Isolated Calf Muscle Venous Thrombosis: A Review of Anticoagulation Strategies

Introduction

Deep vein thrombosis (DVT) of the lower extremities is divided into 2 categories according to the extent of thrombosis involvement. Thrombosis involving the popliteal vein, femoral vein, and iliac vein is classified as proximal DVT, while thrombosis involving the central part of the calf (anterior tibial vein, posterior tibial vein, peroneal vein) and calf muscles veins (gastrocnemius vein and soleus vein) is classified as distal DVT (Figure 1).

The treatment options for proximal DVT have been fully studied and recommended in the latest European Society of Vascular Surgery guidelines and described in detail. Whereas there are still serious debates about the treatment options for isolated distal DVT, most guidelines recommend aggressive anticoagulation therapy. A recent meta-analysis [1] proposed that anticoagulant therapy (whether therapeutic or prophylactic) reduces the recurrence of venous thromboembolism in patients with isolated distal DVT – including local recurrence of isolated distal DVT spread to the proximal heart of the affected limb – and the occurrence of pulmonary embolism, and does not increase the risk of major bleeding.

Calf muscular vein thrombosis (CMVT) accounts for 30–50% of all distal DVT [2]. The incidence of CMVT varies greatly depending on the research focus, diagnostic method, and study population of each study. Among patients with confirmed DVT, 47–79% had CMVT alone or simultaneously with other venous thrombosis [3]. Among patients with isolated distal DVT, 52–67% of patients have involvement of the calf muscle veins [4]. Isolated CMVT is more common and frequently leads to the diagnosis than other distal DVTs. Compared with other distal DVTs, pain of the local region is more common in isolated CMVT (30.4% vs 22.4%). However, isolated CMVT was less likely to have lower-extremity swelling (47.9% vs 62.7%) [5].

To determining whether treatment is necessary for isolated CMVT, prognostic factors must be considered—progression into the proximal deep vein and development of clinical pulmonary embolism (PE). Macdonald et al [6] demonstrated that only 2.9% of all CMVT progressed to the popliteal veins, which is classical proximal deep vein, while 16.3% of the CMVT extended to the level of the adjacent tibial or peroneal veins, which is distal deep vein. Another article reported that 5–10% of patients progress to popliteal vein [7]. Propagation of isolated CMVT appears to occur in the early course. Macdonald et al found that 90.9% of propagations occur within the first 2 weeks after first discovery. Pulmonary embolism has much greater clinical importance. Several studies have reported that in the incidence of PE of isolated CMVT patients has a wide range of 0.0% to 50.0% [8–11]. Therefore, isolated CMVT can progress into the proximal deep vein and lead to PE.

In this review, we examine anticoagulation strategies for isolated CMVT, evaluate the evidence for their effectiveness, and identify any gaps in current research and guidelines.

We conducted a PubMed (www.pubmed.gov) literature search using the following search terms: ‘‘calf muscle vein thrombosis’’, “calf muscular vein thrombosis”, “isolated gastrocnemius and soleal vein thrombosis”, and “isolated distal deep vein thrombosis”. Case series, case reports, and non-English articles were excluded. Trials of isolated distal deep vein thrombosis were used if they specifically identified isolated calf muscle veins in their evaluation.

Controversy Over Anticoagulation Therapy

Studies on the need for anticoagulant therapy in CMVT have reached inconsistent conclusions. Some scholars believe that isolated CMVT has the risk of extending into proximal deep vein thrombosis and pulmonary embolism, and that active early anticoagulation therapy can reduce the risk and benefit patients.

Schwarz et al [12] conducted a prospective, non-randomized, controlled study that enrolled 84 patients with CMVT who received 10 days of compression therapy or heparin anticoagulation. Among them, 52 patients received therapeutic doses of anticoagulation, and 32 patients only received compression therapy. After 3 months of follow-up, no deep vein thrombosis occurred in patients receiving heparin anticoagulation, while 25% of non-anticoagulated patients (compression therapy) developed deep vein thrombosis and recurrent CMVT, indicating that short-term heparin anticoagulation treatment of CMVT is safe and effective.

Gillet et al [9] divided 128 CMTV patients into 3 groups who were given anticoagulant treatment for 1, 3, and >6 months, respectively, and followed up for the occurrence of deep vein thrombosis and pulmonary embolism after anticoagulation. Among patients who received anticoagulation therapy, the MCVT recanalization rates were 54. 8%, 84.7%, and 96.0% at 1, 3, and 9 months, respectively. Pulmonary embolism in patients who are first diagnosed with MCVT is not uncommon. The detection rates of pulmonary embolism in patients with gastrocnemius vein thrombosis and soleus vein thrombosis are 10.3% and 4.1%, respectively; mid-term follow-up results (average 26.7 months) showed that 8% of patients with CMVT experienced at least 1 recurrence of deep vein thromboembolism. The study found that CMVT should be treated with short-term anticoagulation for at least 15 to 30 days. If the patient has high-risk factors for venous thromboembolism, the anticoagulation time should be appropriately prolonged. If the patient is at risk of bleeding, non-anticoagulation treatments such as compression therapy are recommended.

Lautz et al [13] reviewed the impact of anticoagulation therapy on prognoses, such as the development of thrombus and the occurrence of pulmonary embolism in CMVT patients. The results showed that the incidence of VTE in patients without anticoagulation or receiving prophylactic anticoagulation therapy was 30% and 27%, respectively, while it was only 12% in patients who received anticoagulation therapy (P=0.0003), indicating that the risk of embolism in patients who received only prophylactic anticoagulation and no anticoagulation was significantly higher than in patients who received therapeutic anticoagulation. A meta-analysis that included a total of 744 patients with CMVT and compared the benefits of anticoagulation therapy with those without anticoagulation therapy showed that anticoagulation therapy reduced the risk of thrombosis progression and increased the probability of vascular recanalization. However, the article did not comparatively analyze adverse reactions such as bleeding between the 2 groups, and it was not clear whether the benefits of anticoagulation outweighed the disadvantages [14].

However, based on the characteristics of CMVT and the bleeding risk of anticoagulation therapy, some studies have recommended use of non-anticoagulation methods such as compression therapy. MacDonald et al [6] prospectively analyzed 135 patients with CMVT and found through 3-month follow-up only 16.3% of venous thrombosis extended to adjacent tibial or peroneal veins, and 45.9% of venous thrombosis resolved spontaneously during follow-up. The incidence of deep vein thrombosis and pulmonary embolism caused by non-anticoagulation therapy is extremely low. Therefore, the study proposed that non-anticoagulation therapy can be used for patients with CMVT. A meta-analysis that included 8 randomized controlled trials and 13 prospective cohort studies showed that the incidence rate of isolated calf deep vein thrombosis developing into pulmonary embolism was 0–6.2%, and no fatal pulmonary embolisms occurred. Therefore, it is necessary to research the actual risks of isolated calf deep vein thrombosis and pulmonary embolism to select appropriate treatments for patients [15].

Schwarz et al [16] divided 107 patients with isolated CMVT into a short-term anticoagulation+compression therapy group (54 patients) and a compression therapy alone group (53 patients). After 3 months of follow-up, they found that the incidences of deep vein thrombosis in the anticoagulation group and the non-anticoagulation group were not significantly different, no significant difference was found in the recanalization pass rate, and short-term anticoagulation therapy did not achieve additional clinical effects. Therefore, it is recommended that non-anticoagulation methods such as intermittent pneumatic compression can be used to treat CMVT. A study including 384 patients with isolated distal deep vein thrombosis showed that although anticoagulation therapy reduced the risk of proximal deep vein thrombosis and pulmonary embolism, it significantly increased in the risk of bleeding [17].

However, there are still large differences among studies on the selection of clinical treatment strategies for patients with isolated calf deep vein thrombosis. Garcia et al [18] analyzed the treatment methods of 159 patients diagnosed with isolated calf deep vein thrombosis and found that most clinicians at Stony Brook University Medical Institution in the United States chose anticoagulant treatment strategies, but did not choose more appropriate treatments based on the patient’s risk factors. There is insufficient evidence of the natural history of isolated calf deep vein thrombosis, which may partly explain the clinical controversy and diverse treatment strategies. More rigorous randomized controlled trials are still needed to evaluate the effectiveness and safety of current treatment strategies.

Given this, the American College of Chest Physicians (ACCP) antithrombotic treatment guidelines published in 2016 [19] pointed out that CMVT is less harmful than tibial vein and peroneal vein thrombosis. Thrombosis can be closely monitored through Doppler ultrasound. In patients with severe clinical symptoms or an intermuscular vein thrombosis located close to the proximal vein, D-dimer is significantly elevated, and the thrombus is extensive (eg, length >5 cm, maximum diameter >7 mm, and involving multiple veins), and they may have active cancer, anticoagulation therapy is recommended. For patients with a high risk of bleeding, thrombus extension should be actively monitored, and anticoagulation therapy is not recommended.

However, there are still serious disagreements on selection of clinical treatment strategies for patients with isolated calf deep vein thrombosis.

The evidence suggest that compared with isolated distal DVT such as isolated anterior tibial vein, posterior tibial vein, and peroneal vein thrombosis, the risk of isolated CMVT extending to the proximal deep veins and developing into pulmonary embolism is lower [20], and patients with isolated CMVT should be actively evaluated for thrombosis progression. The risks should be considered before deciding on treatment. For low-risk groups, such as those without long-term immobilization, non-tumor patients, stroke patients, non-hypercoagulable blood, and D-dimer-negative patients, it is better to choose treatment strategies such as intermittent ventilation and compression, appropriate exercise, and close monitoring with Doppler ultrasound [21]. In addition, patients with CMVT should be closely monitored by Doppler ultrasound for 2 weeks [6]. When ultrasound indicates that the thrombus extends to the proximal deep vein, anticoagulant therapy is the first choice when high bleeding risk is excluded. For people with a high risk of thrombosis or patients with clinical symptoms, anticoagulant therapy can be started after the high risk of bleeding has been ruled out. It is recommended that anticoagulant therapy should be ended or continued based on the results of the ultrasound Doppler examination [19,20].

Anticoagulation Course

For patients with isolated CMVT who require anticoagulation, there is still a lack of consensus on the duration of anticoagulation therapy, and prospective studies with large sample sizes are needed to provide more clinical evidence. While anticoagulation therapy prevents the progression of thrombosis, clinicians should be alert to the occurrence of adverse events such as bleeding. Therefore, the selection of the length of anticoagulation time is particularly important.

Schwarz et al [12] proposed that 10 days of short-term low-molecular-weight heparin anticoagulation is beneficial in treatment of CMVT patients. The anticoagulation group was treated with low-molecular-weight heparin and compression therapy for 10 days, while the second cohort was treated with compression therapy alone. No deep vein thrombosis was found in the anticoagulation group in the 3-month follow-up, which can prevent CMVT from further thromboembolic complications. In a prospective study with a sample size of 107, Schwarz et al [16] found that there was no superiority of 10 days of low-molecular-weight heparin anticoagulation therapy in preventing deep vein thrombosis and pulmonary embolism versus simple compression therapy. They found that through 3-month follow-up, thrombus progression occurred in 3.7% of patients receiving short-term anticoagulation and in 3.8% of patients with no anticoagulation. However, the results of these 2 studies are conflicting, perhaps because the former study included hospitalized patients who had more high-risk factors for venous thrombosis, so the anticoagulant effect was prominent in that study. Based on these 2 studies, it is unclear whether short-term (10-day) heparin anticoagulation is effective.

Galanaud et al [5] followed up 390 CMVT patients, of whom 76.7% were treated with anticoagulant drugs for 3 months. Results showed that in all MCVT patients the death rate was 3.8%, the thromboembolism recurrence rate was 1.5%, and the major bleeding rate was 0%. Henry et al proposed that people at high risk of thrombosis, such as those with limited mobility, hypercoagulability, and cancer patients, should undergo anticoagulation for at least 1 month and clinicians should review vascular Doppler ultrasound results to determine whether treatment should be stopped or continued [20].

Anticoagulation time that is too long will increase the risk of bleeding, and anticoagulation treatment time that is too short may lead to persistence or progression of deep vein thrombosis in patients with CMVT [11,22]. If patients with CMVT receive anticoagulant treatment at an appropriate time, it can reduce the recurrence rate of deep vein thrombosis and also reduce the potential bleeding risk caused by long-term anticoagulation [23]. Therefore, the ideal anticoagulation duration for patients with CMVT still needs to be confirmed by more convincing research data. The Australian and New Zealand Society of Thrombosis and Haemostasis guidelines recommend that patients with distal deep vein thrombosis whose risk factors for thrombosis have been removed need to be treated with oral anticoagulants for 6 weeks, and for patients with persistent risk factors, the anticoagulation course needs to be 3 months [24]. Ageno et al [25] conducted a randomized, double-blind, placebo-controlled clinical trial to compare the effects of 6-week and 12-week treatment of rivaroxaban in isolated DVT patients. Results showed that 12-week treatment with rivaroxaban reduced the risk of recurrent venous thromboembolism (23 in 200 patients vs 39 in 202 patients). No major bleeding events occurred in either group. ACCP guidelines recommend that patients with high-risk factors for thrombosis should be anticoagulated for at least 3 months [19].

Conclusions

Research on anticoagulation therapy for CMVT has the following problems and challenges: (1) There is still a lack of multicenter, big-data, randomized, controlled trials to demonstrate the benefits or risks of anticoagulation therapy; and (2) There is no consensus on the time limit recommendation of anticoagulation, and more clinical trial data are needed to provide support. There may be several reasons for this. Firstly, isolated CMVT is often under-recognized and misdiagnosed, as symptoms can be nonspecific, leading to delayed diagnosis and treatment. This lack of recognition contributes to the scarcity of data on optimal management strategies. Secondly, isolated CMVT is rarer than proximal deep vein thrombosis and pulmonary embolism, resulting in fewer studies and clinical trials focused specifically on this condition. In addition, the management of isolated CMVT varies widely among practitioners, with no standard approach. Given this, efforts to standardize diagnostic criteria, establish multicenter registries, and conduct well-designed prospective studies are needed to improve the evidence base and optimize patient care in this challenging clinical scenario. In addition, the dosage of anticoagulation and the selection of anticoagulant drugs also need to be further explored, especially the application of new oral anticoagulants. As the research base continues to deepen, further clarifying the anticoagulant effect, safety, anticoagulation course, and selection of anticoagulant drugs for CMVT will bring good news to patients.