By Marzia Lugli (Modena, Italy) and Michel Perrin (Lyon, France)

ABSTRACT

To view the PubMed abstract, please Click here

This prospective series is interesting since it is the first one to report long-term outcome (45 to 68 months) of saphenofemoral junction ligation combined with ultrasound-guided foam sclerotherapy (USGFS) for treating venous ulcer. The authors give information on their ultrasound results, but unfortunately do not document the correlation between the clinical and investigation results.

Another point is unclear: saphenofemoral and popliteal junction ligation is named in the text, when describing the procedures, while the title mentions only saphenofemoral junction ligation.

Ulcer healing after an average of 50 days of treatment was seen in 24 of the 32 patients (75%) with venous ulcer who were followed up. This result is close to that reported by Pang et al,¹ but lower than the 93% reported in the ESCHAR study.²

The presence or absence of either incompetent perforators or primary deep reflux was not assessed and this may account for non-healing ulcers and for ulcer recurrences as well. Nevertheless, the role of perforators in ulcer pathophysiology is a subject of debate,^1,3 while that of axial deep reflux is better documented.⁴

At 4-year follow-up, the ulcer recurrence rate was around 30% in the present study, a value comparable with that in the ESCHAR study² (estimated recurrence rate 31%) in which patients were treated by conventional surgery plus compression.

USGFS combined with saphenous termination ligation might also be compared with thermal ablation, but unfortunately no medium- or long-term data concerning thermal ablation are available, and only short-term outcomes have been reported.^5,6

The authors consider that USGFS must be included as a potential tool for treating ulcer related to superficial venous insufficiency, but surprisingly it is named “palliative treatment”, whereas it seems to have a full therapeutic role.

References:
1. Pang KH, Bate GR, Darwall KAL, Adam DJ, Bradbury AW. Healing and recurrence rates following ultrasound-guided foam sclerotherapy of superficial venous reflux in patients with chronic venous ulceration. Eur J Vasc Endovasc Surg.. 2010;40:790-795.
2. Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomized controlled trial. BMJ. 2007;335:83-89.
3. Lawrence PF, Alkataifi A, Rigberg D, DeRubertis B, Jimenez JC. Endovenous ablation of incompetent perforating veins is effective treatment for recalcitrant venous ulcers. J Vasc Surg. 2011;54:737-742.
4. Danielsson G. Eklof B, Grandinetti A, Lurie F, Kistner RL. Deep axial reflux, an important contributor to skin changes or ulcer in chronic venous disease. J Vasc Surg. 2003;38:1336-1341.
5. Marrocco CJ, Atkins MD, Bohannon WT, Warren TR, Buckley CJ, Bush RL. Endovenous ablation for the treatment of chronic venous insufficiency and venous ulceration. World J Surgery. 2010;34:2299-2304.
6. Harlander-Locke M, Lawrence P, Jimenez JC, Rigberg D, DeRubertis B, Gelabert H. Combined treatment with compression therapy and ablation of incompetent superficial and perforating veins reduces ulcer recurrence in patients with CEAP venous disease. J Vasc Surg. 2012;55:446-450.

By Peter NEGLEN, Trimiklini, Cyprus

ABSTRACT

To view the PubMed abstract, please Click here

The authors evaluated 284 patients with chronic venous disease limited to varicose veins already scheduled for intervention; 67% had uncomplicated varicose veins (C-classification 2-3) and 33% had skin changes/ulcer formation (C4-6). The patients had to fill out a generic health-related quality of life questionnaire (HRQL: Short Form 12; SF-12) and identify whether or not specific symptoms were present (pain or ache, itching, tingling, cramp, restless legs, swelling, and a feeling of heaviness). Analysis revealed several observations:

1. There was no significant relationship between the number of symptoms and the C-classification;
2. Conversely, more symptoms meant a worse HRQL score;
3. Patients reporting tingling, cramp, restless legs, swelling, or heaviness had a significantly worse physical and mental HRQL score than those without these individual symptoms;
4. Greater C-classification and age were also significantly associated with worse HRQL score in a univariate analysis;
5. A linear regression performed to control for age and C-class showed a remaining significant relationship between the previously listed symptoms and worse HRQL score and, in addition, pain was correlated with worse physical HRQL score.

To conclude, symptomatic varicose veins without skin changes/ulcer result in a significant reduction in quality of life and, therefore, warrant intervention.

The CEAP classification was created to give a snapshot description of the presence of venous disease in patients with lower limb complaints.¹ A description of the clinical severity, etiology, anatomical involvement, and whether or not reflux and obstruction are present would make it possible to identify groups of patients in a standardized way and to adequately compare groups of patients in different studies. In addition, it would be a framework for the management thought process and workup of patients. The CEAP classification has, however, been abused.  It was never intended to be used for continuous follow-up (the Venous Clinical Severity Score was created for this purpose) or to be a tool for deciding whom to treat. Unfortunately, the E, A and P in the CEAP-classification are not often reported in studies. The C-class is largely decided by the examining physician disregarding the patient’s own perception of his/her health. Despite this the C-class has been hijacked as a tool to decide whether or not to intervene (by open surgery or endovenous procedures), especially in patients with varicose veins.  It appears that both commercial insurance companies (USA) and public funding directors (Holland, UK, Sweden) have adopted the C-classification as the sole decision tool for intervention and refuse to accept C1-2 and often C3 for intervention considering those varicose veins to be a cosmetic problem when the disease is not complicated by skin changes or ulcer formation. This is an oversimplification as shown by this study.

The American Venous Forum and the Society of Interventional Radiology have published recommended reporting standards for endovenous ablation for the treatment of venous insufficiency.² It is strongly emphasized that the result of treatment has to be described as clinical outcomes that are meaningful to the patients, such as relief of symptoms and improvement of quality of life. It is, therefore, reasonable that indications for intervention for venous disease should be dictated by factors that are important to the patient, such as disease-linked symptoms and decreased quality of life, and not related to physical signs alone. There is no single parameter which can achieve this goal. The C-classification has several potential disadvantages. As pointed out previously, the C-class is mainly based on the physician’s observation. The graded evaluation of symptoms such as pain, cramp, tingling, etc, is limited to symptomatic or asymptomatic. It has been suggested that additional clinical signs such as corona phlebectatica should be included. Swelling is not an uncommon symptom, which can be caused by conditions other than venous disease. The impact of the disease on the patient’s quality of life is subjective, but may be quantified by using validated generic or disease-specific questionnaires. Both of these should be used in outcome assessments. Quality of life assessment may also have its problems.  If a health-related quality of life questionnaire (HRQL) is used as an indication for treatment, the patients may exaggerate their symptoms to justify having an intervention. In this study, though, the patients were already scheduled for intervention and thus had no obvious reason to exaggerate.

This and several other studies show a relationship of varying strength between C-class, VCSS, and HRQL (generic and disease-specific).^3,4,5 This does not preclude that patients with symptomatic uncomplicated varicose veins may have substantial problems affecting their quality of life. Surgical or endovenous intervention for varicose veins has repeatedly been shown to improve symptoms and HRQL score and to result in high levels of patient satisfaction. The improved HRQL score has matched or surpassed the level achieved after laparoscopic cholecystectomy for biliary colic and groin hernia surgery. The use of the C-class of the CEAP as the only decision tool for intervention by insurance companies or public funding authorities is wrong and puts symptomatic patients with uncomplicated varicose veins at a disadvantage. These patients do not always have a cosmetic problem only, but often symptoms that substantially affect their quality of life, and should, therefore, be offered intervention.

References
1. Eklof B, Rutherford RB, Bergan JJ, et al. American Venous Forum International Ad Hoc Committee for Revision of the CEAP Classification. Revision of the CEAP classification for chronic venous disorders: Consensus statement. J Vasc Surg. 2004;40:1248-1252.
2. Kundu S, Lurie F, Millward SF, et al. Recommended reporting standards for endovenous ablation for the treatment of venous insufficiency: Joint Statement of the American Venous Forum and the Society of Interventional Radiology. J Vasc Surg. 2007;46:582-589.
3. Lozano Sanchez FS, Carrasco Carrasco E, Diaz Sanchez S, et al. Chronic venous disease in Spain – patient correlation. Eur J Vasc Endovasc Surg. 2012;44:582-586.
4. Carradice D, Mazari FA, Samuel N, et al. Modeling the effect of venous disease on quality of life. Br J Surg. 2011;98:1089-1098.
5. Passman MA, McLafferty RB, Lentz MF, et al. Validation of venous clinical severity score (VCSS) with other venous severity assessment tools from the American Venous Forum, national venous screening program. J Vasc Surg. 2011;54(6 Suppl.):2S-9S.

By Alberto CAGGIATI, Rome, Italy

ABSTRACT

To view the PubMed abstract, please Click here

Context and background:

The anatomy of venous valves (VVs) has been extensively studied in the past with particular regard to their number and location, as well their shape and structure. With regard to their location, VVs have been designated as “ostial” and “parietal”. Ostial valves have also been called “junctional” or “terminal” because they are located at the end of a vein where it opens into a larger one (1). Parietal valves are those located far from the ostium of the vein and consequently they have also been designated as “axial” or, more correctly, “truncal” (2).

Although the anatomy of VVs was extensively investigated in recent decades, only 10 years ago they were still considered as mere diaphragms passively closed by hydrostatic forces. Ten years ago Fedor Lurie and colleagues introduced an innovative concept regarding the movements of VV leaflets and local hemodynamics (3). They demonstrated that leaflets do not go all the way against venous wall and that, at the time of maximal opening, the orifice of the valve has a funnel shape. The blood forced by muscular contraction through the orifice forms a jet with higher velocities in the center of the vein.

Ten years later, the same group investigated the anatomic relationships between adjacent valves and speculated on the possible functional implications (4). In particular, Lurie and Kistner investigated the orientation of valves in a venous segment that is easily studied by duplex ultrasonography, ie, the last portion of the great saphenous vein (GSV) and of the femoral vein (FV). Leaflet orientation was evaluated with the probe perpendicular to the long axis of the vein. The authors noted that in the last VV of the GSV and of the FV, leaflets were not oriented in a similar manner. In fact, they were placed at about 90° to each other (mean 84° and 88° in GSV and FV, respectively). Importantly, the angle between the two valves correlated with the distance between them. In turn, leaflet orientation did not correlate with vein diameter.

Concluding, the main finding was that VVs, at least those located near venous confluences, are positioned at a significant angle to each other.

Comment

This is the first time that the relative position of VVs has been investigated in depth. The angle between two consecutive VVs may be important in supporting venous return, at least at venous junctions. In fact, the authors speculated that if blood flow is faster at center of the lumen at a VV, the angle between adjacent VVs would result in helical flow. Helical flow has been widely demonstrated to occur in arteries where it represents the natural optimization of fluid transport. Rotational momentum introduced by subsequent VVs would decrease dissipation of energy and enhance flow stability. This seems to be necessary where laminar flow is altered due to the confluence of veins with different hemodynamic patterns. The same probably occurs in varicose vein clusters, thus again reducing dissipation of energy.

Unfortunately, “..only two venous segments were investigated, ..and generalization to other parts of the venous system awaits future investigation..”. In fact, truncal VVs of the GSV are mostly oriented parallel to the muscular and saphenous fasciae (Fig 1).

Be that as it may, Lurie and Kistner have introduced the innovative concept that the relative position of venous valves is probably key to the efficacy of venous return.

Figures

Fig. 1: Ultrasonography of a truncal valve of the great saphenous vein. Leaflets (white arrows) are parallel to the muscular and saphenous fasciae (5).

Click to enlarge the figure

References:
1. Caggiati A, Bergan JJ, Gloviczki P, Eklof B, Allegra C, Partsch H. Nomenclature of the veins of the lower limbs: Extensions, refinements and clinical application. J Vasc Surg. 2005;41:719-724.
2. Caggiati A, Rippa Bonati M, Pieri A, Riva A.1603-2003: Four centuries of valves. Eur J Vasc Endovasc Surg. 2004;28:439-441.
3. Lurie F, Kistner RL, Eklof B, Kessler D. Mechanism of venous valve closure and role of the valve in circulation: a new concept. J Vasc Surg. 2003;38:955-961.
4. Lurie F, Kistner RL. The relative position of paired valves at venous junctions suggests their role in modulating three-dimensional flow pattern in veins. Eur J Vascular Endovasc Surg. 2012;44:337-340.

By Michel Perrin, Lyon, France

ABSTRACT

To view the PubMed abstract, please click here

REVIEW

Patients identified as C_2s, E_p, A_s, P_r represent the most frequent situation in chronic venous disease. The authors review the different treatment modalities in this case, describing their advantages and disadvantages as well as their outcome. The value of conservative treatment is clearly stated and assessed. Compression treatment is an option, but is unlikely to be accepted in the long term by patients, particularly by younger patients, and is costly. Some venoactive drugs mentioned by the authors have been shown to be efficacious on symptoms, but their long-term impact on disease progression is unknown.

There are presently a number of surgical options for treating varicose veins. Unlike the stance of the American Venous Forum and the Society for Vascular Surgery, which recommend endothermal saphenous vein ablation as the primary treatment of symptomatic varicose veins¹, the authors of the present article assign the same recommendation grade to modern high ligation in association with stripping, and to thermal or chemical ablation. In a review of randomized controlled trials of the treatment of varicose veins, the conclusion was that there are a number of treatment options available for ablation of varicose veins, not solely thermal ablation.^{2, 3}

Procedures that preserve the great saphenous veins, such as CHIVA⁴ and ASVAL⁵, are not mentioned, probably because these techniques are not used in the United Kingdom and their long-term efficacy is still debated.

In reality the choice of the surgical procedure has very little to do with medical grounds.
It depends on:

- The skill of the specialist in the different procedures

- National health care system reimbursement policies

- The patient’s ability to pay for a treatment that is not reimbursed

- The patient’s preference

The authors conclude that any acceptable treatment option for ablation of uncomplicated varicose veins can be considered.

References:
1. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care of patients with varicose veins and associated chronic venous diseases: Clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2011;53:2S-48S.
2. Eklöf B., Perrin M. Randomized controlled trials in the treatment of varicose veins. I. Phlebolymphology. 2011;18:196-208.
3. Perrin M., Eklöf B. Randomized controlled trials in the treatment of varicose veins. II. Phlebolymphology. 2012;19:92-99.
4. Franceschi C. Théorie et Pratique de la Cure Conservatrice et Hémodynamique de l’ Insuffisance Veineuse en Ambulatoire. Precy-sous- Thil, France: Editions de l’Armancon; 1988.
5. Pittaluga P, Chastanet S, Rea B, Barbe C. Midterm results of the surgical treatment of varices by phlebectomy with conservation of a refluxing saphenous vein. J Vasc Surg. 2009;50:107-118.

By José Ben-Hur FERRAZ PARENTE – Sao Paulo, Brazil

ABSTRACT

To view the PubMed abstract, please Click here

At the initiative of the Union Internationale de Phlébologie, a large-scale, international, observational, prospective survey, named the Vein Consult Program (VCP), was carried out in 20 countries in 5 regions. The aim of this survey, which was based on the CEAP classification (Clinical (severity)–Etiology–Anatomy–Pathophysiology), was to collect epidemiological data about chronic venous disease (CVD) and assess its management worldwide. This survey was carried out by general practitioners (GPs) trained in the use of the CEAP classification.

A questionnaire including 21 questions was filled by the GPs, starting with 3 questions relating to patient description (age, weight, and spontaneous complaint of venous leg problems), followed by 7 questions on CVD risk factors, and 11 questions related to chronic venous disease screening (clinical symptoms and signs).

This study involved 6232 GPs who screened 91 545 subjects. The mean age of the participants was 50.6 ± 16.9 years, 68% were female, and the mean body mass index (BMI) was 26.17 ± 5.07. The distribution of patients among the CEAP clinical classes (N= 58 497) was as follows: 16 901 (21.7%) in C1, 13 888 (17.9%) in C2, and 18 863 (24.3%) in C3 to C6 (chronic venous insufficiency patients), totalizing 46 451 patients (64%). The number of subjects complaining solely of symptoms, the so-called C0_S patients, was 15 290 (19.7%), indicating that almost 20% of the survey population had CEAP grade C0s.

One particular feature of this study is that it distinguished between C0_A (healthy people) and C0_S. The C0_S group should be analyzed carefully so as not to be confused with symptoms of other causes. Interestingly, these C0s patients were equally distributed throughout the geographical zones, with the exception of the Middle East where the percentage of C0s patients was much higher (47.3% of men and 40.5 % of women), reflecting the younger age of the population and perhaps also the warm climate of this region. It remains to be determined whether such individuals deserve more in-depth investigation and care because of the possible progression of their symptoms to more severe stages of CVD.

Of all the subjects analyzed, 54.3% belonged to CEAP classes C1 to C3 and 9.6% belonged to classes C4 to C6. There was a greater incidence of severe clinical CVD (C4-C6) in the Latin American group (13.3%) and a lower incidence in the Western European group (6.8%).

The high incidence (up to 13.3%) of the most severe clinical form of CVD (C4-C6) in some groups demonstrates the need for health care authorities to pay special attention to this illness.

GPs referred 22.2% of the global population to venous specialists. These patients included 15.7% of the patients in the C1 group, 36.7% of the patients in the C2 group, 43.5% of patients in the C3 group, and 52.4% of patients in the C4-C6 group. It is interesting to note that a relatively low proportion of patients eligible for referral actually visited a venous specialist (less than 50%), showing that the CVD patients themselves do not understand that it is preventable.

Although it produced a wealth of results, the VEIN CONSULT program methodology has its limits. By only considering a population consulting GPs, the program introduces a recruitment bias (more women than men) and perhaps also a behavioral bias.

The VEIN CONSULT program provides a snapshot of the patients affected by CVD, but we do not know the future of these patients or how their disease will progress. Neither do we know whether the symptoms or risk factors that these patients had are predictive of disease progression.

Finally, recruitment procedures varied considerably from one country to another.

Nevertheless, the results of the survey demonstrate that CVD is a global problem that does not solely affect the Western world. In addition, it highlights the role of GPs in correctly identifying the symptoms of CVD, which is particularly important as they frequently are the first point of contact for most patients. GPs with CEAP classification training are more likely to refer patients to specialists (angiologists and/or vascular surgeons), especially in the early clinical stages, but much remains to be done to improve CVD awareness.

With 60% of patients presenting with at least one CVD sign (patients assigned to the C1 to C6 classes of the CEAP) whatever the geographical location, the results of the Vein Consult Program are in line with those of previous studies, which were carried out for the most part in the “Western world.”^1-10

References:
1. Fowkes FGR, Evans CJ, Lee AJ. Prevalence and risk fac¬tors of chronic venous insufficiency. Angiology. 2001; 52(suppl 1):S5-S15.
2. McLafferty RB, Lohr JM, Caprini JA, et al. Results of the national pilot screening program for venous disease by the American Venous Forum. J Vasc Surg. 2007;45:142-148.
3. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based survey. J Vasc Surg. 2001;33:1022-1027.
4. Evans CJ, Fowkes FG, Ruckley CV, Lee AJ. Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh Vein Study. J Epidemiol Community Health. 1999;53:149-153.
5. Scuderi A, Raskin B, Al Assal F, et al. The incidence of venous disease in Bra-zil based on the CEAP classification. Int Angiol. 2002; 21:316-321.
6. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der Deutschen Gesellschaft für Phlebologie. Phlebologie. 2003;32:1-14. [German]
7. Jawien A, Grzela T, Ochwat A. Prevalence of chronic ve¬nous insufficiency (CVI) in men and women in Poland: multicenter cross-sectional study in 40 095 patients. Phlebology. 2003;18:110-122.
8. Carpentier PH, Maricq HR, Biro C, Poncot-Makinen CO, Franco A. Prevalence, risk factors and clinical patterns of chronic venous disorders of lower limbs. A population-based study in France. J Vasc Surg. 2004;40:650-659.
9. Chiesa R, Marone EM, Limoni C, Volonte M, Schaefer E, Petrini O. Chronic venous insufficiency in Italy: the 24-cities cohort study. Eur J Vasc Endovasc Surg. 2005;30:422-429.
10. Criqui MH, Jamosmos M, Fronek A, et al. Chronic venous disease in an ethnically diverse population: the San Diego Population Study. Am J Epidemiol. 2003;158:448-456.

By Michel-René BOISSEAU – Bordeaux, France

ABSTRACT
To view the PubMed abstract, please Click here

Aim of the study

The purpose of this analysis of the “San Diego Population Study”¹ was to investigate the possible association between a biomarker, P-selectin (P-sel), and chronic venous insufficiency (CVI), as P-sel has already been found to be a risk marker for the occurrence of venous thromboembolism. The underlying hypothesis for this study was that platelet and endothelial cell activation may play a role in the genesis, or at least, the evolution of CVI, as both platelets and endothelial cells have been shown to contain, and then release, P-sel in the human body. As the authors state in their introduction: “we hypothesized that higher P-Selectin is a risk factor for CVI.” This hypothesis has not yet been reported in the medical literature and, therefore, this study may help explain the pathogenesis of CVI (at least partly), which is still a rather controversial issue.

Material and Methods

The inclusion criteria are published elsewhere.¹ In this analysis of the relationship between P-sel and the risk of developing CVI, four groups of patients were identified: the lowest severity group consisted of 125 patients with deep venous functional disease (DFD) and no trophic changes (TCS) or symptoms. The second group included 137 patients with superficial functional disease (SFD) and TCS or edema, as well as those with a normal ultrasound and TCS. The third group included 59 participants with DFD, with symptoms including aching or edema, and no TCS. The final and most severely affected group consisted of 49 patients with DFD and TCS, (regardless of symptoms).

The number of participants was reduced from 370 to 199 when the updated definitions of the CEAP classification were used. The 199 patients who remained in the survey were compared with 352 precisely matched control patients. P-sel levels were measured using a reliable ELISA technique. The statistical methods used were particularly sophisticated (P-sel distribution in tertiles, control for potential confounders, assessing of odds ratio…).

Results

The mean P-sel level in the cases was slightly higher but not significantly different than that of the controls (35.2 vs 34.1 ng/ml). In groups 3 and 4 combined, the mean level was 36.2 ng/ml. Interestingly, higher BMI was associated with higher P-sel levels, with a correlation coefficient of 0.16 (P=0.004).

The odds ratios of CVI by tertiles of P-sel using tertile 1 as a reference are also given in the paper. When comparing the two highest CVI case groups (n=80) with the control patients (n=352), the odds ratio for CVI was 1.4 for P-sel in the second tertile and 2.3 in the third. Among all possible confounders, only BMI partially attenuated this association to an odds ratio of 1.9. Similar results were obtained using ordinal regression analysis.

In conclusion, this study showed an association between high levels of P-sel and CVI, although this was mainly for more severe disease.

COMMENTS

P-sel, endothelium, and platelets. This study shows that platelet and endothelial cell activation, which releases P-sel, may be partly responsible for—at least—a worsening of CVI; that is to say that P-sel may not be only an inflammation marker, but also a pathogenic one (ie, increasing leukocyte rolling along the surface of vessel walls and promoting the stable adhesion of leukocytes to endothelial cells). Actually, the authors do not suggest that an increase in P-sel is an argument supporting the old theory of “white cell trapping” on the venous wall, for there is, in this study, nothing to encourage such a hypothesis. However, in the introduction, the authors mention the interaction between P-sel and P-selectin glycoprotein ligand 1 (PSGL-1) on the leucocytes present in flowing blood.

What remains to be determined is which kind of endothelial cell is activated in the severe CEAP classes of CVI; perhaps P-sel may originate not only from the superficial veins, but also mainly from numerous layers of dermal and hypodermal venules in the lower limbs and flowing upstream, a phenomenon that is likely to suggest an ascending pathogenesis for CVI.

P-sel, thrombin, and postthrombotic syndrome. Of course, thrombin generation during vein thrombosis—which is sometimes unnoticed or neglected—activates platelets and increases soluble P-sel.² This latter factor has negative effects: it induces the generation of circulating procoagulant microparticles by leukocytes, which increases the risk of thrombus. So, blood P-sel level is a valuable marker for the occurrence and development of deep venous thrombosis.

P-sel and obesity. This study found a significant relationship between obesity (ie, high BMI) and P-sel levels; this is likely to be due to adipokines secretion by adipose tissue.³ Adipokines operate concomitantly via thrombotic factors: platelet activation, PAI-1 and tissue factor production, and hepatic release of factor WIII and fibrinogen. So, in obese patients, both P-sel and adipokines appear to promote thrombin generation. This means that obesity may be the main risk in CVI.

P-sel as a therapeutic target. Monoclonal antibody rPSGL-Ig and Psel/PSGL-1 inhibitors decrease thrombus size and inflammation in much the same way as enoxaparin.⁴

Genetic aspect. P-selectin-Thr715 variant carriers run a lower risk of venous thromboembolism.⁵

References:
1. Criqui MH, Jamosmos M, Fronek A, et al. Am J Epidemiol. 2003;158:448-456.
2. Kyrle PA, Hron G, Eichinger S, et al. Thromb Haemost. 2007;97;880-803.
3. Allison MA, Cushman M, Callas PW, Denenberg JO, Jensky NE, Criqui MH. J Thromb Haemost. 2010;8:1912-1918.
4. Ramacciotti E, Myers DD Jr, Wrobleski SK, et al. Thromb Res. 2010;125:e138-e142.
5. Ay C, Jungbauer LV, Sailer T, et al. Clin Chem. 2007;53:1235-1243.

€ 25 000

funded by Servier International to a young researcher for an original fundamental or clinical research project in the field of venous and/or lymphatic diseases. The 2013-2015 fellowship competition is now open and the deadline for project submission is

March 29th, 2013.

For further information please download the following files:

Poster Fellowship 2013-15

Application Form_2013-2015

With best regards,

Jean-Jérôme Guex
Coordinator of the Fellowship

 Review

It is fully acknowledged that cancer is a high-risk factor for venous thrombosis and that low weight molecular heparins are the first-line option for the prevention and treatment of venous thromboembolism, with a grade 1A recommendation. Nevertheless, no formal recommendation is found in the literature regarding the systematic treatment of ambulatory patients. Recommendations for this specific type of patients are only based on the advice of experts.

Thromboembolic risk depends on the severity (stage) of the tumor, the associated anticancer treatment, and the general state of the patient. Our team has proposed a grading of the intrinsic and extrinsic risk factors for venous thrombosis (VT) together with a scoring system. This should help better define the profile of the patients at high risk of VT (with proximal VT incidence >5%) who may benefit from an antithrombotic treatment strategy. The profile of these patients can be determined using a four-dimensional approach.

A. Intrinsic factors related to the patient

• Age (>65-70 years).

• Body mass index (BMI>29).

• Personal history of acute thromboembolism.

• Other associated factors of risk: congestive heart insufficiency, chronic obstructive bronchopneumonia, diabetes, myocardial coronary infarction, stroke, lupus, sepsis, intestinal inflammatory diseases, Behçet disease, nephrotic syndrome, hypothyroidism.

B. Intrinsic factors related to CANCER

• Presence of a solid tumor (pancreas, stomach, colon, lungs, ovary).

• TNM classification.

• Histological impairment.

• Time between diagnosis and start of treatment (0-3 months>>3-12 months>>1-3 years).

C. Extrinsic factors related to the TREATMENT

• Surgical intervention.

• Chemotherapy (cisplatin, 5-fluorouracil).

• Previous transfusion.

• Erythropoietin.

• Treatment with bevacizumab and other antiangiogenic agents.

• Treatment with tamoxifen.

• Treatment with IMiDs associated with dexamethasone.

D. Biomarkers of the vascular risk

Biomarkers are the fourth dimension of the grading of the vascular risk related to cancer.

• Hemogram that partly mirrors the inflammatory syndrome associated with cancer.

• Tissue factors associated with hypercoagulability in cancer.

• Soluble P-selectin.

• D-dimers.

• C-reactive protein.

• Factor VIII.

• Capacity to produce thrombin.

• Tumoral and circulating endothelial cells.

Various scores have been proposed but they are not applicable to all cases because they are validated in a given type of patients: those who receive nonspecific chemotherapy in certain types of tumors.^1,2

The Khorana score is proposed:

Parameter	Score
Location of cancer Pancreas, stomach Lungs, lymphoma, gynecological, testicles, bladder	2
Platelets counts before chemotherapy > 350×109/L	1
Hb<10g/dL or Use of growth factors of erythrocytes	1
Leukocyte counts before chemotherapy >11×109/L	1
BMI >35Kg/m2	1
SCORE>3 : high risk of VT (7% at 2.5 months)

The specific features of VTE linked to cancer prompt preventive and treatment strategies that must be adapted to each patient. Therefore, multidisciplinary meetings in which individual strategies are discussed are mandatory.

References:
1. Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol. 2009;27:4839-4847.
2. Ay C, Dunkler D, Marosi C, et al. Prediction of venous thromboembolism in cancer patients. Blood. 2010;116:5377-5382.

*Abstract presented at the 64^th Meeting of the French Society of Angiology, Paris, France, 27-28 January, 2012

Although the contraceptive pill is taken by millions of women daily, cases of venous thrombosis or venous thromboembolism are rare. Yet, such cases are severe and may result in the patient’s death. Therefore, it is important to detect patients at risk of venous problems and choose the most appropriate contraceptive pill.

The risk factors for venous thromboembolism (VTE) are now well-known. They include age, obesity, cancer, surgery, immobilization in plaster casts, long-haul flights, long-haul car or bus trips, pregnancy, in vitro fertilization, and hormonal treatments (contraceptive pill, hormonal replacement therapy in menopause, and treatment of breast cancer). Personal history of VTE and/or established biological thrombophilia (congenital deficiency in antithrombin, protein C, protein S, factor V Leiden, mutation in the prothrombin 20210A gene, and the presence of circulating antiphospholipid antibodies) also increase the risk of venous thrombosis.

Oral estroprogestative contraceptive pills may increase the risk of venous thrombosis (VT) by 4 to 6 times, in particular during the first year of administration. Factors associated with VT include the dose of ethinyl-estradiol (EE) and the type of combined progestogen drug, as the risk is higher with the third generation of progestogen drugs compared with those of the second generation. Some combined contraceptives containing EE and progestogens such as cyproterone acetate and possibly drospirenone lead to a higher risk of VT. The use of EE-based contraceptives whether as a patch or as a vaginal ring is also associated with a significant increase in the risk of VTE. However, the absolute risk of VT related to contraceptive use is low when there is no other associated risk factor, especially before the age of 40.

In the absence of risk factors for VT, the first prescribed contraceptive is usually a pill containing a low dose of EE associated with a second generation progestogen compound (levonorgestrel). Prescription is then further adapted according to the tolerability of the pill.

In women older than 40 years, the benefits of the combined (EE-progestogen) pill should be assessed according to the other associated risk factors.

In women with a personal history of VTE and/or thrombophilia, the estroprogestative contraceptive pill is contraindicated whatever the administration mode (oral, patch, or vaginal ring), the EE dose, or the type of progestogen. Since there is a lack of data on estradiol-based contraception, none of the oral contraceptive pills containing estradiol (not EE) are recommended in this type of patient. Only progestogen contraceptives in the form of oral pills, subcutaneous implants, or intra-uterine devices are advisable for patients at high risk of VT.

In patients with a family history of severe VT without thrombophilia in a first-line relative (in particular, hormone-related VTE in the mother or sister), prescription of a contraceptive should be carefully considered and the combined estroprogestative contraceptive pill is not recommended.

Comment by Michel Perrin, Lyon, France

ABSTRACT
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Review

Following the publication of guidelines devoted to the care of patients with varicose veins in the Journal of Vascular Surgery¹ (reviewed in VEINEWS on August 30th 2011), guidelines on the management of deep venous thrombosis (DVT), with recommendations made according to the grading methodology of Guyatt have now been issued by almost the same group of North American experts in venous disease.²

Please note that the comments made hereafter in this review are the sole responsibility of their author and are, of course, influenced by European practice, which sometimes differs from North American practice.

Click to enlarge the figure

A total of six guidelines, backed up by 107 references are discussed in the paper.

1. Precision in the diagnosis of DVT

Guideline 1.1: “We recommend use of precise anatomic terminology to characterize the most proximal extent of venous thrombosis as involving the iliofemoral veins, with or without extension into the inferior vena cava; the femoropopliteal veins; or isolated to the calf veins in preference to simple characterization of a thrombus as proximal or distal (Grade 1A).”

Comment: Full agreement with the 1C recommendation. Ultrasound imaging does not provide the information needed when early thrombus removal is considered, which is crucial to avoid perioperative pulmonary embolism.

2. Indications for early thrombus removal

Guideline 2-1. “We suggest a strategy of early thrombus removal in selected patients meeting the following criteria: (a) a first episode of acute iliofemoral deep venous thrombosis, (b) symptoms <14 days in duration, (c) a low risk of bleeding, and (d) ambulatory with good functional capacity and an acceptable life expectancy. (Grade 2C).”

Comment: As stated, the 2C recommendation is logical here as there is no precise information on infra inguinal extension of Iliofemoral thrombosis in the wording. In other words the question is: would the recommendation be higher in patients with DVT confined to the iliofemoral segment? This point and the management of femoro-popliteo-crural DVT when iliofemoral DVT is treated by thrombus removal should be clarified.

Guideline 2-2. “We recommend early thrombus removal strategies as the treatment of choice in patients with limb-threatening venous ischemia due to iliofemoral deep venous thrombosis with or without associated femoropopliteal venous thrombosis (phlegmasia cerulea dolens) (Grade 1A).”

Comment: Full agreement with a 1A recommendation.

Guideline 2-3. “We recommend that patients with isolated femoropopliteal deep venous thrombosis be managed with conventional anticoagulation therapy because there is currently insufficient evidence to support early thrombus removal strategies in this patient population (Grade 1C).”

Comment: Full agreement with a 1C recommendation.

3. Techniques for early thrombus removal.

Guideline 3.1. ” We suggest percutaneous catheter-based techniques (pharmacologic or pharmacomechanical) as first-line therapy for early thrombus removal in patients meeting the criteria in 1.1 (Grade 2C).”

Guideline 3.2. “We suggest a strategy of pharmacomechanical thrombolysis be considered over catheter-directed pharmacologic thrombolysis alone if expertise and resources are available (Grade 2C).»

Guideline 3.3. “We suggest open surgical venous thrombectomy in selected patients who are candidates for anticoagulation but in whom thrombolytic therapy is contraindicated (Grade 2C).”

Comment: Full agreement with the 2C recommendation for Guidelines 3.1, 3.2, and 3.3. The available data do not allow for a stronger recommendation. In Guideline 3.1 the wording “patients meeting the criteria in 1.1” must be read as “patients meeting the criteria in 2.1”.

4. Periprocedural inferior vena cava filters

Guideline 4.1. “We recommend against routine use of inferior vena cava filters (permanent or temporary) in conjunction with catheter-directed pharmacologic thrombolysis of the iliofemoral venous segments (Grade 1C).”

Comment: Agreement with the 1C recommendation. This very weak recommendation is related to the fact that there are currently no RCT comparing procedure outcome with or without inferior cava filter.

Guideline 4.2. “We suggest that the relative risks vs benefits of periprocedural retrievable inferior vena cava placement be considered in patients undergoing pharmacomechanical thrombolysis and in those with thrombus extending into the inferior vena cava or who have markedly limited cardiopulmonary reserve (Grade 2 C).

Comment: Although, there is no RCT, grade 2B seems more appropriate according to the small series of data.³

5. Adjunctive use of venous stents.

Guideline 5.1. “We recommend the use of self-expanding metallic stents for treatment of chronic iliocaval compressive or obstructive lesions that are uncovered by any of the thrombus removal strategies (Grade 1C).”

Comment: The 1C recommendation seems weak; we suggest grade 1B as any venous lumen anomaly after thrombus removal increases the risk of rethrombosis.

Guideline 5.2. “We suggest that stents not be used in the femoral and popliteal veins (Grade 2C).”

Comment: Surprisingly a 1C recommendation was given to femoro-popliteal stenting. In the absence of data, it would have made more sense to give a 1C recommendation, as dedicated venous stent for this localization may become available in the future.

6. Early thrombus removal strategies as an adjuvant to conventional management

Guideline 6.1. “We recommend that patients managed with early thrombus removal be treated with a standard course of conventional anticoagulation after the procedure (Grade 1A).”

Guideline 6.2. “We recommend that all patients be treated with knee-high compression stockings (30 to 40 mm Hg) for at least 2 years after the procedure (Grade 1C).”

Comment: Guidelines 6.1 and 6.2 are respectively quoted as 1A and 1C recommendations. We fully agree with both.

As underlined by the authors in the value statement chapter, the quality-of-life benefits and cost-effectiveness of this therapy need to be more thoroughly evaluated. As National Health regulations are different in every country, the task of determining which expenses should be supported by the patients themselves will not be easy.

References:
1. Gloviczki P, Comerota AJ, Dalsing MC, Eklöf BG, Gillespie DL, Gloviczki ML et al . The care of patients with varicose veins and associated chronic venous diseases: Clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2011;53:2S-48S.
2. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest. 2006;129:174-181.
3. Arko FR, Davis CM 3rd, Murphy EH, et al. agressive percutaneous mechanical thrombectomy of deep venous thrombosis. Arch Surg. 2007;142:513-519.