Highlights

  • Currently, there is no guidance regarding the management of patients with congenital abnormalities of the inferior vena cava who present with deep vein thrombosis

  • More than 80% of the patients were males and the mean age at the presentation of their first DVT episode was 23.6 years

  • 42.3% of the patients treated conservatively vs 15.4% of the patients treated with thrombolysis developed chronic symptoms

  • None of the patients treated with thrombolysis developed post-thrombotic syndrome

  • Recurrence of DVT occurred in 13% of the patients treated conservatively vs 7.7% of patients treated with thrombolysis

Introduction

Abnormalities of the inferior vena cava (IVC) are rare congenital conditions that occur during embryogenesis, from the 6th to 10th week of gestation, when the venous system develops [1, 2]. In rare cases, they are developed due to IVC thrombosis in a fetus or neonate with thrombophilia. These abnormalities are found approximately in 0.5% of the population and have been described as absence, atresia, agenesis, anomalous formation, or interruption of a particular segment of the IVC (hepatic, prerenal, renal, or infrarenal). There is no data on whether this condition is equally distributed between genders, however, the majority of patients with clinical presentations are young males [2,3,4]. Absence of the IVC has been associated with deep vein thrombosis (DVT) based on the pathophysiology of stasis of venous blood flow in the lower limbs that may not be adequately drained by the azygous venous system [2]. Compensatory enlargement of the collateral venous network may occur in some patients to outweigh the insufficient drainage [1]. The limited literature, which mainly consists of case reports and case series, has not been summarized and analyzed to provide adequate evidence for the management and clinical course of patients with DVT and abnormalities of the IVC.

Patients with this vascular defect may remain asymptomatic and their condition is mostly reported as an incidental finding in a CT angiography, MRI, or post-mortem examination. However, congenital abnormalities of the IVC should be suspected in cases of DVT, especially in young patients, with no other risk factors and apparent causes of DVT [5]. Current guidance of the European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis suggests early thrombus removal for iliofemoral DVT for patients with low risk for bleeding and without comorbidity of cancer or pregnancy. For patients with low to high risk for bleeding, anticoagulation with Novel Oral Anticoagulants (NOACs) is recommended over Low Molecular Weight Heparin (LMWH) and Vitamin K antagonists (VKAs) along with early compression which will relieve symptoms and residual venous occlusion. Anticoagulation therapy may be discontinued at 3 months if recurrence is not present. In cases of recurrent DVT despite compliance with treatment, modifications in the therapeutic schedule are required including switching the type of anticoagulation, increasing the dose of LMWH or NOAC to therapeutic dose, or switching to VKAs with a higher international normalized ratio (INR) target. Anticoagulation should be extended beyond three months in cases of recurrent unprovoked DVT in accordance with the judgment of the treating physician. However, the ESVS guidelines have no specific recommendation on the management of patients with DVT and congenital absence of IVC [2].

We report a case of Iliofemoral vein thrombosis in a young patient with congenital absence of the IVC and also seek to review the literature to identify evidence about the epidemiology, clinical presentation, management, and prognosis of this rare cause of deep venous thrombosis.

Methods

Case report

Medical notes including detailed patient history, emergency department admission notes, medical charts, imaging (preoperative, intraoperative, and postoperative completion angiogram), lab tests, drug charts, and follow-up notes were retrieved and studied to describe the case in detail. Written informed consent was obtained from the patient for the publication of his case accompanied by respective images.

Systematic literature review

Search strategy

We sought to review the literature to identify additional evidence about the epidemiology, clinical presentation, management, and prognosis of DVT in patients with congenital malformations of the inferior vena cava. To identify relevant articles, we systematically searched PubMed until November 2021 using the following search pattern: (absent IVC or absent inferior vena cava or inferior vena cava atresia or inferior vena cava defect) and (thrombosis, DVT, iliofemoral thrombosis, thromboembolism, acute ischemia, lower extremities ischemia). No limitation on the year of publication or language was set. Furthermore, the references in the relevant articles, including review studies, were checked to identify additional resources. Abstracts of conference proceedings were not sought.

Inclusion criteria

Two of the authors (VGA and AN) independently performed the literature search to locate potentially eligible studies. All studies including reviews, case reports, and case series reporting on the incidence of DVT in patients with congenital anomalies of the IVC were retrieved.

Data extraction

The following data were extracted from all eligible articles: first author, year of publication, clinical details, treatment, outcomes, and follow-up information. The most important findings were tabulated.

The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [6].

Results

Case report

A 24-yrs-old male patient presented with a few hours history of sudden onset pain and swelling of his right limb. On clinical examination, the right calf appeared hot, erythematous, and painful on palpation with edema extending to his proximal thigh. DVT was verified by performing a venous duplex scan. The patient had no history of trauma, or prolonged immobilization and his blood workup including liver function tests (LFTs) and tumor markers appeared within normal limits and factors of protein thrombophilia (dosing antithrombin, homocysteine, protein C and S, factor V of Leiden, and prothrombin mutation) were investigated and found negative. CT of the abdomen and pelvis showed thrombosis at the confluence of the external iliac vein with the interior iliac vein (Image 1), congenital agenesis of the inferior vena cava, and multiple paraspinal collateral channels (Image 2). Angiography (Image 3) showed filling defects of the interior iliac vein which are an indicator of occlusion due to deep venous thrombosis. The patient underwent catheter-directed thrombolysis (CDT). Specifically, he received thrombolytic therapy with 5 mg Actilyse (rtPA) bolus, followed by an infusion of rtPA 0,5 mg/h for 30 h and 500 IU/h heparin. Completion angiogram (Image 4) showed adequate permeability of the internal iliac vein until the spinal external venous plexus which was interpreted as a successful postoperative outcome. Clinically, the patient made an excellent recovery and his limb edema resolved completely. He has been followed up for 9 months and he remains asymptomatic and continues receiving oral apixaban for life as thromboprophylaxis (see Image 5).

Image 1
figure 1

Axial CT of the pelvis demonstrating filling defects as an indicator of thrombosis at the confluence of the external iliac vein with the interior iliac vein (red arrow)

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Image 2
figure 2

Axial CT of the abdomen demonstrating congenital agenesis of the inferior vena cava and multiple paraspinal venous collateral channels

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Image 3
figure 3

Angiography showing filling defects of the interior iliac vein which are an indicator of occlusion due to deep venous thrombosis (first image from right to left) and the insertion of a venous catheter in the inferior iliac vein (second and third image from right to left)

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Image 4
figure 4

Completion angiogram demonstrating adequate permeability of the interior iliac vein up to the spinal external venous plexus

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Image 5
figure 5

Image of the patient at presentation (a) and a week following intervention with thrombolysis (b). The patient had immediate and complete resolution of the right limb edema

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Systematic review

In Fig. 1, we present a flow diagram describing the selection process followed to identify reports included in this systematic review. The PubMed search yielded 320 potentially relevant articles published from 1996 to 2021. After screening the title and the abstract and reading the full text of the articles we decided that the inclusion criteria were fulfilled by 42 articles that presented 56 cases, in total [4, 5, 7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]. Data extracted from the 56 cases are presented in Tables 1, 2. Regarding gender distribution of the reported cases; 83.9% (53/56) of patients were males. The mean age of the patients at the presentation of their first DVT episode is 23.6 years.

Fig. 1
figure 6

Flow diagram of the systematic review

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Table 1 Studies reporting cases of patiens with DVT and congenital malformations of IVC treated with thrombolysis
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Table 2 Studies reporting cases of patiens with DVT and congenital malformations of IVC treated conservatively
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Comorbidities and other risk factors were also analyzed; 8.9% (5/56) of the patients had hereditary thrombosis risk factors (heterozygosity for factor V Leiden gene polymorphism, deficiency of antithrombin, protein C or protein S, heterozygous prothrombin gene 20210 mutation, positive lupus anticoagulant) and 19.6% (11/56) of the patients had non-hereditary risk factors (cancer, acute medical illness, surgery, trauma, immobility, obesity, inflammatory diseases and/or infection, hormone therapy, long-distance travel, recent hospitalization, use of contraceptive pills). Among females, 33.3% (3/9) were on oral contraceptives when the symptoms of DVT occurred. Only 10.7% of the reported cases presented with pulmonary embolism (PE). It should be noted that, in most cases, there were no clinical symptoms of PE, thus no further investigation was undertaken.

Conservative management with anticoagulation was used in 68% of the reported cases (38/56). Thrombolysis was used in 32% of the cases (18/56) followed by anticoagulation therapy. Thrombolysis was combined with thrombectomy, angioplasty, and/or stent placement in 5 patients, and in 1 patient the treatment was completed with open surgery and the use of prosthetic IVC grafting.

Among cases treated conservatively with anticoagulation and cases treated with thrombolysis, 68.4% (38/26) and 72.2% (13/18) had follow-up information available, respectively. Comparing the long-term outcomes of the two treatment groups, recurrence of DVT occurred in 13% (3/26) of the patients treated conservatively and in 7.7% (1/18) of patients treated with thrombolysis. The mean follow-up time was 22.6 and 14.4 months, respectively. At follow-up evaluation, 19.2% (5/38) of the patients treated conservatively presented completely asymptomatic and 42.3% (11/38) developed chronic symptoms (residual heaviness, pain, swelling, and cramping) while 76.9% (10/18) of the patients treated with thrombolysis presented completely asymptomatic and 15.4% (2/18) developed chronic symptoms. Finally, 11.5% (3/38) of patients who received conservative treatment developed post-thrombotic syndrome. None of the patients treated with thrombolysis developed post-thrombotic syndrome.

Discussion

The main finding of this study is that thrombolysis in patients with DVT and congenital abnormalities of the IVC can offer definitive treatment. Most of the patients are free of long-term symptoms and complications and rarely do they have recurrent DVT, especially if they are given long-term thromboprophylaxis. The appropriate dosing regimen or selection of thromboprophylaxis agents is not clear. Most contemporary studies report the use of lifelong prophylaxis with NOACs. Among cases that were identified by our systematic review and were treated with thrombolysis, only 1 suffered recurrent DVT. Furthermore, all patients reported complete resolution of their symptoms including pain and edema. Most importantly, none presented post-thrombotic syndrome. Finally, it should be noted that there were no procedure-related complications and thrombolysis was well tolerated by the entirety of the thrombolysis treatment group.

On the other hand, 42.3% of the patients treated with anticoagulation only developed at least mild chronic symptoms (residual heaviness, pain, swelling, and cramping), and a significant 11.5% of this group had post-thrombotic syndrome. Furthermore, 13% of the patients in this treatment group had recurrent DVT. It should be noted that most of the cases of patients with DVT and congenital malformations of the IVC that were treated conservatively were reported prior to 2010 when CDT was not available in most institutions. The contemporary guidelines for the management of iliofemoral venous thrombosis suggest early thrombus removal for patients with low risk for bleeding and without comorbidity of cancer or pregnancy [2]. Based on the above guidance and the findings of this study, we believe that it is imperative to perform CDT in patients with iliofemoral venous thrombosis and congenital malformations of the IVC.

It is really important to be able to recognize the presence of DVT in patients with IVC defects. The clinical presentation of thrombosis due to the absence of IVC varies according to the acuity and the extent of the thrombosis. Many patients may present with subtle symptoms that are difficult to recognize and correlate with DVT. Symptoms like leg heaviness, pain, swelling, and cramping may be accompanied by nonspecific abdominal/pelvic pain and scrotal swelling. Other symptoms like dyspnea and oliguria may occur due to clot migration and/or embolization into the lungs and renal veins respectively. Most patients with chronic IVC abnormalities have already developed collateral drainage networks and may tolerate an extensive iliofemoral thrombosis better than other patients. There are also reports of less common symptoms like lumbar radicular pain, sciatica, and cauda equina syndrome due to compression of peripheral nerves by dilated veins [45]. If not promptly and adequately treated, thrombosis can result in severe post-thrombotic syndrome with leg cramping, skin pigmentation, venous ulceration, and disabling claudication [2, 45].

The suspicion of IVC congenital malformations is based on the patients’ clinical symptoms that are not in keeping with their young age and the absence of other thrombosis risk factors. Duplex ultrasound is usually the modality of choice for initial screening but it should be followed by a CT angiography and/or MRI. Furthermore, it has been reported that in 30–40% of patients with DVT, PE is also present. The finding of our study that only 10.7% of patients with congenital IVC malformations present with PE may be justified by the abnormal anatomy of the deep veins which makes the propagation of thrombi into the pulmonary arteries less possible. Finally, it should be noted that the results of this study confirm that there is an uneven distribution among genders. More than 80% of the cases of venous thrombosis associated with malformations of the IVC occurred in males.

The result of this systematic review should be considered in view of certain limitations. First, it should be noted that IVC abnormalities are rare and the available evidence comes from case reports and case series. Thus the quality of evidence is low. Furthermore, the “file-drawer effect” should be acknowledged when interpreting the results of this review. Meaning that authors tend to publish cases of patients who had good outcomes, and put the cases with complications in the file-drawer. Finally, the available follow-up information for the reported cases is rather limited.

Due to the rarity of the condition, it may not be possible to organize a clinical trial to further investigate the management and treatment that should be provided to these patients. However, it is of value to organize a national or international registry for rare venous diseases like this. It is imperative to record and analyze all relevant cases and provide data about long-term follow-up with comprehensive and clear outcomes. This way, we will be able to summarise more patients and provide stronger evidence about the appropriate management of patients with IVC abnormalities who present with DVT. Guidelines issued by the relevant scientific societies will then be able to make a clear recommendation about the management of such patients.

In conclusion, it is really important to have high suspicion and be able to recognize congenital IVC malformations in young males who present with DVT and do not have significant risk factors or comorbidities. Thrombus removal by means of thrombolysis is the recommended treatment and can offer excellent short and long-term results. Anticoagulation with NOACs may be prescribed for life to prevent recurrence or for at least 6 months and then reconsidered following further evaluation of patients’ bleeding risk. In asymptomatic individuals, with an incidental finding of congenital absence of IVC, thromboprophylaxis may be considered to prevent DVT.