Predictive factors for iliac vein compression syndrome in patients with varicose veins

Abstract

Objective

This study aimed to identify predictors of iliac vein compression syndrome (IVCS) in patients with varicose veins and to evaluate the necessity of routine lower extremity venography for preoperative assessment of these patients.

Methods

A retrospective analysis was conducted on data from 1165 patients with lower-limb varicose veins who underwent preoperative venography at Wuhan Union Hospital, Tongji Medical College, China, between January 2019 and September 2023. Logistic regression analyses identified factors associated with concurrent IVCS, and a nomogram was constructed based on these findings.

Results

Out of 1165 patients, 75 (6.4%) had IVCS according to venography and 769 had iliac vein ultrasound and found 2 (0.17%) positives. Multivariate analysis revealed the independent predictive value of left-sided involvement (odds ratio (OR) = 3.22, 95% confidence interval (CI): 1.24–8.33, p = 0.016), history of deep vein thrombosis (DVT) in the affected limb (OR = 3.11, 95% CI: 1.21–8.00, p = 0.018), pain (OR = 2.24, 95% CI: 1.17–4.26, p = 0.014), and positive results on iliac vein ultrasound (OR = 25.56, 95% CI: 2.10–311.26, p = 0.011) for the presence of IVCS in patients with lower-limb varicose veins. A nomogram incorporating these predictors demonstrated moderate predictive ability (AUV = 0.689, 95% CI: 0.607–0.771), with good calibration upon validation.

Conclusions

Patients with left lower extremity varicose veins, pain symptoms, history of DVT in the affected limb, and positive iliac vein ultrasound findings are at a higher risk of concurrent IVCS. Patients with varicose veins who have the aforementioned risk factors may need to undergo preoperative angiography.

Keywords

Lower extremity venography iliac vein compression syndrome venous ultrasound of lower extremities

Introduction

Iliac vein compression syndrome (IVCS), also known as May–Thurner syndrome or Cockett syndrome, is a type of pelvic venous obstructive disease,¹ and its incidence in China is not yet clearly defined.² A domestic prospective study reported an IVCS incidence of 1.6% among asymptomatic patients in China.³ Additionally, IVCS is a causative factor for varicose veins. Lower-limb varicose veins are a common vascular surgical condition and a significant disorder treated surgically in vascular surgery.⁴ In China, the prevalence of lower-limb varicose veins is approximately 8.89%, in adult men and women are 10%–15% and 20%–25%, respectively,⁵ with chronic lower-limb venous disease accounting for 63.9% of the population experiencing lower-limb discomfort in the 50-year-old age group.⁶ Lower-limb varicose veins can be classified into two types, reflux and obstruction, based on different pathological changes. The latter type occurs due to deep venous return obstruction resulting in lower-limb venous blood stasis and chronic venous hypertension, gradually leading to the manifestation of chronic lower-limb venous insufficiency.⁷ For patients with varicose veins and IVCS, iliac vein stent implantation to address IVCS results in a lower recurrence rate of varicose veins, more significant symptom improvement, and more assured long-term efficacy compared to patients undergoing endovascular laser ablation.² However, prompt identification of IVCS is essential beforehand.

Doppler ultrasound is often used as an initial examination in clinical practice because of its noninvasive, rapid, and economical advantages. Nevertheless, factors such as pelvic intestinal gas, obesity, and differences in the professional skills of ultrasound technicians limit its use in evaluating iliac vein lesions.⁸ In China, traditional invasive catheter venography is used as the gold standard for diagnosing IVCS.⁹ Besides revealing the overall condition of the veins, it can provide real-time subjective observations of venous patency, thrombus formation, blood flow velocity, pressure gradients, positional flow changes in compressed veins, and venous reflux. A comprehensive evaluation of luminal patency and valve conditions can clearly identify the location and severity of stenosis and display the blood flow pattern in the iliac vein. However, considering its invasive nature, it is worth considering whether patients with high-risk factors for IVCS must undergo lower-limb venography.

This study retrospectively analyzed the characteristics of patients with combined IVCS in a population with lower-limb varicose veins, explored the accurate identification of iliac vein compression in the population with varicose veins, and evaluated the clinical significance of lower-limb venography in diagnosing patients with lower-limb varicose veins by establishing a clinical prediction model.

Material and methods

This study conducted a retrospective evaluation of electronic medical records of patients diagnosed with “lower-limb varicose veins” who underwent preoperative lower-limb venography at the Department of Vascular Surgery of Tongji Medical College, Huazhong University of Science and Technology, affiliated with Union Hospital, from September 2019 to September 2023.

All patients underwent the same procedural approach. They were positioned supine, and after routine disinfection, successful puncture of the ankle’s saphenous vein or the dorsal venous arch of the foot was performed, followed by the placement of an indwelling needle. Antegrade venography involved a unilateral injection of 20 mL of contrast agent, comprising 30 mL of iohexol injection and 20 mL of normal saline. Digital subtraction angiography dynamically observed the imaging of the deep and superficial veins from the foot and ankle to the inferior vena cava, recording the morphology and patency of the deep veins, collateral compensation, and other conditions.

Clinical data were collected, including gender, body mass index (BMI), affected side, underlying diseases, past medical history, clinical manifestations, Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification, and imaging examination data. The outcome of interest was the presence or absence of iliac vein compression in the affected limb, determined using lower-limb venography as the gold standard for diagnosis of IVCS.

Statistical analyses were conducted using SPSS version 23.0 and R version 4.3.1 software. Numerical data are expressed as n (%). The chi-square test compared binary variables between groups, with p < 0.05 considered statistically significant. Factors with p < 0.05 were included in multivariate logistic regression analysis, calculating the odds ratio (OR) and 95% confidence interval (CI) to analyze the characteristic factors of IVCS occurrence. A nomogram model was constructed based on the regression coefficients of independent risk factors, predicting the need for preoperative lower-limb venography. Model performance was evaluated by discrimination and calibration using the concordance index (C-index), receiver operating characteristic (ROC) curve, and area under the curve (AUC). A calibration curve plotted using 1000 bootstrap resamples assessed the nomogram’s calibration, with closer alignment to the standard curve indicating better predictive ability.

Results

From September 2019 to September 2023, we analyzed data from 1165 patients with lower-limb varicose veins. The patient cohort comprised 568 men (48.8%) and 597 women (51.2%), with 426 patients (36.6%) classified as obese (BMI >23.9 kg/m2). Varicose veins were more prevalent on the left side, affecting 854 patients (73.3%) compared to 311 patients (26.7%) on the right side. Additionally, 444 patients (38.1%) were classified as CEAP class <C4, while 721 patients (61.9%) were classified as class ≥C4. Of 1165 patients, 75 (6.4%) were diagnosed with IVCS based on lower-limb venography.

Deep and superficial vein Doppler ultrasound revealed superficial vein thrombosis in 169 patients (14.5%). Iliac vein ultrasound was performed on 769 patients (66.0%), and among them, two tested positive (Table 1). While it showed a high specificity (99.9%) for detecting IVCS, its sensitivity was notably low (4.3%). Only eight patients (1.0%) exhibited abnormal iliac vein ultrasound findings, with three (0.4%) showing possible narrowing or mild compression of the common iliac vein, and the remaining five cases related to thrombus.

Table 1.

Clinical characteristics of patients.

Risk		IVCS		Missing	Total
Risk		No	Yes	Missing	Total
Sex
	Male	529 (45.4%)	39 (3.3%)		568 (48.8%)
	Female	561 (48.2%)	36 (3.1%)		597 (51.2%)
Obesity (BMI >23.9 kg/m²)
	Yes	399 (34.2%)	27 (2.3%)		426 (36.6%)
	No	691 (59.3%)	48 (4.1%)		739 (63.4%)
Left side
	Yes	790 (67.8%)	64 (5.5%)		854 (73.3%)
	No	300 (25.8%)	11 (0.9%)		311 (26.7%)
Surgical history of the affected limb
	Yes	93 (8.0%)	8 (0.7%)		101 (8.7%)
	No	997 (85.6%)	67 (5.8%)		1064 (91.3%)
Pain
	Yes	236 (20.3%)	29 (2.5%)		265 (22.7%)
	No	854 (73.3%)	46 (3.9%)		900 (77.3%)
Intermittent claudication
	Yes	23 (2.0%)	2 (0.2%)		25 (2.1%)
	No	1067 (91.6%)	73 (6.3%)		1140 (97.9%)
DVT history
	Yes	41 (3.5%)	8 (0.7%)		49 (4.2%)(0.2%)%)
	No	1049 (90.0%)	67 (5.8%)		1116 (95.8%)
Pelvic and abdominal surgery history
	Yes	210 (18.1%)	17 (1.4%)		227 (19.6%)
	No	879 (75.5%)	58 (5.0%)		937 (80.5%)
Edema
	Yes	139 (11.9%)	14 (1.2%)		153 (13.1%) (13.186.9%)
	No	951 (81.6%)	61 (5.2%)		1012 (86.9%)
Skin pigmentation
	Yes	606 (52.0%)	37 (3.2%)		643 (55.2%)
	No	484 (41.5%)	38 (3.3%)		522 (44.8%)
Eczema
	Yes	79 (6.8%)	13 (1.1%)		92 (7.9%)
	No	1011 (86.8%)	62 (5.3%)		1073 (92.1%)
Lipoid necrobiosis
	Yes	90 (7.7%)	8 (0.7%)		98 (8.4%)
	No	1000 (85.8%)	67 (5.8%)		1067 (91.6%)
Ulcer
	Yes	165 (14.2%)	11 (0.9%)		176 (15.1%)
	No	925 (79.4%)	64 (5.5%)		989 (84.9%)
CEAP
	Below C4	415 (35.6%)	29 (2.5%)		444 (38.1%)
	C4 and above	675 (57.9%)	46 (3.9%)		721 (61.9%)
Superficial venous thrombosis
	Yes	158 (13.6%)	11 (0.9%)		169 (14.5%)
	No	932 (80.0%)	64 (5.5%)		996 (85.5%)
Iliac vein ultrasound showing compression				396	769 (66.0%)
	Yes	1 (0.09%)	2 (0.17%)		3 (0.3%)
		(0.13%)*	(0.26%)*		(0.4%)*
	No	721 (61.9%)	45 (3.9%)		766 (65.8%)
		(93.8%)*	(5.9%)*		(99.6%)*
Total		1090 (93.6%)	75 (6.4%)		1165

DVT history refers to the history of DVT in the affected limb. A positive result of iliac vein ultrasound indicates whether the iliac vein is narrowed, compressed, or occluded. *. * indicates the ratio of the above data to all ultrasound cases. The sensitivity of iliac vein ultrasound for detecting IVCS = 2/47 × 100% = 4.3%; the missed diagnosis rate = 100% − 4.3% = 95.7%; the specificity = 721/722 × 100% = 99.9%; the misdiagnosis rate = 100% − 99.9% = 0.1%.

Logistic regression analysis

After adjusting for missing data and poor correlation, we performed univariate analysis on the clinical data of 769 patients with complete information, examining the association of nine independent variables with the presence of IVCS. This analysis revealed significant correlations between left-sided involvement, history of DVT in the affected limb, pain, and positive results on iliac vein ultrasound, and the presence of IVCS (p < 0.05). In contrast, characteristics such as gender, history of surgery on the affected limb, history of pelvic and abdominal surgery, CEAP classification, and concomitant superficial vein thrombosis exhibited no statistically significant differences (p > 0.05; Table 2).

Table 2.

Univariate analysis of factors associated with iliac vein compression in patients with varicose veins.

Risk	Total (n = 769)	IVCS		χ2	p
Risk	Total (n = 769)	No (n = 722)	Yes (n = 47)	χ2	p
Sex				0.009	0.926
Male	365 (47.46)	343 (47.51)	22 (46.81)
Female	404 (52.54)	379 (52.49)	25 (53.19)
Side				7.186	0.007*
Right	212 (27.57)	207 (28.67)	5 (10.64)
Left	557 (72.43)	515 (71.33)	42 (89.36)
Surgical history of the affected limb				0.031	0.086
No	698 (90.77)	655 (90.72)	43 (91.49)
Yes	71 (9.23)	67 (9.28)	4 (8.51)
Pain				6.015	0.014*
No	601 (78.15)	571 (79.09)	30 (63.83)
Yes	168 (21.85)	151 (20.91)	17 (36.17)
DVT history				12.991	<0.001*
No	735 (95.58)	695 (96.26)	40 (85.11)
Yes	34 (4.42)	27 (3.74)	7 (14.89)
Pelvic and abdominal surgery history				0.238	0.626
No	617 (80.23)	578 (80.06)	39 (82.98)
Yes	152 (19.77)	144 (19.94)	8 (17.02)
CEAP				0.017	0.896
<C4	285 (37.06)	268 (37.12)	17 (36.17)
≥C4	484 (62.94)	454 (62.88)	30 (63.83)
Superficial venous thrombosis				0.371	0.543
No	646 (84.01)	608 (84.21)	38 (80.85)
Yes	123 (15.99)	114 (15.79)	9 (19.15)
Iliac vein ultrasound showing compression				19.246	<0.001*
No	766 (99.61)	721 (99.86)	45 (95.74)
Yes	3 (0.39)	1 (0.14)	2 (4.26)

*indicates results with statistically significant differences (p < 0.05).

Following the univariate analysis, we conducted a multivariate logistic regression analysis, including the significant factors identified in the univariate analysis. This analysis further confirmed the independent predictive value of left-sided involvement (odds ratio (OR) = 3.22, 95% confidence interval (CI): 1.24–8.33, p = 0.016), history of DVT in the affected limb (OR = 3.11, 95% CI: 1.21–8.00, p = 0.018), pain (OR = 2.24, 95% CI: 1.17–4.26, p = 0.014), and positive results on iliac vein ultrasound (OR = 25.56, 95% CI: 2.10–311.26, p = 0.011) for the presence of IVCS in patients with lower-limb varicose veins (Table 3).

Table 3.

Multivariate analysis: independent predictors of simultaneous iliac vein compression in patients with lower-limb varicose veins.

Risk	Beta	S.E	Z	p	OR (95%CI)
Left side	1.17	0.49	2.41	0.016*	3.22 (1.24–8.33)
Pain	0.81	0.33	2.45	0.014*	2.24 (1.17–4.26)
DVT history	1.14	0.48	2.36	0.018*	3.11 (1.21–8.00)
Iliac vein ultrasound showing compression	3.24	1.28	2.54	0.011*	25.56 (2.10–311.26)

*indicates results with statistically significant differences (p < 0.05).

Establishment and validation of clinical prediction model

Based on these significant factors in multivariate analysis, we developed a nomogram (Figure 1) to predict the probability of IVCS in patients with varicose veins, and the nomogram exhibited moderate predictive performance (AUC = 0.689, 95% CI: 0.607–0.771; Figure 2), demonstrating better than chance prediction of IVCS. Importantly, due to the high missed diagnosis rate of 95.7% for IVCS on iliac vein Doppler ultrasound in our center, even if a patient meets the other three predictive factors (left-sided involvement, pain, and history of DVT), a negative iliac vein ultrasound result would lead to a calculated total score of approximately 96 on the nomogram. This corresponds to a probability of having concurrent IVCS of less than 30%. Despite this high missed diagnosis rate, calibration analysis showed a good linear fit, indicating that the nomogram’s predictions were consistent with actual outcomes (Figure 3).

Figure 1.

Nomogram for predicting simultaneous iliac vein compression in patients with lower-limb varicose veins.

Figure 2.

Receiver operating characteristic (ROC) curve for the nomogram predicting iliac vein compression.

Figure 3.

Calibration curve for validation of the nomogram predicting iliac vein compression.

Discussion

This retrospective study of 1165 patients with lower-limb varicose veins identified four independent predictors of iliac vein compression syndrome (IVCS): left-sided disease, history of deep vein thrombosis (DVT) in the affected limb, pain, and positive iliac vein ultrasound results. However, our study also revealed a low sensitivity of iliac vein ultrasound for detecting IVCS, highlighting the limitations of this diagnostic tool for this condition. These findings underscore the importance of considering IVCS in patients with varicose veins, particularly those presenting with these risk factors, and emphasize the need for alternative diagnostic approaches, such as venography, to ensure accurate diagnosis.

Lower-limb varicose veins are a common condition, particularly prevalent among individuals who sit or stand for extended periods. The severity of varicose veins is classified using the CEAP system,³ with higher grades indicating more pronounced symptoms, including leg swelling, discomfort, pigmentation, and potentially non-healing ulcers. Current guidelines recommend endovascular interventions (e.g., laser, radiofrequency ablation, and ultrasound-guided foam sclerotherapy) for patients with CEAP class 2 or higher,⁴ as these minimally invasive procedures offer advantages such as minimal trauma, fewer complications, and rapid recovery. While open surgical methods like high ligation and stripping of the great saphenous vein are still performed, they do not offer significant advantages over endovascular treatment.⁵

Although venography is not routinely recommended as a preoperative assessment for lower-limb varicose veins, the Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) recommend prompt venous stent implantation for patients with CEAP classes 3–6 who also exhibit venous obstructive disease.^3,6,7 The most common compression site for IVCS is the left common iliac vein, where it is crossed by the right common iliac artery.¹⁰ IVCS can lead to lower-limb deep vein thrombosis, secondary varicose veins, and incomplete deep vein valve function.¹¹ Studies indicate that iliac vein compression is involved in 21.8% of severe chronic venous disease cases and that 66.7%–82% of IVCS patients experience lower-limb varicose veins.^12,13

Doppler ultrasound, commonly used for initial diagnosis of lower-limb vascular diseases, is highly operator-dependent, leading to variability and instability in the results.⁸ While some literature suggests that ultrasound can achieve a specificity and sensitivity of over 60% for diagnosing IVCS,^8,9 our study found a significantly lower sensitivity. This discrepancy may be attributed to our single-center retrospective study with a small number of IVCS cases, potentially leading to a lower detection rate. Additionally, the limited experience of the ultrasound doctors at our center with IVCS might have contributed to the lower sensitivity observed in our study.

The likelihood of concurrent IVCS was significantly higher in patients with left-sided varicose veins than those with right-sided varicose veins (OR = 3.22, p = 0.016). This higher incidence on the left side is primarily attributed to the anatomical relationship of IVCS, where the right common iliac artery crosses over the left common iliac vein, resulting in compression. Consequently, IVCS predominantly affects the left lower limb. This finding aligns with previous studies^10–12 that have also noted more abnormalities in the left common iliac vein in patients with left lower-limb varicose veins, indicating a strong association between left lower-limb varicose veins and IVCS. Therefore, the presence of unilateral right-sided varicose veins in a preoperative assessment suggests a lower likelihood of IVCS.

IVCS typically presents in three stages.^14,15 Initially, patients may be asymptomatic or experience mild symptoms. As the condition progresses, intravenous fibrous bands, known as “venous spurs,” develop, leading to chronic venous insufficiency symptoms such as lower limb swelling, varicose veins, skin pigmentation, venous claudication, eczema, and ulcers. In the most severe stage, IVCS can lead to acute left iliac vein thrombosis, potentially with pulmonary embolism.^16,17 Lower limb pain is a major clinical manifestation of IVCS, identified as an independent predictive factor in our analysis. While many patients with compression, sometimes even exceeding 50%, remain asymptomatic, the relationship between the degree of compression and symptoms remains unclear.^1,10,11 However, the appearance of symptoms may indicate that IVCS has progressed to the point of being accompanied by lower-limb venous insufficiency and DVT. This aligns with our research findings, but detailed clinical records are needed to differentiate pain related to IVCS from pain associated with ulcers.

Clinical research indicates a significant association between left-sided DVT and IVCS. Autopsy studies have revealed “spurs” in 22%–33% of cadavers.¹⁰ Carr et al.¹⁸ conducted a case–control study demonstrating that every 10% increase in left iliac vein narrowing correlates with a 2.18-fold increase in DVT risk, highlighting a strong link between iliac vein narrowing and DVT susceptibility. Chronic pulsatile compression of the left iliac vein by the right common iliac artery can lead to venous reflux obstruction and blood stasis, potentially elevating thrombosis risk compared to individuals without this compression. Patients with unexplained DVT history are more likely to have deep venous hemodynamic issues, consistent with our research findings.

A previous study established a predictive model for IVCS, recommending preoperative venography for patients with CEAP class ≥C4, pitting edema, and abnormal prothrombin time.¹⁹ The model achieved a high C-index and AUC, indicating strong predictive performance. In our study, patients with CEAP class ≥C4 and pitting edema were more prevalent in the IVCS population, yet these factors did not show a statistically significant correlation with IVCS. This is likely due to their nonspecific nature, as symptoms like pitting edema, skin pigmentation, eczema, lipoid necrobiosis, and venous ulcers (corresponding to CEAP classes C3–C6) may reflect the severity and duration of venous insufficiency rather than a direct correlation with iliac vein pathology. While some studies suggest a link between IVCS severity and chronic venous disease duration, our study lacked clear definitions and objective measures of disease duration, precluding its inclusion as a factor.

In conclusion, this study identifies four independent predictors of IVCS in patients with lower extremity varicose veins: left-sided disease, pain symptoms, history of DVT, and positive iliac vein Doppler ultrasound findings. These findings support the development of a clinical prediction model for IVCS and highlight the importance of further investigation with lower extremity venography in patients with varicose veins who exhibit these risk factors. Implementing such a model could potentially reduce postoperative recurrence of varicose veins. However, the necessity of routine preoperative angiography for varicose vein patients should be carefully considered on an individual basis. While the nomogram developed in this study provides a personalized evaluation for the coexistence of IVCS and varicose veins, there are limitations, including single-center bias and incomplete medical records. Further research is needed to explore alternative imaging techniques and validate these findings in larger, multicenter studies.

Footnotes

Acknowledgments

The authors would like to express their gratitude for the generous support provided by Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, during the preparation of this manuscript. Additionally, we extend our appreciation to all hospital personnel for their valuable contributions in enhancing our work.

Author contributions

C.G. and Y.L. conceived and designed this study. C.G., S.T., L.H., and D.A. collected clinical and imaging data. C.G. and L.H. performed the statistical analyses. C.G. and Y.L. wrote, revised, and confirmed the original draft of the manuscript. All authors reviewed, revised, and approved the final version before submission.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics statement

ORCID iDs

ShuTing Gao

Dan Shang

Data Availability Statement

The corresponding author had full access to all study data and final responsibility for the decision to submit for publication. Further data that support the findings of this study are available from the corresponding authors upon reasonable request.*

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