Isolated distal deep vein thrombosis: Diagnosis and management

Abstract

Isolated distal deep vein thrombosis (IDDVT), a subtype of lower extremity deep vein thrombosis (DVT), is a common yet preventable complication in clinical practice. Based on thrombus location, IDDVT can be categorized into axial venous thrombosis (involving the anterior tibial, posterior tibial, and peroneal veins) and intermuscular venous thrombosis (affecting the venous plexus of the gastrocnemius and soleus muscles). IDDVT is recognized as a potential source of embolic events and is associated with poor prognosis. Current evidence indicates that the Wells score is not applicable for IDDVT diagnosis, which primarily relies on D-dimer testing and lower extremity venous ultrasonography. There remains a lack of standardized treatment protocols for IDDVT. The American College of Chest Physicians (ACCP) guidelines recommend a 3-month anticoagulation regimen for patients with significant symptoms or high risk of thrombus extension, prioritizing direct oral anticoagulants; however, the supporting evidence is of low quality. Significant anatomical and physiological differences exist between axial and intermuscular venous thrombosis. Axial venous thrombosis demonstrates higher rates of thrombus extension, recurrence, and pulmonary embolism compared to intermuscular venous thrombosis. Nevertheless, whether anticoagulation therapy is warranted for both types remains controversial. This narrative review systematically elucidates the epidemiological characteristics, risk factors, clinical manifestations, and clinical management of IDDVT. It focuses on the diagnosis and management of IDDVT based on current guideline recommendations and the latest evidence, with the aim of providing a reference for clinical practitioners.

Introduction

Isolated distal deep vein thrombosis (IDDVT) is a subtype of deep vein thrombosis (DVT) that typically occurs in the distal veins of the lower extremities, without accompanying proximal deep vein thrombosis (PDVT) or pulmonary embolism (PE). Based on the location of the thrombus, IDDVT can be categorized into central venous thrombosis (primarily affecting the anterior tibial vein, posterior tibial vein, and peroneal vein) and intermuscular venous thrombosis (primarily involving the venous plexuses of the gastrocnemius and soleus muscles). The risk factors for IDDVT remain unclear; however, increasing evidence suggests that transient and temporary risk factors, such as surgery and acute trauma, may elevate the risk of developing IDDVT. Due to the characteristics of distal veins—including numerous accompanying veins, rich venous branching, and interconnected venous networks ¹ —clinical manifestations of IDDVT are often subtle. Diagnosis primarily relies on D-dimer testing and lower extremity venous ultrasound. There is a lack of standardized treatment protocols for IDDVT, and varying clinical guidelines and expert opinions offer different therapeutic strategies, resulting in discrepancies in treatment approaches among medical institutions. This variation can lead to divergent clinical outcomes for IDDVT patients.

This narrative review is structured using the Systematic Assessment of Narrative Review Articles (SANRA) scale as the methodological framework. ² The literature search was conducted across PubMed, Embase, Cochrane Library, and CNKI databases, utilizing keywords such as “isolated distal deep vein thrombosis,” “calf deep vein thrombosis,” “below-knee deep vein thrombosis,” “axial vein thrombosis,” “muscle interstitial vein thrombosis,” “anticoagulation,” and “direct oral anticoagulants.” To ensure the reliability of the evidence, preprints were not included in this review.

The purpose of this narrative review is to integrate current evidence and systematically analyze the epidemiological characteristics, anatomical features, risk factors, clinical manifestations, diagnostic methods, and management strategies of IDDVT. It also aims to provide an in-depth discussion on the diagnosis and management of IDDVT, integrating current guideline recommendations and the latest evidence. This review is intended to assist clinicians in better managing IDDVT, thereby improving patient outcomes, alleviating patient suffering and burden, and enhancing quality of life.

Epidemiology

The incidence of IDDVT varies across populations, diagnostic timing, and study methodologies. Globally, the incidence of DVT ranges from 1.15‰ to 2.69‰, ³ with IDDVT accounting for 17.5%–59.7% of all DVT cases.^4–6 Notably, Asian populations (e.g. China and South Korea) exhibit lower IDDVT prevalence. ⁷ Hospitalized patients are at significantly higher risk due to comorbidities, surgical interventions, trauma, and prolonged immobilization, with IDDVT incidence reaching up to 60.6% ⁸ —5.02-fold higher than PDVT. ⁹

Anatomical and pathophysiological features

The anatomical and physiological characteristics of the axial veins and intermuscular veins in the calf are fundamentally distinct. ¹⁰ The axial veins, paired with their homonymous arteries, rely on dual mechanisms for venous return: indirect compression from arterial pulsation and the calf muscular pump mechanism. The periodic arterial pulsations induce passive expansion and contraction of venous walls, generating pulsatile blood flow. This process, combined with a densely distributed venous valve system, effectively prevents blood reflux. In contrast, intermuscular veins (including the gastrocnemius and soleus venous plexuses) are embedded within the connective tissue spaces between skeletal muscle bundles. Their venous return primarily depends on intermittent high-pressure gradients generated during muscle contraction phases, while unidirectional valves maintain blood flow direction during relaxation phases, exemplifying a typical “muscular pump mechanism”. When patients are bedridden for extended periods or experience restricted calf movement, the contractile capacity of the muscles diminishes or is completely lost, leading to impaired muscle pump function and reduced blood flow velocity. Additionally, the intermuscular veins are characterized by their thin walls, numerous branches, and sparse venous valves, which predispose them to blood stasis, venous congestion, and dilation. This further weakens or even eliminates the valve function, exacerbating venous stasis. When the veins become excessively distended, endothelial injury occurs, prompting the release of signaling molecules from damaged endothelial cells. These molecules induce platelet adhesion and activation, leading to the formation of platelet thrombi. Simultaneously, vascular wall injury stimulates the activation of endothelial cells, leukocytes, and platelets, triggering inflammation and the formation of microparticles. These microparticles carry tissue factor, initiating the coagulation cascade. Through the activation and interaction of coagulation factors, fibrin and platelet aggregates ultimately form thrombi. Consequently, intermuscular veins are more prone to thrombosis compared to axial veins.^9,11,12 The soleal vein, which has a single main trunk, numerous branches, thin walls, and incomplete or absent valves, is the most common site for IDDVT within the soleal venous network. ¹¹ In long-term bedridden patients, the soleal vein is often the site of DVT. ¹² Among these, the central soleal vein, which serves as the drainage vein for the soleal venous network, has the highest detection rate for thrombi. ¹² There is no significant difference in the incidence of DVT between the two lower limbs. ⁹

Risk factors

All factors that may lead to venous endothelial dysfunction or injury, reduced blood flow, or increased blood viscosity are considered risk factors for IDDVT. The risk profile for IDDVT differs from that of traditional DVT. Growing evidence supports a stronger association between IDDVT and transient risk factors. The OPTIMEV study ¹³ demonstrated that IDDVT is significantly linked to transient triggers (e.g. recent surgery, immobilization with casting, or long-distance travel), whereas PDVT is more strongly correlated with chronic conditions such as active cancer, congestive heart failure, respiratory insufficiency, or advanced age (>75 years). Findings from the GARFIELD-VTE registry ⁸ further confirm that IDDVT is more likely associated with recent transient events, including recent surgery, acute leg trauma, or recent hormonal therapy. Data from the RIETE registry corroborate that IDDVT patients are more likely to have undergone recent surgery or hormonal therapy. ⁵ Similarly, results from the SWIVTER study support the association between IDDVT and recent surgical interventions. ¹⁴

Studies indicate that IDDVT typically manifests at a younger age,^6,14 and patients with comorbidities such as varicose veins, venous insufficiency, or superficial thrombophlebitis are at elevated risk. ⁶ A gender disparity exists in IDDVT incidence, with female patients being more susceptible,^15–17 particularly in the 40–49 age group. ¹⁵ The risk of thrombosis escalates with an increasing number of risk factors. ¹⁸ However, the precise thrombotic risk in patients with multiple concurrent risk factors requires further validation.

Diagnostic methods

The Wells score represents the most widely used clinical prediction rule (CPR) for estimating pretest probability of DVT. The guidelines from the European Society for Vascular Surgery (ESVS) ⁷ and the European Society of Cardiology (ESC) ¹⁹ recommend the initial evaluation of suspected DVT using the Wells score. A score of ≥2 indicates a high suspicion of DVT, suggesting further diagnostic confirmation through D-dimer testing and lower extremity venous ultrasound, which can help reduce unnecessary ultrasound examinations and lessen the economic burden on patients. The Wells score was originally developed to predict the likelihood of PE and DVT. However, its application in the context of PDVT has been a subject of debate. Specifically, studies by Sartori et al.^20,21 have demonstrated that the Wells score exhibits relatively poor diagnostic accuracy for IDDVT. Therefore, it is not considered suitable for assessing the risk of IDDVT occurrence. Currently, there is a lack of validated CPR for assessing the pre-test probability of IDDVT. While the Wells score is a widely used CPR for proximal DVT diagnosis, its accuracy in isolated distal DVT remains limited. A clinical prediction model specifically designed for isolated calf distal muscular vein thrombosis has been developed by Yanxu et al., ²² achieving an area under the curve (AUC) of 0.924 in the training group and 0.902 in the validation group. However, this model has not yet seen widespread application or validation.

D-dimer, a specific degradation product of cross-linked fibrin during fibrinolysis, serves as a critical molecular biomarker for evaluating hypercoagulable states and activation of the fibrinolytic system. However, D-dimer testing in IDDVT patients demonstrates a false-negative rate of up to 14.7%. ²³ Notably, D-dimer levels exhibit age-dependent elevation, potentially leading to false-positive results in elderly patients. To mitigate false-positive rates, age-adjusted D-dimer thresholds are recommended. Specifically, a cutoff of age × 10 µg/L is proposed for patients over 50 years.^24,25 Alternative strategies suggest using probability-adjusted D-dimer thresholds, where a doubled cutoff (1000 µg/L) is applied to patients with low clinical probability (Wells score <2) compared to those with intermediate probability. Studies demonstrate comparable negative predictive values between clinical probability-adjusted and age-adjusted D-dimer approaches. ²⁶ Sartori et al. ²⁷ compared the diagnostic performance of standard, age-adjusted, and probability-adjusted D-dimer thresholds for IDDVT and PDVT detection. Specificity rates were 47%, 61%, and 67% for standard, age-adjusted, and probability-adjusted thresholds, respectively, while all strategies maintained a negative predictive value of 96%. For PDVT diagnosis, negative predictive values increased to 99%. Although age- and probability-adjusted thresholds reduce ultrasound utilization compared to standard protocols, their lower specificity may increase risks of false exclusion.

With advancements in biotechnology, novel thrombotic biomarkers including microparticles (MPs), P-selectin, and thrombin generation markers have been increasingly utilized in thrombosis diagnosis. MPs are 100–1000 nm membrane-derived vesicles shed from platelets, leukocytes, erythrocytes, and endothelial cells. These subcellular particles promote coagulation through phosphatidylserine (PS) exposure and tissue factor expression, ²⁸ establishing their potential as thrombotic biomarkers. ²⁹ In a prospective cohort study by Zang et al. ³⁰ involving 106 trauma patients (53 with DVT and 53 non-DVT controls) and 53 healthy volunteers, circulating levels of PS + MPs, hepatocyte-derived MPs (HMPs), PS + HMPs, and platelet-derived MPs (PMPs) were significantly elevated in DVT patients compared to non-DVT controls (P < 0.05). Notably, PS + HMPs demonstrated superior diagnostic performance for DVT detection (AUC 0.894) compared to conventional D-dimer testing (AUC 0.588). While current MP research predominantly focuses on cancer, autoimmune disorders, and coronary artery disease populations, the pathophysiological role of MPs in IDDVT remains underexplored, warranting future mechanistic investigations.

P-selectin, stored in platelet α-granules and endothelial Weibel-Palade bodies, undergoes surface translocation during cellular activation with subsequent soluble form (sP-selectin) release. This adhesion molecule facilitates leukocyte-platelet-endothelial interactions and mediates inflammatory thrombosis. Multiple clinical studies consistently report elevated sP-selectin levels in DVT populations.^31–35 Gremmel et al. ³² observed significantly higher plasma sP-selectin concentrations in acute DVT patients versus healthy controls (41.4 μg/L [20.6–79.1] vs 33.1 μg/L [11.7–63.9], P = 0.001), with distal DVT cases showing non-significantly lower levels than PDVT (35.7 μg/L [27.3–54.8] vs 43 μg/L [20.6–79.1], P = 0.08). Longitudinal analysis revealed that vitamin K antagonist therapy reduced sP-selectin below control levels at 3–6 months post-DVT, followed by biomarker rebound at 12 months post-anticoagulation cessation—a pattern paralleling D-dimer fluctuations. These findings suggest sP-selectin may reflect both prothrombotic states and anticoagulation responsiveness. Contradictorily, Vandy et al. ³³ reported higher median sP-selectin in distal DVT (75.7 ng/mL vs 57.5 ng/mL PDVT), though lacking statistical significance (P > 0.05). Importantly, combining sP-selectin >90 ng/mL with Wells score ≥2 achieved superior diagnostic specificity (97.5% vs 65.5%) and positive predictive value (91% vs 69%) compared to D-dimer-based algorithms, positioning sP-selectin as a promising diagnostic adjunct.

Thrombin generation markers including prothrombin fragment F1 + 2 and thrombin-antithrombin III complex (TAT) provide mechanistic insights into coagulation activation. F1 + 2, generated during factor II cleavage by prothrombinase complex (FXa/FVa/Ca²⁺/phospholipid), directly reflects thrombin generation, while TAT levels indicate thrombin inactivation dynamics. Elevated TAT concentrations signify hypercoagulable states observed in disseminated intravascular coagulation, postoperative thrombosis, and malignancy-associated thrombosis. Although these biomarkers show potential for early thrombotic risk stratification in oncological and surgical cohorts, their diagnostic accuracy remains controversial across clinical contexts. Particularly, evidence regarding their utility in IDDVT assessment remains conspicuously absent, highlighting a critical knowledge gap requiring multicenter validation studies.

Venography remains the gold standard for DVT diagnosis; ⁷ however, due to its invasive nature, radiation exposure, high cost, and risks of contrast-induced nephropathy or allergic reactions, lower extremity compression ultrasound (CUS) is recommended as the first-line imaging modality in clinical practice. Current CUS protocols include single-point, serial, and whole-leg approaches. Single-point CUS (also termed two-point CUS) exclusively evaluates proximal deep veins (popliteal vein or more central vasculature). Serial CUS is typically performed 5–10 days after an initial negative scan to assess potential progression of distal DVT to proximal segments. Whole-leg CUS (complete CUS) provides comprehensive single-session evaluation of both distal and proximal deep venous systems, enabling simultaneous detection of IDDVT and PDVT. The ESVS guidelines ⁷ advocate whole-leg CUS for all suspected cases to minimize diagnostic omissions, whereas The American College of Chest Physicians (ACCP) guidelines ³⁶ prioritize serial CUS over routine whole-leg imaging, citing concerns about reduced IDDVT detection rates with selective protocols. The Ultrasound Radiology Consensus Conference ³⁷ proposes initial whole-leg CUS, mandating repeat evaluation within 5–7 days if limited or selective protocols are employed. A randomized controlled trial comparing single-point CUS with D-dimer testing versus whole-leg CUS demonstrated equivalent 3-month symptomatic venous thromboembolism (VTE) rates (difference 0.3%), suggesting comparable management efficacy for symptomatic DVT, though IDDVT-specific outcomes were not stratified. ³⁸ A meta-analysis revealed no significant differences in failure rates among these three ultrasound strategies for IDDVT diagnosis. ³⁹

Sonographic diagnosis relies on venous incompressibility, though technical challenges arise in evaluating muscular calf veins due to their deep anatomical position and variable compressibility. Emerging imaging modalities include computed tomography angiography (CTA), conventional magnetic resonance imaging (MRI), and contrast-enhanced MR angiography (CE-MRA). CTA shares venography's limitations of invasiveness, radiation exposure, and contrast risks, constraining its routine use. MRI characterizes thrombi through venous dilatation with intraluminal heterogeneous signals, ⁴⁰ proving particularly valuable for distinguishing IDDVT (primarily presenting with localized pain rather than edema ⁴¹ ) from musculoskeletal injuries. Current protocols recommend supplementary ultrasound evaluation of the entire deep venous system upon MRI-detected IDDVT to exclude concurrent PDVT. ⁴² While CE-MRA offers high sensitivity without ionizing radiation, its clinical adoption remains cautious due to historical associations with nephrogenic systemic fibrosis.

Clinical reliance on ultrasound only when symptoms manifest may delay diagnosis. Notably, ultrasonography alone shows limited sensitivity (56.8%) for IDDVT detection. ³⁷ Combining ultrasound with thrombotic biomarkers improves both sensitivity and specificity to >85%. ⁴³ In clinical practice, D-dimer-ultrasound combination is strongly recommended for IDDVT evaluation, particularly in patients with elevated D-dimer levels. For D-dimer-positive cases with negative initial ultrasound, repeat examination within 1 week or upon clinical deterioration is advised. Persistent ultrasound findings of IDDVT with asymptomatic presentation and normal D-dimer levels over six consecutive weeks should raise suspicion of chronic IDDVT.

Anticoagulation therapy

Is anticoagulation therapy needed?

IDDVT is considered the source of all DVT. ⁴⁴ Previously, IDDVT was regarded as a benign self-limiting disease. However, research findings have demonstrated that IDDVT, like PDVT, can lead to thrombus progression, PE, thrombus recurrence, the development of post-thrombotic syndrome (PTS), and mortality. The current consensus is that IDDVT is not suitable for surgical treatment. The management methods for IDDVT recommended in guidelines include dynamic ultrasound monitoring and anticoagulation therapy (The management recommendations for IDDVT as provided by major international clinical practice guidelines and expert consensus are detailed in Table 1). Ultrasound monitoring, as an important tool for assessing disease progression and severity, is not an effective therapeutic method. Masuda et al. ⁴⁵ proposed that, considering the risks of thrombus propagation, PE, and recurrence, a treatment approach of taking no action should be considered unacceptable. Brewster et al. ⁴⁶ reported that 70% of patients with IDDVT undergoing serial ultrasound imaging did not require anticoagulation therapy within 30 days after diagnosis. However, this study did not compare the clinical outcomes between dynamic ultrasound monitoring and anticoagulation therapy. A retrospective study compared the prognosis of IDDVT patients treated with anticoagulation therapy and those without anticoagulation therapy. The results showed that the thrombus resolution rate was significantly higher in patients treated with anticoagulation therapy than in those without anticoagulation therapy. However, there was no significant difference in all-cause mortality or the incidence of PDVT/DVT between the two groups. ⁴⁷ A meta-analysis including 20 studies with 2936 patients showed that prophylactic or therapeutic anticoagulation therapy effectively reduced the incidence of recurrent VTE without increasing the rate of major bleeding events. ⁴⁸ The study by Huang et al. ⁴⁹ demonstrated that compared with no anticoagulation therapy and prophylactic anticoagulation therapy, therapeutic anticoagulation significantly reduced the incidence of thrombus progression in patients with isolated calf muscle vein thrombosis (RR = 0.33, 95% CI 0.20–0.54, P < 0.01) and increased the rate of thrombus recanalization (RR = 1.96, 95% CI 1.01–3.80, P = 0.05). A study stratifying clinical outcomes of IDDVT patients by management strategy showed that compared with ultrasound monitoring alone, patients receiving anticoagulation therapy had significantly lower rates of thrombus recurrence and propagation. There was no significant difference in mortality or bleeding rates between the two groups. Anticoagulation therapy provided greater net clinical benefit to patients. ⁵⁰ A Cochrane study ⁵¹ showed that compared with no anticoagulation or placebo treatment, vitamin K antagonist therapy reduced the incidence of VTE and DVT events. Although there was an increase in clinically relevant non-major bleeding events, there was no significant difference in the incidence of major bleeding events. The study also found that anticoagulation therapy for 3 months provided more significant clinical benefits than 6 weeks of therapy. Anticoagulation therapy can improve patient prognosis, promote thrombus resolution in the calf, and reduce the incidence of thrombus progression, recurrence, PE, and PTS without increasing the risk of bleeding. Whether to initiate anticoagulation therapy should be determined by clinical practitioners based on patient preferences, weighing the benefits and risks maximizing net clinical benefit for the patient.

Table 1.

The management recommendations for patients with isolated distal deep vein thrombosis according to international clinical practice guidelines and expert consensus.

Guideline (year)	Recommendations
Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report(2021) 36	In patients with acute isolated distal DVT of the leg: and (i) without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over anticoagulation (weak recommendation, moderate-certainty evidence) or (ii) with severe symptoms or risk factors for extension, we suggest anticoagulation over serial imaging of the deep veins (weak recommendation, low-certainty evidence) In patients with acute isolated distal DVT of the leg who are treated with anticoagulation, the same anticoagulation regimen as for patients with acute proximal DVT should be used
Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function(2021) 19	Patients with isolated distal DVT at high risk of recurrence should be anticoagulated, as for proximal DVT; for those at low risk of recurrence shorter LMWH treatment (4–6 weeks), even at lower anticoagulant doses, or ultrasound surveillance may be considered Remarks: Stratification of risk of venous thromboembolic disease recurrence in IDDVT patients Low: Plaster, immobilization, trauma, long trip, etc., provided complete mobilization is achieved, during contraceptive or replacement hormonal therapy (provided therapy has been interrupted) High: Previous VTE, male, age >50 years, active cancer, unprovoked IDDVT, persistent hampered mobilization, IDDVT involving: popliteal trifurcation, and/or >1 calf vein, bilateral, presence of predisposing disease (i.e. inflammatory bowel diseases), known genetic thrombophilia, axial vs. muscular IDDVT
European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis(2020) 7	For patients with symptomatic calf DVT and active cancer, DOACs should be prioritized for treatment extending beyond 3 months. For patients who do not receive anticoagulation therapy, a repeat whole-leg ultrasound after 1 week is recommended

VTE: venous thromboembolism; DVT: deep vein thrombosis; IDDVT: isolated distal deep vein thrombosis; LMWH: low-molecular-weight heparin; DOACs: direct oral anticoagulants.

Indications for anticoagulation therapy

There is currently no definitive evidence to support the universal application of anticoagulation therapy for all patients with IDDVT. However, an increasing number of studies have demonstrated that anticoagulation therapy can effectively mitigate the risk of recurrent VTE and PE in IDDVT patients. Nevertheless, the precise criteria for identifying which patients require anticoagulant therapy remain ambiguous. Table 2 provides a summary of the recommended patient groups for anticoagulation therapy as outlined in major international guidelines and expert consensus documents. According to these guidelines, for low-risk patients—such as those without prolonged immobilization, non-cancer patients, and individuals with negative D-dimer test results—ultrasound surveillance combined with physical interventions may be employed. These interventions include exercise therapy (active or passive), intermittent pneumatic compression therapy, and the use of elastic compression stockings. Patients with high-risk factors for thrombosis recurrence or progression are more likely to benefit from anticoagulant therapy. For patients at elevated risk of bleeding, active monitoring of thrombosis development is advised, while anticoagulant therapy is generally not recommended.

Table 2.

Anticoagulation eligibility criteria for isolated distal deep vein thrombosis: recommendations from major international clinical practice guidelines and expert consensus statements.

Guideline(year)	Recommended candidates
Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report(2021) 36	Elevated D-dimer levels without other identifiable causes, extensive thrombus formation, such as thrombus length >5 cm, diameter >7 mm, involvement of more than one vein, etc., thrombus location close to the proximal deep veins, unprovoked DVT, presence of active cancer, history of prior VTE, hospitalized patients, patients with COVID-19 infection, patients with significant symptoms, patients who are unwilling to undergo repeated ultrasound monitoring
Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function(2021) 19	IDDVT patients with thrombotic recurrence risk factors: History of prior VTE, male sex, age >50 years, presence of active cancer, unprovoked IDDVT, persistent limited mobility, thrombus close to the popliteal vein bifurcation, involvement of more than one vein in one leg, bilateral calf involvement, presence of underlying diseases(e.g. inflammatory bowel disease), known hereditary thrombophilia, axial veins
European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis(2020) 7	IDDVT patients with thrombotic progression risk factors: Hospitalization, advanced age, presence of active cancer

DVT: deep vein thrombosis; IDDVT: isolated distal deep vein thrombosis; VTE: venous thromboembolism.

Does thrombus management require distinction between axial vein thrombosis and calf muscle vein thrombosis?

Axial vein thrombosis and calf muscle vein thrombosis have completely different anatomical and physiological mechanisms. Thrombi in the lower limbs most commonly involve the calf muscle veins. However, it remains unclear whether the management of these two types of thrombi should differ. Schwarz et al. ⁵² compared the outcomes of low-molecular-weight heparin (LMWH) versus compression therapy alone for isolated calf muscle vein thrombosis and found that LMWH anticoagulation therapy effectively prevented thrombus progression and reduced the incidence of recurrent VTE compared with compression therapy alone.

Righini et al. ⁵³ reached an opposite conclusion in their study of low-risk outpatient isolated calf muscle vein thrombosis. A total of 122 patients received nadroparin treatment, while another 130 patients received placebo treatment. There was no significant difference in the composite primary outcome between the two groups. In the nadroparin group, four patients (3%) experienced events, compared with seven patients (5%) in the placebo group (95%CI: −7.8 to −3.5; P = 0.54). The nadroparin group had five patients (4%) with bleeding, whereas no bleeding events occurred in the placebo group (95%CI: 0.4 to 9.2, P = 0.0255). This suggests that nadroparin was not superior to placebo in reducing the risk of proximal thrombus extension or VTE events in low-risk outpatient isolated calf muscle vein thrombosis patients and increased the risk of bleeding.

Wang et al. ¹⁰ found that patients with calf muscle vein involvement had lower rates of thrombus recurrence, resolution, extension to the proximal veins, and PE compared with those with axial vein involvement. However, there was no significant difference in the incidence of bleeding events after anticoagulation therapy between the two groups. Kuczmi et al. ⁵⁴ showed that PE and VTE were more common in patients with axial vein thrombosis. There was no significant difference in bleeding rates or mortality between patients with axial vein thrombosis and those with calf muscle vein thrombosis. However, patients with axial vein thrombosis were more likely to experience thrombus propagation after discontinuation of anticoagulation therapy (3.4% vs 0.9%, P = 0.029). Nevertheless, evidence from Yang et al. ⁵⁵ indicated that the recurrence rates of isolated axial vein thrombosis and isolated calf muscle vein thrombosis were similar within 5 years after anticoagulation therapy (FE model: OR: 1.12; 95%CI: 0.77–1.63, P = 0.91).

The above evidence suggests that compared with axial vein thrombosis, patients with calf muscle vein thrombosis have a lower risk of recurrent VTE events and should be actively monitored for thrombus progression. The ACCP guidelines ³⁶ also point out that the clinical outcomes of isolated calf muscle vein thrombosis are better than those of isolated axial vein thrombosis and can be closely monitored with lower limb venous ultrasound. Based on recommendations from major international guidelines and expert consensus, we have developed a diagnostic and management pathway for IDDVT, as detailed in Figure 1.

Figure 1.

Proposed diagnostic and therapeutic algorithm for IDDVT based on current guidelines.

Selection of anticoagulant drugs

The anticoagulants widely used in current clinical practice include indirect thrombin inhibitors (e.g. heparin, LMWH, fondaparinux), vitamin K antagonists (VKAs), and direct oral anticoagulants (DOACs). Table 3 provides a summary of the pharmacological properties of oral anticoagulants. Table 4 summarizes the pharmacological characteristics of indirect thrombin inhibitors. A retrospective study involving 6509 IDDVT patients, of whom 4939 received DOACs and 1570 received warfarin, showed that the incidence of PE (1.795% vs 3.590%, P = 0.002) and major bleeding events (7.949% vs 10.513%, P = 0.013) was significantly lower in patients treated with DOACs compared with those treated with warfarin. However, there were no significant differences in mortality, PDVT, stroke, or myocardial infarction incidence between the two groups. ⁵⁶

Table 3.

Pharmacological properties of oral anticoagulants.

	Rivaroxaban	Apixaban	Edoxaban	Dabigatran	VKAs
Target	Factor Xa	Factor Xa	Factor Xa	Factor IIa	Factor II, VII, IX, X
Dosing	20 mg qd;15 mg qd	5 mg bid; 2.5 mg bid	60 mg qd;30 mg qd	150 mg bid;110 mg bid	INR adjusted
Time to peak (h)	2–4	3	2–4	3	3–9
Renal elimination (%)	35	27	50	80	—
Bioavailability (%)	80–100	50	60	6	100
Antidote	Andexanet alfa	Andexanet alfa	Andexanet alfa	Idarucizumab	Vitamin K
Routine coagulation monitoring	No	No	No	No	Yes(INR)

AKAs: vitamin K antagonist; INR: international normalized ratio.

Table 4.

Pharmacological characteristics of thrombin indirect inhibitors.

	Unfractionated Heparin	Dalteparin Sodium	Enoxaparin Sodium	Nadroparin Calcium	Fondaparinux Sodium
Target	Factor IIa, IXa, Xa, XIa, XIIa	Factor IIa, Xa	Factor IIa, Xa	Factor IIa, Xa	Factor Xa
Molecular weight (Da)	3000–30,000	5500	3500–5500	3600–5000	1728
Dosing	5000–10000 U q8 h / q12h	100IU/kg bid 200IU/kg qd	0.01 ml bid	0.1 ml/10 kg q12h	2.5 mg qd
Time to peak (h)	1/3–1	2–4	3–5	3	2
Bioavailability (%)	80	90	100	100	100
Liver metabolism	Yes	No	No	No	No
Antidote	Protamine sulfate	Protamine sulfate	Protamine sulfate	Protamine sulfate	-
Routine coagulation monitoring	Yes (APTT)	No	No	No	No

APTT: activated partial thromboplastin time.

Another randomized controlled trial enrolled 260 symptomatic outpatient IDDVT patients who were randomly assigned to receive 6 weeks of LMWH followed by 12 weeks of VKAs therapy. Ultimately, 14 patients (10.8%) in the LMWH group and 5 patients (3.8%) in the VKAs group experienced recurrent or progressive IDDVT, with 1 patient in each group experiencing thrombus progression. There was no significant difference in the incidence of bleeding events between the two groups. ⁵⁷

In another study by Ageno et al., ⁵⁸ rivaroxaban was compared with standard anticoagulation therapy (initial treatment with unfractionated heparin, LMWH, or fondaparinux sodium, often overlapped with and subsequently replaced by a VKAs) for DVT. The results showed that rivaroxaban had lower rates of thrombus recurrence, clinically relevant bleeding events, and all-cause mortality compared with the standard anticoagulation group. However, this trial did not distinguish between PDVT and IDDVT patients.

Guidelines recommend prioritizing DOACs for anticoagulation therapy.^7,36 Of course, there is currently a lack of head-to-head comparisons among DOACs, making it impossible to determine which oral agent is the best choice.

Duration of anticoagulation therapy

A meta-analysis found that patients receiving anticoagulation therapy for more than 6 weeks had a lower risk of recurrent VTE compared with those treated for 6 weeks (OR 0.39, 95%CI: 0.17–0.90), without an increased risk of major bleeding (OR 0.64, 95%CI: 0.15–2.73). ⁴⁸ Li et al. ⁵⁹ found that considering the recurrence rate and proximal propagation rate of VTE, anticoagulation therapy for 6 weeks appears to be an effective and safe treatment for patients with isolated axial vein thrombosis. Asonitis et al. ⁶⁰ followed up on IDDVT patients treated with LMWH for 6 weeks and found that anticoagulation therapy for 6 weeks was safe and effective for IDDVT involving a single vein. However, for IDDVT involving multiple veins, treatment exceeding 6 weeks was necessary to avoid thrombus recurrence. Ageno et al. ⁶¹ reported that in a 24-month follow-up, rivaroxaban treatment for 12 weeks was associated with a lower rate of thrombus recurrence compared with 6 weeks of treatment, without a significant difference in the incidence of PDVT/PE or increased bleeding risk. Wang et al. ⁶² found that for patients with anticoagulation duration less than 6 weeks, there was no significant difference in thrombus recurrence rate between low-dose (10 mg or 15 mg) and standard-dose (20 mg) rivaroxaban treatment regimens. They also found that anticoagulation for more than 1.5 months was superior to short-term anticoagulation. Residual vein obstruction was identified as a predictor of thrombus recurrence.

Another meta-analysis showed that compared with LMWH, urokinase thrombolysis combined with LMWH, and physical therapy combined with warfarin, monotherapy with direct oral factor Xa inhibitors for 3 months was the optimal treatment for IDDVT. ⁶³ A study from the ONCO DVT trial found that for cancer-associated IDDVT, a 12-month edoxaban regimen was consistently superior to a 3-month regimen in terms of thrombus recurrence risk. However, long-term anticoagulation may increase bleeding risk. ⁶⁴ A multicenter randomized trial compared the clinical outcomes of 12 months and 3 months of edoxaban treatment for cancer-associated IDDVT. The study found that among 296 patients in the 12-month edoxaban group, there were 3 cases (1.0%) of symptomatic recurrent VTE events or VTE-related deaths, compared with 22 cases (7.2%) among 305 patients in the 3-month edoxaban group. These results suggest that for patients with IDDVT and cancer, 12 months of edoxaban treatment is superior to 3 months. ⁶⁵

The ACCP guidelines ³⁶ and the ESVS guidelines ⁷ recommend a minimum of 3 months of anticoagulation therapy for IDDVT patients. Prolonging the duration of anticoagulation is associated with an increased risk of bleeding. There is no optimal decision regarding the duration of anticoagulation for IDDVT. Clinical practitioners should consider the patient's preferences, financial situation, thrombus progression, risk of VTE recurrence, and bleeding risk to develop the best treatment plan.

Adverse effects of anticoagulation therapy

It is important to note that all anticoagulant drugs carry the risk of bleeding, and currently, there is a lack of effective tools for assessing bleeding risk. According to statistics, 79.4% of patients visit the emergency department due to bleeding events related to the use of anticoagulants alone. ⁶⁶ Regardless of the type of anticoagulant or the duration of anticoagulation therapy, the incidence of major bleeding after anticoagulation is 4.08%. ⁶⁷ Literature reports indicate that the bleeding risk with heparin during the initial phase of anticoagulation therapy is less than 3%. ⁷ Warfarin is the drug most closely associated with drug-induced hospitalizations,^66,68 with over 80%of patients taking VKAs being hospitalized due to gastrointestinal bleeding events, and 5.6%of patients being hospitalized due to intracranial hemorrhage. ⁶⁸ The incidence of bleeding events with DOACs is the lowest, at only 0.8%. ¹⁷ Table 5 summarizes current research evidence on IDDVT management.

Table 5.

Comparative outcomes of anticoagulant therapies in IDDVT.

Study (year)	Utter et al. 69 (2016)	Ageno et al. 58 (XALIA) (2016)	Pham et al. 56 (2022)	Yamashita et al. 65 (ONCO-DVT), (2023)	Ogihara et al. 70 (ISE CALF DVT), (2024)	Wang et al. 62 (2024)
Study design (sample size)	Single-center retrospective cohort study (n = 384)	Multicenter, prospective, non-interventional study (n = 4768)	Multicenter, retrospective, cohort study (n = 6509)	Randomized, open-label, multicenter clinical trial (n = 601)	Open-label, exploratory, and randomized controlled trial (n = 87)	Single-center retrospective cohort study (n = 1246)
Study population	Patients with first-time IDDVT	Symptomatic IDDVT	IDDVT	Patients with active cancer and IDDVT	IDDVT	IDDVT
Intervention	Therapeutic anticoagulation vs control	Rivaroxaban vs standard anticoagulation therapy	Warfarin vs DOACs	Edoxaban 12 months VS 3 months	Rivaroxaban (15 mg qd) vs physical therapy	Rivaroxaban low-dose (10 or 15 mg/day) vs standard dose (20 mg/day)
Length of follow-up	180 days	12 months	6 months	12 months	90 days	low-dose 33.0 ± 12.2 months, standard dose 32.7 ± 12.3 months
VTE recurrent rate	3.3% vs 9.2%(0.33[0.12–0.87])	1.4% vs 2.6%(0.67[0.44–1.03])	3.590% vs 1.795%	1.0% vs 7.2% (0.13 [0.03–0.44])	0% vs 4.4%,(4.4 [−4.6–15.1])	9.64% vs 5.66%
Major bleeding events	8.6% vs 2.2%(4.87[1.37–17.3])	0.7% vs 2.3%(0.41[0.24–0.70])	10.513% vs 7.949%	9.5% vs 7.2% (1.34 [0.75–2.41])	9.5% vs 0%, (−9.5 [−22.8–−0.7])	3.02% vs 1.68%
Clinically relevant non-major bleeding	-	-	-	9.5% vs 7.2% (1.34 [0.75–2.41])	—	8.68% vs 4.61%
All-cause mortality rate	11.5% vs 14.2%(0.73[0.34–1.56])	-	2.051% vs 2.244%	22% vs 25%(0.85 [0.58–1.24])	0 vs 0	10.75% vs 13.83%

IDDVT: isolated distal deep vein thrombosis; DOACs: direct oral anticoagulants.

Cost-effectiveness analysis of VTE management

VTE imposes substantial economic burdens through recurrent thrombosis, mortality, anticoagulation-related complications, and associated hospitalization costs. In the European Union, the annual healthcare expenditure for VTE management reaches €8.5 billion. ⁷¹ Kepka et al. ⁷¹ conducted a real-world cost analysis comparing rivaroxaban and VKAs over 6 months in the REMOTEV registry. Rivaroxaban demonstrated significantly lower total costs (€5201 ± 3071 vs VKAs €7721 ± 6144), primarily driven by reduced hospital stays and readmission rates. A Dutch economic evaluation corroborated these findings, showing rivaroxaban provided additional 0.047 quality-adjusted life years (QALYs) with €304 cost savings compared to LMWH/VKA therapy. ⁷² Indirect treatment comparison (ITC) by Jugrin et al. ⁷³ revealed comparable VTE recurrence prevention between dabigatran etexilate and rivaroxaban, with dabigatran exhibiting superior cost-effectiveness (lower total costs: £8242/QALY vs £10,075/QALY for warfarin over 24 months ⁷⁴ ) due to reduced clinically relevant bleeding events and higher QALY gains.

While these studies collectively demonstrate the economic advantages of protocolized anticoagulation, evidence regarding IDDVT management remains notably absent. Future research must address this critical knowledge gap through dedicated cost-effectiveness analyses of IDDVT treatment algorithms.

Prognosis

Common complications of IDDVT include thrombus extension, PDVT, PE, recurrent thrombosis, and PTS. PE is a common cause of death in patients with IDDVT. It has been reported that in untreated IDDVT patients, approximately 25–33% of thrombi extend into the proximal veins, ¹² placing patients at high risk for PE. Studies have indicated that in patients with acute PE, IDDVT may be the sole source of embolism.^11,12 The incidence of PE in IDDVT patients ranges from 8.7% to 33.3%,^4,11,75 with a higher rate in patients with bilateral involvement compared to those with unilateral involvement. ⁷⁶ Although the risk of recurrent thrombosis is lower in IDDVT compared with PDVT, the recurrence rate of VTE after IDDVT ranges from 2.7% to 18.8%,^77,78 with a cumulative incidence of up to 27.2% over 10 years. ¹⁷ Patients with unprovoked IDDVT have a higher rate of thrombus recurrence than those with provoked IDDVT.

Several factors can influence the recurrence of thrombosis. The OPTIMEV study confirmed that age >50 years, unprovoked IDDVT, and involvement of ≥1 vein in one or both legs can increase the risk of thrombus recurrence by threefold in IDDVT patients. ⁷⁷ A study from Østfold Hospital found that patients with unprovoked IDDVT are more likely to experience recurrent thrombosis than those with transient provoking factors. ¹⁷ Donadini et al. ⁷⁹ confirmed that a history of prior VTE, unprovoked IDDVT, and the presence of cancer in IDDVT patients are significantly associated with an increased rate of thrombus recurrence. Table 6 presents a comprehensive summary of current evidence on recurrence rates and associated risk factors for thrombosis in IDDVT.

Table 6.

Thrombotic recurrence rates and associated risk factors in IDDVT.

Study (year)	Study design (sample size)	Main inclusion/(exclusion) criteria	Length of follow-up	VTE rate	Risk factors
Sartori et al. 80 (2014)	Prospective, single center study (n = 90)	IDDVT	2 year	4 ± 1% (3 months), 14 ± 4% (1 year), 19 ± 4% (2 years)	Male, cancer
Galanaud et al. 77 (2014)	Prospective, observational, multicenter study (n = 490)	First IDDVT without cancer	3 years	2.7% per patient-year	Age >50 years, unprovoked DVT, multiple unilateral thromboses, bilateral DVT
Elmi et al. 81 (2020)	Observational single center, retrospective cross-sectional study (n = 251)	IDDVT patients in Internal Medicine, Surgery, and ICU	180 days	PE: 11.9%, PDVT:11.3%	PE: Active cancer, trifurcation; PDVT: Intracranial bleeding
Donadini et al. 79 (2022)	Retrospective study (n = 280)	Symptomatic IDDVT	42.3 ± 27.8 months	15% (PE 31%, PDVT 19%, IDDVT 45.2%, Unusual site thrombosis 4.8%)	Unprovoked IDDVT, previous VTE

VTE: venous thromboembolism; DVT: deep vein thrombosis; PDVT: proximal deep vein thrombosis; IDDVT: isolated distal deep vein thrombosis; DOACs: direct oral anticoagulants.

Conclusion and future perspectives

IDDVT is not a benign and self-limiting condition but should be regarded as a potential serious health risk. For patients at risk of IDDVT due to prolonged bed rest, lower limb immobilization, hormone therapy, surgery, etc., clinical probability assessment is recommended before diagnosis, using the Wells score system to evaluate the likelihood of thrombus formation. For patients with a Wells score ≥2, lower limb venous ultrasound is recommended to confirm the diagnosis. If D-dimer levels are elevated, but the ultrasound is negative, it is suggested to recheck D-dimer and perform another ultrasound after 1 week or when symptoms change. When initiating anticoagulation therapy, decisions should be made by integrating patient preferences, financial status, risk of thrombus recurrence, and bleeding risk. For patients with high recurrence risk and low bleeding risk, DOACs are preferred for a 3-month anticoagulation regimen, with subsequent extension of treatment duration based on individual risk assessment. Physical therapy can be used as an adjunctive treatment to alleviate lower limb pain and edema in the acute phase of IDDVT but does not prevent recurrent VTE.

The current evidence base for IDDVT management remains suboptimal in three key aspects. Firstly, the pathogenesis remains incompletely characterized, with no validated risk stratification tools specifically developed for IDDVT. While the Wells score is widely implemented in clinical practice, it warrants critical reappraisal as this prediction model was originally designed for PDVT and demonstrates limited discriminative capacity for IDDVT diagnosis. Secondly, diagnostic approaches present unresolved controversies. The clinical utility of serial D-dimer monitoring requires clarification, particularly regarding optimal threshold selection among conventional, age-adjusted, and pretest probability-adjusted criteria. Emerging biomarkers including circulating microparticles, P-selectin, and advanced imaging modalities like CE-MRA have shown preliminary promise but await validation through large-scale multicenter studies.

Therapeutic decision-making faces three principal challenges: (1) an insufficient evidence base for differential anticoagulation strategies between axial venous thrombosis and muscular calf vein thrombosis; (2) lack of standardized protocols for anticoagulant selection, with current guidelines predominantly extrapolated from PDVT studies rather than robust randomized controlled trial (RCT) data specific to IDDVT; (3) persistent uncertainty regarding optimal treatment duration, particularly when comparing short-course (6-week) versus conventional 3-month regimens in terms of thrombotic recurrence rates, major bleeding events, and long-term PTS incidence. Three strategic priorities emerge for advancing IDDVT management: First, development of IDDVT-specific predictive algorithms incorporating genomic markers and advanced hemodynamic profiling parameters. Second, comparative effectiveness research evaluating novel diagnostic modalities such as high-resolution compression ultrasonography (HR-CUS) and dual-energy CT venography, with particular emphasis on their cost-efficacy ratios and interobserver reliability. Third, implementation of multicenter RCTs with factorial designs to elucidate interactions between anticoagulant class (DOACs vs VKAs), treatment duration, and thrombus anatomical characteristics.