Deep venous thrombosis (DVT) is a condition caused by abnormal clotting of blood in deep veins, mostly in the lower extremities, and the dislodgement of thrombus can cause pulmonary embolism (PE), collectively known as venous thromboembolism. DVT is a common disease, 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.
In China, there is a lack of uniform understanding of the diagnosis and treatment of DVT, 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
The main causes of DVT are venous wall damage, slow blood flow and hypercoagulable blood. The risk factors include primary and secondary factors (see Table 1). DVT is mostly seen in patients after major surgery or trauma, long-term bed rest, limb braking, patients with advanced tumors or those with significant family history.
(II) Clinical manifestations of DVT
1.Symptoms: swelling and pain of the affected limb, aggravated by activity, which 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, and the skin temperature is higher than that of the normal limb. In severe cases, the skin may appear cyanotic and the skin temperature may decrease. If the artery is affected, the distal arterial pulsation may be weakened or absent. 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’ sign and Neuhof’s sign).
Homans’ sign positive: When the affected limb is straightened and the ankle joint is dorsiflexed, the lesioned vein in the calf muscle is stimulated due to passive pulling of the gastrocnemius and flounder muscles, causing pain in the deep part of the calf muscle.
Positive Neuhof’s sign (i.e. gastrocnemius compression test): stimulation of the diseased vein within the calf muscle, causing deep pain in the calf muscle.
Later thrombus mechanization often leaves venous insufficiency with superficial varicose veins, hyperpigmentation, ulceration, and swelling, called postthrombosis syndrome (PTS).
Dislodged thrombus can cause the manifestation of pulmonary artery embolism.
(C) Diagnosis of DVT
Auxiliary examination of DVT
1.Impedance volume tracing measurement: it has high sensitivity and specificity for symptomatic proximal DVT, and it is simple to operate and less expensive. However, the sensitivity for asymptomatic DVT is poor, and the positive rate is low.
2.Plasma D dimer determination: detection by enzyme-linked immunosorbent assay (ELISA), with high sensitivity (>99%). Acute DVT, D dimer >500 ug/L has important reference value. It is of little value for the diagnosis or differential diagnosis of DVT because patients are almost always positive for D dimer in the short postoperative period, but can be used for preoperative screening of patients at high risk for DVT.
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 >500 ug/L, so the predictive value is low, so it cannot 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 test, and it is suitable for screening and monitoring of patients. Careful non-mediated human vascular ultrasound can keep the sensitivity at up to 93% to 97% and specificity at 94% to 99%. Those who are highly suspicious 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 prior to 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, and for patients in the high incidence group, venography should be considered if the second scan is still negative.
4.Radioactive nucleo-vascular scan examination: the use of nuclide in the lower extremity deep vein blood flow or blood clots in the increased concentration, through the scan and the image, for the diagnosis of DVT is a valuable non-invasive test.
5.Spiral CT venography (computedtomo-venography, CTV): it is a new diagnostic method of DVT emerged in recent years, which can examine abdomen, pelvis and deep veins of lower limbs at the same time.
6, venography: is the “gold standard” of DVT diagnosis.
(D) Treatment of DVT
I. 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 of DVT can be subcutaneous injection of low molecular heparin and heparin (ordinary heparin, the same below).
The combination of vitamin K antagonist can be started on the first day of treatment according to the need of the disease, and heparin is discontinued after the INR is stable and greater than 2.0.
Application of regular heparin
Heparin doses vary widely among individuals, so intravenous administration of heparin must be monitored to ensure efficacy and safety. The commonly used monitoring is the activated partial thromboplastin time (aPTT), and the therapeutic effect of heparin should be achieved and maintained as soon as possible at 1.5 to 2.5 times the pre-anticoagulation level. 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 measured by amide hydrolysis equivalent to a plasma heparin level of 0.30.7 IU/mL. Dose adjustments can be made by direct testing of heparin levels in hospitals where available. For heparin-resistant patients who require high daily doses of heparin and do not reach the therapeutic range of aPTT, 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 reference): 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.
Recommendations
Subcutaneous low-molecular heparin or intravenous, subcutaneous heparin is recommended for patients with an objective basis for a confirmed diagnosis of DVT.
In patients with a high clinical suspicion of DVT, if not contraindicated, anticoagulation may be considered while awaiting test results and the decision to continue anticoagulation will be based on the confirmed diagnosis.
A combination of vitamin K antagonist and low-molecular heparin or heparin is recommended starting on the first day of treatment and discontinuing heparin after the INR reaches 2.0. Subcutaneous heparin can be used as an alternative to intravenous heparin in patients with acute DVT.
Application of low-molecular heparin
Low molecular heparin has better predictability of pharmacokinetic and biological effects than heparin. Most patients do not require laboratory monitoring if the dose of subcutaneous low-molecular heparin is adjusted for body weight and administered once or twice daily. 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 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.
Recommendations
For patients with acute DVT, 12-hourly subcutaneous injections of low-molecular heparin are recommended; for patients with severe renal failure, intravenous heparin is recommended and low-molecular heparin is considered with caution.
Thrombolytic therapy
Theoretically, the use of thrombolytic agents to dissolve venous thrombi and rapidly reduce vascular obstruction can be one of the curative measures for patients with DVT. Early thrombolytic therapy is effective, but thrombolytic therapy may increase the risk of bleeding. It is uncertain whether thrombolytic treatment of early DVT reduces the incidence of PTS.
Recommendations
Thrombolysis may be considered for the treatment of severe iliofemoral vein thrombosis in the acute phase with appropriate anticoagulant therapy.
Catheter Thrombolysis
Catheter thrombolysis has some advantages over systemic thrombolysis, but an association between catheter thrombolysis and local and systemic bleeding has been reported and requires a careful benefit/risk assessment in comparison to conventional anticoagulation before it is indicated for 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. In view of the lack of sufficient evidence-based medical evidence in China, the indications for catheter thrombolysis still need to be strictly controlled.
Recommendations
It is recommended that the use of catheter thrombolysis should be limited to certain selective patients, such as those with more severe iliofemoral vein thrombosis.
Surgical Thrombectomy
Surgical venous thrombectomy is mainly used for early proximal DVT, and the usual complication of surgical thrombectomy is recurrence of the thrombus. However, its long-term efficacy such as PTS and patency rate remains 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 pulmonary embolism and recurrence of early thrombosis as well as good long-term outcome of valve function. For long-term outcomes, the majority of cases are currently observational.
Recommendations
In certain selective patients, such as more severe iliofemoral vein thrombosis, embolectomy may be considered.
Inferior vena cava filters
Inferior vena cava filters can prevent and reduce the incidence of pulmonary embolism. Indications for placement of an inferior vena cava filter are patients with proximal DVT with contraindications or complications of anticoagulation, recurrent thromboembolism in the presence of adequate anticoagulation, heparin-induced thrombocytopenia syndrome, recurrent pulmonary embolism episodes combined with pulmonary hypertension, and concomitant application during surgical pulmonary artery thrombectomy 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 does not 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.
Recommendations
For most patients with DVT, a vena cava filter is not recommended as a routine procedure;
For patients with contraindications or complications of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation, placement of an inferior vena cava filter is recommended.
Postural therapy
A period of strict bed rest is recommended in patients with early DVT along with anticoagulation to prevent thrombus dislodgement resulting in pulmonary embolism. However, in patients with chronic DVT, pain and swelling resolve significantly faster with exercise and leg compression than with bed rest. Therefore, bed rest is not strictly required.
Recommendations
Bed rest with elevation of the affected limb is recommended for patients with early DVT.
II. Long-term treatment of DVT
Patients with DVT require long-term anticoagulation therapy to prevent the development of symptomatic thrombosis 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 of DVT secondary to a transient risk factor;
(2) DVT with cancer and first episode;
(3) first-episode spontaneous|born 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 mutations), with antiphospholipid antibodies, homocysteinemia, or factor VIII levels higher than 90% of normal (4) Patients with persistent residual thrombus confirmed by repeated ultrasound examinations;
(5) Recurrent multiple episodes of DVT (two or more episodes of VTE).
The use of vitamin K antagonists in the long-term treatment of DVT
Adjusted doses of vitamin K antagonists such as warfarin are very effective in preventing recurrent VTE. The criteria used to test the anticoagulant effect of vitamin K antagonists are prothrombin time and INR.
Anticoagulation intensity
The strength of anticoagulant therapy with vitamin K antagonists has been confirmed abroad by randomized trials. Low standard intensity (INR l.5 to 1.9) therapy is poorly effective and does not reduce the incidence of concomitant bleeding. Therefore, high-intensity warfarin therapy (INR 3.1 to 4.0) did not provide better antithrombotic treatment. High-intensity therapy has also been shown to be 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.
Recommendations
It is recommended that vitamin K antagonists should maintain an INR of 2.0 to 3.0 throughout the course of therapy, and regular monitoring is required.
Duration of long-term treatment
Randomized trials and prospective cohort studies have shown that three months of treatment in patients with a first episode of DVT secondary to a transient risk factor is sufficient to reduce the recurrence of VTE. A randomized trial of the risk-benefit ratio of extending the duration of anticoagulation therapy to 1 to 2 years in patients with primary|biologic DVT was compared with a control group of patients treated with conventional therapy for 3 to 6 months;
It was found that extending the course of therapy was very effective in reducing the incidence of recurrent VTE, but that there was an increased risk of bleeding during treatment, so the decision to extend the course of anticoagulation in patients with primary DVT should be made after full consideration of its advantages and disadvantages.
The coronary risk of VTE recurrence is higher in patients with a propensity for thrombosis. 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.
Recommendations
Vitamin K antagonists are recommended for at least 3 months in patients with a first episode of DVT secondary to a transient risk.
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.
Physical therapy for post-venous thrombosis syndrome
Only a small sample of controlled trials have shown that intermittent pneumatic compression therapy and compression stockings help to reduce symptoms.
Recommendations
For patients with mild edema of the lower extremities due to PTS, the use of compression stockings is recommended.
For patients with severe lower extremity edema due to PTS, intermittent compression therapy is recommended.
Attachment: Clinical staging of DVT
Acute stage: refers to within 7 days after the onset of the disease;
Sub-acute stage: from day 8 to day 30 (1 month) after onset;
Chronic stage: after 30 days of onset;
The early stage referred to in this guideline includes both acute and subacute stages.