Servier – Phlebolymphology

Abstract

Calf deep vein thrombosis, defined as thrombosis confined to the calf veins of the lower limbs, is a frequent finding in symptomatic outpatients and inpatients when the ultrasound examination is extended to the deep veins of the whole leg. The prevalence of the disease is between 5% and 33% of all deep vein thrombosis (DVT) cases detected by ultrasound, low in symptomatic patients and higher in asymptomatic patients at high risk of DVT. Thrombi in the calf veins can extend to proximal veins, lyse spontaneously, or recanalize over several weeks or months. Focusing on the embolic risk, data are heterogeneous: the rates of propagation to proximal veins and pulmonary embolism (PE) during surveillance have been reported to range from 0% to 35% and from 0% to 5.8% respectively, whereas the prevalence of silent PE was 13%. There are different diagnostic approaches: the preference for a proximal rather than a complete ultrasound approach could be safely guided by the presence of symptoms in the calf. Therapeutic anticoagulation in patients with isolated calf DVTs may be warranted to reduce the risk for proximal venous thromboembolism. However, randomized studies are needed to draw firmer conclusions. Because the benefits of anticoagulation seem unclear, it is important to evaluate the risk for bleeding when determining whether anticoagulation is appropriate.

Introduction

Clinical relevance and treatment of calf vein thrombosis are controversial because thrombosis can propagate to the proximal deep vein with possible pulmonary embolism (PE).

Calf vein thrombosis is defined as any clot involving the deep veins of the calf that did not extend into the popliteal vein. The calf veins are 3 paired veins, posterior tibial, fibular (also known as peroneal), anterior tibial, and 2 nonpaired muscular veins, soleal and gastrocnemial. Usually, the most common veins involved are the peroneal veins.¹ The following terms should be used in clinical practice to identify thrombosis of the calf according to the nomenclature: isolated calf muscle vein thrombosis (ICMVT) for a thrombosis confined to the muscle veins only; deep calf vein thrombosis (DCVT) for a thrombosis present in the paired calf veins; isolated distal deep vein thrombosis (IDDVT) for the composite of ICMVT and DCVT, occurring either in isolation or in combination.²

The confluent segment that joins axial veins to the popliteal vein, called the “trifurcation area,” is often considered as proximal.

Anterior tibial vein thromboses are uncommon, so these veins are generally excluded from ultrasound investigation. When specifically assessed during venous duplex ultrasound (DUS), IDDVTs account for approximately half of all DVTs.³

Prevalence, incidence, and distribution

The prevalence of calf vein thrombosis is between 5% and 33% of all DVT cases detected by ultrasound3; prevalence is low in symptomatic patients and higher in asymptomatic patients at high risk of DVT: 15% after knee or hip surgery, and 45% after coronary artery bypass surgery.⁴

In 2007, a study from Nord-Trøndelag, Norway, based on all residents aged ≥20 years (n=94 194), identified the incidence of venous thromboembolism (VTE) between 1995 and 2001 from diagnosis characteristics retrieved from medical records.⁵ A total of 740 patients with a first-time VTE event were identified (incidence rate, 1.43 per 1000 person-years), with a DVT incidence rate of 0.93 per 1000 person-years. Proximal DVT was 3-fold more frequent than was distal DVT, and it was mostly located on the left side. The incidence increased exponentially with age and was higher in cancer patients.

A new, retrospective, single-center study on ultrasound-verified DVT has illustrated the large diversity of thrombus distribution.^6,7 The analysis concerned patients >18 years old presenting with unilateral DVT who were referred to 1 hospital in Antwerp between 1994 and 2012 (n=1338). Calf-vein DVT (distal DVT) occurred in 28% of the cohort; femoropopliteal DVT, in 33%; and iliofemoral DVT (proximal DVT), in 38%.

Calf thrombosis can be asymptomatic or symptomatic: thrombi in the first case are smaller and with fewer complications. Seinturier et al⁸ studied 1913 patients with vein thrombosis of the lower limbs for 2 years: they found that at 2 years, survival rate was 80% in patients with unilateral distal thrombosis, and 67% for bilateral-distal, 72% for unilateral proximal, and 65% for bilateral-proximal thrombosis. Thromboembolic disease was present in 7.7% of patients with unilateral-distal thrombosis, and 13.3% with bilateral-distal, 14% with unilateral proximal, and 13.2% with bilateral-proximal thrombosis.

Evolution of calf vein thrombosis

Thrombi in the calf veins can extend to proximal veins, lyse spontaneously, or recanalize over several weeks or months. The evolution of untreated IDDVT in symptomatic outpatients was well-reported in the CALTHRO (CALf deep vein THROmbosis) study.⁹ This study suggests that IDDVT can be diagnosed in about 15% of high-risk symptomatic outpatients. Proximal extension within 5–7 days occurs in about 3% of patients, whereas over 90% have complete resolution without anticoagulant treatment.

The balance between clot-propagating risk factors and counteracting repair mechanisms in IDDVT is different than in proximal DVT or PE, and therefore IDDVT might be regarded as a distinct disease entity, even if it needs to be confirmed in other cohorts.¹⁰ This disease has a prognosis similar to proximal thrombosis, probably due to a more intense thrombophilic status. Patients with bilateral distal vein thrombosis are older, suffer heart failure or respiratory failure, cancer, bed rest, venous insufficiency, recurrence of thrombosis, and higher mortality.

In a systematic review, proximal extension was reported in 10% of non-anticoagulated patients.¹⁰ In the CALTHRO study, propagation into the popliteal vein 5–7 days after the first compression ultrasound (CUS) was observed in 3.1% of 64 untreated high-risk outpatients.⁹

This result is consistent with findings reported by MacDonald and colleagues in patients with untreated muscular IDDVT (3%), and with studies that evaluated serial proximal CUS (1% to 5.7%).¹¹

Risk of embolism

Focusing on the embolic potential, data are heterogeneous, as in recent systematic reviews, the rate of propagation to proximal veins and PE during surveillance have been reported to range from 0% to 35% and from 0% to 5.8% respectively, whereas the prevalence of silent PE was 13%.^12,13

In our study, the extension to the proximal veins greatly increases the risk of PE: 4 of 34 patients (11.7%) with calf DVT who developed proximal DVT detected by color-flow duplex scanning (CFDS) and phlebography had a subsequent symptomatic PE.¹⁴

Risk of recurrence or death

Regarding the late complication, in a study that involved 154 patients with unprovoked IDDVT, the cumulative risk of recurrence was 17% and 30%, respectively, 10 and 20 years after the diagnosis.¹⁵

Cancer was the main independent predictive factor of death: patients with cancer-related IDDVT had a 9 times higher long-term risk of death than subjects without cancer (3.5% versus 38.3%).¹⁶

More recently, observations from the GARFIELD-VTE Registry confirmed that DVT location was a less important prognostic factor for recurrence and death in patients with cancer or unprovoked IDDVT.¹⁷

Risk of post-thrombotic syndrome

Post-thrombotic syndrome is not a usual complication after distal vein thrombosis: Masuda et al¹⁸ showed complete lysis of thrombi at 3 months in 88% of distal vein thrombosis studied and, at 3 years, only 5% of patients had hyperpigmentation and varicose vein development. The post-thrombotic syndrome is not correlated to the venous segment involved, and symptoms are very few.

Finally, the risk of post-thrombotic syndrome was 2.3-fold higher in proximal DVT (PDVT) patients than in patients affected by IDDVT.^19,20

Diagnostic approaches

The introduction of the CFDS brought advantages in the diagnosis of DVT.²¹ More recently, a meta-analysis revealed that a CFDS examination is more sensitive for distal veins (75% vs 59%) and slightly less specific (94% vs 98%) than with CUS only.²²

Schellong¹⁷ affirms that the distal ultrasound, using a well-structured protocol of examination, is a valid 4-minute procedure that can easily be added to the examination of proximal veins.

Two ultrasonographic approaches, both based on vein compression, are validated: the whole-leg ultrasound, consisting of CUS that may be helped by color flow and spectral Doppler, and the proximal CUS, confining the examination up to the trifurcation area, without detecting calf veins. The latter approach, when negative, has to be repeated after 1 week to exclude proximal extension of a calf thrombosis, assuming that IDDVT may cause complications only in this case, and is seldom occurring, generally within the first 2 weeks after the onset of symptoms. However, as suggested by the American College of Chest Physicians (ACCP), and more recently by the American Society of Hematology (ASH) guidelines, assessment of pretest probability (PTP) and D-dimer measurement significantly reduced the number of repeated ultrasounds.^23,24 Hence, whereas these algorithms have been widely validated for the diagnosis of PDVT, their accuracy in patients with suspected IDDVT is not well-defined.

The preference for a proximal rather than a complete ultrasound approach could be safely guided by the presence of symptoms in the calf.^25,26

In the PALLADIO study (Simplification of the Diagnosis of Deep Vein Thrombosis), which enrolled 1162 symptomatic outpatients with suspected DVT, both ultrasound strategies were incorporated, restricting the use of the whole-leg CUS to patients with both a likely PTP and positive D-dimer levels. Safety of the algorithm was demonstrated by the 3-month low incidence of events in untreated patients (0.87%), which nevertheless reached 1.49% (95% CI 0.51–4.27) in the highest risk group.²⁷

Doubts concerning the safety of a single complete ultrasound in high-risk patients emerged in other studies and are also raised in the ASH 2018 guidelines for diagnosis of VTE²⁴ and in the recommendations of the Society of Radiologists in Ultrasound Consensus Conference.²⁸ The Consensus Conference took a net position, suggesting the use of the complete DUS as the safest strategy, with CUS at 2-cm intervals from the inguinal ligament to the ankle, spectral Doppler analysis in common femoral and popliteal veins, and color Doppler images. The expert panel emphasized the importance of examining calf veins regardless of the therapeutic strategy.

However, this choice could virtually lead to an increased diagnosis of IDDVT, exposing patients to the risk of overtreatment. In this regard, neither Consensus Conference nor ASH guidelines addressed the screening use of ultrasound in subgroups of asymptomatic high-risk trauma/intensive care patients. This growing practice, which varies among clinicians and hospitals, leads to a higher detection of IDDVT that is difficult to date and of questionable relevance.

A contribution to correctly differentiate between an acute and a chronic thrombosis could possibly be provided by a novel technique, ultrasound elastography, based on evaluation of tissue elasticity. Preliminary results with this technique are encouraging but need to be confirmed in prospective research.29

Therapeutic approaches

The therapeutic approach to IDDVT is a relevant challenge and varies among centers and clinicians.³⁰

Few small randomized controlled trials (RCTs) and numerous observational studies, which differed by clinical setting and IDDVT definition (not all authors classified the trifurcation area as proximal, other authors enrolled only patients with clot diameter >5 mm), have analyzed the need for anticoagulation and have compared intensity and duration of different regimens, with discordant results. Since no strategy has been evaluated in the context of sufficiently powered RCTs, guideline recommendations are weak and not based on solid evidence.³¹

In the treatment of IDDVT, Pinede et al³² randomized about 200 patients with IDDVT to receive low-molecular-weight heparin (LMWH) followed by oral anticoagulants for 12 weeks or for 6 weeks; the incidence of the thromboembolic events was 3.4% and 2%, respectively, in both groups. The authors concluded that a treatment of 6 weeks was adequate.

In another study,³³ the efficacy of a treatment with LMWH was evaluated in patients with isolated thrombosis of the muscular veins of the calf. Patients allocated in the treatment group received subcutaneous full-dose, weight-adjusted LMWH, whereas patients allocated in the control group received only graduated compression stockings and clinical surveillance.

Patients belonging to the first group showed no progression to the proximal deep venous system, whereas in the control group, 25% of patients showed an extension of IDDVT in the proximal veins.

Many, but not all,^20,34,35 of the available observational studies have underlined the dangers of conservative management; others have reported an increased risk of major bleeding during anticoagulation. Conversely, in some research, the use of reduced therapeutic regimens resulted in a safe strategy, and authoritative experts have also suggested it when limited to carefully selected patients.^34,35 As commented by Sartori et al, both in the CALTHRO and in the CACTUS (anticoagulant therapy for symptomatic calf deep vein thrombosis) studies, a 3-month event rate of 8% and 11%, respectively, in untreated patients was not negligible. Instead, in their recent observational study, lower doses of LMWH seemed to be safe, with a low VTE event rate, except for cancer patients.^36,37

In recent years, systematic reviews and meta-analyses have been published with the aim of finding stronger evidence from the literature. Many of these have showed that an anticoagulant treatment, even at reduced doses, was safer than a conservative management, whereas others underlined the lack of solid evidence clearly supporting one strategy instead of another.^38-40 The 2 most recent meta-analyses showed a significant advantage of anticoagulation versus no anticoagulation, suggesting that a treatment >6 weeks should be preferred over a shorter duration, as a longer course was associated with a lower rate of recurrent VTE and proximal extension. However, caution is suggested in interpreting these results, as only a few studies have been included in the analysis.^39,40

According to the 2016 update of the ACCP guideline, it is probable that not all IDDVTs deserve an anticoagulant treatment; patients at high bleeding risk are more likely to benefit from ultrasound surveillance; serial imaging of calf veins for 2 weeks is suggested over anticoagulation (grade 2C) in patients without severe symptoms or risk factors for extension; otherwise, the treatment is suggested (grade 2C) “using the same anticoagulation as for PDVT” (grade 1B).⁴¹

Conclusion

Whether all IDDVTs require an anticoagulant treatment, and what the optimal intensity and duration may be, is currently a gray area and one of the most difficult challenges for clinicians. Whereas in the ACCP guidelines,⁴¹ both 3 months of therapy and 2 weeks ultrasound surveillance are suggested, the International Consensus Statement on Prevention and Treatment of VTE affirmed that 3 months of oral anticoagulant therapy should be prescribed to all patients with symptomatic IDDVT.⁴² As advised by expert opinion, once diagnosed, IDDVT should receive an anticoagulant treatment, for which dose and duration should be reasonably modulated based on the patient’s overall risk profile.





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