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 the thrombus can cause pulmonary embolism, collectively known as Venotls Thromboembolism. 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. 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 biscuit injury, slow blood flow and blood hypercoagulation. The risk factors include primary and secondary factors, see Table 1. DVT is mostly seen after major surgery or trauma, prolonged bed rest, limb braking, patients with advanced tumors or those with obvious family history.
Risk factors for DVT
Primary factors secondary factors, antithrombin deficiency, congenital abnormal fibrinogenemia, thrombomodulin, hyperhomocysteinemia, anticardiolipin antibodies, excess inhibitors of fibrinogen activator, prothrombin 20210A gene variant, protein C deficiency, factor V Leiden mutation (activated protein C resistance), fibrinogen Abnormal fibrinogen deficiency, protein S deficiency, factor Ⅻ deficiency 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, chemotherapy for malignancy, obesity, heart failure , long-distance travel oral contraceptives, lupus anticoagulant, artificial material surface.
(B) 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 accelerated heart rate.
2.Signs: swelling of the distal limb of the thrombus or the whole limb is the main feature, the skin is mostly normal or mildly bruised and may be cyanotic in severe cases, and the skin temperature is reduced. If the artery is affected, the distal artery 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, which is called postthrombosis syndrome (PTS).
Dislodged thrombus can cause the manifestation of pulmonary artery embolism.
(C) Diagnosis of DVT
I. 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 of 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 μg/L has important reference value. It has 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 it 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, as many fibrin-producing conditions such as tumor, inflammation, infection, necrosis, etc. can have a D-dimer greater than 500
The specificity of this test is low for the elderly patients over 80 years old, so it is not suitable for these people.
3, color Doppler ultrasound exploration: its sensitivity and accuracy are high, it is a non-invasive test, and is suitable for screening and monitoring of patients. Careful non-invasive vascular ultrasound can maintain 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 therapy, and patients in the high incidence group should be considered for venography if the second scan is still negative.
4.Radionuclide 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: It 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 treatment for DVT can be subcutaneous injection of low molecular heparin and heparin (refers to 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 1.5-2.5 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 plasma heparin levels of 0.3-0.7 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 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 6,250 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.
For patients with a high clinical suspicion of DVT, if not contraindicated, anticoagulation may be considered while awaiting the results of the test “and the decision to continue anticoagulation will be based on the confirmation of the diagnosis
The combination of vitamin K antagonist and low molecular heparin or heparin is recommended to be started on the first day of treatment and discontinued 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 low molecular heparin is adjusted for body weight by subcutaneous injection 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 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 most of it does not require monitoring.
Recommendations
For patients with acute DVT, 12-hourly subcutaneous doses of low molecular heparin are recommended;
In patients with severe renal failure, intravenous heparin is recommended and low-molecular heparin should be considered with caution.
Thrombolytic therapy
The use of thrombolytic agents to dissolve venous thrombi and rapidly reduce vascular obstruction is theoretically indicated as a treatment measure for patients with DVT. Early thrombolytic therapy is effective, but thrombolytic therapy may increase the risk of bleeding. It is uncertain whether early DVT treatment with thrombolytic agents can reduce the incidence of PTS.
Recommendations
Thrombolysis may be considered in 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 in 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 recurrence of pulmonary embolism and early thrombosis as well as good long-term outcome of valve function. For long-term outcomes, the majority of cases are currently observational.
Recommendations
Embolization may be considered for certain elective patients, such as more severe iliofemoral vein thrombosis.
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 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.
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
In patients with early DVT, a period of strict bed rest is recommended 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 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 classified into 5 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, mutations in prothrombin genes such as factor V
Leiden or prothrombinogen 20210 mutations), patients with antiphospholipid antibodies, homocysteinemia, or higher than 90% of normal levels of factor VIII, or persistent residual thrombus confirmed by repeated ultrasound examinations; (5) recurrent multiple episodes of DVT (two or more episodes of VTE).
Application of vitamin K antagonists in 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. The low standard intensity (INR
1.5-1.9) treatment is poorly effective and does not reduce the incidence of concomitant bleeding. Therefore, high-intensity warfarin therapy (INR
3.1-4.0) did not provide a better antithrombotic treatment effect. 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 2.0-3.0 throughout the course of therapy and require regular monitoring.
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 an extended course of anticoagulation in patients with primary DVT, extending the course to 1-2 years compared with a control group of patients treated conventionally for 3-6 months, found that the extended course was highly effective in reducing the incidence of recurrent VTE, but with an increased risk of bleeding during treatment. Therefore, the decision of whether or not to extend the course of anticoagulation in 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.
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%-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
Recommended
For patients with mild lower extremity edema due to PTS, compression stockings are recommended
Intermittent compression therapy is recommended for patients with severe lower extremity edema due to PTS
Attachment: clinical stage of DVT
Acute stage: within 7 days after the onset of the disease;
Subacute stage: from day 8 to day 30 (one month) of onset
Chronic stage: after 30 days of onset
The early stage referred to in this guideline includes the acute and subacute stages