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Keywords:

  • calf;
  • deep vein thrombosis;
  • diagnosis;
  • distal;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Summary.  Thromboses that are restricted to the infra-popliteal deep veins of the lower limbs (isolated distal deep vein thrombosis, IDDVT) are frequently diagnosed in subjects with suspected pulmonary embolism (PE; 7–10%) or DVT (4–15%), accounting for 31–56% of all diagnosed leg DVTs. Despite their frequency, IDDVTs still remain one of the most debated issues in the field of venous thromboembolism (VTE). Conflicting clinical results have resulted in differing opinions on the need to test for IDDVTs and how to treat them. Due to discordant results, the real risk of IDDVT-associated PE is not well established. IDDVTs are associated with (i) lower risk of recurrence when compared with other VTEs, and (ii) fewer late sequelae than proximal DVT. Diagnosis of IDDVT is based on ultrasound examination of all calf veins, which is more operator-dependent and less sensitive than proximal vein examination. A series of studies has shown, however, that a single complete ultrasound strategy in symptomatic patients has comparable clinical results to serial proximal ultrasound, allowing approximately 15% better DVT diagnosis. Optimal treatment of IDDVT is still controversial. Guidelines recommend anticoagulation for 12 weeks, although 6 weeks may be sufficient. There is, however, insufficient data to support the diagnosis and treatment of all IDDVTs, and the necessary criteria to identify subjects at higher risk of complication are lacking. It also seems likely that different approaches may be better for unprovoked or secondary events and for deep or muscle veins. Specifically designed and adequately powered clinical studies addressing the issue of IDDVT need to be urgently undertaken.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Deep calf veins include all the infra-popliteal deep veins of the lower limbs. While thrombosis often affects these veins as part of a wider pathology, it may also occur in distal deep veins alone (isolated distal deep vein thrombosis, IDDVT). Despite its frequency, IDDVT currently is one of the most debated issues in the field of venous thromboembolism (VTE). It is likely that the natural history of IDDVT and the potential risk associated with the disease have, to date, not been properly investigated. Thus, conflicting clinical results have resulted in differing opinions about the need to test for IDDVT and how to treat it. This explains the lack of a coherent approach in clinical practise and of a set of standard recommendations.

The aim of the present article is to review the data currently available on IDDVT. While sharing most views on the issue, the authors do, however, acknowledge differences in evaluating study results and opinions on certain specific issues. Our hope is that this review may not simply update the reader with the current state of knowledge but prompt further clinical research.

Anatomical considerations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

At first glance, the term ‘distal’ means distal to the knee. Without doubt this includes the paired deep calf veins – the peroneal, posterior tibial and anterior tibial veins that closely accompany the three arteries of the lower leg. In most people, each group has two veins but this may vary from one to four. The positions relative to the fibular and tibial bone and the interosseous membrane are invariable. The peroneal group is located medially to the fibula, the posterior tibial dorsal to the tibia, while the anterior tibial on its way to the ankle crosses the interosseous membrane in the anterior compartment from the fibula to the tibia (see Fig. 1).

image

Figure 1.  Schematic representation of leg veins as discussed in this review: 1, external iliac vein; 2, common femoral vein; 3, greater saphenous vein; 4, profound femoral vein; 5, (superficial) femoral vein; 6, popliteal vein; 7, anterior tibial confluent segment; 8, posterior tibial confluent segment; 9, peroneal confluent segment; 10, anterior tibial veins; 11, posterior tibial veins; 12, peroneal veins; 13, gastrocnemius muscle veins (medial head); 14, soleus muscle veins.

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When followed from distal to proximal, the paired calf veins unify into one respective collector or confluent segment. The confluent segments of the peroneal and posterior tibial may sometimes have web-like cross-links. Further proximal, these two lie along both sides of the popliteal artery. After a few centimetres, the confluent segments unify to become the popliteal vein, which at this point also collects the anterior confluent segment. This ultimate unification point may be located at different levels and while it is mainly found at the level of the knee joint, unification below and above this level is common. There is some uncertainty as to whether the confluent segments have to be referred to as proximal or as distal. In a classical anatomic sense, they are distal because only the popliteal vein is the first proximal segment [1]. However, this has been challenged by the emergence of ultrasound examination. Because the confluent segments located either medially or laterally to the popliteal vein are easily identified in the hollow of the knee, it has become standard to address them as ‘the trifurcation area’ and to classify them as proximal.

A distinct anatomic entity is formed by the calf muscle veins. Two groups exist: the gastrocnemius and the soleus muscle veins. Drainage of the two groups is different. The soleus muscle veins perforate the inner fascia at two to four different levels and connect to the posterior tibial or peroneal veins. The gastrocnemius muscle veins drain via two stem veins (medial and lateral) into the popliteal vein at the same level as the lesser saphenous vein. There is some uncertainty as to whether calf muscle veins should be referred to as ‘deep’ veins and, as a consequence, whether a calf muscle vein thrombosis is really a DVT. Even if anatomy does not solve this nomenclature problem, the following terms should be used in clinical practise. ‘Isolated calf muscle vein thrombosis’ (ICMVT) is a thrombosis confined to the muscle veins only. ‘Deep calf vein thrombosis’ (DCVT) is a thrombosis present in the paired calf veins. IDDVT is the composite of ICMVT and DCVT – occurring either in isolation or in combination.

Epidemiology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Rates of IDDVT vary greatly between studies. This depends on both the method of detection (leg scanning by 123I-fibrinogen, uni- or bilateral venography or duplex ultrasound) and the different clinical settings (asymptomatic patients screened for DVT in clinical studies in surgical or medical settings who may or may not have received antithrombotic prophylaxis; out- or inpatients symptomatic for DVT or pulmonary embolism [PE]). It may, however, be concluded that IDDVT accounts for the great majority of asymptomatic DVTs in subjects in high-risk situations (i.e. surgery, hospitalization, etc.) and represents a considerable proportion of all DVTs diagnosed in clinical practise, if the diagnostic procedure is extended to the calf veins. This review focuses on symptomatic patients and patients with confirmed DVT only.

Rates of IDDVT in in- or outpatients who are symptomatic for DVT or PE

In outpatients with suspected VTE, either PE or DVT, only one out of every four or five subjects actually has the disease. Table 1 shows the results of clinical studies, either prospective or retrospective, using whole leg ultrasound examination for diagnosis. The patient populations investigated in these studies varied, including cohorts of patients with diagnosed DVT or PE, in- or outpatients with suspected DVT or PE, DVT-symptomatic patients after major orthopedic surgery, or community-based populations. Though the prevalence of diagnosed DVT varied in the different patient populations investigated, the prevalence of IDDVT was fairly consistent, ranging from about 7 to 11% in suspected PE, and 4 to 15% in cases of suspected DVT.

Table 1.   Results of studies reporting the prevalence of proximal deep vein thrombosis (DVT) or isolated distal deep vein thrombosis (IDDVT) in the total population of in- or outpatients examined for suspected deep vein thrombosis of lower limbs and/or pulmonary embolism (A), or in patients with diagnosed DVT of lower limbs (B)
AuthorDesign of studyPopulation typeDiagnostic criteriaPopulation examinedTotal VTEProximal DVTIDDVTAnnotations
A %B %A %B %
  1. VTE, venous thromboembolism; NA, not available; CUS, compression ultrasonography limited to proximal deep veins; PE, pulmonary embolism; DD, D-dimer. *The patients included in these two studies were randomized to receive an ultrasonography investigation limited to the proximal veins or to the whole leg veins; the data shown in the table refer to the results recorded in the group randomized to a complete ultrasonography examination.

Schulman [14]Prospective multicenter,Cohort with diagnosed VTEVenography for DVT suspicion  790 56.1 43.9 
Mattos [47]RetrospectiveIn- & outpatients with suspected DVTComplete ultrasound655 (limbs) 159 DVTs16.266.78.133.3 
Bendick [48]ProspectivePatients with suspected PEComplete ultrasound507  79 DVTs8.957.06.743.0 
Warwick [2]RetrospectivePatients symptomatic for DVT after total knee replacementVenography in 119 pts1000  89 DVTs1.516.97.483.1 
Kazmers [8]RetrospectiveIn- & outpatients with suspected DVTComplete ultrasound3096 457 DVTs10.974.23.825.8 
Labropoulos [49]RetrospectiveIn- & outpatients with suspected DVTComplete ultrasound5250 742 DVTs9.366.24.833.8 
Oger [50]Prospective, epidemiological, 320 000 subjects for 1 yearCommunity-based population in western FranceComplete ultrasound  423 63 37 
Pinede [15]Prospective multicenterCohort with diagnosed VTEComplete ultrasound or venography  703 64.2 35.8 
Eichinger [51]Prospective multicenterCohort with diagnosed VTEComplete ultrasound or venography  349 59.9 40.1 
Elias [27]ProspectiveOutpatientsComplete ultrasound623 204 DVTs1854.914.845.1 
Schellong [28] In- & outpatients with suspected DVTComplete ultrasound1646 275 DVTs7.3449.356 
Stevens [29]ProspectiveNAComplete ultrasound445  61 DVTs9.468.84.331.2 
Subramaniam [30]ProspectiveOutpatientsComplete ultrasound526 113 DVTs9.343.412.256.6 
Seinturier [6]RetrospectiveIn- and outpatients with DVTComplete ultrasound 1913 DVTs 53.2 46.8 
Subramaniam [52]ProspectiveOutpatientsComplete ultrasound309  67 DVTs8.740.312.959.7 
Bernardi [36]Prospective, randomized*OutpatientsComplete ultrasound1053 278 DVTs20.276.66.223.4 
Palareti [53]Prospective multicenterCohort with diagnosed VTECUS or complete ultrasound, or venography 1772 DVTs 90.4 9.6 
Gibson [37]Prospective, randomized*NAComplete ultrasound264  99 DVTs23.161.614.438.4Patients with DVT unlikely and normal DD were excluded
Sevestre [54]RetrospectiveNAComplete ultrasound38711023 DVTs11.744.414.755.6 
Righini [55]ProspectivePatients with suspected PEComplete ultrasound541 112 PE9.847.310.952.7Only patients with high clinical probability or altered DD were included
Palareti [10]ProspectiveOutpatientsComplete ultrasound424   15.3 Patients with proximal DVT and those with unlikely and normal DD were excluded

Rates of IDDVT in patients diagnosed with leg DVT

As can be seen in Table 1, the prevalence of total DVTs (proximal and distal) in the studies examined ranged between 14% and 37% (the study that also used venography for diagnosis was excluded [2]), while the proportion of IDDVTs varied between 23.4% and 59.7%. It seems reasonable to attribute the large variability in the prevalence of total DVTs and IDDVTs in the studies considered (at least partially) to differences in the investigated patient populations (e.g. the prevalence of IDDVT can be expected to vary in in- or outpatients with suspected DVT or suspected PE). However, it is also likely that differences in examination protocols (symptomatic leg vs. both legs, specifications of ultrasound protocol) may explain at least part of this variability. It is interesting to note that the anatomic distribution of DVT in pregnancy and puerperium is particular to the extent that most DVTs are left-sided and are confined to the iliofemoral segments [3].

Risk factors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

There is growing evidence that the risk factor profile of IDDVT is different for proximal DVT and PE. A study in the RIETE registry, involving more than 11 000 patients with confirmed leg DVT [4] revealed that IDDVT was less prevalent in elderly patients (≥ 75 years), in women during pregnancy or puerperium, and in other chronic states, such as previous VTE or active cancer. In contrast, IDDVT was associated with transient risk factors such as hospitalization, recent surgery or trauma, recent travel, and the presence of leg varicosities. In this study, as well as another [5], the presence of inherited thrombophilic alterations had no effect on the prevalence of IDDVT. As no evidence is currently available, it cannot be excluded that the seriousness of symptoms (mild or heavy) leading to examination, as well as the time interval between onset of symptoms and examination, may affect ultrasound results. A systemic etiology or a prothrombotic condition seems more frequent in subjects with bilateral distal DVT [6]. These data, which need to be confirmed in other cohorts, suggest that 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.

Natural history

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Though acute DVTs may start anywhere in the venous system it is generally accepted that most start in the calf veins and then propagate to proximal veins. The rate of proximal extension is a clinically important issue and is closely tied to the need for diagnosis and treatment of IDDVT.

Few studies have addressed the issue of the evolution of calf DVT, and results are difficult to compare because of their different designs, different selection criteria and clinical contexts, different diagnostic methodologies, and different treatments given (or not) after diagnosis.

In a retrospective study, 49 symptomatic patients with IDDVT had serial ultrasonography with proximal propagation detected in two cases (4%), both in the 26 subjects who had not received any anticoagulant treatment (8%) [7]. Another retrospective study found proximal extension in 15.5% of IDDVT patients undergoing serial testing, with cancer being more prevalent in those with progression [8]. In their review of studies up to January 2005, Righini et al. [9] found that the rate of extension of IDDVT to proximal veins was 10% and 4% in untreated and treated patients, respectively. The authors concluded that the rate of extension in the various studies was highly variable (from 0% to 44%) and that ‘the variations in study design and target populations were too large to allow a pooled estimate’.

The evolution of untreated IDDVT in symptomatic outpatients was the subject of a specially designed clinical study: the blind, prospective CALTHRO study [10]. All patients enrolled in the study were prospectively managed by serial compression ultrasonography of proximal veins alone (CUS). Those with positive CUS (diagnosis of proximal DVT) were treated and did not enter the study. Patients with negative CUS having high pretest clinical probability or altered D-dimer assay underwent repeated CUS after 5–7 days, or earlier if clinical conditions worsened. These patients were not treated with anticoagulants, were recommended to wear below-knee elastic stockings and were asked to take part in the study. In consenting cases, patients underwent immediate examination of calf veins. The results were kept blind for both the treating physician and the patient, and were disclosed only after 3 months. Among the 431 subjects included in the study, seven did not return for the second CUS examination and five new VTE events not prevented by repeat ultrasound were recorded at the end of the follow-up period (1.2%; 95% CI, 0.4–2.7). However, IDDVT involving at least one calf vein was present in 65 subjects (15.3%; 95% CI, 12–19), five of whom had symptomatic VTE at the end of the follow-up period (one was lost to follow-up). As two of these VTEs had been picked up at repeat ultrasound, the difference between the two diagnostic procedures was limited to 3 (0.7%) more events that would have been prevented by an initial examination of calf veins. At the end of the 3-month follow-up it was found that two VTE events had not been prevented by either procedure. 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% while over 90% have complete resolution without anticoagulant treatment.

Clinical relevance of IDDVT

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

It is well known that asymptomatic PEs can be detected in a large proportion of patients with proven leg DVT. In an early study, V-Q lung scanning was performed in patients with venography-proven leg DVT; PE was found in 50% of cases with proximal DVT and 33% of patients with calf DVT; the majority of the latter only had minor emboli [11]. A recent systematic review concluded that the prevalence of silent PE was higher (36%) in patients with proximal DVT than in those with IDDVT (13%) [12]. Clinically more important is the potential of IDDVT to cause symptomatic PE. This information, however, cannot be derived from cohorts investigating patients with established PE. The DVTs found in these patients are due to the clot remaining in the legs after a PE event but no conclusions can be drawn about the emboligenic potential of either proximal or distal DVT. Only close surveillance studies in untreated patients can provide accurate estimates. A recent review [13] found an incidence of symptomatic PE during surveillance of 0–6.3%, with no deaths attributable to PE. This is in line with the results of the CALTHRO study [10], in which only one non-fatal PE (1.6%) occurred during 3 months of follow-up in 64 patients with confirmed but untreated IDDVT.

Isolated distal deep vein thromboses are associated with a lower risk of recurrence than proximal DVT or PE [14–16]. It has been reported that while unilateral IDDVT is at lower risk of recurrence, the risk is similar to that of proximal DVT in the case of bilateral IDDVT [6]. The analysis of clinical outcomes at 3 months of follow-up of patients included in the RIETE registry showed that IDDVTs were associated with a significantly lower risk of recurrence, as well as of major bleeding and death when compared with proximal DVTs [4]. A recent patient-level meta-analysis has confirmed that the 5-year cumulative rate of recurrent VTE was 4.8-fold higher in patients with proximal vs. isolated distal DVT [17].

Very few studies have addressed the issue of late sequelae of IDDVT, and with conflicting results. A systematic review and meta-analysis of studies examining patients after surgery calculated that the overall relative risk of developing post-thrombotic syndrome(PTS) was 1.58 (95% CI, 1.24–2.02) in patients suffering from asymptomatic DVT as compared with subjects without DVT [18]. While the review did not specify the proportion of IDDVTs, it can be assumed that in many cases the diagnosed asymptomatic DVT was limited to the calf. Signs and symptoms of venous insufficiency were detected after long-term follow-up (on average 5 years) in 37% of subjects with venographically diagnosed symptomatic calf DVT [19]. In another more recent study, patients were re-examined at an average of 3.4 years after IDDVT, and signs of mild to moderate venous valvular insufficiency were found in approximately one-third. These signs, however, were mostly present in segments not involved with the index event while only few of the patients had significant clinical symptoms that could be attributed to venous disease [20]. In the most recent study on PTS after acute DVT, it was found that subjects with IDDVT (40% of all patients) had a PTS score significantly lower than those with femoral or iliac DVT [21].

Diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Historically, venography has been the gold standard for the diagnosis of DVT. In particular, distal veins could be visualized in great detail if the examination was performed properly. Venography has never been tested formally to evaluate sensitivity or specificity in detecting or excluding DVT. In fact, there was no pre-existing gold standard against which venography could be tested. The only quasi external validation was the prospectively followed cohort by Hull et al. [22] that demonstrated that a negative venogram in a symptomatic patient with suspected DVT meant safe exclusion of the disease for the next 3 months (‘recurrence’ or ‘failure’ rate 1.3%).

The emergence of venous ultrasound has changed the field significantly. Venous ultrasound as a new test had to be formally evaluated against venography. Validation studies revealed that sensitivity of venous ultrasound for distal DVT, even in symptomatic patients, was significantly lower than for proximal DVT [23,24]. This finding was very stable through different, and even recent, meta-analyses [25]. However, it did not impede the broad and now almost universal acceptance of venous ultrasound as the first-line imaging procedure for diagnosis of DVT, which in fact means for proximal DVT.

The detection rate of isolated distal DVT with ultrasound depends on the examination protocol. As early as in 1987 Elias et al. [26] found excellent sensitivity of ultrasound for distal DVT when using a meticulous examination strategy, which mainly relies on compression manoeuvres in cross-sections of the calf closely following venous anatomy from the hollow of the knee down to the ankle. A prerequisite is to examine the lower leg while hanging down or standing on a stool in order to provide sufficient distension of the veins by increasing filling pressure through gravitation. Other authors have developed similar examination protocols following the same principles. In the meantime, however, it became no longer possible to perform venography as the standard test for both ethical and performance reasons. In line with the study of Hull et al. for venography, four large cohort studies were performed to assess the safety of a single complete compression ultrasound (CCUS) in a symptomatic patient with suspected DVT [27–30], something that may be regarded as an indirect measure of sensitivity for distal DVT. When combining these studies the ‘failure rate’ of venous ultrasound within 3 months is around 0.5% [31], which compares favourably with venography. Specificity is not addressed by this type of study. From early venography studies with a sensitivity of around 70% for ultrasound for distal DVT the false-positive rate was around 6%. This rate may be higher in a setting where the sensitivity is above 90%, as is the case in some of the dedicated centres. Caution therefore is required with regard to false-positive findings in CCUS. There is only a single set of data on inter-observer variability of CCUS. One mono-centre cohort study in 100 consecutive patients revealed a kappa coefficient of 0.9 (95% CI, 0.79–1.00) for all distal veins, and of 0.74 (95% CI, 0.57–0.91) even for calf muscle veins only, which is a better result when compared with venography [32].

Treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

The last published Consensus Conference of the American College of Chest Physicians [33] recommended short-term anticoagulation with unfractionated heparin, low-molecular-weight heparin (LMWH) or fondaparinux (all Grade 1A), followed by at least 3 months of anticoagulant treatment for all diagnosed DVT (without any further distinction). The need for long-term anticoagulation in IDDVT is still and almost exclusively based on the randomized study by Lagerstedt et al. [34]. Based on 51 randomized patients followed for 3 months by serial isotope tests, physical examination and venography in case of suspected recurrence, it was concluded that oral anticoagulants should be given for 3 months to all patients with symptomatic IDDVT. These results and conclusions were immediately challenged by results of long-term follow-up of patients managed with serial impedance plethysmography in whom, although IDDVTs were not diagnosed and not treated, the rates of recurrence were very low (< 2%) [35]. Similarly, a review by Righini et al. [9] demonstrated via a pooled analysis of all available studies, that the 3-month thromboembolic risk was no different in studies using proximal vs. complete ultrasound, indicating that it is not indispensable to diagnose and treat IDDVT. However, a repeat ultrasound is required in patients testing negative for proximal DVT. This conclusion was confirmed by the results of two more recent studies that randomized symptomatic patients to two different diagnostic procedures: complete or only proximal CUS examination [36,37]. In both studies, the two strategies provided similar results in terms of thrombotic complications after 3 months of follow-up. Again, a second ultrasound was required for patients without proximal DVT in the first examination.

All this evidence suggests that only a minority of IDDVT cases actually require treatment (and therefore diagnosis). However, only a very few studies have directly addressed the issue of treatment in confirmed IDDVT. Full anticoagulant treatment, including initial LMWH followed by warfarin, was given for 6 or 12 weeks to surgical patients with calf DVT [38]. While in patients with only one DVT there was no difference in endpoints, those with thrombosis in two or more deep veins had significantly more complications (proximal thrombus extension) when treated for the short period. From a recent cohort study [39], it was concluded that patients with unprovoked IDDVT require longer and more intense anticoagulation than those with secondary IDDVT. For the latter, a 4-week course of LMWH (1 week full dose, 3 weeks half dose) seemed to be adequate.

Particular interest has recently been shown in the treatment of thrombosis limited to calf muscle veins (including soleal and gastrocnemial veins, ICMVT), a condition which may be found in 20–40% of patients with calf vein DVT and for which retrospective studies have consistently revealed a risk of extension to proximal veins [40,41]. Schwarz et al. [42] prospectively followed two cohorts of consecutive patients – the first receiving a therapeutic dose of LMWH for 10 days plus compression therapy, the second receiving compression therapy only. Progression to deep calf veins occurred in 13/32 patients in the cohort without anticoagulation and in only one out of the 52 patients who received LMWH therapy. More recently, the same investigators reported the results of a randomized study that addressed the same issue [43]. No difference in 3-month progression rates was detected in low-risk patients with ICMVT when randomized to 10 days of therapeutic LMWH doses and compression therapy or to compression therapy only. The discrepancy may be explained by the fact that in the previous cohort study significantly more patients had persistent risk factors such as cancer or prolonged immobilization. In line with these results, a recent retrospective analysis of subjects with ICMVT failed to find any efficacy of anticoagulation in the management of patients with gastrocnemius and/or soleal vein thrombosis [44]. As only hospitalized patients were included, the rate of progression was much higher than that recorded in the randomized study by Schwarz et al. [43]. These results indicate that in ICMVT anticoagulation has an effect only on unprovoked episodes if risk factors persist, while compression therapy seems to be sufficient in low-risk patients. Interestingly, the use of class-II-calf elastic stockings was the only ‘therapy’ for all subjects with suspected IDDVT in the CALTHRO study, which had a very low rate of thrombotic complications [10].

At present, optimal treatment of IDDVT is still a controversial issue. There is no conclusive proof that all IDDVTs need to be diagnosed and anticoagulated and, when diagnosed, there is still a great deal of uncertainty on the type and duration of anticoagulation needed. It seems likely that different approaches need to be adopted for unprovoked or secondary events as well as for deep or muscle veins and more studies are needed to investigate the therapeutic and preventive role of calf compression.

Options for daily practise

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Isolated distal deep vein thrombosis can potentially extend to proximal veins, putting the patient at risk of PE and PTS. The rate of extension to proximal veins is not known with any precision but seems to be < 10%. There are two options, which, on the basis of these assumptions, are clearly not appropriate. One is to examine proximal veins only using just one single procedure, and to treat only proximal DVTs found in this single examination. This option could overlook a risk, which is at least as great as major orthopedic surgery without thromboprophylaxis. The other no-go option is to examine distal veins in all patients, and to treat all IDDVTs once detected. This would result in significant over-treatment in around 90% of patients.

In order to enhance care, two strategies can be followed, both of which are prevalent in current clinical practise. The first strategy revolves around the view ‘examine proximal veins only’. Ultrasound examination of proximal veins is combined with any strategy that identifies those patients at risk of IDDVT extension to proximal DVT. The best strategy is to repeat ultrasound of proximal veins after 1 week, a strategy that has been proven to be safe. It does, however, require a second examination in 80–90% of patients. In a real-world setting, only 70% or less return for the second examination, which means it is not feasible [45]. Combination with D-Dimer and repeating ultrasound in positives only has also been established as safe, and lowers the number of cases where the test needs to be repeated to 30% [46]. The question of adhering to strategies and ultrasound resources still, however, remain critical issues.

The second strategy revolves around the viewpoint ‘complete examination in all patients’. Two issues have to be considered: resource utilization in terms of duration of the ultrasound examination, and potential for over-treatment of patients with IDDVT who are not at risk of extension. Resource utilization critically depends on the training of the sonographer. After sound training, examination of distal veins in an outpatient takes an additional 2 min per leg [32]. Availability of trained sonographers should not be a problem once it is recognized as an important issue. However, identification of patients with IDDVT at risk of extension is an unresolved question. Possible risk markers include: D-Dimer; absence or presence of traditional VTE risk factors (permanent, transient); and extent of IDDVT at first ultrasound examination. None of these, or combinations of these, has been formally tested for their predictive value. Physicians choosing the option ‘examine all veins in all patients’ therefore are left to rely on their own judgments. A plausible strategy to minimize the bleeding risk of over-treatment is administration of limited courses of anticoagulation (i.e. short durations and/or reduced dosages in combination with follow-up ultrasound to adjust treatment parameters according to thrombus regression). If no regression occurs after 4 weeks of anticoagulation the full 3-month treatment course may be given. Reduced dosages may include half therapeutic or even prophylactic regimens of LMWH.

As far as resource utilization is concerned the following should be considered. The symptomatic patient seeks advice from a physician. If the physician, by means of the ‘proximal veins only’ strategy, is unable to ascribe symptoms to a particular disease the patient will seek advice from other physicians. If, however, the physician discovers a reason for the symptoms (e.g. IDDVT, muscle fibre rupture, hematoma or venous incompetence) and gives advice based on this information, the patient will comply and use fewer resources. This argument favours the ‘examine all veins in all patients’ strategy.

Practical advice for daily practise

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Two ultrasound diagnostic procedures in subjects with suspected leg DVT are currently performed in clinical practise.

  • 1
     ‘Serial proximal vein examination’: subjects without proximal DVT and with high clinical probability and/or altered D-dimer are invited to repeat ultrasound within 1 week to detect possible proximal extension to a calf DVT.
  • 2
     ‘Complete vein examination’: all deep veins in the leg are examined in a single procedure; all IDDVTs are diagnosed and treated.

Both procedures have been found to be effective and safe and are accepted in clinical practise. The first is simple to perform but requires organization and extra work to stage a second examination in an appreciable number of subjects. The second requires more skilful, specially trained operators and leads to over-diagnosis and unnecessary anticoagulant treatment in an appreciable number of subjects. The aim of finding factors useful to limit the second procedure to only high-risk subjects is still under investigation and cannot reasonably be adopted in daily practise.

The first procedure is less advisable for patients that, for personal or logistic reasons, are less likely to come back for the second examination. The second procedure is more advisable in subjects who, due to their clinical conditions, may benefit from an immediate diagnosis/exclusion of distal DVT and subsequent therapy. It is advisable that operators/clinicians explicitly declare in their medical report which procedure has been adopted in each patient.

Issues for further research

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References

Many important issues, such as pathophysiology and natural course, clinical relevance and risk, optimal treatment of venous thrombosis limited to the calf, still remain unclear and at times controversial and give rise to discrepancies between diagnostic strategies currently used in daily practise by clinical centres and professionals. As outlined in the previous section, two diagnostic/therapeutic approaches are currently adopted, each of which has its own advantages and disadvantages. Although it is likely that final clinical outcomes do not differ much in terms of thrombotic complications, the two approaches may lead to different diagnoses for single patients and for a non-negligible number of subjects. It should be stressed, therefore, that the use of these different diagnostic strategies in everyday clinical practise can raise uncertainty about what to do in cases of suspected DVT and may also lead to embarrassing discrepancies in the final diagnosis for patients who may depend simply on the vascular centre or professional they are referred to.

This is the main reason why we strongly believe well-designed and properly powered clinical studies addressing the issue of IDDVT need to be undertaken. If we improve our understanding of the disease, its evolution and its characteristics, as well as the best treatment options available, we may be able to come up with a standardized diagnostic and therapeutic strategy that can be used by vascular centres and professionals.

A necessary preliminary step for any future clinical research is to establish a universally accepted and standardized way of performing ultrasound in deep calf veins and diagnosing thrombosis. Operators willing to participate in this clinical research should be given thorough training. It will then be possible to start specially designed, collaborative, properly powered studies. Different approaches may be chosen. (i) A controlled trial randomizing patients with objectively documented IDDVT to anticoagulation or placebo/no treatment with a clinical endpoint after 90 days; the risk of this design is that investigators will intuitively include only patients with low risk of progression. (ii) Close ultrasound surveillance of randomized patients of all risk classes with a surrogate endpoint of progression. (iii) Observational, non-interventional studies with patient subgroups defined by risk factors (cancer, immobilization, other on-going trigger events, extension at diagnosis or D-Dimer). Different possible pharmacological treatment schemes (drug, dose, duration) can be investigated as well as non-pharmacological tools worthy of special investigation, such as compression therapy.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Anatomical considerations
  5. Epidemiology
  6. Risk factors
  7. Natural history
  8. Clinical relevance of IDDVT
  9. Diagnosis
  10. Treatment
  11. Options for daily practise
  12. Practical advice for daily practise
  13. Issues for further research
  14. Disclosure of conflict of interests
  15. References
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