Servier – Phlebolymphology

V. What is new in our understanding
of the chronic venous disease?

Our current understanding of the chronic venous obstruction
Christopher Lattimer (UK)

Christopher Lattimer explained the different aspects of obstruction, depending on if it is in a vein (anatomical lesion), on a vein (radiological compression), concerned with venous drainage (hemodynamic), or its clinical definition (symptoms and signs). He elucidated the importance of collaterals on the symptoms and signs and emphasized that symptoms and signs are not specific for postthrombotic syndrome. Radiologically following measurements are possible, including the minor diameter, area, shape, length, tortuosity, aspect ratio. He also introduced the venous filling index (mL/s) and the venous drainage index (mL/s), which can be used to assess the reflux and the obstruction, as well as the difference between waterfall drainage and hydrostatic drainage. Patients with obstructions had a reduced venous drainage index, increased venous drainage time, a hydrostatic curve (not waterfall drainage line), and increased drainage reserve volume. It is important to differentiate leg obstruction from obstruction of a vein. Diameter measurements are unrealistic, but the pathobiology is postthrombotic fibrosis. Christopher Lattimer pointed out that hydrostatic pressure is an obstruction to drainage that patients with suspected obstruction have increased filling and air-plethysmography measurements both in mL/s.

What is new in our understanding of the cerebral venous outflow? – possible link with neurodegeneration
Marian Simka (Poland)

Marian Simka, introduced the term chronic cerebrospinal venous insufficiency (CCSVI). Venous abnormalities in the internal jugular veins can be found not only in patients with multiple sclerosis, but also in patients with other neurological diseases and even in many healthy controls. Three prospective randomized clinical trials (in the US, Canada, and Italy) assessed whether endovascular treatment for CCSVI is effective in patients with multiple sclerosis. The US study concluded that venous angioplasty is not an effective treatment for multiple sclerosis over the short term and may exacerbate underlying disease activity. The data from the Canadian study did not support the continued use of venoplasty of extracranial jugular and/or azygos venous narrowing to improve patientreported outcomes, chronic multiple sclerosis symptoms, or the disease course of multiple sclerosis. The Italian study summarized that venous percutaneous transluminal angioplasty is a safe, but largely ineffective technique; the treatment cannot be recommended in patients with multiple sclerosis. The Italian study is the only one that used experienced interventionalists. The reasonable conclusion should be that hemodynamically ineffective venous angioplasty, especially if performed by inexperienced interventionalists, is not an effective treatment for multiple sclerosis. However, other studies have shown that only some CCSVI lesions can be successfully managed with balloon angioplasty. In the Brave Dreams study, there were better clinical outcomes (fewer new multiple sclerosis lesions) after successful angioplasty (Zamboni P et al; Brave Dreams Research Group. JAMA Neurol. 2018;75(1):35-43). Endovascular treatment for CCSVI may be effective in some patients, but unfortunately, no new studies have been planned.

Chronic venous thrombosis – does it really exist
Nicos Labropoulos (US)

Nicos Labropoulos opened his talk saying he opposed acute thrombosis to chronic changes. Chronic changes are characterized by decreased vein diameter, wall thickening, rough borders, heterogeneous texture, intraluminal septa, reflux, and increased echogenicity. In addition, secondary chronic venous disease progresses faster than primary.

The diagnosis of recurrent deep vein thrombosis can be difficult; one clue could be if a thrombus in new location is detected in a different vein segment, a different extremity, or it is propagated to a new level. If the thrombus is in a previously affected segment, possible indicators are increments of thrombus thickness >4 mm in proximal veins or >2 mm in calf veins. The problem is that many patients receive anticoagulation and sometimes thrombolysis for the diagnosis of chronic deep vein thrombosis, which is connected to significant costs and puts the patients at risk of bleeding.

Nicos Labropoulos then explained the histological findings. Tissue causing chronic postthrombotic venous obstruction is made up of 80% to 90% type I collagen and 10% to 20% type II collagen, and it shows dystrophic calcification. A prospective clinical study showed that both patients with acute deep vein thrombosis and patients with postthrombotic syndrome had an increase in vein wall thickness localized to the affected segments as compared with controls, demonstrating that the term chronic deep vein thrombosis is erroneous and could be dangerous.

Nicos Labropoulos finished by stating that a new term is needed and he proposed chronic postthrombotic luminal changes, chronic venous or endovenous fibrosis, synechia, or other.

Neck vein obstruction: diagnosis and the role of chronic Chlamydophila pneumoniae infection
Paul Thibault (Australia)

Neck vein obstruction associated with chronic diseases is a chronic vascular condition characterized by multiple obstructions of the principal pathways of extracranial venous drainage. Obstruction of venous outflow leads to the development of various collaterals. This condition is usually silent due to the development of collaterals and shunting of the internal jugular vein system to the cerebrospinal system and vice versa. Internal jugular veins are the predominant drainage of the brain in a supine position and the cerebrospinal venous system is the predominant system in an erect position. The cerebrospinal venous system is a unique, large-capacitance, valveless, plexiform venous network in which flow is bidirectional, which plays an important role in the regulation of intracranial pressure; whereas, in a diseased state, it provides a potential route for the spread of infection, emboli, or tumors. Chlamydophilia pneumoniae was first isolated in 1965 and recognized as a human pathogen in 1985. C pneumoniaeis is an obligate intracellular bacterium that causes 10% of community-acquired pneumonia, bronchitis, pharyngitis, sinusitis, and otitis media. By the age of 20, 50% of the population have antibodies, and, by the age of 65, 75% have antibodies. Reinfection is common and is accompanied by a stronger antibody response (IgG and IgA). C pneumoniaeis can survive, multiply, and persist within macrophages and lymphocytes. Infected monocytes transmit C pneumoniaeis to the vascular endothelium. It cannot be eliminated from infected monocytes using standard antichlamydial or antimicrobials agents. Transmission to monocytes can occur via the arterial system or via the lymphatic venous system, and there is evidence of C pneumoniaeis infecting the venous system. Diagnostic markers of chronic persistent C pneumoniaeis infection include C pneumoniaeis serology (sensitivity 60% to 80%), disturbed cholesterol and low-density lipoprotein metabolism, inflammatory markers (C-reactive protein), liver disorders, disturbed iron homeostasis (ferritin, low iron, low transferrin). These five factors and extracranial venous drainage neck veins create an algorithm that can predict the likelihood of a diagnosis of chronic persistent C pneumoniaeis infection in appropriate clinical settings. The diagnostic markers can also be used to monitor treatment effectiveness.

What is new in our understanding of the chronic venous disease pathogenesis at the cell and tissue level
Ferdinando Mannello (Italy)

Although chronic venous disease is among the most frequent diseases worldwide, biomolecular pathophysiology of both chronic venous disease and chronic venous insufficiency is poorly understood. Cytokines, chemokines, and matrix metalloproteinases (MMPs) are implicated in the etiopathogenesis and progression of the disease. A harmful link among hypertension, inflammation, and proteolysis has been proposed, and the five steps in the pathophysiology include: (i) hemodynamic alterations; (ii) endothelialglycocalyx dysfunction and leucocyte infiltration; (iii) inflammation and proteolysis; (iv) extracellular matrix and vein remodeling; and (v) chronic venous disease/chronic venous insufficiency evolution.

Ferdinando Mannello reported that MMPs are implicated in varicose vein pathology because, experimentally, MMPs cause venous dilatation, meaning they are also implicated in chronic venous insufficiency progression and they may delay healing. Several venoactive drugs improve venous functions. For example, sulodexide improves vein contraction and decreases MMP-2 and MMP-9 levels in veins under prolonged stretch. Sulodexide may be important both in venous leg ulcers and in treating varicose veins and symptoms. Venous hypertension characterizes chronic venous disease/chronic venous insufficiency. Changes in venous hypertension and shear stress lead to a proinflammatory state, as well as active proteolytic remodeling. Inflammatory mediators and proteinase MMPs are key regulators in venous leg ulcers and varicose veins conditions. MMP-2 and MMP-9 (gelatinases) and MMP-12 (elastase) play crucial roles in venous dilation during varicose veins and extracellular matrix remodeling during venous leg ulcer formation. Glycosaminoglycan sulodexide restores the vessel glycocalyx, protects the vascular endothelium, presents anti-inflammatory properties, shows antiproteolytic.

Every valve tells a story! What to do we know from HR ultrasound research on the valve impact on the CVD occurrence and progression – clinical implications
Johann Christof Ragg (Germany)

Healthy valves are so tender they sometimes do not show up on ultrasounds, and B-flow may indicate the outlines. It takes high-resolution ultrasound to visualize valves and valve action. Johann C. Ragg presented The Berlin Vein Valve study performed between 2016 and 2019, where the main objective was early stage evaluation. The participants were children between 4 and 18 years old. The incidence of embryonic valve lesions was 47.8% in children aged 6 to 8 years and 62.2% in children aged 14 to 18 years. There were missing valves in 19%, commissural mismatch in 62%, and single-cusp malformation (fastest progression) in 13% of the participants. In most cases, only 1 valve was initially concerned (74%; children aged 4 to 10 years). The mains factors of severity were height of the unseparated diastolic blood column and the vein diameter. The proposed therapy is valve repair with perivenous hyaluronan, which reduces commissural gaps.

Pressure stress, indicated by dilatation, may be focal (valve), segmental (several leaking valves), or general (congestion). Decompensation may be spontaneous or gradual over the years. Primary pressure-related decompensation means the first valve to be concerned in this region. Secondary pressure-related decompensation means that a consecutive valve below the primary leaking valve is involved. Johann C. Ragg divided pressure-related valve decompensation into 3 stages, IR, P1, P2, and P3. P1 is predecompensation with a functional reserve of <20% of the vein diameter at the valvular level, P2 is a diastolic gap and reflux, and P3 is an extending gap, covering >75% of the vein cross section, cusps flipping over, or cups partially or totally reversed. The proposed therapy for P1 is external or internal compression; for P2, internal compression, (if effective) or external compression; and for P3, internal compression. Stress-related valve degeneration correlates with low flow/stasis and it occurs at the largest distance from the muscle pump. There are three stages of stasis-related valve degeneration: S1a, alteration of sinus hemodynamics; S1b, restriction of cusps function; and S1c, fixation of cusps without reflux. There are three mechanical causes of primary venous insufficiency: embryonic valve lesions, pressurerelated valve degeneration, and stasis-related valve degeneration. The data presented in this talk showed a clear demonstration of the physical origins and reasons for progression, meaning that high-resolution ultrasound is the key to understanding venous valve function/dysfunction. The better we understand vein valve function, the better we can learn to stabilize its function.

Venous diameter, clinical severity and quality of life – does the size of incompetent vein matters?
Sarah Onida (UK)

Sarah Onida discussed vein diameter versus reflux, stating that, in a clinical study, a great saphenous vein <5.5 mm in diameter showed an absence of abnormal reflux and a great saphenous vein >7.3 mm in diameter showed critical reflux. She also discussed vein diameter versus CEAP, showing that, in a French study, >50% of the patients had great saphenous vein diameters <6 mm. Great saphenous vein diameter showed a weak association with venous clinical severity scores in two other trials. In a British trial, great saphenous vein diameter was a poor surrogate marker for assessing the effect of varicose veins on a patient’s quality of life. Vein diameter is not a parameter on which to rationalize treatment. In a systematic review on the relationship between vein diameters, clinical severity, and quality of life, it was concluded that there is a weak correlation between truncal vein diameter and clinical severity of disease, but there was no association between vein diameter and health-related quality of life. In addition, there is no mention of vein diameter in treatment strategies. Sarah Onida concluded by stating that vein diameter should not be used as a stand-alone assessment to determine whom to treat. Clinical and quality of life assessments should lead to the decision, whereas, vein diameter is important to determine which treatment modality to use.


Obesity and inflammation in venous and lymphatic diseases?
Gabriele Färber (Germany)

Gabriele Färber presented the epidemiological facts about obesity in Germany and discussed how it relates to venous and lymphatic diseases. Normal-weight individuals are a minority. At the end of their working life, 74.2% of men and 56.3% of women are overweight. The proportion of obesity in the population was 12% in 2000, 15% in 2009, and 23.6% in 2015. The proportion of morbid obesity in the population (BMI ≥40 kg/m2) increased by 300% (males) and 175% (females) between 1999 and 2013. There is an age-related increase in the prevalence of thromboembolic events, chronic venous insufficiency, and secondary lymphedema. Consequently, the number of patients with these conditions, who are also severely obese, increased. Obesity is not only cause for deterioration, but also often the sole cause. There is a correlation between visceral obesity, chronic inflammation, insulin resistance, and venous thromboembolic events, postthrombotic syndrome, secondary functional venous insufficiency, venous ulcers, obesity-associated secondary lymphedema, and secondary lymphedema in lipedema. There are different explanatory approaches. Mechanical mechanisms that may play a role are increased intra-abdominal pressure and increased intertriginous pressure leading to increased venous pressure in leg vessels. Metabolic, chronic inflammatory, and prothrombotic changes are important factors. Abdominal obesity increases the risk of thrombosis by increasing the activity of the coagulation cascade, decreasing the activity of the fibrinolytic cascade, increasing the inflammatory process, and elevating oxidative stress and endothelial dysfunction. Disorders of lipid metabolism and glucose tolerance, in the context of metabolic syndrome, further affect the proinflammatory effects and enhance endothelial dysfunction. The risk for thromboembolic events is increased by the proinflammatory effects of visceral fat tissue, activation of coagulation, and the decrease in fibrinolysis and endothelial dysfunction. Postthrombotic syndrome occurs earlier and more frequent starting from a BMI of 28 kg/m2, and the symptoms are improved by weight loss.

Gabriele Färber introduced the term secondary functional venous insufficiency or “obesity-associated dependency syndrome.” The responsible mechanical factor is an increased intertriginous pressure in the groin. Chronic inflammatory changes are mediated by cytokines, interleukins, tumor necrosis factor α, and increased capillary permeability. Of the patients with lymphedema, 76% are overweight. Obesity worsens all forms of lymphedema. Obesity associated lymphedema is the most common form of secondary lymphedema. Obesity causes secondary lymphedema in lipedema, not progression of lipedema. Possible pathomechanisms are compression of lymph vessels, immobility, failure of lymphatic transport mechanisms, and an increase in lymphatic load. Secondary lymphedema is reversible after weight loss. Obesity in phlebological and lymphological diseases consists of at least two different diseases; both must be treated. Chronic inflammation and insulin resistance are at the core besides treating the respective acute or chronic symptoms with anticoagulation, compression, lymphatic drainage, or wound therapy. Focus on reducing visceral adipose tissue, hyperinsulinemia, and chronic inflammation through dietary and lifestyle changes is mandatory. Weight reduction can improve secondary venous insufficiency, secondary lymphedema, and reduce thrombogenic risk factors.