Deep venous thrombosis (DVT) of the lower extremities is a common and frequent clinical disease []. It is well known that it is harmful and has a high incidence of long-term complications, such as post-thrombotic syndrome (PTS), which seriously affects the quality of life of patients, and even worse, sudden death due to pulmonary embolism (PE). The aim of DVT treatment is to prevent PE, restore venous patency, prevent recurrence of DVT, and maintain the function of venous valves to the maximum extent to reduce the occurrence of PTS. At present, the commonly used clinical treatment methods include anticoagulation, thrombolysis, interventional therapy, surgical thrombosis and other treatments. This paper mainly discusses how to choose various anticoagulant drugs and how to establish the course of anticoagulation therapy.
1.Clinically used anticoagulant drugs
At present, the main anticoagulant drugs in clinical practice are heparin (unfractionated heparin, UFH), low molecular weight heparins (LMWH), vitamin K antagonists (warfarin) and new oral anticoagulant drugs that have attracted much attention recently.
1.1. common heparin (UFH) UFH is a mucopolysaccharide extracted from the digestive tract of pigs or bovine lungs, with a molecular weight of 3000-30,000 Daltons. the anticoagulant effect of UFH can prevent the formation of new thrombi, and also activate fibrin by enhancing the action of fibrinogen activator (PA), which starts the fibrinolytic process and thus dissolves the formed thrombi. In addition, UFH protects vascular endothelial cells, stabilizing and preventing endothelial cell detachment.
The adverse effect of UFH is bleeding, the incidence of which is about 5-10%, depending on the dose and route of administration. If bleeding occurs with UFH, the dose should be reduced or discontinued depending on the severity. If necessary, the last dose of UFH should be used as a ratio of 1 mg of fisetin to 100 U of UFH administered intravenously. Another adverse effect is heparin induced thrombocytopenia (HIT), after the occurrence of HIT, UFH should be discontinued immediately and replaced by direct thrombin inhibitors, such as argatroban [], or new oral anticoagulants such as Bactrim.
1.2. Low molecular weight heparin (LMWH) LMWH is a smaller molecular weight heparin made by cleavage of UFH, with an average molecular mass of about 4000-6500 Daltons. It is highly bioavailable after subcutaneous injection and has a half-life of about 150 min in the body, with a duration of action of up to 24 h. LMWH is mainly excreted through the kidneys, so it should be used with caution in patients with renal insufficiency, and the incidence of thrombocytopenia and sensitization is much lower with LMWH. LMWH generally does not require monitoring, but it is recommended that factor Xa levels be measured every 4 h in patients with advanced renal disease, morbid obesity, or pregnancy, LMWH can also be neutralized by the use of fisetin in the same way as UFH.
1.3. Vitamin K antagonist (warfarin) Warfarin is a bicoumarin derivative, which has no anticoagulant effect in vitro. Warfarin mainly serves to inhibit the formation of new thrombus and has no thrombolytic effect on the formed thrombus. It is rapidly and completely absorbed through the gastrointestinal tract after oral administration. The anticoagulant effect of warfarin depends on the degree of reduction of functional factor X and prothrombin levels, which have a half-life of 24 and 72 hours, respectively, and therefore have a delayed anticoagulant effect. In patients with established thrombosis or at high risk of thrombosis, the initial administration of oral warfarin is often bridged by the concomitant application of a fast-acting anticoagulant, such as heparin or LMWH.
The anticoagulant effect of warfarin is influenced by genetics, diet, medications, and various disease states, with large individual differences, and changes in dietary vitamin K intake can also affect warfarin activity; therefore, it has a narrow therapeutic window and requires regular monitoring of coagulation indicators and adjustment of dosage, usually monitoring the prothrombin time INR. for most indications, warfarin dosage with an INR between 2 -For most indications, a warfarin dosage of INR between 2 and 3 is the standard, but an INR between 2.5 and 3.5 is recommended for patients with prosthetic heart valves. Warfarin dosage should be individually formulated, usually with an initial dose of 2.5-5 mg. Because II, IX, and X are depleted after approximately 3 days before they begin to show anticoagulant effects, overlapping applications of fast-acting anticoagulants such as UFH or LMWH are required for at least 5 days to monitor INR and adjust dosing. The main complication of warfarin is bleeding, which can pass through the placenta and cause teratogenic and neurological abnormalities, with high rates of miscarriage and stillbirth, and is therefore contraindicated in pregnant women.
1.4. New oral anticoagulants (direct factor Xa inhibitors) Rivaroxaban is an oral anticoagulant that directly inhibits factor Xa in a highly selective manner. It interrupts endogenous and exogenous coagulation pathways by directly inhibiting factor Xa, inhibits thrombin production and thrombosis, and inhibits factor Xa in the bound state as well as thrombinogen activity, but has no direct effect on platelet aggregation.
The EINSTEIN-DVT phase III clinical trial of rivaroxaban for the treatment of patients with acute symptomatic DVT was published at the European Society of Cardiology (ESC) 2010 meeting [] and included 3449 patients with acute proximal DVT without clinical evidence of pulmonary embolism, treated for 3, 6, or 12 months. The results of the trial confirmed that rivaroxaban had no hepatotoxic effects, that adverse events were rare, that the benefit of rivaroxaban in preventing venous thromboembolic events was not inferior to that of the standard treatment regimen (administration of LMWH followed by transition to warfarin long-term maintenance therapy), and that the safety profile was comparable to that of standard therapy. The extension trial, EINSTEIN-EXT, was a randomized, double-blind, placebo-controlled, event-driven superiority study enrolling patients with confirmed symptomatic DVT or PE who had completed 6 or 12 months of treatment with rivaroxaban or VKA in the EINSTEIN VTE study for 6 or 12 months. Results: 82% reduction in relative risk of recurrent VTE (HR=0.184; p<0.0001), 5.8% reduction in absolute risk, low incidence of major bleeding events (0.7%; p=0.11; NNH approximately 139), efficacy and safety outcomes independent of patient weight and creatinine clearance, modest increase in the incidence of clinically relevant non-major bleeding events (5.4% vs 1.2%; p<0.01), and no manifestations of hepatotoxicity.
2. Selection of anticoagulant drugs
The anticoagulant efficacy of LMWH is equal to or even better than UFH, and the incidence of adverse reactions such as bleeding and death is low, and the safety is significantly better than that of common heparin. Allergic reactions can shorten the hospitalization time. Compared with UFH, LMWH can significantly inhibit tumor metastasis and prolong the survival time of patients, which is more suitable for patients with tumors that are difficult to monitor or require long-term anticoagulation therapy. The new oral anticoagulant drugs can be preferred for patients with inconvenient monitoring, high risk of bleeding and intolerance of subcutaneous injection because of the features of no monitoring of coagulation index, high safety and convenience of administration. Regarding the selection of anticoagulant drugs for DVT, the Chinese Medical Association’s Vascular Surgery Group (2012) broadly recommends that
①In acute DVT, vitamin K antagonist (warfarin) combined with LMWH or UFH is recommended; stop LMWH or UFH after the INR is achieved and stabilized for 24 h. Direct (or indirect) factor Xa inhibitors can also be used.
If there is no contraindication to anticoagulation therapy, anticoagulation therapy is feasible while waiting for the test results, and the decision to continue anticoagulation is based on the confirmed results.
The use of UFH is recommended for patients with severe renal insufficiency, but in clinical practice it is often necessary to individualize the choice according to the patient’s specific situation, for example, in elderly patients, those with inconvenient monitoring of the national normalized ratio (INR) or those with combined malignancy, the choice of low-molecular-weight heparin may be safer and more convenient. The new oral anticoagulant drugs are more acceptable to patients in terms of convenience of use.
3. Determination of the course of anticoagulation therapy
3.1. recurrence of DVT and PE Clinical recurrence of DVT and PE (venous thromboembolism, VTE) is not uncommon despite standard systematic anticoagulation therapy. prandoni P et al [] reported the results of a cohort study with a large sample of long-term follow-up. A total of 1626 patients were enrolled with a mean follow-up of 50 months, with the longest follow-up period being 10 years. Patients with cancer, history of VTE, and other indications for long-term anticoagulant use were excluded. The study defined secondary VTE as the presence of at least one of the following risk factors: pregnancy or childbirth within 3 months; trauma, fracture, or surgery to the leg within 3 months; and prolonged bed rest due to chronic medical illness. The study defined unexplained VTE as VTE without these risk factors, with 53.1% of patients with unexplained VTE. The cumulative recurrence rates at 1, 5, and 10 years were 11%, 29.1%, and 39%, respectively. A comparative analysis of VTE of unknown cause versus secondary VTE showed a cumulative recurrence rate of 15% vs 6.6% at 1 year, 40.5% vs 16.1% at 5 years, and 52.5% vs 22.5% at 10 years. Analysis of data from all patients in the study showed that thrombus-prone status, short anticoagulation course (less than 6 months) and age were independent risk factors for VTE recurrence. This study suggests that we.
(i) VTE is prone to recurrence and deserves serious attention; (ii) the recurrence rate of VTE increases significantly with longer discontinuation of anticoagulation therapy, so it is worthwhile to pay attention to how long is the appropriate duration of anticoagulation therapy?
3.2. Anticoagulation course As mentioned above, the course of anticoagulation therapy has always been one of the problems that plague clinical work. For this reason, in 2012, the Chinese Medical Association Vascular Surgery Group gave the following general recommendations.
① For patients with primary DVT secondary to transient risk factors, use vitamin K antagonists for 3 months;
②Patients with primary DVT with unknown risk factors should be treated with vitamin K antagonists for 6 to 12 months or longer;
③ For DVT with cancer and first occurrence, use vitamin K antagonist for a long time after 3 to 6 months of LMWH; ④ For patients with recurrent DVT and thrombosis-prone patients, long-term anticoagulation is recommended, but risk-benefit assessment should be performed periodically.
3.3. The course of anticoagulation therapy should be individualized Although the Chinese Medical Association Vascular Surgery Group has given general recommendations regarding the course of anticoagulation therapy, some specific issues still lack operable rules in clinical work. For this reason, the author reviewed the clinical randomized controlled studies that could be retrieved up to now (Table 1). Based on the guidelines, the results of the above studies and the author’s own clinical experience, the author proposes the following for reference: for all patients with proximal DVT and PE, the anticoagulation course should be at least 3 months, where.
(i) 3 months of anticoagulation for all sites of VTE secondary to surgical risk and other factors;
②Patients with DVT or PE secondary to non-surgical, temporary risk factors, anticoagulation for 3 months;
(iii) 3 months of anticoagulation in patients with unexplained proximal DVT without residual venous obstruction and with persistent negative D-dimer;
④For patients with unexplained proximal DVT with a low probability of clinically predicted recurrence, anticoagulation for 3 months;
⑤ Anticoagulation for 6-12 months in patients with unexplained isolated PE that is currently hemodynamically stable, without right heart insufficiency, with a low clinically predicted likelihood of recurrence, and with persistent negative D-dimer;
(6) Patients with permanent serious risk factors, patients with unexplained VTE with a high probability of clinically predicted recurrence, patients with unexplained VTE with persistent positive D-dimer, and patients with persistent residual venous obstruction require long-term anticoagulation (periodic assessment of bleeding risk and determination of anticoagulation regimen);
Patients with PE with chronic thromboembolic pulmonary hypertension require long-term anticoagulation (periodic assessment of bleeding risk and determination of anticoagulation regimen).
Conclusion: DVT is a common and frequent clinical disease, and it is easy to recur and clinically dangerous. Anticoagulation is the most basic therapeutic measure for DVT, and a full understanding of the characteristics of commonly used anticoagulants is the basis for individualized clinical selection with the guidelines of safety, effectiveness, economy and convenience. The comprehensive multi-factor individualized determination of anticoagulation treatment course is the key to prevent recurrence of VTE and benefit patients in the long term.