Acute and chronic venous occlusion

Abstract

This review article provides an overview of acute and chronic venous occlusion, a condition that can cause significant morbidity and mortality if not diagnosed and treated promptly. The article begins with an introduction to the anatomy of the venous system, followed by a discussion of the causes and clinical features of venous occlusion. The diagnostic tools available for the assessment of venous occlusion, including imaging modalities such as ultrasound, CT, and MRI, are then discussed, along with their respective advantages and limitations. The article also covers the treatment options for acute and chronic venous occlusion, including anticoagulant therapy and endovascular interventions. This review aims to provide radiologists with an updated understanding of the pathophysiology, diagnosis, and management of acute and chronic venous occlusion.

Introduction

Deep vein thrombosis (DVT) has an annual incidence of approximately 1 in 1,000. ^1,2 The severity ranges from mild calf swelling to limb-threatening phlegmasia cerulea dolens and life-threatening pulmonary embolus (PE). ³ Chronic venous occlusion, resulting from vessel inflammation and scarring, brings about significant morbidity due to post-thrombotic syndrome (PTS). This review examines the aetiology, symptoms, diagnosis, and treatment of acute and chronic venous occlusion, primarily focusing on lower limb occlusion.

Lower limb venous anatomy

Lower limb venous drainage is divided into superficial and deep systems. Superficial veins include short and long saphenous veins, their tributaries and perforators. The deep calf veins are the paired anterior and posterior tibial and peroneal veins which drain into the popliteal vein, which drains primarily via the femoral vein as well as the profunda femoris veins. The femoral vein continues as the common femoral vein (CFV) after receiving profunda and long saphenous veins. The CFV continues as the external iliac, receiving the internal iliac to form the common iliac vein, which joins with its contralateral common iliac vein to form the inferior vena cava (IVC). Awareness of anatomical variations is essential when treating lower limb venous occlusion.

Proximal vs distal deep venous thrombosis

Lower limb DVT can be categorised into distal and proximal. Distal thrombosis involves the deep veins below the knee. Isolated distal DVT is generally less debilitating than proximal DVT, as when the femoral vein is occluded, drainage occurs through the profunda network. The Lower Extremity Thrombosis (LET) classification system divides the lower limb venous anatomy into nine segments and categorises thrombosis into four classes (Figure 1). ⁴ LET class III corresponds to thrombosis of the CFV segment, affecting the entire lower limb venous drainage and causing worsening symptoms.

Figure 1.

Lower limb venous anatomy segments and lower extremity thrombosis classification as described by Ardnoldussen and Wittens.

Proximal DVTs are at higher risk of PE. It is unclear whether all isolated below-knee DVTs should be treated with anticoagulation or only high-risk cases; for example, trauma-related immobility is associated with higher rates of isolated below-knee thrombus propagation or PE. ^5,6 Studies in non-trauma patients show overall above-knee propagation rates of less than 5%, the majority occurring within two weeks. ^7,8 The American College of Chest Physicians recommends at least three months of anticoagulation in patients with isolated distal DVT if the thrombus is greater than 5 cm, involves multiple veins, or is close to the popliteal vein, or in patients with cancer, immobility, positive D-dimer, highly symptomatic, have a history of venous thromboembolism (VTE) or has COVID-19. Otherwise, serial ultrasound for two weeks is recommended, and to commence anticoagulation if the thrombus propagates, especially into the proximal veins. ⁹

DVT risk factors

Virchow’s triad of venous stasis, endothelial injury, and hypercoagulability is still the cornerstone of risk stratification, prevention, and treatment of DVT.

Patients with malignancy, especially those undergoing chemotherapy or radiotherapy, have a fourfold to sevenfold increased risk of DVT. ^10–12 Venous occlusion can also result from external compression by metastatic lymphadenopathy or pelvic/mediastinal masses. ¹³

Constitutional factors are also contributory. External compression of the left common iliac can occur from the overriding right common iliac artery at the May-Thurner point. This is present to some extent in almost everyone but is more severe in 14–30% of people. ¹⁴ Virchow initially described this in 1851, with May and Thurner later microscopically identifying spur-like intraluminal fibrous band causing stenosis. ¹⁵

Oral contraceptive pills increase VTE risk. A 2014 Cochrane meta-analysis found a fourfold increase in venous thrombosis, particularly with third-generation pills. ¹⁶

Thrombophilia increases DVT risk. The two most common predisposing genetic polymorphisms are factor V Leiden and prothrombin G20210A. ¹⁷ Antiphospholipid syndrome or deficiencies in antithrombin, Protein C and Protein S can all increase DVT risk. Interestingly, patients with thrombophilia are not more prone to developing PTS, and those with factor V Leiden or prothrombin G20210A mutations are at less risk of developing PTS. ¹⁸ More recently, COVID-19 infection has also demonstrated an increased risk of VTE. ¹⁹

Diagnosing DVT

While a thorough history and examination are the beginnings of any evaluation, even experienced observers are correct only 30% of the time in diagnosing DVT with clinical examination alone. ²⁰

Pre-test probability scores streamline patients presenting to Emergency Departments with potential DVT. The Wells score, which is the most widely used, includes risk factors such as immobility, cancer, and recent trauma combined with clinical signs such as unilateral limb swelling, tenderness along the deep veins, and pitting oedema. ²¹ Developed in 1995, it stratified patients into high-risk, intermediate risk, and low-risk groups with 85%, 33%, and 5% pre-test probability of DVT, respectively. These scores were initially combined with ultrasound as the rule-out test, and if there was discordance, venography was performed. Since then, D-dimer has become a valuable DVT biomarker, replacing ultrasound as the rule-out test in low pre-test probability patients. The National Institute for Health and Care Excellence (NICE) recommend D-dimer as the rule-out test in patients with a low Wells score (≤1). ²²

D-dimer, a fibrin degradation by-product, is highly sensitive in DVT and can also have a role in suspected aortic dissection. ^23–25 False negatives can occur with anticoagulant treatment or cases greater than two weeks. False positives include renal impairment, trauma, cancer, pregnancy, and post-surgery. Blanket testing of D-dimers at the door of the Emergency Department is discouraged.

Acute and chronic thrombosis

Acute DVT is defined as thrombosis occurring less than 14 days ago; anything over 28 days is chronic, and subacute between 14 and 28 days. ²⁶ Practically speaking, this timing may be difficult to discern. A long-standing, asymptomatic venous occlusion presenting with subsequent acute thrombosis may require more complex treatment as an acute-on-chronic occlusion.

This distinction is important as managing acute thrombus is usually more straightforward, with clot removal followed by potential stenting of a stenotic lesion. Treating chronic venous occlusion is more complex with less chance of technical and clinical success, often with scarred, fibrotic veins, which may take several hours to cross, followed by potentially painful venoplasty and stenting, often requiring general anaesthesia. Certain imaging features can help differentiate acute from chronic thrombus.

Imaging

Ultrasound

Ultrasound is the first-line imaging modality for suspected DVT. This can be in cases with low pre-test probability and a positive D-dimer, or in cases with high pre-test probability where one would likely forgo the initial D-dimer test. It is inexpensive, readily available and portable but limited in patients with thrombus in abdominal or pelvic veins or very oedematous limbs. The primary means of assessing venous patency is compressibility. When combined with Doppler imaging, waveform analysis can be carried out with respiratory augmentation to evaluate the patency of more proximal veins indirectly. Ultrasound can help differentiate acute from chronic thrombosis, with the latter being more echogenic and eccentric. Collaterals usually take 2–3 weeks to develop, another helpful differentiator.

Elastography

Elastography determines tissue stiffness by measuring the degree of deformation of an object due to an applied external force, referred to as Young’s modulus. It is used in liver imaging for assessing cirrhosis by ultrasound and MRI techniques. ^27,28

As thrombus matures, its composition changes from predominantly erythrocytes and platelets to a more fibrinous and collagenous tissue, becoming organised and endothelialised. ^29–31 Theoretically, elastography can differentiate between the softer, more acute thrombus and the firmer, more chronic thrombus. Animal studies have supported this hypothesis with an accuracy of up to 0.8 days in rats. ^32,33 More recently, it has shown promise in differentiating between acute, subacute and chronic thrombi. ³⁴

CT venography

CT venography (CTV) can be used in the initial diagnosis and further assessment of venous occlusion. It can also help differentiate between acute and chronic disease (Table 1).

Table 1.

Differences between acute and chronic venous disease seen with CT venography ³⁵

	Acute	Chronic
Vein diameter	Large	Small
Intraluminal attenuation	Low	High
Presence of collaterals	Few	Many
Vein wall thickness	Thin	Thick
Intraluminal synechiae	Absent	Sometimes present (seen with direct CTV)
Intraluminal calcification	Absent	Sometimes present

Indirect CTV involves imaging the deep venous system after a fixed delay (usually 180–200 s) following intravenous contrast injection. It is helpful in cases of acute venous occlusion to assess the proximal extent of the thrombus and identify any venous anatomical variation or external compression. Direct lower limb CTV involves intravenous cannulation of the foot with a high rate and high volume antegrade contrast injection. It is used in chronic venous occlusion and helps predict the dominant inflow when planning venous reconstruction. ³⁶ Tourniquets should be applied to the lower limb to force contrast through the deep veins. There is no role for direct CTV in cases of acute DVT.

MR venography

MRI has advantages with no ionising radiation, and with modern sequences, intravenous contrast is sometimes unnecessary. Common non-contrast MRI sequences employed include fast spin echo or single-shot turbo spin echo imaging with hyperintense blood signal, time-of-flight imaging relying on flow, or magnetic resonance direct thrombus imaging (MRDTI). MRDTI measures the high T1 signal returned from methaemoglobin in an acute thrombus. ^37,38 It is a valuable sequence that is sensitive and specific to the diagnosis of DVT and has been shown to differentiate between acute and chronic thrombus. ^39–41

MR venography can assess pelvic organs potentially causing occlusion and visualise synechiae associated with chronic occlusion. It cannot assess the lumen of stents, so post-intervention follow-up is preferred with CT or US.

Intravascular ultrasound

Intravascular ultrasound (IVUS) is useful in treating acute and chronic venous disease. Compared with venography, IVUS is more accurate in assessing the degree of vessel stenosis, facilitates more precise stent placement, and better evaluates stent expansion and patency. ^42–44

Other advantages of IVUS include the ability to assess the venous wall, detect intraluminal webs and decrease the amount of intravenous contrast and ionising radiation. It has been effective when used without contrast venography for assessing lower limb deep venous lesions, treatment planning, and stenting. ⁴⁵

Treatment

The primary aim of acute DVT treatment is to prevent potentially fatal pulmonary emboli and, secondly, to avoid developing PTS. PTS affects approximately one-third to one-half of DVT patients and increases in cases of recurrent DVT. ^46–49 Symptoms classically include pain, oedema, venous engorgement, painful venous ulcers, and venous claudication. ⁵⁰ It more commonly affects the left leg, likely due to May-Thurner compression.

Pharmacological treatments

Medical therapy is most commonly used as the first line in treating acute DVT. Given the risk of morbidity and mortality, anticoagulation should be commenced as soon as possible in acute DVT, especially proximal DVT.

Heparin

Unfractionated heparin (UFH) administered intravenously has an immediate onset and is valuable in cases of significant occlusion with proximal DVT. It can be reversed with protamine sulphate making it useful in patients with increased bleeding risk. A complication of UFH use is heparin-induced thrombocytopenia, a prothrombotic condition occurring in 2–3% of cases. UFH has an unpredictable pharmaco-mechanical profile, requiring regular monitoring of APTT.

Low molecular weight heparin (LMWH) has a more stable pharmacokinetic profile and can be reliably given in once-daily subcutaneous formulations. LMWH is primarily excreted renally, whereas UFH is excreted via the reticuloendothelial pathway and is helpful in cases of impaired renal function.

Vitamin K antagonists

Warfarin and other vitamin K antagonists work by inhibiting the Vitamin K associated clotting factors II, VII, IX, and X. Until the advent of direct oral anticoagulants (DOAC), they were widely used to treat and prevent the recurrence of DVT. They require regular monitoring, given their narrow therapeutic window. The international normalised ratio (INR) is based on the prothrombin time, and generally, an INR of 2–3 is desirable. When commencing a patient on warfarin, there is a 5-day lead-in time where the patient should be anticoagulated with an alternative agent, usually LMWH.

Direct oral anticoagulants

Initially licenced for non-valvular atrial fibrillation, DOAC use has expanded to include DVT treatment. Dabigatran, a direct thrombin inhibitor, was the first FDA-approved DOAC in 2010. Several others are now approved, including rivaroxaban, apixaban, edoxaban and betrixaban, all of which are direct factor Xa inhibitors. Factors to consider include once or bd administration, patient reliability, and the expense of monitoring therapeutic effects such as anti-Xa assays. ⁵¹ DOACs are now recommended as first-line treatment for acute DVT or PE. They are preferred to vitamin K antagonists in patients without severe renal or liver impairment or antiphospholipid syndrome. ⁵²

Antiplatelets

Observational studies have demonstrated that antiplatelets can reduce the risk of VTE coincidentally in patients being treated for atherosclerosis. ⁵³ However, a 2020 systematic review of randomised control trials comparing different DOACs to Warfarin in which a proportion of patients were taking concomitant antiplatelet agents showed no difference in the rate of VTE and an increased risk of major haemorrhage of 2.1vs 1.1%. ⁵⁴

A Cochrane review protocol looking at antiplatelets for treating DVT was published in 2016, but the review itself has yet to be published ⁵⁵ ; this would help decide whether these agents are beneficial, but for now, there needs to be strong evidence to support their use.

Thrombolysis

Anticoagulation aims to prevent further thrombus propagation, allowing the body’s natural fibrinolytic activity to lyse the thrombus. In this way, anticoagulation can be thought of as passively contributing to decreasing clot burden. Thrombolysis, either systemically or locally with catheter-directed thrombolysis (CDT), aims to actively dissolve the thrombus. Systemic thrombolysis for treating DVT carries an unacceptable haemorrhage risk, and CDT is therefore preferred.

The CaVenT study, a multicentre randomised control trial from 2012, demonstrated a modest reduction in PTS at two years in those receiving CDT in addition to anticoagulation with an absolute risk reduction of 14·4% and a number needed to treat (NNT) of 7. ⁵⁶ This difference became greater after five years, with an absolute risk reduction of 28% and an NNT of 4. ⁵⁷

NICE recommend CDT for patients with symptomatic iliofemoral DVT who have:

• Symptoms lasting less than 14 days

• Life expectancy greater than one year

• Low bleeding risk. ²²

Ultrasound-assisted catheter-directed thrombolysis is also available with the EKOS Endovascular System (Boston Scientific). In addition to delivering CDT, this device uses ultrasound energy to accelerate fibrinolysis, thereby reducing treatment time and the required quantity of the thrombolytic agent. In addition to treating acute DVT, it is used in treating massive and submassive PE. ^58,59

Mechanical/PHARMACOMECHANICAL TREATMENTS

For acute DVT, pharmacomechanical thrombectomy (PMT) is seen as a “one-stop shop” for removing the thrombus in a single session. Several devices have been approved in the last decade for treating acute DVT. These devices involve the mechanical removal of fresh thrombus by maceration or aspiration with or without the local administration of thrombolytics. Regardless of the device used, the goal is to restore vessel patency with or without adjuvant stenting. In PMT, establishing good inflow is critical before stenting to prevent re-occlusion. In practical terms, this suggests that CDT is preferable in cases where the popliteal or deep calf veins are also occluded.

ATTRACT was an eagerly awaited multicentred randomised control trial assessing the occurrence of PTS in patients randomised to CDT or PMT plus anticoagulation versus anticoagulation alone. ATTRACT did not show a reduction in PTS occurrence in patients with a proximal DVT undergoing CDT or PMT versus those treated with anticoagulation alone. Furthermore, the PMT group had more major and minor bleeding events. The results of the ATTRACT study were surprising, given the continued benefit seen with CDT in the CaVenT study. However, the ATTRACT study did show a reduction in the severity of PTS at 24 months in patients with iliofemoral DVT.

ATTRACT was unsatisfactory for various reasons, and the CLEAR DVT trial may better reflect modern practices. ⁶⁰ The initial results of the first phase of CLEAR DVT of the initial 35 patients who underwent PMT with the Angiojet ZelanteDVT (Boston Scientific) with or without venous stenting and who have reached at least 12-month follow-up have shown no PTS in 96% of cases with the remaining 4% having mild PTS. ⁶¹

NICE guidelines currently advise that due to a relative paucity of evidence, PMT for iliofemoral DVT should only be performed with special arrangements for clinical governance, consent and audit or research and that there should be multidisciplinary input, including a vascular surgeon, an interventional radiologist and a haematologist. ⁶² These guidelines are expected to be updated in 2025. This raises a potential dilemma facing interventionalists when consenting patients. Currently, the evidence is not as robust as would be desired, although PMT is still considered as an effective treatment. As with any procedure, an open and frank discussion with the patient is essential, outlining the risks, benefits and alternatives and allowing time for questions, preferably with a cool-off period before proceeding.

IVC filters

IVC filters (IVCF) have been used for over four decades, with the primary indication being patients with VTE, in whom anticoagulation is contraindicated. Examples include those undergoing major surgery or who have had recent intracranial haemorrhage are at high bleeding risk or recently suffered significant trauma. NICE guidelines advise IVCF insertion in patients with proximal DVT or PE when anticoagulation is contraindicated or a PE has occurred on anticoagulation. ²²

Up to 45% of patients with PE have a concomitant DVT. ⁶³ Iatrogenic symptomatic pulmonary emboli related to percutaneous venous intervention for acute DVT occur in 5% or 10% of patients with asymptomatic pre-procedure PE. ⁶⁴ The question of whether an IVCF should be inserted before endovenous intervention is important.

The recent Society of Interventional Radiology guidelines on IVCF insertion made 18 expert recommendations based on a systematic review of 34 studies. ⁶⁵ These guidelines addressed IVCF placement in cases of advanced therapies, including CDT and PMT. Three studies met the inclusion criteria, two being low-quality retrospective cohort studies showing no difference between groups. The third study, a randomised control trial (RCT) published in 2012, demonstrated an eightfold reduction in iatrogenic pulmonary emboli with the use of IVCF but without a benefit in mortality for patients treated for above-knee DVT using either the Angiojet DVX (Boston Scientific) or the now discontinued Trellis (Covidien). ⁶⁶ This trial also demonstrated an incidental PE rate of 20–23% on admission before any venous intervention.

The SIR consensus guidelines recommend IVCF placement only in select cases where the interventionalist believes there is a high risk of clinically significant iatrogenic PE.

If an IVC filter is placed, the preference would be for a removable filter, which should be removed as soon as possible. This is also in line with NICE recommendations. ²²

Managing post-thrombotic syndrome

PTS can be a very debilitating condition, severely impacting a patient’s quality of life. A swollen, painful limb with the potential for ulceration are some of the effects of PTS. There are also more insidious issues such as weight gain (either from swelling or inability to exercise) and significant alterations to lifestyle from venous claudication (no longer being able to bring the dog for a walk or play golf, for instance). It can also have a significant economic impact on both the patient and wider society if patients cannot continue working.

For a nonfatal condition that severely impacts quality of life, quality-of-life measurements are essential in assessing the outcomes of interventions to treat PTS. These scores should be validated, relevant and reproducible.

Several clinical severity and quality-of-life scoring systems have been developed, validated and revised for chronic venous disease. The literature’s most widely used scoring systems are the ChronIc Venous Insufficiency Questionnaire (CIVIQ) and the VEnous Insufficiency Epidemiological and Economic Study on Quality of Life (VEINES-QOL). Another important scoring system is the Villata scale. A score less than 10 is mild, 10–15 is moderate, and a score greater than 15 indicates severe PTS. ^50,67–71

The Venous Severity Scoring System has been revised with a particular focus on characterising the patient’s pain with heaviness, soreness, burning, aching, and fatigue are all now included. ⁷² Understanding patient symptomatology is vital for managing patient expectations in the pre-procedure consultation.

Venous stenting

The first reports of deep venous stenting used stents designed for arterial use. More recently, stents have been developed specifically for venous intervention, which require strong radial force to resist external compression and flexibility, as the iliac veins can be tortuous.

Generally, stents are matched to the “normal” vessel diameter. IVUS is now widely used to plan the lengths, diameters and landing zones for stent placement and assess adequate stent expansion post-dilatation. At the time of writing, no other technique matches the accuracy and repeatability of IVUS, and it is a tool that should be readily available in any deep venous reconstruction program.

Stenting is most commonly performed for iliofemoral venous stenosis. However, stents have occasionally been extended below the CFV into a dominant inflow vein with good results. ^73–75 When treating a May-Thurner lesion, it is essential to cover the entire affected segment, ideally without covering the right common iliac vein ostium entirely. Venography can be less accurate in this scenario, and IVUS is a valuable tool when treating May-Thurner compression. An anatomical landmark-based technique between the spinous process and the right pedicle of L5 has also been described. ⁷⁶

Single-arm trials have demonstrated satisfactory results with primary patency rates after one year between 84% and 88% across different venous stents. Long-term data for outcomes longer than 20 years have yet to be available for most endovenous interventions, and this should be considered when treating younger patients with longer life expectancies.

Surgical management

Surgical treatment of PTS requires expertise that may not be widely available, but awareness of the indications is important in cases requiring referral. Surgery for PTS is reserved for cases where endovenous therapy has failed or is impossible (e.g., prior venous injury requiring ligation). Various options exist, including the femoral-femoral greater saphenous vein crossover graft (the Palma procedure). ⁷⁷ This procedure requires patent contralateral iliofemoral veins and a patent greater saphenous vein. Other bypass grafts using PTFE grafts can also be performed. An arteriovenous fistula is required to increase the flow through the graft to preserve patency. The fistula should be kept open as long as possible but can be closed in cases of high-output cardiac failure.

Compression stockings

Class II graduated compression stockings, at least to the knee, are advised for at least two years post-venous stenting. The evidence of stockings is relatively weak, but their use is not harmful. ⁷⁸ No difference between knee and thigh-high stockings has been shown, which may help compliance.

Upper limb deep venous thrombosis

Upper limb DVTs account for 5–10% of all DVTs, and their incidence is increasing, likely due to the increasing frequency of central venous catheters. ⁷⁹ The primary form, known as Paget-Schroetter syndrome, accounts for 10–20% of upper limb DVTs and classically involves the dominant arm of young athletes involved in sports that require excessive and repeated upper limb motion, such as swimming or baseball. ⁸⁰ There is compression of the neurovascular bundle at the thoracic outlet from cervical ribs or enlarged scalene muscles. In these cases, treatment of acute DVT is usually with CDT, followed by prompt referral for surgical decompression of the thoracic outlet, ideally in a high-volume centre. The majority of upper limb DVTs occur secondary to the presence of central lines or pacemaker leads. ^81,82 Clinical judgement should be used when deciding to remove the offending line. A trial of anticoagulation prior to removal is reasonable and should be continued as long as the line remains and for three months after that. ^9,83

On the horizon

Without a doubt, the next two decades will see the advent of new stents, new thrombectomy and thrombolysis devices and the development of new advanced techniques that will be used to manage acute and chronic venous occlusion. Reducing vascular inflammation may be one target. ⁸⁴ However, one of the most critical aspects of the future of endovascular venous intervention will be the long-term clinically driven data concerning the interventions that have been carried out up to this point.

Conclusion

Diagnosing and treating acute and chronic venous occlusion are becoming increasingly complex as our understanding of the pathophysiology of the disease grows. Managing venous occlusion is a multidisciplinary undertaking; Interventional Radiology is well placed with much to offer both diagnostically and therapeutically.