and missing renal or postrenal portions. Moreover, the five patients with IVC anomalies were clinically and statistically younger than the 92 patients without them (mean age with anomalies, 25 ± 6 years; mean age without anomalies, 53 ± 19 years; p = 0.002), leading the authors to conclude that an anomaly of the FVC should be suspected for young patients whenever thrombosis involving the iliac veins is seen. Ruggeri et al.16 and Chee17 independently reached similar conclusions in their separately published reports. In the first instance, over a 5-year period, the authors diagnosed four cases of absent IVC among young patients who presented with "idiopathic" lower-extremity DVTs. Using epidemiological data, they estimated the rate of co-occurrence of the two conditions to be ~5%. In the second report, Chee17 described a retrospective series of four young patients with anomalous IVCs who presented to his clinic over a 3-year period with "spontaneous unprovoked DVT." He also estimated a co-occurrence rate of 5%. The cumulative evidence from these reports suggests that, in the absence of large controlled studies designed to prove causality or to accurately quantify an association, anomalies of the FVC are a likely risk factor for proximal lower-extremity VTEs among young patients without a more common source.

Summary

Advances in imaging technology are demonstrating that spontaneous lower -extremity DVTs can be associated with venous stasis from a hypoplastic IVC. Although the exact prevalence of IVC malformations in the general population is not known (but is probably low), their presence is associated with increased risk of recurrent VTEs. Anomalies of the IVC should thus be ruled out as a cause of proximal lower-extremity DVTs, particularly among young patients without other identifiable causes. Patients with VTEs who are found to have malformed IVCs should receive anticoagulation therapy indefinitely, to reduce their risk of recurrent events, including life-threatening or fatal PEs.

Acknowledgments

I acknowledge the encouragement received from friends and colleagues Dana Stombaugh, MD, Mary Jane Herden, MD, and Francisco Gomez, MD, who also reviewed preliminary drafts of this article.

References

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Guarantor; CDR David A. Lane, MC USN

Contributor: CDR David A. Lane, MC USN

U.S. Naval War College, Newport, RI 02841.

Clinical data for the subject case were obtained while the author was on the medical staff of U.S. Naval Hospital Rota, Spain, FPO AE 09645-0018.

Presented at the Uniformed Services Academy of Family Physicians Scientific Assembly. March 24, 2004, San Diego, CA.

The views expressed in this article are the author's and do not reflect those of Navy Medicine, the Department of the Navy, or the U.S. Government.

This manuscript was received for review in March 2004 and was accepted for publication in August 2004.

Copyright Association of Military Surgeons of the United States Sep 2005
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