Servier – Phlebolymphology

III. Pathophysiology

Andreas Fiebig, Germany


This presentation described the results of a study performed in Germany in a group of 2701 patients with chronic venous disease (CVD), examined clinically and by duplex ultravenography. The patients’ genetic contribution was assessed by estimating the heritability of CVD using a pedigree-based likelihood approach as implemented in the SOLAR software package.

The results of the study confirm that heritability in CVD is high. Heritability was found to vary only little with disease severity by CEAP classification (18.5% C2 and 16.7% C4). There was a statistically significant association between heritability and a higher CEAP class after adjusting for age and sex.

Vincent Crebassa, France


The heredity of chronic venous disease (CVD) has been examined in a French prospective, observational, multicentric study, performed by 1040 GPs, which enrolled 21 319 adult patients, over two consecutive days. The conclusions from the study were that CVD is most probably either autosomal recessive or autosomal dominant with incomplete penetration and variable expression. The female hormonal influence can explain increased female prevalence. In patients with parenteral antecedents, CVD treatment should probably commence earlier. The final conclusion: the end of the maternal heredity dogma!

Ferdinando Mannello, Italy


This “in vitro” study examined the action of sulodexide (SDX) in macrophagelike cells. SDX showed a dose-dependent inhibitory effect on inflammatoryinduced isoforms of matrix metalloproteinase 9 (MMP-9) in macrophage cells (both leukocytes and active proteases are known to play key roles in chronic venous disease [CVD] and chronic venous ulcers). SDX is able to down-regulate the secretion of several inflammatory interleukins from macrophages (also found in tissues and fluids collected from patients affected by CVD and chronic venous ulcers). SDX specifically reduces MMP-9 activity in endothelial cells of varicose veins. These new findings related to SDX underline the pleiotropic properties of this GAG mixture, not only as an antithrombotic profibrinolytic agent, but also as an inhibitor of specific macrophage pathways involved in the biomolecular mechanism of CVD. The conclusion drawn from this study is that SDX may be a potential treatment for patients with CVD and venous ulcers.

Tristan Lane, UK


Patients with larger vein diameters presented with worse clinical disease severity (CEAP and VCSS), but not with a worse quality of life.

Alun Davies, UK


For decades, the primary aim of interventions has been the correction of aberrant flow into the saphenous vein to reduce venous hypertension and improve the clinical signs and symptoms of chronic venous insufficiency. High ligation and stripping of the saphenous vein and later endovenous laser or radiofrequency of the saphenous vein were the standard methods employed for the surgical management of superficial venous disease. Some reports suggest that surgical saphenectomy may reverse deep reflux in the majority of patients with both superficial and deep vein reflux. The ablation of truncal reflux improves the hemodynamics, but the correlation between hemodynamic measurements and anatomical reflux (number of refluxing veins or Venous Segmental Disease Score [VSDS]) is poor. Abolition of saphenous reflux while sparing the saphenous vein is the basis of ASVAL and CHIVA treatment strategies.

The pattern of hemodynamic abnormality may influence the clinical severity of chronic venous insufficiency. Accurate preoperative assessment of reflux is thus key to determining the most appropriate treatment strategy for the patient. There is a weak correlation of anatomical reflux or hemodynamic function and quality of life at baseline, but no significant correlation is found post-intervention.

Further studies are required to determine which disease pattern is best suited to one or a combination of therapeutic options, permitting individualization and optimization of treatment.

Nicos Labropoulos, USA


Venous obstruction can be intraluminal, extraluminal, or both. The consequences of venous outflow obstruction are seen during thrombotic events or in cases of iliac vein compression syndrome. Symptoms are more pronounced and more often present during standing or walking. When should we evaluate for iliac obstruction? If signs and symptoms of venous claudication, skin changes, diffuse limb pain, or swelling are present, or when a history of iliofemoral deep venous thrombosis is found, exploration of the superficial and deep venous system is advised.

Hugo Partsch, Austria


The target of compression is gravity! So, how much compression should we apply in venous incompetence? To summarize, the comfortable resting pressure is around 40 mm Hg. Pressure is increased by standing (30-40 mm Hg) in order to work against the increased pressure in the veins. The pressure peaks during walking at 70-90 mm Hg. Good compression is a balance between application of the most efficient pressure to reduce reflux and a comfortable compression pressure to achieve compliance with treatment.

Joseph Raffetto, USA


The microcirculation is composed of terminal arterioles, capillaries and venules, which drain capillary blood and have several functions such as regulating blood flow, perfusion to tissues, fluid homeostasis, oxygen, and carbon dioxide transport. The endothelium is a key regulator of vascular tone, hemostasis, and coagulation. In chronic venous disease, there is a persistent elevated ambulatory venous pressure leading to altered shear stress on the endothelial cells, which causes them to release vasoactive agents, express E selectin, intercellular adhesion molecule (ICAM-1, CD54), and transient receptor potential vanilloid channels (TRPVs). ICAM-1 is overexpressed in chronic venous disease (CVD) and is important in initiating inflammation in the venous wall. In addition, endothelial glycocalyx, composed of glycosaminoglycans, is an important structure that prevents leukocyte adhesion, inflammation, and thrombosis. Altered shear stress and stretch could lead to injury and loss of the glycocalyx. A key component of inflammation is the expression of matrix metalloproteinases, which have effects on the endothelium, venous smooth muscle, and adventitia. Due to venous hypertension, inflammation and remodeling, a fibrin and collagen deposition is formed in the postcapillary venule, resulting in a major abnormality in the dermal microcirculation and the formation of a postcapillary cuff. Recently, venous microvalves have been found in a network of the venous microvasculature with up to six generations of microvalves in the microvenous network of the skin. A microvalve reflux could exist in the absence of greater saphenous vein reflux, and once it has compromised the third generation set of microvalves, there is a greater risk for the development of dermal venous ulceration. In patients with CVD, reflux in the microvalve and microvenous network is more extensive. Further research will make it possible to have specific pharmaceutical targets to restore the integrity of the microcirculation.

The aim of the symposium entitled ‘Understanding venous pain,’ chaired by Jean-Jérôme Guex (France) and Bo Eklöf (Sweden), was to release the latest evidence on the epidemiology, pathophysiology, and clinical research on venous disease, with a focus on venous pain.

Why focus on venous pain? It is acknowledged that leg pain is the commonest complaint in venous disease, and its chronic nature means that it impacts significantly on patients’ quality of life.

Little is known about the prevalence of venous pain around the world for the simple reason that venous symptoms are usually not sought in epidemiological surveys, wherever the survey is performed, Europe or USA.

Eberhard Rabe, Germany raised the question as to whether we should consider venous pain as part of chronic venous disease. The recent Vein Consult Program (VCP), which updated information on the prevalence of primary chronic venous disease (PCVD) in 22 different geographic areas, showed that there are many similarities between continents in venous pain perception and in the prevalence of both venous symptoms and signs. The program revealed that three symptoms are common to all surveyed countries and that risk factors for these symptoms are also common with those of PCVD. In addition, a systematic search for venous symptoms helped detect PCVD in 6 out of 10 subjects in the VCP population. For all these reasons, one should consider venous symptoms, even at an early stage, as part of PCVD.

Nicos Labropoulos, USA explained the current understanding of the pathophysiology of pain during venous disease, and what triggers symptoms. For this, it is necessary to take into account the properties of the venous and perivenous nociceptors described by Vital’s team,¹ as well as the inflammatory mechanisms that characterize venous disease from its earliest stages. The likely trigger for these mechanisms is disturbed blood flow in large veins and capillaries that cause changes in the forces exerted on the venous endothelium. These mechanical changes activate endothelial cells resulting in the synthesis and local release of mediators that modulate pain and are pro-inflammatory. Evidence of such an inflammatory reaction has accumulated dramatically in recent years and the biochemical changes identified suggest that endothelial cells and neutrophils are the source of this local inflammation.²

Interest in the mechanisms underlying PCVD has received new impetus with the increasing recognition of the importance of the venous microvalves in the occurrence of skin changes,³ and possibly venous symptoms. Extension of microvalvular reflux into the microvenous network and the resulting activation of the perivenous nociceptors in the microcirculation could lead to painful sensations. This new hypothesis needs to be validated.

In his presentation entitled Is venous pain reduction a meaningful treatment outcome?, Peter Neglén, Cyprus, emphasized the importance of targeting pain in the treatment of PCVD, knowing that CEAP and VCSS classifications as well as hemodynamic parameters are not sufficient to judge the success of a treatment. Symptoms can be present at all stages of PCVD and should not be neglected as they have an important impact on patient quality of life. The availability of specific and validated scales such as CIVIQ-14 now permit an accurate assessment of the impact of PCVD on patients’ quality of life and how it can be improved with treatments such as Micronized Purified Flavonoid Fraction (MPFF)*.

In a review of the efficacy of MPFF on venous symptoms, Armando Mansilha, Portugal, summarized the positive results of MPFF on symptoms and edema that have ensured its recognition as a grade 1 venoactive drug in the latest consensus documents.⁴

It is hoped that enhanced awareness among physicians of the impact of venous symptoms will result in more patients receiving effective treatment in the early stages. This will improve quality of life and delay or prevent the progression of the disease and the development of severe complications.

References
1. Vital A, Carles D, Serise JM, Boisseau MR. Evidence for unmyelinated C fibers and inflammatory cells in human varicose saphenous veins. Int J Angiol. 2010;19:e73-e77.

2. Bergan JJ, Schmid-Schönbein G, Coleridge-Smith P, Nicolaides A, Boisseau M, Eklöf B. Chronic venous disease. N Engl J Med. 2006;355:488-498.

3. Vincent JR, Jones GT, Hill GB, van Rij AM. Failure of microvenous valves in small superficial veins is a key to the skin changes of venous insufficiency. J Vasc Surg. 2011;54(6 Suppl):62S-69S.

4. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: rationale, results and unanswered questions. Eur J Vasc Endovasc Surg. 2011;41:117-125.

Daniel Myers, USA


Even though Virchow’s triad is still relevant, the author introduced a variation and believes that thrombus may arise from a combination of activated endothelium, altered blood flow, and thrombophilia.¹ Inflammation therefore has an important role in triggering thrombosis. In this context, the author’s group looked at the potential relevance of P-selectin in the thrombotic process. The expression of this glycoprotein is first increased in activated platelets and endothelial cells. The interaction of P-selectin with its receptor P-selectin glycoprotein ligand-1 (PSGL-1) facilitates the initial rolling of neutrophils and thrombus amplification. Accordingly, they have demonstrated that soluble P-selectin is elevated in acute thrombosis and consequently may be considered as a biomarker for the diagnosis of venous thromboembolism.² Moreover, they have demonstrated the effectiveness of oral P-selectin inhibition for modifying venous thrombogenesis, increasing vein lumen opening, and decreasing inflammation in a primate model.³


References
1. Moll S, Mackman N. Arterioscl Thromb Vasc Biol. 2008;28:367-369.

2. Ramacciotti E, Blackburn S, Hawley AE, et al. Clin Appl Thromb Hemost. 2011;17:425-431.

3. Myers DD Jr, Wrobleski SK, Longo C, et al. Throm Hemost. 2007;97:400-407.

Peter Henke, USA


Leukocytes play an important role in thrombosis leading the author’s group to examine how different leukocytes act during the thrombotic process. They found that polymorphonuclear leukocytes (PMN) may contribute to very early venous thrombogenesis by neutrophil extracellular traps and elastase-mediated functions.¹ PMN may also impair venous thrombosis resolution via matrix metalloproteinase 9 (MMP-9) and urokinase-type plasminogen activator (uPA). On the other hand, monocytes appear to be more involved in mid to late thrombosis. They also appear to participate in the recanalization of the thrombus.² The role of stem cells remains unclear.


References
1. Henke PK, Varma MR, Deatrick KB, et al. Thromb Hemost. 2006;95:272-281.

2. Ali T, Humphries J, Burnand K, et al. J Vasc Surg. 2006;43:601-608.

Nigel Mackman, USA


Tissue factor (TF) is essential for hemostasis, but can also contribute to thrombosis in many pathological conditions. TF can be present in the active form (the most prevalent form; located in the vessel walls) and in an encrypted form (with little or no thrombogenic activity; at very low levels in blood where it is transported in small membrane vesicles released from activated or apoptotic cells, the so-called microparticules [MP]). Cancer patients have an increased risk of thrombosis. Importantly, tumor cells express high levels of TF and release TF+MPs. Consequently, the author’s group hypothesized that TF+MPs may trigger venous thrombosis. In fact, they were able to demonstrate that TF+MPs can enhance venous thrombosis in an animal model. Furthermore, they have found that elevated levels of TF+MPs were associated with an increased incidence of venous thrombosis and a worse prognosis in pancreatobiliary cancer patients.¹


Reference
1. Bharthuar A, Khorana AA, Hutson A, et al. Thromb Res. 2013;132: 180-184.

José Diaz, USA


Galectins are a family of carbohydrate-binding proteins that have a high affinity for galactosides on cell surfaces and extracellular glycoproteins. They are involved in a variety of biological functions, including modulation of cell apoptosis, cell activation, and inflammation. Using microparticle proteomics analysis, the author’s group has shown that galectin-3 binding protein (Gal-3BP) is upregulated in patients with deep venous thrombosis (DVT) compared with negative controls. These proteins also appear to be able to promote an upstream regulation of both P-selectin and phosphotidylserine. As the inhibition of these two molecules prevents thrombus amplification, a specific galectin inhibitor could be a potential new pharmacological approach to venous thromboembolism management.

Mark Meissner, USA


The pathophysiology of deep venous thrombosis (DVT) is related to abnormalities of blood, blood flow, and the vessel wall, but blood stasis and venous injury are also involved. DVT is a chronic disease of coagulation, where hypercoagulability plays a primary role. If DVT is a multicausal disease, risk factors are synergistic and not additive. The early natural history is a dynamic balance between recanalization and recurrent thrombotic events. Neutrophils and then monocytes are involved in the early stage of recanalization as well as tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and plasmin. The greatest changes in thrombus load occur over the first 3 to 6 months, and 55% of DVT cases have complete recanalization at 6 months. Thrombolysis, organization, peripheral fragmentation of the thrombus, and cellular migration can all be observed. Determinants for recanalization are sex (better if female vs male), and thrombus localisation (calf vein > proximal vein), but there is no relation regarding age. Activated coagulation and fibrinolytic inhibition are, of course, highly correlated with recanalization. The restoration of the venous lumen is not always associated with a reflux.

The late natural history of DVT is dominated by recurrent venous thromboembolism (VTE). Early anticoagulation therapy prevents recurrence because recurrent VTE is a systemic disease with underlying thrombotic risk factors. An incomplete recanalization of the thrombus is a powerful factor for recurrent VTE.

The long-term outcome of DVT is related to the natural history: a rapid recanalization protects valve function and a recurrent DVT predicts reflux and postthrombotic syndrome.