Basic concepts in the physiopathology of edema are reviewed. The mechanisms of fluid exchange across the capillary endothelium are explained. Interstitial flow and lymph formation are examined. Clinical disorders of tissue and lymphatic transport, microcirculatory derangements in venous disorders, protein disorders, and lymphatic system disorders are explored. Techniques for investigational imaging of the lymphatic system are explained.
The VEIN CONSULT Program, a joint initiative between the Union Internationale de Phlébologie and Servier, is the largest global effort to raise awareness of chronic venous disease (CVD) among patients, health care professionals, and health authorities. The aim is to update information on the prevalence of primary CVD in different geographic areas, to compare the management of the disease between countries, and to improve our understanding of the relationship between general practitioners and venous specialists, in order to propose a straightforward approach to earlier diagnosis. The survey was conducted in primary care centers as face-to-face interviews. Questionnaires were completed by practitioners and established the subjects' characteristics and risk factors for venous disease. Complaints likely to be of venous origin and when they were most likely to occur were reported together with the presence of visible signs on the legs. All data were pooled according to geographic area. Thirteen countries have already completed the survey, in Eastern Europe, Western Europe, South and Latin America (Brazil, Mexico), and the Middle and Far East, totaling almost 70 000 patients. Primary care patients were mostly women (>66%) except in Pakistan (48%) and were older in Europe (mean age >52 years) than in the other geographic areas (≤45 years). A majority (>60%) said they had a maternal history of primary CVD and around 10% had a personal history of venous thrombosis. Reported symptoms in order of importance were heaviness, pain, sensation of swelling, and night cramps, and were found to intensify mainly at the end of the day or after prolonged standing. Symptoms significantly increased with age and with severity of disease. Most screened subjects (>52%) believed they had leg problems at the time of consultation, while 19% to 26% presented spontaneously for venous care. After examination of the legs by physicians, it appeared that more than 61% of subjects had visible signs on at least one leg. Around 17% of them complained of venous symptoms only. Patients consulting specially for venous problems had more severe signs compared with the whole sample. Regarding costs, it appeared that CVD is responsible for large productivity losses, as well as the physical and psychological suffering of patients, which is reflected in worsened quality of life.
The Clinical Practice Guidelines of The Society for Vascular Surgery and The American Venous Forum, published in the 2011 Journal of Vascular Surgery supplement, is the most complete document on the management of varicose veins ever published in English. It is the work of leading members of the American Venous Forum, who are major contributors to advances in this field. However, most of them are vascular surgeons and this may have influenced their recommendations. A total of 14 guidelines are recommended or suggested using the recommendation grading system of Guyatt et al. The present article will specifically review these recommendations, bearing in mind that as Europeans we may have some divergence of opinion with our American colleagues.
Long-haul flights increase the risk of venous thromboembolism (VTE) for several weeks after the flight by 3-fold among passengers compared with the general population. The risk increases with flight duration and persists for several weeks (until week 8) after landing. This risk is not the same for all passengers and should be determined before any long flight, especially among frequent travellers. The calculation of risk is based on simple clinical data, easily obtained by the treating physician. If the patient has a personal history of VTE and chronic venous disease, a full assessment by a vascular specialist is justified. Risk management for any passenger taking a long flight is based on some simple advice to follow during the flight. This article summarizes the current position and recommendations from cardiovascular physicians faced with managing the risk of VTE in patients planning long-haul flights.
Chronic venous disease (CVD) is a common condition and represents a spectrum of disorders. The CEAP classification has been adopted worldwide to facilitate meaningful communication about the disease and to serve as a basis for more scientific analysis of treatment options. In addition to improved methods of defining CVD, there is also now increased understanding of the pathological processes involved in its development. Leukocyte-endothelium interactions are one of the earliest pathophysiological mechanisms at work and appear to be important in many aspects of the disease. The sequence of leukocyte adhesion, endothelial interaction, activation, and migration, and its association with valvular damage has focused attention on available molecules with activity known to modify this chain of events. The micronized purified flavonoid fraction (MPFF, Daflon 500 mg), consisting of 90% diosmin and 10% other flavonoids expressed as hesperidin, diosmetin, linarin, and isorhoifolin, currently possesses the most appropriate profile. It has been shown to reduce leukocyte interaction with the endothelium in acute venous hypertension and inflammation and is used clinically to treat CVD.
In the last two decades, the study of the microcirculatory system has played an important role in research into chronic venous insufficiency. Microcirculatory disorders are the consequence of venous stasis and venous hyperpressure on the lower limbs. During these processes, the velocity of blood flow through the capillaries is reduced. The white blood cells come into contact with the endothelium, and an interactive process starts between them. Endothelial adhesion molecules, such as selectins (E, L, and P), CD11/CD18, intercellular adhesion molecules (ICAM), and vascular cell adhesion molecules (VCAM), are liberated from leukocytes and the endothelium. These substances favor the adhesion of leukocytes to the endothelium.
The aim of this clinical study was to compare the intensity of postoperative pain using a 10-cm Visual Analog Scale (VAS), a quality-of-life questionnaire (CIVIQ), and a patient diary between two groups of patients, consisting of: a treatment group: patients who underwent a stripping procedure of the great saphenous vein (GSV), and were treated with Daflon 500 mg®* 14 days before and 14 days after the operation, 2 tablets 500 mg/day; a control group: patients who underwent stripping of the GSV, but were not treated with Daflon 500 mg®. In addition, the two groups were also compared for the size of postoperative hematoma, analgesic consumption, and for the incidence of other symptoms associated with chronic venous disease (edema, tired and heavy legs, cramps, sensation of itching), using the VAS scale. Lastly, overall efficacy of the treatment was assessed. The present trial included 181 patients from 15 medical centers throughout the Czech Republic. High ligation and partial stripping of the GSV in one lower limb was performed in all patients (short stripping from groin to knee). Patients were randomly assigned either to the treatment group (92 patients) or to the control group (89 patients). The degree of pain and the patient's condition were evaluated by the physician 14 days prior to the surgery (D-14), then 7 days (D7) and 14 days (D14) after surgery. Results indicated that Daflon 500 mg reduced the intensity of postoperative pain, which resulted in decreased consumption of analgesics. The size of postoperative hematoma was significantly smaller in the treatment group compared with the control group (P<0.001), and associated symptoms of CVD and quality of life were significantly better in this group. Effective phlebotropic drugs, like Daflon 500 mg, administered to patients 14 days before and 14 days after stripping surgery may improve postoperative morbidity.
Edema is often an early sign of significant fluid retention, which could eventually result in venous complications. It is commonly associated with venous symptoms. This study assesses the contribution of Daflon 500 mg to improving symptoms and reducing venous edema in patients with chronic venous disease. METHODS Patients, aged >18 years, with venous edema without skin changes, assessed as at least 4 cm on a 10-cm visual analogue scale, complaining of at least 3 symptoms (among pain, heaviness, sensation of swelling, sensation of tension, and restless legs), were included. They received Daflon 500 mg 2 tabs/day for 6 months. Primary end points were the reduction of leg perimeter and leg volume assessed respectively by tape and the disk model method of calculation. Improvements in clinical symptoms using different scales were the secondary criteria. RESULTS From month 2, edema was significantly reduced by Daflon 500 mg (P<0.001), in terms of both leg perimeter measurement and volume calculation. Symptoms (sensation of swelling, of tension, pain, heavy leg sensation, and restless legs) were significantly improved by Daflon 500 mg from month 2 (P<0.001). No treatment-related side effects were reported and the acceptability was considered excellent by most patients.
Background: Lower limb symptoms have frequently been associated with increased severity of venous disease. In clinical practice they are reported by patients at all stages of chronic venous disease. This study assessed the contribution of Daflon 500 mg in improving venous symptoms and promoting venous ulcer healing in patients with primary chronic venous disease. Methods: Patients aged >18 years, with at least 3 symptoms (including pain, sensation of heaviness in the legs, sensation of swelling, and night cramps), assigned to clinical classes C0 to C6 of the Clinical (severity)-Etiology- Anatomy-Pathophysiology (CEAP) classification following leg examination (recording the highest CEAP class for each patient), and presenting either with or without venous reflux, but not with obstruction, were included in the trial and received Daflon 500 mg 2 tablets per day for 6 months. Results: Between month 3 and month 6, there was a significant (P<0.05) improvement in patients' symptoms (sensations of heaviness in the legs, swelling, pain, and cramps) following treatment with Daflon 500 mg. After 6 months, 13% of recalcitrant ulcers had healed, which was deemed satisfactory by the health care team.
Because the venous system is in many respects more complex than the arterial system, because chronic venous disease (CVD) is common in Western populations, and because both specialists and general practitioners have to deal with this disease, there is a need for practical support regarding CVD management in daily practice. This article summarizes the most recent guidelines regarding the place of venoactive drugs (VADs) such as Daflon 500 mg in the management of this disease. In addition, it makes suggestions regarding expected improvements in future guideline documents.
Chronic pelvic pain is common in women of childbearing age and causes disability and distress, which result in significant costs to health services. A specific diagnosis for the condition is often difficult because the pain may be of abdominal, neurogenic, or psychogenic origin, or may be caused by other pelvic conditions such as endometriosis, pelvic inflammatory disease, and ovarian cysts. Due to the possible interlinked factors, no diagnosis is made in 60% of patients. 1 The pathogenesis of chronic pelvic pain is poorly understood. The vascular hypothesis offers the most likely explanation for chronic pelvic pain, which is thought to arise from overdistension of the pelvic venous system in which blood flow is markedly reduced. In pelvic congestion syndrome (PCS), pelvic varices are seen in a significant proportion of patients and may be the underlying etiology of chronic pelvic pain. 1 Undetected severe diseases such as endometriosis, adhesions, interstitial cystitis, active chronic pelvic inflammatory disease, and irritable bowel syndrome may cause pain and should be excluded to confirm a diagnosis of PCS. Investigation using laparoscopy is controversial since it often reveals no obvious cause of pain. Complementary investigation uses selective ovarian venography, which is commonly recommended by gynecologists. Newer, noninvasive methods such as magnetic resonance imaging and duplex ultrasound are gaining favor for the diagnosis of pelvic varices. Using the example of micronized purified flavonoid fraction (MPFF, Daflon 500 mg, Servier, France), this review will provide an update on the diagnosis and management of PCS and on the benefits of MPFF 500 mg in the treatment of pelvic pain.
Extraluminal and intraluminal devices using monopolar energy have been utilized in the past to treat varicose veins. This report describes the development of these minimally invasive electrosurgical techniques. Saphenous nerve injury, full-thickness skin burns, and high recurrence rates were the usual complications after such procedures. Radiofrequency ablation (VNUS Closure) is a new endovenous computer-feedback controlled application of bipolar electrothermal energy which reduces thermal spread to neighbouring tissues, thus avoiding the above problems. Preliminary clinical VNUS Closure results demonstrate that this is a safe and effective minimally invasive alternative to the traditional high saphenous tie and strip.
Endovenous ablation is a frequently used method for treating varicose veins. Endovenous laser ablation is the most frequently used technique, followed by radiofrequency ablation. Endovenous thermal treatments heat the vein, leading to thrombotic occlusion and finally fibrosis of the vein wall. Endovenous steam ablation is a new technique that has not yet been extensively studied. In this article, the procedures, strengths, and weaknesses of the currently available endovenous thermal ablation treatments are discussed.
Acute hemorrhoids occur during the symptomatic period of the illness, and their onset is correlated with triggering factors of different types. Three objectives of the treatment of hemorrhoids are: • to eliminate mechanical and local triggering factors, through the observance of lifestyle and dietary measures, • to reduce the inflammation, always present in acute manifestations, by the use of substances that interfere with the biochemical mediators of inflammation, • to reestablish optimal hemodynamic and microcirculatory conditions. Among the numerous substances that can be used with this aim, two flavonoids are of particular importance: diosmin and hesperidin. The results of their pharmacological combination are particularly effective in this pathology, as has been demonstrated in two multicenter clinical studies coordinated by the Department of Angiology at the University of Palermo.
An important question involving the management of patients with acute deep venous thrombosis (DVT) is whether thrombus removal improves outcome, either by reducing postthrombotic morbidity or reducing recurrence rates. Eliminating thrombus is intuitively appealing since persistent thrombus causes venous obstruction and destroys valve function, leading to ambulatory venous hypertension and, ultimately, symptoms of the postthrombotic syndrome. Natural history studies of acute DVT have demonstrated that when spontaneous lysis of thrombus occurs, valve function is preserved, especially when lysis occurs within 1-2 months of diagnosis. Early in the course of the development of thrombolytic agents, investigators evaluated the use of systemic thrombolysis for management of patients with acute DVT. While observations were made that postthrombotic morbidity was reduced, failure rates remained high and bleeding complications increased. Intrathrombus delivery of plasminogen activators facilitated thrombus resolution and reduced bleeding complications. This manuscript reviews the evolution of thrombolytic therapy for patients with acute DVT and addresses the integration of pharmacomechanical techniques and the development of new pharmacologic agents. The standard recommendation for treatment of patients with acute DVT is antithrombotic therapy, beginning with heparin (intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin), followed by oral anticoagulation with warfarin.1 Therapeutic anticoagulation prevents thrombus extension, pulmonary embolism (PE), and death from PE, and reduces the risk of recurrent venous thrombosis. Elastic compression stockings are recommended to reduce the risk of postthrombotic syndrome. The majority of patients with symptomatic DVT have involvement of the popliteal vein, the femoral vein, or more proximal veins.2 Approximately 50% of patients with proximal DVT develop symptoms of the postthrombotic syndrome, and in 25 % of patients with proximal DVT, the chronic postthrombotic complications are severe.3 Two well-designed randomized trials have demonstrated that wearing 30-40 mm Hg compression stockings reduces the risk of postthrombotic morbidity by approximately 50%.3,4 Postthrombotic complications of acute DVT are the result of persistent venous obstruction and destruction of vein valve function.5,6 Natural history studies of acute DVT have demonstrated that when spontaneous lysis of thrombus occurs, valve function is preserved, especially when lysis occurs within 1 to 2 months of diagnosis.7 It seems intuitive that adopting a strategy that eliminates acute thrombus in patients presenting with acute DVT would significantly reduce postthrombotic morbidity. Early in the course of the development of thrombolytic agents, investigators evaluated the use of systemic thrombolysis for management of patients with acute DVT. While observations were made that postthrombotic morbidity was reduced, failure rates remained high and patients paid the price of significantly increased bleeding.8 Iliofemoral DVT is associated with the most severe postthrombotic morbidity. The percentage of iliofemoral DVT patients suffering postthrombotic complications and the severity of those complications substantially exceed the postthrombotic complications occurring in patients with infrainguinal DVT. These individuals represent a valid subset of patients with acute DVT who can justifiably be approached with a strategy of thrombus removal. The evolution of management of these patients has demonstrated the value of intrathrombus delivery of plasminogen activators to speed thrombus resolution and reduce bleeding complications. This manuscript will review the development of thrombolytic therapy for patients with acute DVT and follow its evolution to catheter-directed thrombolysis and the integration of pharmacomechanical techniques. In addition, we will briefly address the development of new pharmacologic agents.
Postthrombotic syndrome (PTS) is the late complication of lower extremitiy deep venous thrombosis (DVT). Its incidence is approximately 3/1000 per year in the adult population. A combination of reflux and obstruction is often seen in limbs with more advanced clinical disease than obstruction alone. A thorough workup of the patient with disabling PTS is necessary to identify patients amenable to open surgical or endovascular intervention. Duplex scanning is the gold standard for diagnosis of chronic venous disease. The superficial system should be addressed first, followed by or in conjunction with the perforator and deep systems. Chronically obstructed veins are amenable to endovascular interventions, sometimes in combination with disobliteration of the veins ("endophlebectomy"), bypasses or valvular repair. A novel autologous valve reconstruction (the Italian neo-valve) that involves the construction of a valve in postthrombotic veins by using an intimal flap has been performed with satisfactory results. A percutaneously-implantable, non-immunogenic venous valve that remains patent and competent is an attractive alternative to deep venous reconstructions. Results from animal studies with a bioprosthetic valve (the Portland valve) are encouraging.
Failure of the vein wall continues to be a subject of intense research, the aim of which is to establish a cause that will allow us to prevent or at least slow down this undesirable process. We have investigated the role played by inflammatory cells, especially leukocytes, in the etiology of varicose veins. We hypothesize that venous insufficiency could result from the interaction between two processes: tissue aging and abnormalities in the leukocyte/endothelial cell interaction. These two processes, the individual contribution of which depends on the context, are believed to compound each other resulting in venous insufficiency. Thus, in young individuals, venous insufficiency might be induced by accelerated tissue aging, whereas in older subjects, it could be due to an interaction between the aging process, which is slower and prolonged, and abnormalities in the interaction between leukocytes and endothelial cells. The venous circulation is today perhaps among the most well-understood systems of the human body. However, the insidious and often prolonged nature of venous insufficiency hinders investigation into the factors that could trigger this disease, the progression of which is intimately linked to the natural process of tissue aging. Hence, in this area of medicine, as in many others grouped under the term "chronic," the clear conscience of the clinician occurs at the expense of the despair of the specialist. We believe that through analyzing some aspects of our understanding of this "silent" disease, patients, doctors, and health care managers will soon act together in combating venous disease. Chronic venous insufficiency (CVI) as a clinical definition indicates a loss in efficiency of normal vein function. Its symptoms, however, are a product of effects secondary to the inefficiency of the system, and thus the origin of this disease is not yet clearly established. The vein wall is a highly dynamic structure with 2 well-differentiated sides that guarantee its correct functioning: the luminal and adventitial sides. The luminal side of the vein wall, where the presence of valves indicates that the complex interaction between blood and wall takes on a particularly dynamic and metabolic dimension, is lined with an endothelium whose characteristics differ from the well-known properties of the arterial or microvascular endothelium. The adventitial side, the site of mechanical support and nutrient intake for the entire wall, also plays an active role in fighting against the forces of gravity. This complex role of the vein wall is, nevertheless, discrete and any decrease in its efficiency runs a slow course; hence its ambiguous assigning to the group of "chronic diseases." Our interest lies in the role that certain endogenous or environmental factors have in the development of CVI. Among the intrinsic factors, aging is being ascribed an ever more relevant role. Some of the genetic features of the aging process, such as the loss of function of telomerases and their involvement in maintaining the cell population or changes in the expression (dysregulation) of other genes, lead to qualitative and quantitative changes in cellular and extracellular proteomics that enter into the realm of consequences more than cause. The participation of white blood cells where they release in the development of venous disease is well established, and aggregated when they are known to be the most common cause of venous stasis. Stasis of blood flow, whether at the luminal level due to valve failure or at the adventitial microvascularization level, triggers the activation of leukocytes as part of an inflammatory process aimed at functional recovery and tissue repair. Hence, what in principle is a protective mechanism can turn hostile to the detriment of the blood vessels. Little is known about how CVI leads to the local tissue destruction seen so commonly in clinical practice. Increased evidence points to a central role for abnormal leukocyte-endothelial cell interactions in the pathogenesis of this condition. Some theories have suggested that leukocytes are sequestered in the legs of patients with CVI. This sequestering leads to the activation of white cells, which results in the generation of free radicals, proteases, histamine, neutrophil chemoattractants, and complement. The actions of these substances destroy the endothelial layer of the vessel and their basement membranes, increasing vascular permeability and disturbing microcirculatory flow. Other authors propose other factors that might activate leukocytes and cause them to act inappropriately in the venous system. Some factors present in the plasma of patients can activate unstimulated leukocytes. Such a factor could be any of a variety of stimuli, including bacteria, fungi, and their products. Endothelial cells also need to be activated so that leukocytes can migrate into the tissue through the endothelium. Scarce cytokine expression has been observed in some investigations, even though a considerable number of monocytes have been noted to adhere to the endothelium and migrate into tissue, suggesting that factors other than inflammatory mediators (high pressure, low shear stress) may activate the endothelium. Little is known about the role of inflammatory cells in the biochemical and histological changes observed in varicose disease. Increased numbers of macrophages/monocytes and mast cells have been observed in varicose veins, suggesting that vein damage in refluxing saphenous veins is associated with a leukocyte infiltrate. Mononuclear cells such as neutrophils normally circulate in a quiescent state, but when activated are capable of adhering to the endothelium and entering tissues a variety of noxious substances known for their ability to cause tissue damage. Active proteases can either be secreted directly by inflammatory cells, including elastase and cathepsin G produced by polymorphonuclear leukocytes, chymase and try ptase by mast cells, and granzymes by lymphocytes, or can be generated from circulating zymogens by activation in close contact with the cells. The aim of the present study was to establish the influence of age on the changes that occur in the vein wall and to characterize leukocyte infiltration in the wall, exploring its association with the varicose condition.
Air travel-related venous thromboembolism (ATVT) was first described by Homans in 1954. Our interest in this problem started in 1993 at the Straub clinic and hospital in Honolulu, when we noted in several patients that were admitted for extensive, symptomatic deep vein thrombosis (DVT), often complicated by pulmonary embolism (PE), after long air flights. We have published 69 cases of ATVT, with a special interest in predisposing risk factors that could influence Virchow's well-known triad. We divided the risk factors into patient-related internal risk factors and cabin-related external risk factors. Patient-related risk factors were overweight, chronic heart disease, estrogen intake, malignancy, previous DVT/PE, smoking, recent lower limb injury, or surgery. We speculated on the role of seven cabin-related risk factors: low humidity, relative hypoxia, diuretic effect of alcohol, insufficient fluid intake, smoking, "coach position" and immobilization. There has been an increasing worldwide interest in this subject since the tragic death of 28-year-old Emma Christofferson at Heathrow airport from PE after a flight from Sydney. It raised the question of the true association between air flights and venous thromboembolism: one symptomatic DVT in 100 000 passengers as suggested by Lord at our meeting in Hawaii in 1999, or one asymptomatic calf vein thrombosis in 10 passengers as suggested by Scurr at the same meeting. In March 2001, the WHO organized a consultation in Geneva with the intention of reviewing and synthesizing available scientific information; defining the extent of the problem; identifying priority areas of research to find possible solutions if a problem exists; and trying to reach a consensus on pragmatic strategies for prevention. Three major areas of research have been planned and accepted: epidemiological studies including a large cohort of passengers to answer the question if there is an association; studies of cabin-related risk factors in hypobaric chambers; and interventional studies to assess preventive measures. We hope that funding for the planned projects through the WHO will be available as soon as possible to clarify the issue. Air travel-related venous thromboembolism (ATVT) was first described by Homans in 1954. This was followed by many case reports and retrospective studies. Our interest in this problem started in 1993 at the Straub Clinic and Hospital when we noted in several patients that were admitted for extensive, symptomatic deep vein thrombosis (DVT), often complicated by pulmonary embolism (PE), after long air flights. The Straub Foundation started a retrospective study of 254 patients who had been admitted to Straub for DVT and/or PE from 1988 to 1993, and we identified 44 patients who developed symptoms during or after air flight. Most of the patients had extensive proximal DVT, and in 36% this was complicated by PE. We were specially interested in predisposing risk factors that could influence Virchow's well-known triad: endothelial lesions, venous stasis, and hypercoagulability, and divided the risk factors into patient-related internal risk factors and cabin-related external risk factors. In this first study we identified five patient-related risk factors: history of previous DVT, presence of chronic disease or malignancy, estrogen intake, recent lower-limb injury, and recent surgery or femoral catheterization. We speculated on the role of seven cabin-related risk factors: low humidity, relative hypoxia, diuretic effect of alcohol, insufficient fluid intake, smoking, "coach position," and immobilization. In 1993 we sent a letter to 56 airlines which had links with Hawaii, and informed them about our findings and asked for research collaboration. There was only one positive response, from Philippine Airlines, where the medical director was a physician at Straub! To further study the risk factors we started a "prospective" study where we tried to involve all the hospitals in Hawaii in order to obtain some information about how common this problem was. We failed to get this collaboration, but recruited, between July 1995 and October 1998, 25 patients with recent air travel from Straub, all with extensive DVT, in 36% complicated by PE. Of these, 92% had one or more risk factors; the mean was three. Overweight was present in 76%, chronic heart disease in 44%, estrogen intake in 40%, chronic disease other than heart disease and malignancy in 32%, history of previous DVT in 28%, malignancy in 28%, smoking in 20%, recent lower-limb injury in 16%, and recent surgery in 12%. In 1999 the Straub Foundation organized the 3rd Pacific Vascular Symposium on Venous Disease at Mauna Lani Bay hotel where we had a special session on air travel-related venous thromboembolism. Eighty-three of the overseas participants had duplex scanning of both legs. No DVT was diagnosed. Forty-nine of these participants had a repeat duplex scan performed when they returned home, and one of these scans showed an asymptomatic small mural thrombus in a valve pocket of the superficial femoral vein. Since this Hawaiian meeting there has been increasing worldwide interest in this subject, to which the following elements have contributed: the tragic death of 28-year-old Emma Christoffersen at Heathrow airport in London from pulmonary embolism after a flight from Sydney in September 2000; which started a media coverage, still accelerating; which initiated a number of law suits against airlines, particularly in Australia. The House of Lords in the UK presented their report on Air Travel and Health in November 2000 where they recommended, eg, an epidemiological research program to remedy the paucity of data on ATVT. Several papers on the association between recent travel and venous thromboembolism have been published. Parsi et al published an extensive review with 283 references including their own findings of coagulation defects in 72% of patients with ATVT. Lapostolle et al recently published a study from Charles de Gaulle airport in Paris where, over an 86-month period, 56 of 135.3 million passengers were reported to have severe pulmonary embolism. The frequency among those who traveled more than 5 000 km was 150 times higher than the frequency among those who traveled less than 5 000 km. An interim analysis of the New Zealand study on ATVT in 1000 low-to-moderate risk air travellers was recently presented: 1.4% were found to have ATVT (5 PE, 3 promal DVT, 2 calf DVT, and 2 extensive superficial thrombophlebitis). What is the true association between air flights and venous thromboembolism: one symptomatic DVT in 100 000 passengers as suggested by Lord from Sydney at our meeting in Hawaii; one asymptomatic calf DVT in 10 passengers as suggested by Scurr? Alerted by the worrying reports in the media, the World Health Organization reacted responsibly and organized a consultation in Geneva from March 12-13, 2001 with the intention of: reviewing and synthesizing the available scientific information on ATVT; defining the extent of the problem; identifying priority areas of research to find possible solutions if a problem exists; trying to reach a consensus of pragmatic strategies for prevention based on currently available evidence. Ten experts were invited to present available scientific information under the chairmanship of Fred Paccaud, an epidemiologist from the university of Lausanne. Fifteen of the major airlines were represented, none from the USA. The experts agreed that: an association probably exists between air travel and venous thrombosis; such an association is likely to be small and mainly affects passengers with additional risk factors for venous thromboembolism; similar links may exist for other forms of travel; the available evidence does not permit an estimation of actual risk, and therefore public health recommendations cannot be made at the present time. The representatives of the airlines agreed that: an association between venous thrombosis and travel in general probably exists; there are insufficient data on which to make recommendations; consequently the airlines and IATA are committed to support further research.
Varicose veins are the most common manifestations of chronic venous insufficiency. The etiology and pathophysiology of varicose veins still remain poorly understood. Although previously there was much controversy over the primary role of valve alteration in the development of venous diseases, evidence has now accumulated to suggest that defects in the vein wall may be regarded as the primary cause of varicosities. Changes in the media layer of the venous wall, including ultrastructural signs of smooth muscle transition from a contractile to a metabolic phenotype, disturbed smooth muscle cell/extracellular matrix balance, and a loss of contractile properties of the venous wall, appear to be general features of varicose veins. There is growing evidence that implicates deficient smooth muscle function in the pathogenesis of chronic venous insufficiency. Recently, better knowledge of the molecular mechanisms that regulate smooth muscle contraction has raised several hypothesis to explain the decreased contractility of varicose veins. The various possible mechanisms will be presented in this article.
Mixed arterial and venous ulcers often heal poorly if there is no revascularization, as observed in the elderly, diabetics, and chronic renal failure patients who often have diffuse, distal, and calcified vascular lesions. Treatment therefore is based on optimized local wound care, pain control, and management of the risk of infection inherent in these types of patients with chronic wounds. Current avenues of research in treatment are based on the development of angiogenesis and the use of growth factors to promote healing. Placental tissue is known to contain a large quantity of growth factors. Use of the latter was indirectly reported by Davis in 1910 and Sabella in 1913, who described the use of fresh amniotic membrane (AM) in the management of chronic wounds occurring in the aftermath of burns. Since then, many studies have reported the use of placental tissue or AM in the management of chronic wounds. Currently, AM is used after freezing in the management of corneal defects. The aim of this article is to provide an updated literature review of this technique and its therapeutic prospects in the management of refractory vascular ulcers.
Knowledge of the exact location of tissue fluid (TF) and stagnant lymph (L) in lymphedema is indispensable to rational physiotherapy and specifically defines where to apply external pressure and how much. We visualized the "TF&L" space in the skin and subcutaneous tissue of the foot, calf, and thigh in various stages of lymphedema, using special staining techniques, in specimens obtained during lymphatic microsurgical procedures or tissue debulking. With the collecting trunks obliterated, L was present only in the subepidermal lymphatics, whereas the bulk of mobile TF accumulated in the spontaneously formed spaces in the subcutaneous tissue, around small veins, above and below the muscular fascia. Deformation of subcutaneous tissue by free fluid led to formation of multiple interconnecting tissue channels. Thus, massaging of tissues can propel TF through the spontaneously formed tissue channels, but not the partially or totally obliterated lymph collectors. The subepidermal lymphatic network conducts only a small fraction of L. Pneumatic compression therapy promoted formation of TF fluid channels.
The aim of this paper is to demonstrate the major role played by the new computerized imaging tools available today in the fields of morphology and vascular anatomy. For anatomical studies or educational purposes, they enhance classic techniques. Three-dimensional reconstruction, which is already used in daily clinical practice, will be the basis for computation of validated volumetric protocols enhancing our diagnostic, prognostic, and therapeutic methods. It is also a fantastic educational tool: interactivity and virtual dissection make it simple, efficient, attractive, and easily understandable, particularly in the field of venous anatomy.
An anatomical study of 200 foots injected with latex demonstrates that the concept of the plantar sole of Lejars is wrong: the true plantar pump is composed by the plantar veins, located deeply between the plantar muscles and compressed during the weight-bearing phase of the walk. The normal venous sole (of Bourceret) is a thin network and its dilatation (Lejars) is a pathological state, ascribed to a severe distal venous stasis. The blood reservoir moved up by a plantar compression either by manual or during the support phase at each step is truly located along the plantar veins. This is the reason why, for CVI patients, it is so important to make sure that the static of the foot is normal. In fact, the foot pump is the prst step of the venous return during walk, just before the calf pump.
Background: The foot venous pump is located in the plantar veins, where both its anatomy and connections with the saphenous roots and the foot perforator veins are not well known, and therefore, they are underinvestigated in daily practice. The aim of this paper is to describe the unique anatomy and the functional role of the foot perforator veins and emphasize their key role during the activation of the foot venous pump. Ankle perforator veins also play a crucial role in the venous blood return, giving rise to the anterior tibial and fibular veins. Materials and methods: A total of 400 cadaveric feet from the “don des corps” of the Descartes University (Paris, France) were injected with green Neoprene latex, which was followed by an anatomical dissection and a colored segmentation of the venous system. Duplex color sonography and CT venography with 3D modeling were used to investigate the foot perforator veins and their connections with the foot venous pump and the saphenous systems in patients with venousdisease. Results: Some foot perforating veins are characterized by flow that is oriented from deep to superficial veins, due to the presence of one-way valves, a unique feature in the venous system of the lower limbs. From a hemodynamic point of view, the foot veins should not be classified into deep and superficial systems, but into medial and lateral functional units. The medial unit is comprised of the medial plantar veins, the medial marginal vein, and the medial foot perforator veins. The lateral unit is comprised of the lateral plantar veins, the lateral perforator veins, and perforator veins of the calcaneus. Ankle perforator veins are mainly the dorsal perforator veins that are connected to the initial segment of anterior tibial and fibular veins and the lateral perforator veins along the distal fibula. Conclusion: Despite the small volume of blood ejected at each step, the foot venous pump plays a key role in the venous blood return of the lower limbs. The foot perforator veins are the main outlet of the foot venous pump into the superficial venous system, working from deep to superficial; therefore, they are responsible for the systolic ascending flow in both the great and small saphenous systems during foot venous pump activation.
Venous return from the foot is worthy of interest for both research and clinical purposes. This review summarizes the available knowledge of venous return from the foot with a special focus on research and clinical implications. The anatomy and physiology of venous return are described with an emphasis on the differences between standing and walking and the interplay between the venous systems of both the foot and the calf. Selected conditions of clinical interest are discussed and mechanistically interpreted, including the distinctive localization of leg ulcers, the corona phlebectatica, the possible independence of dilatation of the veins of the foot from refluxing varices, and the arteriovenous fistulae of the foot. From this perspective, the practice of using a postoperative lower-leg bandage is also discussed. Little attention has been devoted to the veins of the foot: surgeons begin the saphenectomy where the foot ends and echographists do not extend their exploration distally to the malleolus. Even anatomists have been more interested in the arteries of the foot, rather than the veins, as demonstrated by the more detailed description of arteries in anatomical tables. Finally, experts in hemodynamics focus on the calf to explain the mechanism of the limb pump, leaving the blood in the foot "und rained." However, as shown in the present bibliography, a few well-conducted classic studies have clarified the anatomical and functional characteristics of venous circulation in the foot, although some areas of uncertainty still exist. The main concepts concerning the anatomy and physiology of venous return from the foot will be revisited in this article, followed by observations of clinical interest and hypotheses for research and daily practice.
Visceral venous aneurysms are considered rare clinical entities with not variable pathogenesis, clinical presentation, natural history, and management. In an electronic search of the pertinent English and French literature, ninety-three reports were identified, including 176 patients with 198 visceral venous aneurysms. Patients' ages ranged from 0 to 87 years, and there was no apparent male/female preponderance. The commonest location was the portal venous system (87 of 93 reports, 170 of 176 patients, 191 of 198 aneurysms). Portal system venous aneurysms were present with abdominal pain (44.7%), gastrointestinal bleeding (7.3%), or were asymptomatic (38.2%). Portal hypertension was present in 30.8% and liver cirrhosis in 28.3%. Thrombosis and rupture occurred in 13.6% and in 2.2%, respectively. Adjacent organ (common bile duct, duodenum, inferior vena cava) compression was reported in 2.2% The management ranged from watchful waiting to intervention. Indication for operation was symptoms and complications. In 94% of the cases, aneurysm diameter remained stable with no complications during follow-up. Aneurysms of the renal veins and inferior mesenteric vein were also reported. Of six cases of renal vein aneurysm, three were treated surgically and the remaining three were asymptomatic. Venous aneurysms are reported in the popliteal, jugular, and saphenous veins, but rarely occur in other veins. Visceral venous aneurysms have been increasingly described in recent years probably because of the increasing availability of advanced radiologic imaging in clinical practice. Their prevalence, clinical presentation, and complications have not been adequately reviewed. Most visceral aneurysms are reported in the form of case reports, and there are few published case series that specifically address indications for surgery and optimal surgical techniques. In a systematic Medline search undertaken to identify all reported cases of visceral venous aneurysms using the keywords "visceral vein", "splachnic vein" "portal vein", "intrahepatic portal vein", "extrahepatic portal vein", "splenic vein", "superior mesenteric vein", "umbilical vein", "inferior mesenteric vein", "renal vein", and "aneurysm" ninety-three reports were identified, including 198 visceral venous aneurysms in 176 patients.
Venous aneurysms are rare lesions that have been described throughout the venous system and are seen at any age. The lower extremities are the most frequently involved, with the popliteal vein being the main location. A wide variety of clinical presentations has been reported in the literature and they can be diagnosed as a subcutaneous mass, a widening mediastinal mass, an incidental finding on an imaging study, or during the workup for abdominal pain or chronic venous disease of the lower limb. Although the natural history of these venous aneurysms is usually benign, depending on their location they have the potential for serious complications and may present initially as an episode of pulmonary embolism, thrombosis, or rupture with bleeding. The management of venous aneurysms still remains controversial, and the indication for surgery should take into consideration the potential for thromboembolic or bleeding complications. Numerous types of surgical repair have been described, and the most common procedures are tangential excision with lateral suture or excision with interposition grafting. Technical choice is usually dictated by the type of aneurysm and by the anatomical location.
Primary lymphedema is a clinical outcome of lymphatic malformation (LM) following developmental arrest in the latter stage of embryogenesis, and known as the truncular (T) form. LM caused by developmental arrest in the earlier stage of lymphangiogenesis, often termed cystic/cavernous lymphangioma, is referred to as the extratruncular (ET) form. Primary lymphedema has been managed as a chronic lymphedema together with secondary lymphedema, although its etiopathophysiology is entirely different from that of secondary lymphedema. However, lately primary lymphedema has been recognized as being related to the ET form of LM, and new the classification of congenital vascular malformation (CVM) has finally included the ET and T forms of LM as types of CVM. The ET form of LM, known as cavernous and/or cystic lymphangioma, and the T form, known as primary lymphedema, are now considered as members of the LM family, which develop at different stages of lymphangiogenesis. A retrospective review of the clinical data of a total 254 patients with LM (186 T form and 68 ET form) has therefore been done, aiming to provide a proper basis for advanced management of the T and ET forms as aspects of LM, based on newly developed concepts. Patients and methods: The diagnosis of LM was made using various combinations of different noninvasive diagnostic tests: MRI and/or CT, Tc-99m RBC whole-body blood pool scintigraphy, Tc-99m antimony sulfide colloid lymphoscintigraphy, and duplex ultrasonography. For the 186 T form LMs, diagnosed following proper clinical/laboratory staging, treatment was instituted using various combinations of MLD (manual lymphatic drainage)-based CDP (complex decongestive therapy) and SIPC (sequential intermittent pneumatic compression)-based compression therapy depending upon the clinical stage of the chronic lymphedema. Various surgical therapies, either reconstructive or ablative, were also implemented as adjunct therapies for primary lymphedema to improve the efficiency of CDP-based therapy in the earlier clinical stage, and compression therapy in the later stage. For the 68 ET LMs, the best treatment option was selected per indication, from the various combinations of sclerotherapy and/or surgical therapy; OK-432 sclerotherapy as the option of choice as a primary therapy and absolute ethanol sclerotherapy and/or a surgical excision as the second option, preferably after the first option had failed. The T form was evaluated using clinical and laboratory assessments of chronic lymphedema status every 6 months including treatment response, either medical (physical) only or surgical combined. The evaluation of the ET form was made by duplex sonography and MRI where feasible, and by clinical assessment. Results: Of 68 ET form patients, 51 pediatric patients, treated with OK-432 sclerotherapy for a total of 108 sessions, showed satisfactory lesion control in the majority of cases (84.3%): a complete to marked shrinkage in 88.9% of the limited cystic type. Seventeen ET forms of the total 68 underwent preoperative embolo/sclerotherapy and subsequent surgical excision, which gave clinically good to excellent results for 14 of the 17. One hundred and eighty-six T form patients, treated for chronic lymphedema, showed an excellent to good response in the majority in clinical stages I and II, and a good to fair response in stages III and IV. Long-term results of additional surgical therapy, either reconstructive or ablative, on 8 patients were totally dependent on patent compliance to maintain postoperative CDP/compression therapy-based maintenance care. Conclusion: Conventional management of the T form of LM as for primary lymphedema is limited even with supplemental surgical therapy. The treatment of the ET form of LM, especially of the infiltrating cavernous type, is also limited by conventional sclerotherapy. Therefore, the overall management of LMs should be further improved by adopting an innovative genetic approach to the correction of (lymph) angiogenesis and/or vasculogenesis defects.
Angiogenesis is a fundamental biological process that is involved in all aspects of tissue growth and repair. It is regulated by a range of physical factors, including hypoxia as well as many tissue growth substances. It has long been known that the skin changes in venous disease include evidence of proliferation of blood vessels. This has been observed in histological and capillary microscope investigations. It has been shown that capillary proliferation in the skin of patients with chronic venous insufficiency (CVI) is strongly associated with the more severe stages of venous disease, including the tendency to leg ulceration. Recent immunohistochemical investigations have shown that a number of tissue growth substances can be detected in increased amounts in the skin of patients with CVI. These include vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β), and platelet-derived growth factors (PDGF). Increased plasma levels of VEGF have been found in patients with the more severe stages of venous disease (CEAP stages C4 and C5) compared with those with less severe stages. In a pilot study, reduced plasma levels of VEGF were observed in patients following 60 days' treatment with Dalton 500 mg. This may be attributable to the anti-inflammatory effects of Dalton 500 mg, which have been observed in a number of studies. Treatment of patients with topically applied growth factors has met with limited success in achieving leg ulcer healing. Therapeutic modulation of angiogenic factors in patients with CVI has not been studied.
In 2000, Rutherford proposed a new tool to measure the severity of venous disease. Its aim was to quantify the progression and treatment of chronic venous disease. It consists of three scores comprising clinical aspects, anatomic and pathophysiologic abnormalities (venous segmental disease score), and disability. French angiologists, in order to evaluate the relevance and usefulness of such scores in their daily practice, conducted an observational study. The scores were tested on 1900 patients by 398 angiologists, who completed an opinion questionnaire. In any class of the CEAP classification, the three scores were low, specifically the segmental score. Although considered as easy to grade and relevant by the majority of respondents, only a minority of angiologists, stated their intention to use these scoring parameters in everyday practice for C4-C5-C6 patients (71.8% of the 1900 patients): 42.0% for the clinical severity score, 32.9% for the segmental score, and 38.7% for the disability score. These figures were even lower for C1-C2 and C3 patients: 21.6%, 19.6%, and 26.9% respectively. The new severity scores to assess chronic venous disease seem difficult to use in daily practice, in particular the venous segmental score. They seem more appropriate to evaluate the evolution and efficacy of therapy in severe chronic venous disease.
Venous embryology can explain many of the defects resulting in venous anomalies in later life, yet is often overlooked. Venous malformations are vascular malformations that only affect the venous system. They are classified into two different types depending on the embryological stage when the defective development occurs. Venous malformations originating during the early stage of embryogenesis are termed extratruncular, while those originating during the late stage of embryogenesis are classified as truncular. A defect at any point in the complex development stages of the evolution and involution of multiple paired embryonic veins can result in various conditions of defective venous trunk Therefore, truncular lesions in general are associated with more serious hemodynamic consequences than extra-truncular lesions due to their direct involvement with the truncal venous system. This review provides a detailed overview of venous embryology and a number of truncular venous malformations to illustrate how a thorough knowledge of this subject can aid in their diagnosis and treatment.
Over the past decade, a number of new anticoagulant compounds have been developed, including the low-molecular-weight heparins (LMWHs) and the factor Xa inhibitors fondaparinux and idraparinux. Factor Xa inhibitors are powerful anticoagulants that act by producing a reversible conformational change in the antithrombin III molecule. Unlike unfractionated heparin and warfarin, these new compounds, which have a linear pharmacokinetic profile, do not require frequent patient monitoring. Factor Xa inhibition has been studied in the prevention and treatment of venous thromboembolic problems in orthopedic, general surgical, and medical patients, and, more recently, in the reduction of thrombotic complications associated with acute coronary syndrome. At present, most of the randomized trial data pertain to fondaparinux, the first selective factor Xa inhibitor to become available for clinical use. The purpose of this review will be to present clinical support for the use of selective factor Xa inhibitors for thrombosis prevention and treatment.