Deep venous thrombosis (DVT) is a condition caused by abnormal blood clotting in the deep veins, mostly in the lower extremities, and the dislodged thrombus can cause pulmonary embolism (PE), collectively known as venous throboembolism (VTE). DVT is a common condition, the consequences of which are mainly pulmonary embolism and post-DVT syndrome, which can lead to death and significantly affect the quality of life in severe cases. There is a lack of uniform understanding of the diagnosis and treatment of DVT in domestic clinics, and the efficacy varies greatly. In order to improve the diagnosis, treatment and prevention of DVT in China, we have developed guidelines for the diagnosis and treatment of DVT.
I. Epidemiology and risk factors At present, there is a lack of accurate statistics on the incidence of DVT in China. the main causes of DVT are venous wall damage, slow blood flow and blood hypercoagulation. The risk factors include primary factors (Table 1) and secondary factors (Table 2).DVT is most often seen after major surgery or trauma, prolonged bed rest, limb braking, patients with advanced tumors, or those with significant family history.
Table 1 Primary risk factors for DVT
Primary factors
Antithrombin deficiency
Congenital abnormal fibrinogenemia
Thrombomodulin (thrombomodulin)
Hyperhomocysteinemia
Anti-cardiolipin antibodies
Fibrinogen activator inhibitor excess
Prothrombin 20210A gene variant
Protein c deficiency
Factor V Leiden mutation (activated protein
c resistance)
Fibrinogen deficiency
Abnormal fibrinogenemia
Protein s deficiency
Ⅻ factor deficiency
Table 2 Secondary risk factors for DVT
Secondary factors
Injury/fracture
Stroke
Advanced age
Central venous cannulation
Lower extremity venous insufficiency
Smoking
Pregnancy/postpartum
Crohn’s disease
Nephrotic syndrome
Blood hypercoagulation (erythrocytosis, Waldenstrom’s macroglobulinemia)
Platelet abnormalities
Surgery
Braking
Malignancy chemotherapy
Obesity
Heart Failure
Long distance travel
Oral contraceptives
Lupus anticoagulants
Artificial materials
II. Clinical manifestations of DWIF
1. Symptoms: swelling and pain of the affected limb, which is aggravated by activity and can be improved by elevating the affected limb. Occasionally there is fever and rapid heart rate.
2.Signs: swelling of the distal limb or the whole limb of the thrombus is the main feature, the skin is mostly normal or mildly bruised, but in severe cases it may be cyanotic and the skin temperature is reduced. If the artery is affected, the distal arterial pulsation may be weakened or disappear. If the thrombus occurs in the muscular plexus of the lower leg, pressure pain at the site of the thrombus may be present (positive Homans’ and Neuhof’s signs).
Homans’ sign: When the affected limb is straightened and the ankle joint is dorsiflexed, it is positive because the lesioned vein within the calf muscle is stimulated by passive pulling of the gastrocnemius and flounder muscles, causing pain in the deep part of the calf muscle.
Neuhofs sign (i.e. gastrocnemius compression test): stimulation of the diseased vein within the calf muscle, causing deep pain in the calf muscle, is positive.
Later thrombus mechanization often leaves venous insufficiency with superficial varicose veins, hyperpigmentation, ulceration and swelling, called postthrombosissyndrome (PTS).
Thrombus dislodgement can cause the manifestation of pulmonary artery embolism.
Third, the diagnosis of DVT
(a) Auxiliary examination of DVT
1.Impedance volume tracing measurement: it has high sensitivity and specificity for symptomatic proximal DVT, and the operation is simple and low cost. However, the sensitivity to asymptomatic DVT is poor and the positive rate is low.
2.Plasma D-dimer determination: detected by enzyme-linked immunosorbent assay (ELISA), with high sensitivity (>99%). Acute DVT, D-dimer >500 g/L has important reference value.
Since patients are almost always positive for D-dimer in the short postoperative period, it is of little value for the diagnosis or differential diagnosis of DVT, but can be used for preoperative DVT
screening of patients at high risk. In addition, it is not specific for the diagnosis of venous thromboembolism, such as tumor, inflammation, infection, necrosis and many other conditions that can produce fibrin, D-dimer can also be greater than 500 g/L, so the predictive value is low, so it can not be used to diagnose DVT. this test has low specificity for elderly patients over 80 years old, and should not be used for these people.
3, color Doppler ultrasound exploration: its sensitivity and accuracy are high, it is a non-invasive examination, and is suitable for screening and monitoring of patients. Careful non-invasive vascular ultrasound can keep the sensitivity at 93% to 97% and the specificity at 94% to 99%. Highly suspicious cases should be reviewed daily if negative.
Combined with the presence or absence of thrombotic favorable factors, patients can be classified as having high, moderate, or low DVT likelihood before performing ultrasound. If two consecutive ultrasound examinations are negative, patients with low likelihood can be clinically observed, patients with moderate and high likelihood can be given anticoagulation therapy, and patients in the high incidence group should be considered for venography if the 2nd scan is still negative.
4. Radionuclide vascular scan examination: using the increased concentration of nuclide in the deep venous flow or clot in the lower limbs, which is visualized by scanning, is a valuable non-invasive examination for the diagnosis of DVT.
5.Spiral CT venography (computed tomo-venography, CTV): It is a new diagnostic method of DVT emerged in recent years, which can check abdomen, pelvis and deep veins of lower limbs at the same time.
6, venography: is the “gold standard” of DVT diagnosis.
(B) Clinical possibility assessment and diagnosis process of DVT
1.Clinical possibility assessment of DVT: refer to Wells clinical score
(Table 3).
Table 3 Clinical characteristics score for the diagnosis of DVT of lower limbs
Clinical features
Tumor
Paralysis, or recent lower extremity cast immobilization
Recent bed rest >3 days, or within l2 weeks after major surgery
Localized pressure pain along deep veins
Edema of the entire lower extremity
Calf swelling >3 cm compared to the healthy side (measured 10 cm below the tibial tuberosity)
Previous history of DVT
Depressed edema (worse in the symptomatic leg)
presence of collateral circulation of superficial veins (non-varicose)
Other diagnosis (likelihood greater than or equal to DVT)
Clinical likelihood: low ≤ 0; moderate 1 to 2 points; high ≥ 3. If both lower extremities are symptomatic. The side with severe symptoms shall prevail.
2.Diagnostic process of DVT: The diagnosis of DVT must have objective auxiliary examination to confirm the diagnosis, please refer to Figure 1 for its assessment process.
IV. Treatment of DVT
(A) Treatment of early DVT
Anticoagulation is the standard treatment for venous thromboembolism, and a large number of clinical randomized controlled trials have confirmed that anticoagulation can inhibit the spread of thrombus, reduce the incidence of pulmonary embolism and death rate, as well as recurrence. early anticoagulation treatment for DVT can be subcutaneous injection of low molecular heparin or heparin (refers to ordinary heparin, the same below).
According to the need of the disease, the combined application of vitamin K antagonist can be started on the 1st day of treatment, and heparin will be discontinued after the INR is stable and greater than 2.0.
1. Application of common heparin: Heparin doses vary greatly among individuals, so intravenous administration of heparin must be monitored to ensure efficacy and safety. Currently commonly monitored is the activated partial thromboplastin time (APTT), the therapeutic effect of heparin should be reached and maintained as soon as possible 1.5 to 2.5 times before anticoagulation. However, APTT does not always reliably reflect plasma heparin levels or heparin antithrombotic activity. The laboratory can determine the therapeutic range of APTT in this laboratory based on the anti-factor X activity determined by amide hydrolysis equivalent to plasma heparin levels (0.3 to 0.7) IU/ml. Dose adjustments can be made by direct testing of heparin levels in hospitals where available. For heparin-resistant patients requiring high daily doses of heparin that do not reach the am treatment range, the dose of heparin can be adjusted based on the determination of anti-factor Xa. Intermittent intravenous heparin is associated with a higher risk of bleeding than continuous intravenous administration. Usage of heparin for the treatment of DVT (for information): The starting dose of heparin can be given as a single dose of 6250 U, with subsequent adjustment of the heparin dose based on APTT results.
Recommendation: For patients with an objective basis for a confirmed diagnosis of DVT. Subcutaneous low-molecular heparin or intravenous and subcutaneous heparin is recommended. For patients with a high clinical suspicion of DVT. If not contraindicated. While awaiting test results. Anticoagulation therapy may be considered. Decide whether to continue anticoagulation therapy based on the confirmation of the diagnosis. A combination of vitamin K antagonist and low molecular heparin or heparin is recommended starting on day 1 of treatment. After INR reaches 2.0. Discontinue heparin. For patients with acute DVT subcutaneous heparin can replace the treatment with intravenous heparin.
2. Application of low-molecular heparin: Low-molecular heparin has better predictability of pharmacokinetics and biological effects than heparin. Most patients do not require laboratory monitoring if the dose of low molecular heparin is adjusted according to body weight by subcutaneous injection once or twice a day. Use with caution in renal insufficiency or pregnant women.
Recent studies have shown no statistically significant difference in the risk of recurrent venous thrombosis, pulmonary embolism, or major bleeding between low-molecular heparin and regular heparin, and the results were the same for both. Survival was better with low molecular heparin than with heparin in patients with malignancy. There was no significant difference in safety and efficacy between different low-molecular heparins. The efficacy and risks of low-molecular heparin were comparable to those of heparin. The main advantage of low-molecular heparin is that it is easy to use and mostly does not require monitoring.
Recommendation: For patients with acute DVT. 1 subcutaneous dose of low molecular heparin/12 h is recommended: for patients with severe renal failure. IV heparin is recommended. Consider low-molecular heparin with caution.
3.Thrombolytic therapy: theoretically, the use of thrombolytic drugs to dissolve venous thrombus and rapidly reduce vascular obstruction can be one of the therapeutic measures for DVT patients. Early thrombolytic therapy is effective, but thrombolytic therapy may increase the risk of bleeding. It is uncertain whether thrombolytic therapy for early DVT reduces the incidence of PTS.
RECOMMENDATION: Treatment of severe iliofemoral vein thrombosis in the acute phase with appropriate anticoagulation therapy. Thrombolytic therapy may be considered.
4. Catheter thrombolysis: Catheter thrombolysis has some advantages over systemic thrombolysis, but catheter thrombolysis has been reported to be associated with local and systemic bleeding and requires careful evaluation of benefits/risks in comparison with conventional anticoagulation before it can be applied to patients.
There are national controlled clinical studies of systemic and catheter thrombolysis that have concluded that placement thrombolysis has a higher apparent efficiency, shorter treatment time, and fewer complications than conventional drug therapy. There are case reports of small samples supporting local application of thrombolytic agents. Given the lack of sufficient evidence-based medical evidence in China, the indications for catheter thrombolysis still need to be strictly controlled.
Recommendation: It is recommended that the use of catheter thrombolysis should be limited to certain selective patients, such as patients with more severe iliofemoral vein thrombosis.
5.Surgical thrombectomy: Surgical venous thrombectomy is mainly used for early proximal DVT, and the usual complication of surgical thrombectomy is thrombus recurrence. However, its long-term efficacy such as PTS and patency rate is still uncertain. Therefore, it can be considered for severe patients, such as certain severe iliofemoral vein thrombosis, and patients with femoral cyanosis.
There are no domestic clinical randomized controlled trials of surgical versus non-surgical procedures. There are clinical controlled trials showing that surgery is beneficial in reducing the incidence of post-thrombotic syndrome.
Only a very small number of randomized controlled clinical trials abroad have confirmed that surgery reduces recurrence of pulmonary embolism and early thrombosis as well as good long-term outcome of valve function. For long-term outcomes, the vast majority are currently observational case studies.
Recommendation: For certain elective patients. Such as more severe iliofemoral vein thrombosis. The use of embolization may be considered.
6.Inferior vena cava filter: Inferior vena cava filter can prevent and reduce the occurrence of pulmonary embolism. The indications for placement of inferior vena cava filter are patients with proximal DVT who have contraindications or complications of anticoagulation therapy, recurrent thromboembolism with adequate anticoagulation therapy, heparin-induced thrombocytopenia syndrome, recurrent pulmonary embolism episodes combined with pulmonary hypertension, and simultaneous application of pulmonary artery surgery for embolization and endothelial dissection. Anticoagulation therapy should be performed immediately after filter placement. Although placement of inferior vena cava filters on the basis of anticoagulation therapy can reduce the occurrence of pulmonary embolism, it cannot improve the early and late survival of patients with initial VTE. However, there is a tendency for higher recurrence of deep vein thrombosis in patients with filter placement as time increases. Foreign data show that the incidence of fatal pulmonary embolism can be below 1% after adequate anticoagulation therapy. Therefore, inferior vena cava filters are indicated for patients at high risk of pulmonary embolism.
Recommendation: For most patients with DVT. It is recommended that vena cava filters are not routinely applied; for patients with contraindications or complications of anticoagulation therapy. Or in patients with recurrent thromboembolism in the presence of adequate anticoagulation therapy. Placement of an inferior vena cava filter is recommended.
7.Position therapy: Early DVT patients are recommended to have a period of strict bed rest along with anticoagulation therapy to prevent thrombus dislodgement causing pulmonary embolism. However, in patients with chronic DVT, the rate of pain and swelling resolution is significantly faster in patients with exercise and leg compression than in patients with bed rest. Therefore, bed rest is not strictly required.
Recommendation: Bed rest is recommended for patients with early DVT. Elevate the affected limb.
(B) Long-term treatment of DVT
Patients with DVT require long-term anticoagulation to prevent the development of symptomatic thrombosis (15%-50%) and/or recurrent venous thrombotic events.
The optimal course of treatment for patients on long-term anticoagulation therapy can be divided into five classes based on observations. The grading is as follows: (1) first-episode DVT secondary to transient risk factors; (2) DVT with cancer and first-episode DVT; (3) first-episode spontaneous DVT (defined as DVT occurring in the absence of known risk factors); (4) first-episode DVT with prothrombin genes and prognostic markers associated with an increased risk of thromboembolic recurrence (including anticoagulant factor III. protein C or protein S deficiency, prothrombin gene mutations such as factor V Leiden or prothrombin 20210 gene mutations), patients with antiphospholipid antibodies, homocysteinemia, or factor VIII levels higher than 90% of normal , or patients with persistent residual thrombus confirmed by repeated ultrasound; (5) recurrent multiple episodes of DVT (two or more episodes of VTE).
Vitamin K antagonists in DVT: Adjusted doses of vitamin K antagonists such as warfarin are very effective in preventing recurrent VTE. Detection of vitamin
The criteria for testing the anticoagulant effect of vitamin K antagonists are prothrombin time and INR.
1. Anticoagulation intensity: The intensity of anticoagulation therapy with vitamin K antagonists has been confirmed by randomized trials abroad. Low standard intensity (INR 1.5 to 1.9) treatment has poor effect and does not reduce the incidence of concurrent bleeding. In contrast, high-intensity warfarin therapy (INR 3.1 to 4.0) did not provide a better antithrombotic treatment outcome. High-intensity therapy was associated with a high clinical risk (20%) of severe bleeding. Only a small sample of domestic observations has been reported, and strong evidence is lacking.
Recommendation: It is recommended that vitamin K antagonists should maintain the INR at 2.0-3.0 throughout the course of treatment. regular monitoring is required.
2. Duration of long-term treatment: Randomized trials and prospective cohort studies have shown that three months of treatment in patients with first-episode DVT secondary to transient risk factors is sufficient to reduce the recurrence of VTE. Randomized trials of extended courses of anticoagulation in patients with primary DVT, extending the course of therapy to one to two years compared to control patients treated conventionally for three to six months, found that extended courses were very effective in reducing the incidence of recurrent VTE, but with an increased risk of bleeding during treatment, so the decision to extend the course of anticoagulation in patients with primary DVT Therefore, the decision of whether to extend the course of anticoagulation therapy for patients with primary DVT should be made after full consideration of its advantages and disadvantages.
Patients with a propensity for thrombosis have a higher risk of VTE recurrence. These include protein C, protein S, factor V Leiden and prothrombin 20210A mutations, increased levels of coagulation factor VIII, elevated homocysteine levels and the presence of positive antiphospholipid antibodies. Stratified analysis of randomized trials and studies of non-randomized clinical trials have demonstrated the benefit of extending the course of warfarin.
RECOMMENDATION: For patients with a first episode of DVT secondary to a transient risk. Vitamin K antagonists are recommended for at least 3 months; for patients with a first episode of idiopathic DVT. Anticoagulation with a vitamin K antagonist for at least 6 to 12 months or longer is recommended; for patients with more than two episodes of DVT, long-term therapy is recommended. For patients on long-term anticoagulation, risk-benefit assessments should be performed periodically to determine whether to continue treatment.
Post venous thrombosis syndrome (PTS): Post venous thrombosis syndrome (PTS) is defined as a cluster of symptoms and signs in patients who have had venous thrombosis, with an incidence of PTS of approximately 20% to 50%. It is usually associated with chronic venous insufficiency. The predominant symptom is chronic postural swelling, pain, or local discomfort. The severity of symptoms varies over time, with the most severe manifestation being venous ulceration of the ankle. Usually the symptoms are non-acute and the need for treatment is determined by the patient’s degree of self-consciousness. Randomized trials have confirmed the effectiveness of wearing compression stockings for PTS.
3. Physical therapy for post-phlebitis syndrome: There are only small controlled trials showing that intermittent pneumatic compression therapy and compression stockings can help reduce symptoms.
Recommendations: For patients with mild edema of the lower extremities due to PTS. The use of compression stockings is recommended, and for patients with severe lower extremity edema due to PTS. The use of intermittent compression therapy is recommended.
Appendix: Clinical staging of DVT: acute stage: refers to within 7 d after onset; subacute stage: refers to the 8th-30th d (1 month) of onset; chronic stage: after 30 d of onset.
The early stage referred to in this guideline includes both acute and subacute stages.