Venous valve hypoxia as a possible mechanism of deep vein thrombosis: a scoping review.

INTRODUCTION: The pathogenesis of deep vein thrombosis (DVT) has been explained by an interplay between a changed blood composition, vein wall alteration, and blood flow abnormalities. A comprehensive investigation of these components of DVT pathogenesis has substantially promoted our understanding of thrombogenesis in the venous system. Meanwhile, the process of DVT initiation remains obscure. This systematic review aims to collect, analyze, and synthesize the published evidence to propose hypoxia as a possible trigger of DVT. EVIDENCE ACQUISITION: An exhaustive literature search was conducted across multiple electronic databased including PubMed, EMBASE, Scopus, and Web of Science to identify studies pertinent to the research hypothesis. The search was aimed at exploring the connection between hypoxia, reoxygenation, and the initiation of deep vein thrombosis (DVT). The following key words were used: "deep vein thrombosis," "venous thrombosis," "venous thromboembolism," "hypoxia," "reoxygenation," "venous valve," and "venous endothelium." Reviews, case reports, editorials, and letters were excluded. EVIDENCE SYNTHESIS: Based on the systematic search outcome, 156 original papers relevant to the issue were selected for detailed review. These studies encompassed a range of experimental and observational clinical research, focusing on various aspects of DVT, including the anatomical, physiological, and cellular bases of the disease. A number of studies suggested limitations in the traditional understanding of Virchow's triad as an acceptable explanation for DVT initiation. Emerging evidence points to more complex interactions and additional factors that may be critical in the early stages of thrombogenesis. The role of venous valves has been recognized but remains underappreciated, with several studies indicating that these sites may act as primary loci for thrombus formation. A collection of studies describes the effects of hypoxia on venous endothelial cells at the cellular and molecular levels. Hypoxia influences several pathways that regulate endothelial cell permeability, inflammatory response, and procoagulation activity, underpinning the endothelial dysfunction noted in DVT. CONCLUSIONS: Hypoxia of the venous valve may serve as an independent hypothesis to outline the DVT triggering process. Further research projects in this field may discover new molecular pathways responsible for the disease and suggest new therapeutic targets.

Venous Claudication: a Scoping Review of the Pathophysiology and Clinical Importance.

OBJECTIVE: Venous claudication (VC) is under studied, often being excluded from clinical trials and scales. The purpose of this scoping review was to give a historical perspective of VC and analyse the prevalence, pathophysiological aspects, and clinical implications. METHODS: An extensive search of the books and databases (PubMed, MEDLINE, Scopus, and Cochrane) was performed from inception until October 2021. Studies were considered eligible provided they reported on the topics of interest, whereas strict exclusion criteria with regards to the studied sample of patients, year of publication, or location of the obstruction could not be applied, because of the limited relevant literature. RESULTS: Twenty nine articles were included. VC is found almost exclusively in patients with iliofemoral obstruction. Prevalence was reported in seven studies having a wide range from 10.6% to 74.0%. Dominant findings include increased venous volume and pressure. Pressure in capillaries also rises subsequently causing compartment oedema and increased intramuscular pressure resulting in tissue ischaemia and hypoxia. The time required for the venous pressure to return to the pre-exercise levels in the affected limbs is prolonged compared with normal (39.1 ± 14.4 seconds vs. 1.1 ± 1.1 seconds). CONCLUSION: VC is an important symptom of venous outflow obstruction that is under studied, and merits further recognition. Better understanding of the pathophysiology will be achieved through investigations at tissue level. Diagnosis and improvement after treatment should be reported in an objective and standardised manner.

Extended anticoagulation for venous thromboembolism: A survey of the American Venous Forum and the European Venous Forum.

OBJECTIVE: Extended anticoagulation therapy should always be considered after standard treatment of an unprovoked episode of venous thromboembolism (VTE). It can also be considered for selected patients with provoked VTE. However, the evidence-based protocols suggested by some clinical guidelines and risk assessment tools to guide this practice are limited and ambiguous. The goal of the present survey research was to analyze current practices in applying extended anticoagulation therapy for patients with VTE among members of the American Venous Forum (AVF) and European Venous Forum (EVF). METHODS: An online survey was created by the AVF Research Committee. The survey consisted of 16 questions to identify the country of practice, specialty, experience of the participating physicians, and their clinical practice patterns in applying extended anticoagulation therapy for VTE patients. The survey was distributed via e-mail to the members of the AVF and EVF. RESULTS: A total of 144 practitioners, 48 AVF members (33%) and 96 EVF members (66%), participated in the survey. Most of the respondents identified themselves as vascular specialists with primary certification in vascular surgery (70%), vascular medicine or angiology (9%), and venous disease or phlebology (3%). Of the 144 respondents, 72% believed that the risk of VTE recurrence will generally overweigh the risk of bleeding for patients with unprovoked VTE. Extended anticoagulation therapy might be used by 97% of providers. Different patterns in real world clinical practice were identified. More than one half of the practitioners estimated the VTE recurrence and bleeding risk subjectively. The antithrombotic drugs most commonly used for secondary prophylaxis were rivaroxaban, apixaban, warfarin, dabigatran, and aspirin, in decreasing order of frequency. Among the reasons selected for not regularly considering extended anticoagulation therapy were the lack of specific clinical practice guidelines (24%), lack of reported evidence (9%), and absence of valid VTE and/or bleeding risk prediction calculators (8%). Twelve participants (8%) stated that extended anticoagulation therapy would not be beneficial for most patients with VTE. Ten participants (7%) indicated that prescribing extended anticoagulation therapy was outside the scope of their specialty. CONCLUSIONS: Different practice patterns exist regarding extending anticoagulation therapy beyond the standard treatment for patients with VTE. Major gaps in knowledge remain a serious challenge at least partially explaining the inaccuracy and inconsistency in long-term VTE management. Appropriately designed studies are needed to evaluate risk stratification tools when contemporary best medical therapy is used, accurately predict VTE recurrence and its long-term outcomes, and tailor safe and effective secondary prophylaxis.

The 2020 update of the CEAP classification system and reporting standards.

The CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classification is an internationally accepted standard for describing patients with chronic venous disorders and it has been used for reporting clinical research findings in scientific journals. Developed in 1993, updated in 1996, and revised in 2004, CEAP is a classification system based on clinical manifestations of chronic venous disorders, on current understanding of the etiology, the involved anatomy, and the underlying venous pathology. As the evidence related to these aspects of venous disorders, and specifically of chronic venous diseases (CVD, C2-C6) continue to develop, the CEAP classification needs periodic analysis and revisions. In May of 2017, the American Venous Forum created a CEAP Task Force and charged it to critically analyze the current classification system and recommend revisions, where needed. Guided by four basic principles (preservation of the reproducibility of CEAP, compatibility with prior versions, evidence-based, and practical for clinical use), the Task Force has adopted the revised Delphi process and made several changes. These changes include adding Corona phlebectatica as the C4c clinical subclass, introducing the modifier "r" for recurrent varicose veins and recurrent venous ulcers, and replacing numeric descriptions of the venous segments by their common abbreviations. This report describes all these revisions and the rationale for making these changes.

Comparison of endovenous ablation techniques, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Extended 5-year follow-up of a RCT.

BACKGROUND: This study compares the outcome 5 years after treatment of varicose veins with endovenous radiofrequency ablation (RFA), endovenous laser ablation (EVLA), ultrasound guided foam sclerotherapy (UGFS) or high ligation and stripping (HL/S) by assessing technical efficacy, clinical recurrence and the rate of reoperations. METHODS: Five hundred patients (580 legs) with Great Saphenous Vein (GSV) reflux and varicose veins were randomized to one of the 4 treatments. Follow-up included clinical and duplex ultrasound examinations. RESULTS: During 5 years there was a difference in the rate of GSV recanalization, recurrence and reoperations across the groups, KM P<0.001, P<0.01, P<0.001 respectively. Thus 8 in the RFA group (Kaplan Meier [KM] estimate 5.8%), 8 in the EVLA group (KM estimate 6.8%), 37 (KM estimate 31.5%) in the UGFS group and 8 in the HL/S group (KM estimate 6.3%) of GSVs recanalized or had a failed stripping procedure. Nineteen (RFA) (KM estimate 18.7%), 42 (EVLA) (KM estimate 38.6%), 28 (UGFS) (KM estimate 31.7%) and 38 (HL/S) (KM estimate 34.6%) legs developed recurrent varicose veins. Within 5 years after treatment, 19 (RFA) (KM estimate 17%), 19 (EVLA) (KM estimate 18.7%), 43 (UGFS) (KM estimate 37.7%) and 25 (HL/S) (KM estimate 23.4%) legs were retreated. CONCLUSIONS: More recanalization's of the GSV occurred after UGFS and no difference in the technical efficacy was found between the other modalities during 5-year follow-up. The higher frequency of clinical recurrence after EVLA and HL/S cannot be explained and requires confirmation in other studies.

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

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

Does prescription of medical compression prevent development of post-thrombotic syndrome after proximal deep venous thrombosis?

AIM: The aim of this review is to try to explain the controversy by critical analysis of previously published randomized controlled trials on the value of elastic compression stockings in the treatment of acute proximal deep vein thrombosis in prevention of post-thrombotic syndrome, which forms the scientific basis for our present management. METHODS: A research was made through Medline and Embase databases to identify relevant original articles, not abstracts, with the following keywords: post-thrombotic syndrome, deep venous thrombosis, venous thromboembolism, compression stockings, prevention and compliance. RESULTS: We identified five randomized controlled trials (RCTs) before the SOX trial including 798 patients with acute proximal deep vein thrombosis. Brandjes (1997): at two years' follow-up, elastic compression stockings reduced post-thrombotic syndrome by 50%;Ginsberg (2001): no difference in post-thrombotic syndrome with or without elastic compression stockings after more than two years' follow-up;Partsch (2004): elastic compression stockings with routine above knee and early ambulation reduced the incidence and severity of post-thrombotic syndrome after two years' follow-up;Prandoni (2004) showed significantly less post-thrombotic syndrome after elastic compression stockings for two years with a five-year follow-up;Aschwanden (2008) showed no difference with elastic compression stockings after three years' follow-up. CONCLUSION: Prescription of elastic compression stockings for the prevention of post-thrombotic syndrome is now in doubt. Immediate compression after diagnosis of acute deep vein thrombosis to prevent swelling and reduce pain, permitting early ambulation in combination with adequate anticoagulation has proven benefit, although a secondary analysis of the SOX trial refutes this belief. Continued long-term compression treatment is questioned. Two major questions remain:Is the lack of positive outcome on the development of post-thrombotic syndrome after proximal deep vein thrombosis due to the fact that there were a few patients with iliofemoral extension in the quoted randomized controlled trials who may benefit from prolonged medical compression treatment?Compliance is the major issue, and the two randomized controlled trials with excellent control of compliance showed significant reduction in the rate of post-thrombotic syndrome, but we know that in daily practice the adherence is closer to Kahn's data.

The role of Kuwait in the development of early thrombus removal in patients with acute iliofemoral vein thrombosis: in memory of Dr. Nael Al-Naqeeb.

Many physicians in Kuwait have contributed to the development of the management of acute iliofemoral deep venous thrombosis utilizing open surgical thrombectomy for early thrombus removal. This concept is now accepted around the world, with new endovascular procedures replacing open surgery. Its development is described and the latest guidelines for early thrombus removal are presented.

Randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years.

OBJECTIVE: This is the first randomized controlled trial with a 5-year follow-up comparing endovenous laser ablation (EVLA) with high ligation and pin-stripping in patients with great saphenous vein (GSV) incompetence. METHODS: One hundred twenty-one consecutive patients (137 legs) with GSV incompetence were randomized to EVLA (980 nm bare fiber) or high ligation and stripping using tumescent local anesthesia with light sedation. Mini-phlebectomies were performed in all patients. The patients were examined with duplex scanning before treatment and after 12 days, and then after 1, 3, and 6 months, and yearly thereafter for up to 5 years. The primary end point was open refluxing GSV. Secondary end points were recurrent varicose veins, frequency of reoperations, Venous Clinical Severity Score, and quality of life scores (Aberdeen Varicose Vein Symptoms Severity Score and Short Form-36). RESULTS: In the EVLA and stripping group, nine (Kaplan-Meier [KM] estimate, 17.9%) and four (KM estimate, 10.1%) of GSVs had open refluxing segments of 5 cm or more (ns). Clinical recurrence was recorded in 24 (KM estimate, 46.6%) and 25 (KM estimate, 54.6%), whereas reoperations were performed in 17 (KM estimate, 38.6%) and 15 (KM estimate, 37.7%) legs (ns). Venous Clinical Severity Score and Aberdeen Varicose Vein Symptoms Severity Score improved whereas Medical Outcomes Study Short Form-36 quality of life score improved in several domains in both groups with no difference between the groups. CONCLUSIONS: Five-year follow-up of our randomized controlled trial comparing EVLA with open surgery in patients with GSV incompetence did not show any significant difference between the two groups in primary or secondary end points, perhaps because of the small sample size. EVLA seems to be a valid alternative to open surgery.

Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy, and surgical stripping for great saphenous varicose veins with 3-year follow-up.

INTRODUCTION: This study compares the outcome 3 years after treatment of varicose veins by endovenous laser ablation (EVLA), radiofrequency ablation, ultrasound-guided foam sclerotherapy (UGFS), or surgery by assessing recurrence, Venous Clinical Severity Score (VCSS), and quality of life (QOL). METHODS: A total of 500 patients (580 legs) were randomized to one of the three endovenous treatments or high ligation and stripping of the great saphenous vein (GSV). Follow-up included clinical and duplex ultrasound examinations and VCSS and QOL questionnaires. Kaplan-Meier (KM) life-table analysis was used. P values below .05 were considered statistically significant. RESULTS: At 3 years, eight (KM estimate, 7%), eight (KM estimate, 6.8%), 31 (KM estimate, 26.4%), and eight (KM estimate, 6.5%) of GSVs recanalized or had a failed stripping procedure (more than 10 cm open refluxing part of the treated GSV; CLF, EVLA, UGFS, and stripping, respectively; P < .01). Seventeen (KM estimate, 14.9%), 24 (KM estimate, 20%), 20 (KM estimate, 19.1%), and 22 (KM estimate, 20.2%) legs developed recurrent varicose veins (P = NS). The patterns of reflux and location of recurrent varicose veins were not different between the groups. Within 3 years after treatment, 12 (KM estimate, 11.1%), 14 (KM estimate, 12.5%), 37 (KM estimate, 31.6%), and 18 (KM estimate, 15.5%) legs were retreated in the CLF, EVLA, UGFS, and stripping groups, respectively (P < .01). VCSS, SF-36, and Aberdeen QOL scores improved significantly in all the groups with no difference between the groups. CONCLUSIONS: All treatment modalities were efficacious and resulted in a similar improvement in VCSS and QOL. However, more recanalization and reoperations were seen after UGFS.

Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.

BACKGROUND: The anticoagulant treatment of acute deep venous thrombosis (DVT) has been historically directed toward the prevention of recurrent venous thromboembolism. However, such treatment imperfectly protects against late manifestations of the postthrombotic syndrome. By restoring venous patency and preserving valvular function, early thrombus removal strategies can potentially decrease postthrombotic morbidity. OBJECTIVE: A committee of experts in venous disease was charged by the Society for Vascular Surgery and the American Venous Forum to develop evidence-based practice guidelines for early thrombus removal strategies, including catheter-directed pharmacologic thrombolysis, pharmacomechanical thrombolysis, and surgical thrombectomy. METHODS: Evidence-based recommendations are based on a systematic review and meta-analysis of the relevant literature, supplemented when necessary by less rigorous data. Recommendations are made according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, incorporating the strength of the recommendation (strong: 1; weak: 2) and an evaluation of the level of the evidence (A to C). RESULTS: On the basis of the best evidence currently available, we recommend against routine use of the term "proximal venous thrombosis" in favor of more precise characterization of thrombi as involving the iliofemoral or femoropopliteal venous segments (Grade 1A). We further suggest the use of early thrombus removal strategies in ambulatory patients with good functional capacity and a first episode of iliofemoral DVT of <14 days in duration (Grade 2C) and strongly recommend their use in patients with limb-threatening ischemia due to iliofemoral venous outflow obstruction (Grade 1A). We suggest pharmacomechanical strategies over catheter-directed pharmacologic thrombolysis alone if resources are available and that surgical thrombectomy be considered if thrombolytic therapy is contraindicated (Grade 2C). CONCLUSIONS: Most data regarding early thrombus removal strategies are of low quality but do suggest patient-important benefits with respect to reducing postthrombotic morbidity. We anticipate revision of these guidelines as additional evidence becomes available.