Viral Coagulopathy in Patients With COVID-19: Treatment and Care.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

Risks and contraindications of medical compression treatment - A critical reappraisal. An international consensus statement.

OBJECTIVES: Medical compression therapy is used for non-invasive treatment of venous and lymphatic diseases. Medical compression therapy-associated adverse events and contraindications have been reported, although some contraindications are theoretically based. This consensus statement provides recommendations on medical compression therapy risks and contraindications. METHODS: A systematic literature search of medical compression therapy publications reporting adverse events up until November 2017 was performed. A consensus panel comprising 15 international experts critically reviewed the publications and formulated the recommendations. RESULTS: Sixty-two publications reporting medical compression therapy adverse events were identified. The consensus panel issued 21 recommendations on medical compression therapy contraindications and adverse event risk mitigation, in addition to reviewing medical compression therapy use in borderline indications. The most frequently reported non-severe medical compression therapy-associated adverse events included skin irritation, discomfort and pain. Very rare but severe adverse events, including soft tissue and nerve injury, were also identified. CONCLUSION: This consensus statement summarises published medical compression therapy-associated adverse events and contraindications, and provides guidance on medical compression therapy. Severe medical compression therapy-associated adverse events are very rarely encountered if compression is used correctly and contraindications are considered.

Comparison of Four Haemodynamic Tests that Quantify Superficial Venous Insufficiency.

OBJECTIVES: Reflux assessment with ultrasound (U/S) is usually qualitative. Quantitative measurements of superficial venous insufficiency (SVI) include the venous arterial flow index (VAFI), recirculation index (RCI), venous filling index (VFI), and the postural diameter change (PDC) of the saphenous trunk. The aim was to investigate their relationship. MATERIALS AND METHODS: This was an observational study performed on patients with varicose veins and hospital employees. Four haemodynamic parameters were measured in 21 legs from 16 subjects. Legs were divided into no reflux (n = 7) and reflux (n = 14). The VAFI is the U/S ratio of common femoral vein volume flow divided by the common femoral artery volume flow, performed supine. The RCI is the U/S ratio of reflux volume over antegrade volume within the saphenous trunk after calf compression, standing. The VFI is the rate of calf volume increase on dependency measured in mL/s, using air plethysmography. The PDC is the percentage reduction of the saphenous trunk diameter from standing to lying, using U/S. RESULTS: The clinical part of the CEAP classification was: C0 = 3, C1 = 4, C2 = 5, C3 = 1, C4a = 1, C4b = 6, C5 = 1. All four tests demonstrated significant differences between the two groups with minimal overlap (Mann Whitney U test): VAFI (p = .028), RCI (p < .0005), VFI (p = .001), and PDC (p = .014). Furthermore, significant correlations were observed with the tests: VAFI vs. RCI (r = .532, p = .015), VFI (r = .489, p = .025) and PDC (r = -.474, p = .030); RCI vs. VFI (r = .446, p = .043) and PDC (r = -.527, p = .014). CONCLUSIONS: Superficial venous drainage insufficiency should not be confined to an U/S assessment of the presence of reflux, which is qualitative. Quantitative data may be provided using the VAFI, RCI, VFI, and PDC. Understanding why there are significant correlations among these parameters and the preferred objective reference test requires further work.

The Discord Outcome Analysis (DOA) as a Reporting Standard at Three Months and Five Years in Randomised Varicose Vein Treatment Trials.

OBJECTIVES: Treatment success for chronic superficial venous insufficiency could be defined as an improvement in three domains: (i) disease specific quality of life, (ii) clinical severity, (iii) reflux. The aim was to report these at five years using a Venn diagram to profile the outcomes: a discord outcome analysis (DOA). METHODS: Patients (n = 50 patients/legs in each treated group) were randomised to endovenous laser ablation (EVLA) with concurrent phlebectomies vs. ultrasound guided foam sclerotherapy (UGFS). Outcomes were assessed using three domains: (i) Aberdeen varicose vein questionnaire (AVVQ), (ii) venous clinical severity score (VCSS), (iii) venous filling index (VFI) of air plethysmography. Change scores were calculated by subtracting the final score after treatment from the baseline score before treatment to quantify the improvement. This was followed by a DOA profile for each patient where a discord was defined as the percentage of patients with a numerical deterioration in one or two domains. RESULTS: The median [interquartile range] follow up was 68 [64-72] months. Follow up in all three domains was EVLA: 45/50, UGFS: 42/50. On ultrasound examination, GSV occlusion at some point above the knee was 93% for EVLA and 64% for UGFS (p = .001). There was no significant difference in improvement between the two treatment groups in the VCSS and the VFI. However, the EVLA group had a statistically significant AVVQ improvement (p = .004). Using a DOA, only 76% EVLA versus 60% UGFS had success in all three domains. Using improvement thresholds, this reduced to 54% and 39%, respectively. The commonest discord pattern was an improvement in the VCSS and VFI but deterioration in the AVVQ. CONCLUSIONS: A DOA demonstrated that the definition of success is reduced if deterioration in one or two domains is taken into account. A DOA should be considered as a reporting standard for comparative analyses.

Validation of a Gravitational Model to Study Local Endogenous Biomarkers in Chronic Venous Insufficiency.

OBJECTIVE/BACKGROUND: Unlike most systemic chronic diseases, chronic venous insufficiency (CVI) is ideal to study using endogenous biomarkers. The stimulus causing damage can be turned on and off with gravitational positioning and venous blood samples can be taken locally. Annexin V (apoptosis) and microparticles (cell membrane debris) were used as markers of cell destruction, with matrix metalloproteinases (MMPs) as markers of tissue remodelling. The aim of this proof of concept study was to validate a gravitational model by investigating whether standing induced biochemical stress and whether recovery occurs on lying and after compression. METHODS: Fourteen patients (C4a-b) and 14 volunteers (C0-1) were tested under three supervised laboratory conditions for 1 h on separate days: (i) stationary standing on a small paper square; (ii) lying with both legs elevated 20°; (iii) compression standing using a 23-32 mmHg below knee stocking. Immediately after each condition, venous blood was withdrawn from the ankle. Commercial enzyme linked immunosorbent assay kits were used for batch analysis of the plasma samples. RESULTS: Median (interquartile range [IQR]) values of annexin V (AU/mL) and microparticles (nM) standing were as follows: volunteers 2.9 (2 - 3.4) and 10.2 (8.8 - 13.8), and patients 2.2 (1.3 - 6) and 11.3 (7.7 - 20), respectively. Significant reductions were observed lying: volunteers 2.1 (1.5 - 2.7; p = .019) and 8.5 (7.4 - 9.4; p = .041), patients 1.7 (1.2 - 2.7; p = .004) and 8.5 (7.0 - 11.4; p = .041), respectively. Globally, all median MMP values in the patients reduced with lying and with compression versus standing (p = .004). Individually, significant reductions occurred in MMPs 2 and 13 with compression and MMPs 3, 7, 8, 9, 10, and 12 on lying. Lying was more effective at reducing MMP levels than compression. CONCLUSION: Annexin V and microparticle concentrations are responsive to elevation and compression after 1 h. In the patients, all the tested MMPs decreased after lying and with compression versus standing. This model provides evidence supporting gravitational protection in the treatment of CVI.

Neuromuscular electrical stimulation reduces sludge in the popliteal vein.

BACKGROUND: The common peroneal nerve stimulator (CPNS) is a UK-approved device for reducing venous thromboembolism (VTE) risk. It resembles a wrist watch and is placed over the common peroneal nerve, discharging electricity at a rate of 1 impulse/s. It has been presumed that as blood flow slows, erythrocytes aggregate into ultrasound-detectable echogenic particles, described as venous sludge. The aim of the study was to determine whether the CPNS reduces venous sludge by using an ultrasound-derived gray-scale (0-255) venous sludge index (VSI). METHODS: Twenty-five healthy volunteers had their right popliteal vein video recorded using B-mode ultrasound at 22 frames/s in longitudinal and transverse views, standing and lying. This was performed first with the CPNS off and then with the CPNS on. The CPNS impulse intensity used was set from 1 to 7 for each individual, and the level was sufficient to cause an outward jerking movement of the foot. A single frame of the possible 154 frames, lasting 7 seconds, was selected using a random number generator for the image analysis. The "brightness" of the erythrocyte aggregates (pixels) within a circular sampling area was quantified using the VSI. The brighter the sample, the greater the sludge. RESULTS: Values are expressed as median (interquartile range). On standing with the device off, there was a significantly higher VSI (P < .0005) compared with lying (longitudinal view, 27.7 [18.8-41.4] vs 11.7 [5.5-17.5]; transverse view, 20.7 [13.6-32.2] vs 11.4 [6.3-15.9]). Activation of the CPNS significantly reduced all the VSI values (P < .0005) shown (longitudinal view, 2 [1.1-3.2] and 1.5 [0.5-3.1]; transverse view, 1.1 [0.6-2.7] and 0.8 [0.5-2.1]). CONCLUSIONS: The CPNS device significantly reduces venous sludge within the popliteal vein irrespective of whether the subject is standing or lying down or of the longitudinal or transverse position of the ultrasound transducer. The principal mode of action of the device in the claim that it may reduce venous thromboembolism risk may be through a reduction of venous sludge. However, the relationship between erythrocyte aggregation, venous stasis, and venous thromboembolism risk requires more investigation.

Venous Thromboprophylaxis With Neuromuscular Stimulation: Is It Calf Muscle Pumping or Just Twitches and Jerks?

The common peroneal nerve stimulator (CPNS) is a UK-approved device for reducing venous thromboembolism risk. It resembles a wrist watch and is placed over the common peroneal nerve to fire at 1 electrical impulse/sec. The aim was to quantify the claim that it drives the venous muscle pump and imitates walking. Twelve healthy volunteers performed 10 tip-toe maneuvers and 10 ankle dorsiflexions to imitate walking movements. The reductions in calf volume were recorded using air plethysmography (APG). The common peroneal nerve was stimulated for over 10 seconds at each of the 7 increasing electrical impulse settings, and the volume reductions were measured for comparison. The results are expressed as median (interquartile range) absolute (mL), and percentage reduction in calf volume. Tip-toe and dorsiflexion pumping maneuvers were not significantly different: 59 (33.6-96.1), 81.9% vs 51.4 (34-68.5), 59.7%, respectively ( P = .53). However, they both outperformed the CPNS: 10.8 (7.3-18), 13.2% at P = .002 and P = .002, respectively. Qualitatively, the CPNS registered on the tracings as a small spike (muscle twitch) at low settings, with larger amplitudes (ankle jerk) at higher settings. The CPNS activity spikes were discrete, lasting a median (range) of 0.24 (0.16- .3) seconds. The claim that the CPNS empties veins by pumping is supported statistically. However, the amount is small versus the tip-toe and dorsiflexion maneuvers. Furthermore, the CPNS has a short activity profile on the APG trace. Innovations that produce sustained contraction and involve the posterior calf compartments may improve pumping.

Optimizing calf muscle pump function.

Background The tip toe manoeuvre has been promoted as the gold standard plethysmography test for measuring calf muscle pump function. The aim was to compare the tip toe manoeuvre, dorsiflexion manoeuvre and a body weight transfer manoeuvre using the ejection fraction of air-plethysmography and evaluate which has the best pumping effect. Methods Sixty-six archived tracings on 22 legs were retrieved from an air-plethysmography workshop and analysed. Pumping performance was measured using the calf volume reduction after each manoeuvre. Results Expressed as median [inter-quartile range], body weight transfer manoeuvres resulted in a significantly greater ejection fraction (%) than tip toe manoeuvres at 59.7 [53.5-63.9] versus 42.6 [30.5-52.6], P < 0.0005 (Wilcoxon). There was no significant difference in the ejection fraction between the tip toe manoeuvre versus dorsiflexion manoeuvre, P = 0.615. The repeatability (confidence interval: 95%) of 66 ejection fraction tests was excellent: tip toe manoeuvre (±1.2), dorsiflexion manoeuvre (±1.3) and body weight transfer manoeuvre (±1.6). Conclusion The body weight transfer manoeuvre appears to be a better method of measuring the full potential of the calf muscle pump with a 40.1% relative increase in the ejection fraction compared to a tip toe manoeuvre. Exercises which involve body weight transfers from one leg to the other may be more important in optimizing calf muscle pump function than ankle movement exercises.

Validation of the novel venous drainage index with stepwise increases in thigh compression pressure in the quantification of venous obstruction.

BACKGROUND: Venous drainage from the leg is poorly understood, and it is difficult to quantify it hemodynamically. Attempts have been made using duplex ultrasound scanning and venous occlusion air plethysmography (APG). However, they have limited value in day-to-day clinical practice. This is because venous drainage measurements have never been validated successfully against increasing obstruction pressures. The hypothesis is that the novel gravitational venous drainage index (VDI) in milliliters/second is reduced in response to increasing venous obstruction, and the aim was to quantify this, using stepwise inflations of a thigh cuff. METHODS: Venous drainage tracings were obtained with APG using a dependency to elevation maneuver on the right legs of 21 volunteers (9 female) without venous disease. The test was performed once without a thigh cuff and then with a contoured thigh cuff (18 cm wide) inflated in steps at 10, 20, 30, 40, and 50 mm Hg just before elevation. The function of the thigh cuff was to mimic venous obstruction. The drainage volumes were obtained once the tracing from the elevated cuffed leg decreased to a steady line, when arterial inflow equals venous outflow. The VDI was calculated in the same way as the opposite maneuver, the venous filling index, is obtained from the venous filling tracing (elevation to dependency maneuver), namely, VDI = 90% venous drainage volume/venous drainage time to 90%. The drainage reserve volume (DRV) was defined as the undrained volume caused by the venous obstruction from the thigh cuff. RESULTS: With stepwise inflations of the thigh cuff at 0, 20, 30, 40, and 50 mm Hg, the median VDI is reduced (26.1, 24.1, 12.1, 7.8, 5.4) and the DRV is increased (0, 5.3, 15.4, 45.5, 62.6). Furthermore, the VDI reductions and the DRV increases correlated significantly (P < .0005) with increasing obstruction pressure at r = -0.69 and r = 0.793, respectively (Spearman). CONCLUSIONS: The VDI is a novel APG parameter derived from a dependency to elevation maneuver that represents the gravitational venous drainage rate of the leg. The DRV is the undrained venous volume caused by the obstruction from an inflated thigh cuff. Both parameters have been demonstrated to respond to and to correlate with increasing venous obstruction pressures. Their potential clinical value in assessing the hemodynamic significance of an iliac or femoral stenosis and in the screening and selection of patients requiring iliac stenting and follow-up requires further investigation.

Are Inflammatory Biomarkers Increased in Varicose Vein Blood?

OBJECTIVES: To test for the presence of inflammatory biomarkers in blood taken from varicose veins versus antecubital blood of the same patient and compare this to levels in healthy controls. METHODS: Using a multiplex biochip array method (Randox, United Kingdom), the interleukins (ILs) IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10; vascular endothelial growth factor; interferon γ, tumor necrosis factor α ; monocyte chemotactic protein 1 (MCP-1); and epidermal growth factor were measured in citrated plasma samples drawn from the arms and legs of 24 patients with varicose veins and 24 controls. RESULTS: Expressed as median (interquartile range) in pg/mL, leg samples from patients with varicose veins had significantly higher levels of IL-8 and MCP-1 compared to their own arm samples (IL-8: local 2.3 [1.71-3.3] vs systemic 2.3 [1.62-2.98], P = .023; MCP-1: local 114.42 [84.29-139.05] vs systemic 103.56 [79.75-126.42], P < .0005). This was not observed in the control group. Leg samples from both patients with varicose vein and controls had higher levels of IL-6 compared to their own arm samples (patients: local 1.67 [0.82-4.48] vs systemic 1.24 [0.58-3.26], P = .002; controls: local 1.23 [0.83-1.7] vs systemic 1.03 [1.7-1.52], P = .005). No significant differences were detected with the other biomarkers. CONCLUSIONS: Blood drawn from the site of varicose veins appears to have significantly increased concentrations of IL-6, IL-8, and MCP-1 when compared to the same patient's arm blood. This supports the hypothesis that inflammation is activated from the tissues drained by the varicose veins.

Venous hemodynamic changes in lower limb venous disease: the UIP consensus according to scientific evidence.

There are excellent guidelines for clinicians to manage venous diseases but few reviews to assess their hemodynamic background. Hemodynamic concepts that evolved in the past have largely remained unchallenged in recent decades, perhaps due to their often complicated nature and in part due to emergence of new diagnostic techniques. Duplex ultrasound scanning and other imaging techniques which evolved in the latter part of the 20th century have dominated investigation. They have greatly improved our understanding of the anatomical patterns of venous reflux and obstruction. However, they do not provide the physiological basis for understanding the hemodynamics of flow, pressure, compliance and resistance. Hemodynamic investigations appear to provide a better correlation with post-treatment clinical outcome and quality of life than ultrasound findings. There is a far better prospect for understanding the complete picture of the patient's disability and response to management by combining ultrasound with hemodynamic studies. Accordingly, at the instigation of Dr Angelo Scuderi, the Union Internationale de Phlebologie (UIP) executive board commissioned a large number of experts to assess all aspects of management for venous disease by evidence-based principles. These included experts from various member societies including the European Venous Forum (EVF), American Venous Forum (AVF), American College of Phlebology (ACP) and Cardiovascular Disease Educational and Research Trust (CDERT). Their aim was to confirm or dispel long-held hemodynamic principles and to provide a comprehensive review of venous hemodynamic concepts underlying the pathophysiology of lower limb venous disorders, their usefulness for investigating patients and the relevant hemodynamic changes associated with various forms of treatment. Chapter 1 is devoted to basic hemodynamic concepts and normal venous physiology. Chapter 2 presents the mechanism and magnitude of hemodynamic changes in acute deep vein thrombosis indicating their pathophysiological and clinical significance. Chapter 3 describes the hemodynamic changes that occur in different classes of chronic venous disease and their relation to the anatomic extent of disease in the macrocirculation and microcirculation. The next four chapters (Chapters 4-7) describe the hemodynamic changes resulting from treatmen by compression using different materials, intermittent compression devices, pharmacological agents and finally surgical or endovenous ablation. Chapter 8 discusses the unique hemodynamic features associated with alternative treatment techniques used by the CHIVA and ASVAL. Chapter 9 describes the hemodynamic effects following treatment to relieve pelvic reflux and obstruction. Finally, Chapter 10 demonstrates that contrary to general belief there is a moderate to good correlation between certain hemodynamic measurements and clinical severity of chronic venous disease. The authors believe that this document will be a timely asset to both clinicians and researchers alike. It is directed towards surgeons and physicians who are anxious to incorporate the conclusions of research into their daily practice. It is also directed to postgraduate trainees, vascular technologists and bioengineers, particularly to help them understand the hemodynamic background to pathophysiology, investigations and treatment of patients with venous disorders. Hopefully it will be a platform for those who would like to embark on new research in the field of venous disease.

Quantifying saphenous recirculation in patients with primary lower extremity venous reflux.

BACKGROUND: The great saphenous vein (GSV) in patients with superficial venous insufficiency might act as a beneficial conduit for antegrade venous drainage and also as a harmful conduit for promotion of reflux and/or recirculation and subsequent skin changes. The aim of this study was to measure the antegrade and retrograde GSV volume displacements during calf compression and release maneuvers. This was used to quantify harm over benefit with a recirculation index (RCI). METHODS: Sixteen legs (nine right) from 16 patients (nine male) with primary superficial venous insufficiency were scanned standing with duplex ultrasound, at the upper thigh GSV, 10 cm below the sapheno-femoral junction. The clinical, etiological, anatomical, pathophysiological class was C2 = 3, C3 = 2, C4a = 6, C4b = 4, C5 = 1. The median age (range), venous clinical severity score, and refluxing GSV diameter were 63 (21-79) years, 8 (4-16), and 7 (5-10) mm, respectively. A manual calf compression and release (MCCR) maneuver was performed once, and a cyclical calf compression and release (CCCR) three times for repeatability. With the CCCR maneuver, the calf-cuff and inflation-deflation pump provided a cyclical compression pressure of 120 mm Hg (3 seconds) with a release time of 16.4 seconds to standardize venous refilling time. RESULTS: The results are expressed as median [interquartile range]. The CCCR compared with the MCCR resulted in longer reflux duration (16.4 [8.2-16.4] seconds vs 5.7 [3.7-6.8] seconds; P < .0005), higher time-averaged mean velocities in reflux (23.5 [14.9-27.9] cm/s vs 14.1 [9-17.6] cm/s; P < .0005) and greater reflux volume displacements (81.7 [38.8-152.8] mL vs 27.3 [16.4-53.4] mL; P < .0005). There were significant correlations between increasing antegrade volume measurements and increasing reflux volume measurements irrespective of whether CCCR, (r = 0.841; P < .0005) or MCCR (r = 0.762; P = .001) was used. This implies that the displaced antegrade volume might have a causal effect on the resulting reflux volume. The ratio of reflux volume/antegrade volume (RCI) was 2.14 [1.58-2.74] with the CCCR. This supports the recirculation phenomenon. Adjusted to a standard median for each leg, the repeatability limits (three times) of the RCI was excellent at 2.14 (95% confidence interval, 2.09-2.21). CONCLUSIONS: In this study we measured the behavior of the GSV in terms of harmful reflux over beneficial drainage using the RCI. We recognize that reflux values depend on the type of provocation test and the amount of displaced antegrade volume. This limitation might be overcome by factoring reflux as an expression of antegrade flow using the RCI. When standardized, a test for quantifying saphenous recirculation might have many clinical applications. The next step should be a prospective study to validate the RCI with clinical and quality of life parameters.

Gravitational venous drainage is significantly faster in patients with varicose veins.

OBJECTIVES: It has been proposed that varicose veins may be caused by a degree of impeded proximal venous drainage (pelvic venous obstruction) in the same way that biological tubes dilate in response to an obstruction. The venous drainage index (VDI) of air-plethysmography (APG) was used to test this hypothesis. A dependency to elevation manoeuvre was used to provoke gravitational venous drainage. A rapid reduction in calf volume implied good drainage. METHODS: This was a single centre, proof-of-concept study comparing gravitational venous drainage in varicose vein patients and controls. Leg filling and drainage manoeuvres (elevation to dependency and dependency to elevation) were performed three times per leg in 15 patients (7 male, 8 right) and 16 controls (3 male, 8 right). The VDI was measured in the same way the established venous filling index (VFI) is calculated to quantify filling: VDI = 90% of venous drainage volume (90VDV)/90% venous drainage time (VDT90). RESULTS: The patients were significantly older at 58 (41-75) years versus the controls 47 (18-58), p = 0.001. There was no significant difference between the groups in weight, height, BMI or common femoral vein diameter. The patients were (C2 = 8; C3 = 1, C4 = 6), VCSS 4 (1-11) with a median refluxing proximal thigh saphenous diameter of 6 (5-11) mm. The median (inter-quartile range) VFI and VDI (both in mL/s) in the control tests (n = 48) were 1.3 (0.9-1.9) and 33.8 (21.5-55), respectively. The VFI and VDI in the patient tests (n = 41) were significantly faster at 6.2 (3.5-9.4), p < 0.0005, and 47.1 (36.1-66.3), p = 0.002, respectively. Adjusted to a standard mean for each leg, the reproducibility limits (×3) of the VDI was very good at 39.7 (95% CI: 36.5-42.9) in controls and 52.9 (95% CI: 49.7-56.1) in patients. CONCLUSION: The VDI was significantly greater in patients with varicose veins compared to controls. It is unlikely that impeded gravitational drainage is a significant factor in the pathophysiology of varicose veins.