[Abstract] Post-thrombotic syndrome (PTS) is the most common complication after deep vein thrombosis (DVT), and it has been one of the problems for vascular surgeons due to the lack of effective prevention and treatment methods. In this paper, we start from the pathogenesis, clinical manifestations and diagnosis of PTS, and then summarize the prevention and treatment strategies of PTS based on the latest progress at home and abroad.
Post deep vein thrombosis syndrome is a chronic venous insufficiency secondary to impaired deep venous valve function after DVT. PTS can occur in about 50% of acute DVT patients within 2 years, and severe PTS, such as venous ulcers, can occur in 5%-10% of patients, which seriously affects the long-term quality of life of DVT patients.
1.Pathogenesis of PTS
Most scholars believe that PTS is a series of clinical symptoms caused by impaired venous return, reduced calf muscle perfusion, and increased tissue permeability due to abnormal microvascular function as a result of long-term venous hypertension. chronic venous hypertension can be caused by two mechanisms after DVT, including complete or partial venous obstruction and venous reflux, of which the former is more important. Although standard anticoagulation therapy after DVT can prevent thrombotic progression and pulmonary embolism, it cannot directly dissolve and remove acute thrombus. valve regurgitation often occurs after DVT, which may be caused by activation of post-thrombotic inflammatory response, fibrous scar formation in the valve leaflets, and incomplete valve closure due to distal venous dilatation in the obstructed segment of the vein.
2, High risk factors for PTS
According to the literature, iliofemoral vein (as opposed to N or calf vein) thrombosis, previous history of ipsilateral deep vein thrombosis, obesity, and advanced age are high risk factors for the development of PTS. A prospective cohort study found that incomplete resolution of lower extremity symptoms within 1 month after acute DVT was a risk factor for the development of PTS within 2 years thereafter. In addition, the results of another study showed that oral warfarin anticoagulation after DVT can increase the risk of PTS if the INR does not meet the therapeutic criteria, and this result also re-emphasizes the importance of close monitoring of coagulation indicators in oral anticoagulation therapy.
In terms of molecular biological markers, recent studies have shown that the persistent elevation of certain inflammatory factors (such as ICAM-1, IL-6 and C-reactive protein) and D-dimer in the months after DVT is correlated with the occurrence of PTS, and in-depth studies in this area are underway.
3.Diagnosis and grading of PTS
(1) Clinical manifestations of PTS
PTS usually occurs 1~2 years after DVT, and the typical symptoms include pain, swelling, swelling, cramping and itching in the affected limb, which may occur alone or in combination, intermittently or continuously, and usually worsen after standing or prolonged walking, and decrease with rest or elevation of the affected limb. The common signs of PTS include limb edema, dilated capillaries in the ankle or more, skin pigmentation in the foot and boot area, stasis dermatitis, and, in severe cases, chronic, untreated venous ulcers. In addition, secondary varicose veins may also occur.
(2) Diagnosis of PTS
PTS can be diagnosed in patients with previous DVT and the above signs and symptoms, but for some patients, the diagnosis of PTS should be established in the chronic phase following acute DVT because the initial pain and swelling due to acute DVT takes several months to subside. In patients with no clinical manifestations of PTS, but only abnormal venous function (e.g., reflux, venous obstruction, venous hypertension, etc.) detected by imaging (e.g., ultrasound, venography, etc.), PTS cannot be diagnosed even if they have had DVT previously; therefore, in patients with previous DVT and typical clinical manifestations of PTS, further imaging is not necessary. For patients with typical manifestations of PTS but without a clear history of previous DVT, further imaging is required.
(3) Grading criteria of PTS
The clinical scoring system is based on the severity of symptoms and signs of PTS, which includes 5 clinical symptoms (heaviness, pain, cramping, pruritus and abnormal sensation) and 6 clinical signs (anterior tibial edema, skin nodules, hyperpigmentation, venous dilatation, flushing and Each indicator was scored from 0 to 4 on a scale from none to severe. If the total score is 0~4 without PTS, 5~9 is mild PTS, 10~14 is moderate PTS, >14 or ulcer formation is severe PTS.
4.Prevention of PTS
(1) Prevention of primary and recurrent thrombosis
For people at high risk of DVT, systematic thromboprophylaxis should be performed to prevent the occurrence of DVT and PTS according to the methods recommended in the evidence-based medical guidelines. In addition, since recurrent DVT in the ipsilateral limb is one of the important risk factors for PTS, in order to reduce the recurrence rate of DVT, adequate anticoagulation should be given and an adequate treatment course should be ensured during the treatment of patients with primary DVT.
(2) Wearing elastic medical stockings
Elastomeric medical stockings (ECSs) with pressure gradients can reduce venous hypertension, reduce edema and improve tissue microcirculation. Several clinical trials have demonstrated the effectiveness of long-term use of ECSs in preventing PTS after symptomatic proximal DVT. In a Dutch study, 194 patients were randomized to a group wearing ECSs and a control group, with the former wearing below-knee compression stockings with a daily compression of 30-40 mmHg for at least 2 years. Musani et al. concluded from a meta-analysis summarizing five randomized controlled studies that wearing compression stockings in patients with proximal DVT reduced the incidence of PTS from 46% to 26%. A recent randomized controlled trial showed no significant difference in the incidence of PTS at 2 years after DVT when wearing below- or above-knee compression stockings. Based on several studies, the American College of Chest Physicians (ACCP) guidelines recommend wearing compression stockings with an ankle pressure of 30-40 mmHg for at least 2 years in patients with acute symptomatic proximal DVT, or longer if the patient has developed PTS symptoms. The need to wear compression stockings for symptomatic peripheral DVT remains uncertain. In addition, it remains uncertain whether ECSs can completely prevent or simply reduce the symptoms of PTS, and the duration of wear of compression stockings is also uncertain, with some studies suggesting more than 2 years of use, but recent studies suggesting only 6 months of wear, with no significant benefit for the subsequent 18 months for the prevention of PTS. Finally, it remains to be evaluated whether lower pressure (20-30 mmHg) compression stockings have the same effect, as they are easier to wear than high pressure stockings and are particularly suitable for elderly patients.
(3) Thrombolysis for acute DVT to prevent PTS
This hypothesis is supported by the results of systemic thrombolytic therapy and the newly developed transcatheter thrombolytic therapy technique (CDT), which may be able to preserve venous valve function and prevent PTS by rapidly restoring venous patency in the shortest possible time. For proximal venous DVT (iliofemoral vein) the incidence of PTS at 24 months with CDT was significantly lower than with anticoagulation alone (41.1% vs 55.6%, p=0.047). Recently, preliminary results published in the randomized, controlled design TORPEDO study showed that intraluminal thrombolysis significantly reduced the incidence of PTS and VTE at 6 months after DVT compared with anticoagulation alone. According to ACCP guidelines, direct thrombolysis by catheter or systemic thrombolysis in combination with standard anticoagulation therapy can reduce the symptoms of acute DVT and prevent PTS in patients with acute migratory central DVT (iliofemoral DVT, symptomatic for less than 14 days, in good general condition, and with an expected survival time of more than 1 year) and a low risk of bleeding.
5.Treatment of PTS
(1) Pressure therapy
Compression therapy and intermittent elevation of the affected limb are the basic treatment for a clear diagnosis of PTS. It is usually recommended to elevate the affected limb above the atrial level for ≥30 min three times a day. ecss can help reduce limb swelling, heaviness and pruritus. An absolute contraindication to the application of ECSs is in patients with symptomatic peripheral arterial disease, as intermittent claudication may be exacerbated by the wearing of compression stockings. The choice of compression for ECSs should vary from person to person, with 30-40 mmHg usually applied and a length usually up to the knee being sufficient. In addition to ECSs, compression therapy includes intermittent compression pump therapy. In a randomized crossover controlled trial, application of an intermittent pressure pump twice daily (20 min each at 50 mmHg) was effective in reducing edema and improving PTS symptoms compared to the control group. More recently, there has been widespread acceptance of the portable lower extremity venous return aid (VenoWave), an easy-to-use, battery-powered device that is worn on the lower leg below the knee to give intermittent calf compression therapy, and the VenoWave is now FDA-approved. A randomized controlled study has shown that the application of VenoWave and the use of ECSs can reduce the symptoms of PTS and improve the quality of life.
(2) Drug therapy
There is evidence that some intravenously active drugs, such as mazerin (the active ingredient is anhydrous hesperidin from horse chestnut seed extract) or brassinosteroids, can reduce the symptoms of PTS. An Italian clinical trial enrolled 120 patients with PTS who improved PTS symptoms (improvement defined as a reduction in Villalta score to <5, or a 30% reduction in score from baseline) with regular oral administration of hydroxyethylrutinoside for 1 year, with effects similar to those of below-knee ECSs, but the combination of the two treatments did not result in increased efficacy. Another controlled study on chronic venous insufficiency showed that the application of 12-week ECSs compared with oral horse chestnut seed extract, which included 240 patients, showed no significant difference between the two treatments in terms of reduction of limb edema. In addition, another meta-study, which analyzed 17 studies comparing horse chestnut seed extract, placebo, ECSs and other drugs, showed that horse chestnut seed extract was effective in relieving the short-term symptoms of chronic venous insufficiency, such as limb swelling and pain, and that it had a milder and less frequent side effects. However, its long-term efficacy and safety need to be confirmed by more rigorous studies. According to my experience, patients whose PTS symptoms are still unsatisfactorily controlled after the application of ECSs can be treated with additional medications such as Mizarin for a long time.
(3) Surgical treatment
Surgical treatment is usually indicated for patients with moderate to severe PTS. The aims and methods of surgical treatment of PTS are divided into
Improving venous return obstruction: through various venous diversion procedures to make the high-pressure venous blood in the distal cardiac segment return from the bypass vessels to achieve the purpose of relieving venous hypertension. The traditional methods include: saphenous vein crossover diversion, in situ saphenous vein-N vein diversion, etc. In cases where there is anatomic external pressure in the iliac vein resulting in luminal stenosis (e.g., Cocket syndrome), the stenosis can be relieved by endoluminal stenting.
Reconstruction of deep venous valves and correction of blood backflow: Surgical methods include direct vision deep venous valve suture reduction, venous valve repair with a silicone capsule (Venocuff) (also known as lower extremity deep vein ringing), and venous valve grafting.
Relief of superficial venous hypertension: for those with venous ulcers in the foot and boot area, even if the deep veins are not completely recanalized, high saphenous vein ligation, superficial calf vein stripping and traffic branch ligation are all feasible. It has been proven that surgical stripping of superficial veins does not aggravate deep venous reflux obstruction. To date, only a few cases have been reported in the literature regarding surgical or endovenous treatment of PTS, and there are still no rigorous randomized controlled studies comparing whether these methods help to improve PTS symptoms in clinical practice, which still needs to be confirmed by the results of prospective randomized controlled studies.