Deep vein thrombosis (DVT) is one of the common diseases in vascular surgery, with an incidence of about 1 per 1,000. the acute phase of DVT can cause progressive increase in venous obstruction due to thrombus multiplication, even causing femoral cyanosis leading to limb necrosis requiring amputation, and once the free thrombus is dislodged, it can also cause fatal pulmonary embolism. The thrombus eventually tends to ablate or undergoes mechanization and neovascularization under the action of its own fibrinolytic activity, and the venous lumen blocked by the thrombus is gradually recanalized, while the venous valve structure is destroyed in the process of thrombus mechanization.
Therefore, the late stage of DVT is usually the coexistence of venous reflux due to proximal venous occlusion and venous reflux due to venous valve destruction, causing lower extremity venous hypertension and the corresponding clinical manifestation, namely post-thrombotic syndrome (PTS), which has a serious impact on the quality of life of patients.
Therefore, once DVT develops, the aim of treatment is to inhibit the spread of thrombus, remove thrombus, restore venous patency and protect the structure and function of venous valves, prevent and reduce the incidence and mortality of pulmonary embolism, and reduce the incidence of thrombotic recurrence and PTS. This paper summarizes the application of catheter-directed thrombolysis (CDT) in the treatment of acute lower extremity DVT, with the aim of forming a consensus and standardizing treatment.
I. Current status of acute lower extremity DVT treatment
Currently, the treatment methods used for acute lower extremity DVT include anticoagulation therapy and thrombectomy. Anticoagulant drugs can prevent the further formation of thrombus to a certain extent, but they cannot remove the existing thrombus, so the therapeutic effect is limited. Thrombectomy includes: surgical thrombectomy, mechanical thrombectomy and CDT. Surgical thrombectomy has never been the treatment of choice for acute thrombosis of the skeletal femoral vein due to its complications such as bleeding, vascular injury and high recurrence rate of thrombosis; CDT is an interventional thrombolytic method in which a thrombolytic catheter is inserted directly into the iliofemoral N vein thrombus through the deep vein under DSA fluoroscopy, which can improve the rate of thrombus removal with the premise of reducing the risk of bleeding, improve the efficiency of thrombolysis of drugs and rapidly open the obstructed vein. And it has been rapidly popularized and developed in the clinic.
II. Indications for CDT treatment
For acute skeletal femoral vein thrombosis, there are indications for CDT if there is no contraindication to thrombolysis and the thrombolytic catheter can be successfully placed.
(1) Acute skeletal femoral vein thrombosis;
(2) Acute femoral N vein thrombosis; (3) DVT of ≤14 days duration It is currently believed that ambulatory young healthy patients may benefit the most, while patients with prolonged bed rest, high bleeding risk, advanced age, with other serious diseases, and life expectancy <1 year should have strict indications.
Note: Clinical staging of DVT: acute stage refers to a history of <14 days; subacute stage refers to a history of 15-30 days; chronic stage refers to a history of >30 days.
III. Contraindications to CDT treatment
(1) Contraindicated or allergic to the use of anticoagulants, contrast agents and thrombolytic drugs;
(2) History of cranial, gastrointestinal or other active internal bleeding or cerebral infarction within the past 3 months;
(3) History of severe trauma or major surgery within the last 4 weeks;
(4) Pregnancy;
(5) Uncontrollable hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >110 mmHg);
(6) Bacterial endocarditis;
(7) Those with coagulation disorders.
Operation method and route of CDT
1.Inferior vena cava filter placement: Under DSA, the patient is placed in the horizontal position, and the Seldinger technique is used to enter the femoral vein on the healthy side, and the iliac vein and inferior vena cava imaging on the healthy side is performed first. If the thrombus is found to involve the inferior vena cava, the inferior vena cava imaging is performed by puncturing the right internal jugular vein to observe the thrombus, the position of the opening of both renal veins and the bifurcation of the inferior vena cava, and the diameter of the inferior vena cava is measured. The inferior vena cava filter was placed below the opening of the renal vein in the inferior vena cava. For patients with a retrievable filter, an inferior vena cava angiogram was performed before removal of the thrombolytic catheter, and the filter was removed if no thrombus remained below the filter, or placed permanently if it did. If there is no thrombus residue under the filter, it will be removed, and if there is, it will be placed permanently. The indications for filter placement refer to the Guidelines for the Diagnosis and Treatment of Deep Vein Thrombosis formulated by the Vascular Surgery Group of the Chinese Society of Medical Surgery.
2.Catheter thrombolysis access and method
(1) Parallel access.
Trans-saphenous vein placement: Applicable to central type and mixed type DVT of lower extremity, prone position, take a longitudinal skin incision of about 50px at the middle of the outer ankle and Achilles tendon of the affected limb, expose the small saphenous vein, place a 4-5F catheter sheath through the small saphenous vein, select a 4-5F thrombolytic catheter with a lateral hole length of 20-1000px and place it into the common iliac vein of the affected limb.
(2) Trans-saphenous vein placement: It is suitable for central and mixed type of lower limb DVT, where the saphenous vein above the inner ankle can often be exposed under the body surface; it is also suitable when the patient has fracture and cannot be turned in the position.
Methods of saphenous vein placement.
① Direct puncture through the beginning of the saphenous vein in the inner ankle;
(2) Cut the skin and subcutaneous tissue and puncture under direct vision;
Placement: After successful puncture, a 4-5F vascular sheath is placed and the guidewire is placed into the N vein via the femoral vein to the inferior vena cava via the traffic branch with the aid of the path mapping technique.
Trans-N vein placement: For central DVT where the thrombus is confined to the iliofemoral vein and the patient has no restriction of limb movement. The patient is placed in the prone position, and the N vein is punctured and the catheter sheath is inserted under ultrasound guidance or dorsalis pedis venogram showing the localization of the N vein.
(3) Retrograde access: The following accesses can be chosen if the patient cannot be placed through the above accesses
(1) Transjugular vein placement: The right jugular vein is punctured and the catheter sheath is inserted, and the thrombolytic catheter is placed into the iliofemoral vein of the affected limb through the jugular vein, with the head of the thrombolytic catheter placed as far as possible at the distal end of the femoral vein.
②Transfemoral vein placement: puncture the femoral vein on the healthy side and place the catheter sheath, then with the help of the cobra catheter, place the guidewire retrograde into the iliofemoral vein of the affected limb and finally exchange it for the thrombolytic catheter, with the head end of the thrombolytic catheter placed at the distal end of the femoral vein of the affected limb.
IV. Use of anticoagulant and thrombolytic drugs
Heparin is a commonly used anticoagulant drug, which can be injected subcutaneously or by intravenous drip. The half-life in the body is 90 minutes, and the effect will disappear in 2-3 hours. Low molecular heparin is mostly injected subcutaneously and has a longer half-life of 12 hours.
Urokinase, recombinant tissue-type fibrinogen activator and streptokinase are clinically available thrombolytic drugs. The use of streptokinase is limited due to allergic reaction and bleeding risk, while urokinase and recombinant t-PA have become the first choice for clinical treatment of DVT because of their better thrombolytic effect and lower bleeding incidence, but due to the higher cost of the latter, the use of urokinase is still more popular in clinical practice.
There is no uniform standard for the dose and method of urokinase use. We recommend that 250,000 units of urokinase be added to 50 ml of saline for one-time injection through the thrombolytic catheter during catheter thrombolysis, and then (1) a high-pressure pump be used to inject urokinase through the thrombolytic catheter in a pulsatile manner, 600,000-800,000 units/24h, divided into two doses, each time within one hour. Heparin 100-150 mg/24h was drip injected via catheter during the interval between urokinase injections; ② urokinase was continuously and uniformly pumped via catheter (total 600,000~800,000 units/24h), while patients were given subcutaneous injection of low molecular heparin 5000 U every 12h, generally applied continuously for 7 days.
rt-PA can selectively activate the fibrinogen at the thrombus site, so that it can be converted into fibrinolytic enzymes and dissolve the thrombus, the adverse effects of systemic fibrinolytic state are small, and the incidence of bleeding complications is low. The disadvantage of rt-PA is that it cannot be applied for a long time, and no additional dose can be given after the planned dose is used up if the expected thrombolytic effect is not achieved.
The coagulation index should be reviewed daily during anticoagulation and thrombolysis.
During anticoagulation therapy, it is necessary to monitor.
①Clotting time, heparin for therapeutic purposes requires 2-3 times longer clotting time, i.e. 20-30min. When clotting time <12min, the dosage of heparin should be increased, and when clotting time >30min, the dosage of heparin should be reduced.
② Activated partial thromboplastin time (APTT), the normal value can vary from laboratory to laboratory, after using heparin to extend 1.5-2.5 times is appropriate. Serum heparin concentration can also be monitored if available, so that it reaches 0.3-0.5u/ml.
The indicators that should be monitored in thrombolytic therapy include.
①Prothrombin time: the normal value is 11-13s, and more than 25s is abnormal.
②Plasma fibrinogen measurement: normal value is 2-4g/L. If the blood fibrinogen level is <1.5g/L, the dosage of urokinase should be reduced, and if the blood fibrinogen level is <1.0g/L, the dosage should be stopped immediately if the monitoring is continued.
The normal value of prothrombin time is 16-18s, which should not exceed 3-4 times the normal value during thrombolysis, and 60s is ideal.
The catheter can be withdrawn 20-750 px depending on the length of the thrombolytic segment if the thrombus is mostly or completely dissolved in the lateral orifice of the catheter, and the thrombolytic catheter can be withdrawn 4-5 d after the procedure if the history is within 7 days, or 6-8 days if the history is 7-14 days.
Indicators of discontinuation of catheter thrombolysis include: (1) when bleeding or serious infection complications occur during thrombolysis; (2) when fibrinogen level is <1.0g/L; (3) when patency is restored in the main vein above the N vein; and (4) when no progression of thrombolytic findings is seen on post-thrombolysis imaging for 4-5 consecutive days.
V. Management of iliac vein stenosis
As the role of anatomical abnormalities of the left iliac vein in the development of DVT has received more and more attention, it is recognized that it is not enough to remove the thrombus without dealing with iliac vein stenosis. Several domestic clinical studies have shown that the incidence of iliac vein lesions in cases of left lower extremity DVT is as high as 65-73%, and the lesions are mostly located at the left common iliac vein converging into the IVC. The literature reports a 3-year patency rate of 89-94.6% in iliac vein stenosis or occlusion without secondary thrombosis treated with stenting, which proves that stenting is safe for the treatment of iliac vein lesions.
The results of several studies have also shown that in the treatment of lower extremity DVT with iliofemoral vein thrombosis followed by placement of iliac vein stents to correct iliac vein stenosis, the one-year patency rate of deep veins was significantly higher in those with stents than in those without stents, indicating that self-expanding stent placement is necessary when skeletal vein stenosis is combined with thrombosis. We recommend that for cases with complete dissolution of femoral N vein thrombosis and stenosis of the iliac vein of the affected limb found by imaging, balloon dilation should be performed for the iliac vein lesion and stent should be placed, with a recommended balloon diameter of 10-12 mm and stent diameter of 12-16 mm.
VI. Post-discharge follow-up and treatment
Patients with DVT require long-term anticoagulation therapy to prevent the development of thrombosis or recurrence. Patients who are usually treated with long-term anticoagulation therapy include the following four types.
1.First episode of DVT with malignancy;
2.First-episode DVT with no obvious cause;
3, first episode of DVT with genetic and prognostic markers associated with increased risk of thrombotic recurrence (e.g. protein C, protein S deficiency, factor V Leiden mutation, etc.);
4, recurrent multiple episodes of DVT.
Warfarin is very effective in preventing recurrence of DVT. The criteria for monitoring the anticoagulant effect of warfarin are prothrombin time and INR, and the prothrombin time is prolonged by more than 50% (normal value is 12-14s) and the international normalized ratio (INR) is between 2.0 and 2.5 during the drug administration. Trials of extended warfarin regimens in patients with primary DVT have shown that warfarin regimens extended to 1-2 years are more effective in reducing recurrence of DVT than 3-6 months, but with an increased risk of bleeding, so the decision on anticoagulation regimens for primary DVT needs to be made after weighing the pros and cons according to the patient’s condition.
In recent years, some new oral anticoagulants have been used in the treatment of acute DVT, such as direct factor Xa inhibitors (rivaroxaban, etc.). Available evidence shows that oral direct factor Xa inhibitors are as effective as standard treatment for DVT (heparin or low-molecular heparin combined with vitamin K antagonists), but significantly improve the benefit-risk ratio of anticoagulation therapy. Rivaroxaban’s approximate kinetic and pharmacodynamic parameters are less influenced by gender, weight or age, and interactions with other drugs are less likely to occur. With a fixed dose once a day, no special blood monitoring is required, making it an ideal new oral anticoagulant that provides a simple monotherapy option for the acute treatment and ongoing treatment of DVT patients. It also requires the affected limb to wear elastic stockings for 6 months~2 years.
VII. Management of common complications
1.Bleeding: bleeding around the puncture site. It may manifest as oozing blood or hematoma. The literature reports that the incidence of bleeding after CDT is 5-11%, including intracranial bleeding <1%, retroperitoneal bleeding 1%, musculoskeletal system, urinary system and gastrointestinal tract about 3%, bleeding can occur in the puncture local or distant tissues and organs. The number of patients requiring blood transfusion for severe bleeding is 0-25%, which is related to the dose and duration of thrombolytic drugs, as well as to the degree of simultaneous anticoagulation and individual differences. Therefore, all patients undergoing thrombolysis by catheter need to be closely monitored for vital signs. This complication can be reduced by choosing a suitable sheath, avoiding multiple punctures, properly stopping the bleeding of the incised subcutaneous tissue, ligating or suturing the small capillary bleeding, and applying appropriate pressure bandages. At the same time, blood oozing around the puncture site is often a sign of overdose of thrombolytic drugs.
2, peri-catheter thrombosis: peri-catheter thrombosis is caused by obstruction of venous return after catheter placement and/or inadequate anticoagulation therapy. Key points to avoid this complication include.
(1) Choose a suitable size of thrombolytic catheter, e.g., a 4F catheter should be used for placement through the saphenous vein and the small saphenous vein to avoid too thick a catheter that interferes with the reflux in the large and small saphenous veins;
(2) Heparin can be injected drip from the external sheath.
(3) Adequate anticoagulation therapy: such as low molecular heparin 5000U every 12h, usually applied continuously for 7 days or heparin 100-150mg/24h via catheter drip between urokinase injections.
3, catheter secondary infection: mostly manifested as the symptoms of superficial phlebitis in the catheter placement route, may be accompanied by fever. Treatment can be applied to the affected area with hot and humid magnesium sulfate, while giving penicillin anti-infection treatment, if the symptoms still can not improve after 3 days, remove the catheter and discontinue thrombolysis. If the patient has symptoms of bacteraemia, blood culture + drug sensitivity should be performed to select sensitive antibiotics for treatment.