2020 Volume 84 Issue 10 Pages 1862-1865
Background: There is insufficient evidence regarding the optimal treatment method for distal deep vein thrombosis (DVT), including indications for anticoagulation therapy. Treatment results of patients with distal DVT were evaluated to clarify the risk factors that result in extension of distal DVT to the proximal vein and indications for anticoagulation therapy.
Methods and Results: Among 430 patients with DVT between January 2018 and December 2019, 253 were diagnosed with distal DVT; 41 patients who had already started anticoagulation therapy were excluded, and the remaining 212 were included as study subjects. Anticoagulation therapy was not started immediately; conservative treatment with compression stockings was performed. Ultrasonography after 2 weeks revealed thrombus disappearance in 39 patients (21%), and thrombus reduction in 38 patients (20%). In contrast, extension of thrombus to the proximal vein was noted in 12 patients (6.3%) and anticoagulation therapy was commenced. After 3 months, the thrombus had disappeared in 75 patients (52%). No patient developed pulmonary thromboembolism during follow-up. With respect to the risk factors for extension to proximal vein during conservative treatment, active cancer (P=0.03), prolonged bed rest (P<0.01), and D-dimer level >8µg/mL (P=0.01) were identified.
Conclusions: It is reasonable to consider anticoagulation therapy in distal DVT patients with active cancer, prolonged bed rest or high D-dimer level.
Deep vein thrombosis (DVT) can be classified as proximal, which includes thrombus in the popliteal vein and above, and distal, which includes thrombus localized in the veins of the lower legs. In the 1980s, in approximately 20% of symptomatic distal DVT patients, the thrombus reportedly extended to the proximal vein, and anticoagulation therapy was indicated.1 However, thereafter, with the natural history of symptomatic distal DVT, the reported rate of extension to proximal vein was 3–3.7%, with low incidence of pulmonary thromboembolism (PE) and low recurrence rate.2–4 Furthermore, a randomized comparative study of the use of low-molecular-weight heparin against symptomatic distal DVT showed that anticoagulation therapy was not only ineffective but also increased bleeding complications.5
Meanwhile, the guidelines for diagnosis, treatment and prevention of PE and DVT were revised in Japan in 2017. As per the guidelines on distal DVT that has localized to the lower legs, instead of undertaking blanket treatment with anticoagulation therapy, follow-up with physical therapy such as the use of compression stockings and ultrasonography, is recommended in patients at lower risk.
However, in some cases of distal DVT there is extension to the proximal vein, and so anticoagulation therapy is still performed for all DVT patients in many institutes, a practice that is believed to be related to an insufficiency of evidence regarding the optimal treatment method for distal DVT, including indications for anticoagulation therapy.
A flowchart of the medical treatment method for venous thrombosis is described in the medical safety handbook of Kitasato University Hospital, and most patients who develop DVT in hospital have a consultation in the Department of Cardiovascular Surgery. In accordance with the guidelines, anticoagulation therapy is not the first-line treatment for patients with distal DVT; the patients are re-evaluated using ultrasonography 2 weeks and 3 months after their first visit. Anticoagulation therapy is only initiated for patients who showed DVT exacerbation.
Therefore, the present study aimed to retrospectively investigate the treatment results of patients with distal DVT to clarify the risk factors for extension to the proximal vein and indications for anticoagulation therapy.
The subjects were patients with DVT who were referred to the Department of Cardiovascular Surgery of Kitasato University Hospital for the first time between January 2018 and December 2019. During this period, 430 patients were diagnosed with primary DVT, of whom 177 diagnosed with proximal DVT were excluded. In addition, 41 patients who had already started therapeutic anticoagulation therapy because of atrial fibrillation were excluded. Finally, 212 subjects were retrospectively investigated.
Diagnosis and TreatmentAnticoagulation therapy was not performed in all patients with distal DVT at diagnosis. These patients were re-evaluated by ultrasonography after 2 weeks and 3 months; if extension of thrombus to proximal vein was observed, contrast-enhanced computed tomography was performed to confirm the presence or absence of PE and anticoagulation therapy was started. All patients used compression stockings or elastic bandage. Age, sex, risk factors, presence or absence of symptoms, and presence or absence of thrombus on ultrasonography were confirmed via medical records.
DefinitionSymptomatic DVT was defined as swelling or pain in the lower extremity. Active cancer was defined as a condition wherein patients were undergoing radiation therapy or chemotherapy at the time of diagnosis of DVT, those who were scheduled to undergo surgery for cancer, those with metastasis to multiple organs, and those with terminal cancer. Proximal DVT was defined as a thrombus located in the popliteal vein, femoral vein, or iliac vein, whereas distal DVT was defined as a thrombus localized in the veins of the lower legs, such as the soleus vein, anterior tibial vein, posterior tibial veins, or fibular vein. Patients with a score on the Clinical Frailty Scale6 >7 were categorized as prolonged bed rest. Extension to the proximal vein was defined as confirmation of thrombus extension to the popliteal vein and above on follow-up ultrasonography, and patients with extension to the proximal vein or the appearance of thrombus in a different branch of the same side or opposite side were considered to have exacerbation.
Statistical AnalysisStatistical data are presented as mean±standard deviation. Statistical analyses were conducted using χ2 test and Mann-Whitney U test, and P<0.05 was regarded as statistically significant.
Table 1 summarizes the baseline characteristics of the 212 patients with distal DVT. During the follow-up period, 10 patients died of cancer. After 2 weeks, 189 patients underwent ultrasonography (Figure 1), and the following findings were observed: thrombus disappearance in 39 patients (21%), thrombus reduction in 38 patients (20%), no change in 97 patients (51%), new distal thrombus appearance at a different branch of the lower leg vein in 9 patients (4.8%), and thrombus extension to the proximal vein in 12 patients (6.3%) (Figure 2). There was no case of PE among the patients with extension to the proximal vein, and oral anticoagulation therapy was initiated in them. The 21 patients with disease progression underwent repeat ultrasonography, which was performed 2 weeks after the initiation of anticoagulation therapy and revealed thrombus reduction in all the patients. The D-dimer level of these 21 patients decreased from 12±8 µg/mL to 4±3 µg/mL in 2 weeks, and there were no bleeding complications. After 3 months, 145 patients underwent ultrasonography: the thrombus had disappeared in 75 patients (52%) and reduced in 30 patients (21%). No patients developed PE during the follow-up period.
| n=212 | |
|---|---|
| Age (years) | 73±14 |
| Female (%) | 160 (76) |
| Symptomatic (%) | 74 (35) |
| Hospitalization at diagnosis (%) | 164 (78) |
| After orthopedic surgery (%) | 112 (53) |
| Preoperative screening (%) | 29 (14) |
| Cancer at diagnosis (%) | 41 (19) |
| Active cancer at diagnosis (%) | 28 (13) |
| Bed rest (frailty scale >7) (%) | 41 (19) |
| Clinical Frailty Scale | 4.4±1.9 |
| Steroid use (%) | 27 (13) |
| History of VTE (%) | 7 (3) |
| Pregnancy/postpartum (%) | 2 (1) |
| FDP (μg/mL) | 31±33 |
| D-dimer (μg/mL) | 9±13 |
DVT, deep vein thrombosis; FDP, fibrin degradation product; VTE, venous thromboembolism.
Flow chart of patients’ assessment. AC, anticoagulant; DVT, deep vein thrombosis; FU, follow-up.
Results of thrombus propagation. DVT, deep vein thrombosis.
In addition to the cases of extension to the proximal vein, cases of new distal thrombus in a different branch of the lower leg vein were combined and regarded as DVT exacerbation, and the exacerbation factors of DVT under conservative treatment were investigated (Table 2). The presence or absence of clinical symptoms and orthopedic disorder were not risk factors, whereas prolonged bed rest (P<0.01), active cancer (P=0.03), and D-dimer level >8 µg/mL (P=0.04) were risk factors for DVT exacerbation. Cancer-bearing status and steroid use did not reach statistical significance. Among the 100 patients who underwent orthopedic surgery and then ultrasonography at 2 weeks, 56 received preventive anticoagulation (enoxaparin 51, fondaparinux sodium 5). Preventive administration did not reduce the progression of DVT. Unprovoked DVT7 occurred in 41 cases, and it was not a risk factor for extension of distal DVT.
| Distal DVT (n=189) |
Proximal and distal new DVT (n=21) |
Odds ratio | P value |
|---|---|---|---|
| Symptomatic (n=69) | 6 (8.7) | 0.66 | NS |
| Hospitalization at diagnosis (n=145) | 15 (10) | 0.73 | NS |
| After orthopedic surgery (n=100) | 10 (10) | 0.79 | NS |
| Preventive administration (n=56) | 5 (9) | 0.76 | NS |
| Preoperative screening (n=29) | 6 (21) | 2.52 | NS |
| Cancer at diagnosis (n=36) | 7 (19) | 2.4 | NS |
| Active cancer at diagnosis (n=25) | 6 (24) | 3.14 | 0.03 |
| Bed rest (frailty scale >7) (n=37) | 10 (27) | 4.75 | <0.01 |
| Steroid use (n=29) | 5 (17) | 1.86 | NS |
| History of VTE (n=7) | 1 (14) | 1.35 | NS |
| D-dimer >8 μg/mL (n=77) | 13 (17) | 2.64 | 0.04 |
DVT, deep vein thrombosis; NS, not significant; VTE, venous thromboembolism.
Among patients with distal DVT, the prognosis of asymptomatic DVT is reported to be favorable without anticoagulation therapy;8 however, there is no clear consensus on the treatment policy, and it has not been extensively studied. Furthermore, Japanese guidelines do not recommend performing anticoagulation therapy uniformly for distal DVT. It is stated that anticoagulation therapy can be performed for high-risk VTE patients, including those with symptomatic DVT, cancer-bearing patients, and those who undergo orthopedic surgery of the lower extremity, while taking into consideration the bleeding risks. In Japan, lower extremity venous ultrasonography is often performed in the perioperative period based on medical safety. As a result, distal DVT accounts for half of all patients, indicating there are many asymptomatic cases.9 In Kitasato University Hospital, patients with distal DVT (253 patients) accounted for 60% of all patients, and 60% of them were asymptomatic. It is reported that the incidence of DVT found on screening tests before and after orthopedic surgery is high.10 In Kitasato University Hospital, 50% of cases of distal DVT are found after orthopedic surgery. Our patients included approximately 20% cancer-bearing patients, 13% steroid users, and 19% patients with prolonged bed rest. This study shows the outcomes of follow-up with conservative treatment based on compression stockings without anticoagulation therapy in real DVT patients in a local core hospital including high-risk VTE patients.11 No patient developed symptomatic PE; however, 6.3% of patients had extension to the proximal vein, which is more than has been reported in other studies.9,10 This may be due to the present patient group including many high-risk VTE patients, such as those with active cancer. No patient developed PE during the follow-up period, so we consider that conservative treatment against distal DVT was adequate if ultrasonography is repeated after 2 weeks.
Regarding the risk factors of DVT extending to the proximal vein, strong correlations were noted for prolonged bed rest, active cancer, and D-dimer level >8 µg/mL. Prolonged bed rest is considered to be a high-risk factor because the action of compression stockings to strengthen muscle pumps does not work while lying in bed; therefore, combined use of intermittent pneumatic compression is recommended for patients with prolonged bed rest. Active cancer was significantly correlated with disease extension, whereas cancer-bearing status itself was not; symptomatic DVT was not a risk factor either. We believe that anticoagulation therapy can be considered in the early stage for patients with risk factors for DVT extension to the proximal vein or DVT exacerbation; that is, bed rest, active cancer, or D-dimer level >8 µg/mL. However, a high risk of anticoagulation-related bleeding has been reported in cancer patients, particularly those with active cancer.12 Therefore, care must be taken with the administration of anticoagulation therapy in these patients. In the present study, a significant number of patients were diagnosed with distal DVT on preoperative screening ultrasonography, but they did not exhibit a significant association with proximal extension of the thrombus. Therefore, surgical treatment without preoperative anticoagulation therapy can be safely performed for these patients without increasing the risk of perioperative PE.
Study LimitationsFirst, it was a single-center retrospective study and because the number of patients with the event was small, a multivariate analysis could not be performed. Furthermore, some patients changed hospitals for rehabilitation after orthopedic surgery and could not be followed up. In addition, contrast-enhanced computed tomography was not performed in all patients. Therefore, the actual number of patients with asymptomatic PE was unknown. D-dimer level is affected not only by DVT but also by malignant tumors and infections.
The exacerbation risk factors of thrombus in patients with distal DVT included prolonged bed rest, active cancer, and D-dimer level >8 µg/mL. It is reasonable to consider the introduction of anticoagulation therapy in distal DVT patients with these risk factors.
The authors declare no conflicts of interest.
Kitasato University Hospital IRB (3897-1).
