| Background and ObjectiveIn 1960s,Deep Venous Thrombosis(DVT)in lower extremities is regarded as a disease that occurred less frequently.Since 1980s,along with the rapid growth of vascular surgery in China and the widespread application of various diagnosis techniques,DVT in lower extremities has been a common and frequently-occurred disease among the vascular diseases,whose detectable rate increases gradually.In the developing countries,approximate 30～60 million people are affected by this disease.In United States,the incidence of simple DVT is 145 cases per 100,000 people and along with the increase of the ages,the incidence that is less than 5 cases per 100,000 people in people under the age of 15,jumps to 500 cases per 100,000 people in people who are 80-year old.According to the statistics,200,000 cases of venous thromboembolism occur each year.Although the anticoagulation and thrombolysis treatments have been performed,in half year after the first onset of this disease,the recurrence rate is 7%.20%～50%of patients affected with DVT suffer the post-thrombosis syndrome (PTS)within one or two years.Within 5 years,the incidence of PTS exceeds 50%. The follow-up performed by Ziegler S to DVT patients who had been hospitalized during 1978 to 1988 shows that the incidence of PTS is as high as 82%.Among them,5-10%patients suffer the severe symptoms such as the pain in affected limbs,swelling,ulcer in calves and difficulty in walking,which cost a great deal of medical resources and bring the heavy burdens to families and the society.The traditional therapeutic methods for DVT mainly consist of three categories including anticoagulation,thrombolysis and thrombus removal.Among them,the anticoagulation therapy is regarded as the basic therapy.On the basis of the anticoagulation therapy,the acute DVT can be treated with the thrombolysis treatment and thrombus removal treatment.But to the non-acute DVT,currently the traditional thrombolysis treatment and thrombus removal treatment can not achieve the satisfying therapeutic effectiveness yet.The anticoagulation treatment can postpone the blood coagulation and prevent the growth,proliferation and recurrence of thrombuses,but can not dissolve the thrombuses that have already formed.Therefore,you can not ask for more from the anticoagulation drug and expect it to heal DVT.The anticoagulation drug can only be used in the adjuvant therapy and prevent the recurrence of the thrombosis. The removal surgery of venous thrombus is very controversial.It can improve the venous patency and have good short-term therapeutic effectiveness.But this surgery has the relatively high recurrence rate of the thrombus and the time window for performing the operation is 48 to 72 hours after the onset of the disease.Therefore,currently it is widely accepted that the operation is suitable to patients who are severely affected with iliofemoral deep venous thrombosis such as phlegmasia cerulea dolensthe and are exposed to the danger of limb necrosis. The thrombolysis therapy based on the anticoagulation is being used widely. Theoretically the thrombolysis treatment should be better than the pure anticoagulation treatment,but thrombolysis treatment increases the danger of clinical hemorrhage and the thrombolysis drug can only release its fibrinolysis power by going through the opened venous vessel and flowing with the blood to reach the thrombus.Moreover,currently in the basic research,it is agreed that the fibrinolytic drugs can not dissolve the old thrombus that has formed for more than 72 hours.The catheter directed thrombolysis is brought out and put in use in the background of the above-mentioned information.The local thrombolysis therapy has the better therapeutic effectiveness than the systemic administration of drugs,having the better thrombolytic efficiency.It is proved by a great deal of research that the thrombus dissolving rate is significantly improved through using the catheter directed local thrombolysis combined with the anticoagulation treatment to cure the acute DVT,comparing with using the anticoagulation treatment only or the systemic thrombolysis combined with the anticoagulation treatment.The functions of deep venous valves can be well protected and the incidence of PTS (post-thrombosis syndrome)can be dramatically reduced.The infusion catheter can be placed in via femoral veins and internal jugular veins or veins in foot,but it is common to place the catheter in via the popliteal veins.But the catheter directed thrombolysis that is currently in use commonly is only applicable to patients affected with the venous thrombosis,whose disease course is less than 10 days.Moreover,the course of treatment commonly is 48 hours or shorter and the total dosage of urokinase is 7 million U or more.The large dose of thrombolytic drug that is administered in short period unavoidably increases the danger of getting the hemorrhage complication,which limits the widespread application.In addition,due to various reasons,the timely and systematic treatment can not be accessed by a great number of patients who are in the acute stage of DVT.Instead,the patients commonly accept the medical treatment during the sub-acute stage or chronic stage.This situation makes the treatment for DVT in sub-acute stage become the issue that is needed to be solved urgently by vascular surgeons in our country.On the basis of summarizing the domestic and international experiences of catheter directed local thrombolysis used to cure the DVT in acute stage,and integrating with the most current development of therapeutic techniques of vascular surgery and the lab research,we utilize the catheter directed local thrombolysis conducted via the popliteal vein,which are complemented by PTA (Percutaneous transluminal angioplasty)and endovascular stent implantation of iliac vein,to cure DVT in the non-acute stage,hoping to find(1)the way to use the comprehensive endovascular techniques to improve the dissolving rate and recanalizing rate of deep venous thrombus in non-acute stage;(2)the relation among the thrombus dissolving rate and recanalizing rate,disease history of venous thrombus,urokinase dosage,method of drug administration and course of treatment during the process of using the comprehensive endovascular techniques to cure the deep venous thrombus in non-acute stage;(3)the relation between the comprehensive endovascular technique and the post-thrombosis syndrome(PTS) of patients affected with DVT in non-acute stage.Clinical studyMethodwith the clean diagnosis and the disease course is longer than seven days.The patients are divided up into two groups,treatment group and control group.The control group(100 patients):the systematic medical therapy.All patients remain in the beds and raise their affected limbs 15～30°.The subcutaneous injection of 5000 IU of low molecular weight heparin(LMWH)is performed two times per day.The intravenous injection of urokinase(300,000 U per day)is conducted.The dosage of urokinase is adjusted according to series of indexes of anticoagulation examination.The treatment lasts 12～14 days.Patients start to take warfarin orally before they come out of hospital.Adjust PT-INR to approximate 2.0.After they come out of hospital,the patients are asked to insist on taking the anticoagulation treatment for over six months and wear medical support socks.Therapy group(110 patients)Therapy course:All patients remain in the beds and raise the affected limbs 15～30°.The subcutaneous injection of 5000 IU of low molecular weight heparin (LMWH)is performed two times per day.The infusion catheter is placed in by means of skin puncture via the popliteal vein and urokinase is pumped in via the infusion catheter.Every 3～5 days the venography is conducted via the infusion catheter to adjust the position of infusion catheter.During the process of thrombolysis,the dosage of urokinase is adjusted according to series of anticoagulation indexes.The treatment lasts 7～14 days.Every 3～5 days the venography is conducted via the infusion catheter.Whether stop the endovenous treatment or perform it further is decided on the results of venography. The catheter directed thrombolysis is terminated when the thrombus is dissolved completely and after going through the venography examination,no obvious change is found in the thrombus within 3～5 days.Patients start to take warfarin orally before they come out of hospital.Adjust PT-INR to approximate 2.0.After they come out of hospital,the patients are required to take warfarin orally for the anticoagulation purpose for over 6 months and ware medical support socks.Grouping:1.According to the disease course,the patients are divided up into two groups: Subacute group,which consists of patients whose disease courses are longer than 7 days but shorter than or equal to 30 days;Chronic group,in which the disease courses are longer than 30 days.2.According to the dosage of urokinase,the patients are divided up into three groups:the standard group:the daily average dosage of urokinase is 300,000~U; Small dosage group:the daily average dosage of urokinase is less than 300,000~U; Large dosage group:the daily average dosage of urokinase is greater than 300,000~U.3.According to the frequency of administering urokinase,the patients are divided up into three groups:No.1 therapy group,in which the administration of drug is performed four times a day;No.2 therapy group,in which the administration of drug is performed three times a day;No.3 therapy group,in which the administration of drug is performed two times a day.Observation standard of medical effectivenessIn the control group,the venous ultrasound diagnosis is performed to evaluate the venous recanalization condition.In the therapy group,the venous venography is performed to evaluate the venous recanalization condition.(1)Evaluation to veins:Veins in the affected limbs can be divided up into six segments to do the evaluation,including the common iliac vein,external iliac vein, common femoral vein,the near end of superficial femoral vein,the far end of superficial femoral vein and popliteal vein.The venous vessel is unobstructed and the wall of venous vessel is smooth.0 point is given to such condition;The vein is unobstructed and the venous wall is rough.1 point is given to such condition;The part of vein is unobstructed and the patency rate is greater than 50%.2 points is given to such condition;The part of vein is unobstructed and the patency rate is less than 50%.3 points is given to such condition;When the vein is blocked completely,4 points is given.The total points gathered from six segments will be the general evaluation score for thrombus affected veins.Thrombolytic rate = (general evaluation score before the thrombolysis—general evaluation score after the thrombolysis)/ general evaluation score before the thrombolysis.(2)Evaluation for clinical effectiveness:The circumferences of thigh and calf are measured at 15cm above the upper edge of patella and 15cm below the lower edge of patella respectively,and the circumference differences between the affected limbs and healthy limbs are calculated.The swelling reducing rate of affected limbs =(circumference difference before the thrombolysis- circumference difference after the thrombolysis)/ circumference difference before the thrombolysisFollow-up method:The clinical follow-up or telephone follow-up is conducted to every patients.The Color Doppler Ultrasonography is performed to every return-visit patient.The durations of follow-ups range from 1 month to 2 years.The common conditions of patients suffering the heavy feeling,swelling,varicose veins,pigmentation,ulcer etc.on affected limbs,and recurrence rate of DVT and incidence of PTS are observed 1 month,3 months,6 months,1 year and 2 years after patients come out of hospital,and the clinical grades are calculated.The patients affected with the recurrence of thrombosis are sent to the hospital again for treatment.2.3 Processing method in statisticsAll calculation materials are analysised by SPSS.When P＜0.05,it means that the difference is significant.Result After patients received the medical treatment in hospitals,their symptoms are significantly eased.The swellings on the affected limbs are greatly reduced.The swelling reduction rate is as high as 85.5%in the therapy group while this rate in control group is 81.1%.There is no much difference between two groups.The thrombus dissolving rate in the control group is 17.3%while this rate in the therapy group is 50.8%.There is a significant difference between two groups.In the therapy group,there are 96 patients in the sub-acute group,whose average disease duration is 10.1 days(8～30 days),and the thrombus dissolving rate is 58.2%;In the chronic group,there are 14 patients,whose average disease duration is 37.3 days(31～50 days),and the thrombus dissolving rate is 47.2%.The thrombus dissolving rate calculated with the urokinase dosage:in the small dosage group,it is 38.7%and the daily average dosage of urokinase is 185,000~U (100,000～200,000 ~U);in the standard group,it is 54.8%and the daily average dosage of urokinase is 300,000~U;in the large dosage group,it is 53.0%and the daily average dosage of urokinase is 421,000~U(400,000~600,000 ~U);The thrombus dissolving rate calculated with the frequency of urokinase administration: 63.8.0%in NO.1 therapy group;49.3%in NO.2 therapy group;38.9%in NO.3 therapy group.The average treatment duration of catheter directed local thrombolysis is 12.34 days(4～27days).The thrombus dissolving rate calculated with the treatment duration(19cases):31.6%for patients whose thrombolysis durations are 7 days; 60.3%for patients whose thrombolysis durations are 10 days;60.5%for patients whose thrombolysis durations are 14 days;79.8%for patients whose thrombolysis durations are 20 days.In the thrombus affected veins,the thrombus dissolving rate is only 15.1%to common iliac veins and thrombosises in 78.8%of patients are suspected of being related to Iliac Vein Compression Syndrome.After the catheter directed local thrombolysis,iliac vein dilation and stent implantation is performed to 16 patients; PTA(Percutaneous transluminal angioplasty)of the iliac vein is performed to 8 patients.In the therapy group,28 patients have not taken the treatment of inferior vena cava filter placement and 82 patients have.During the thrombolysis,and after the thrombolysis,no symptom-type PE(pulmonary embolism)occurred. Among them,3 patients suffered the symptom-type PE(pulmonary embolism) before the thrombolysis was undergone,and their symptoms were reduced after the filter was placed in.In 33 cases,the filters were reclaimed after the thrombolytic therapies had been finished.In 62 cases,the filters were placed in permanently.(among them,the filters in six patients were attached with large blocks of thrombuses.)After the catheter directed local thrombolysis,the iliac vein dilation and stent implantation was performed to 16 patients.One patient returned to hospital for treatment 6 months after he came out of hospital,due to the recurrence of thrombosis in the popliteal vein at the same side.PTA(Percutaneous transluminal angioplasty)of the iliac vein was performed to 8 patients.After two years,one patient was affected with the recurrence of DVT.Two patients suffered the DVT in the opposite limbs 5 months and 2 years respectively after they came out of hospital. Empirical studyMethodsFifty-four rabbits were randomly divided into two groups which are control group,thrombolytic group,besides the normal group.Each group was subdivided into 4 subgroups according to the time for killing the animal(lday,5day,14day, and 28day).The animal model of thrombosis were developed by the method of the ligation of the inferior vena cava below the renal veins and the injection of thrombin.The heparin and urokinase were given at 2 hours after thrombosis and once a day for ten days in thrombolytic group.The animals were killed at 1 day, 5day,14day,and 28day after thrombosis respectively.The affected veins were processed and analyzed for histopathological examination,scan electron microscopic changes and the expression ofα-actin by immunohistochemistry.Results1.Pathological examination①Gross examination:Normal inferior vena cava is soft and the intima is white in color,smooth and regular.In the control group,at 1 day after thrombosis,the thrombi looked fresh,soft,and did not adhere to the vessel wall, there was no changes of the vessel wall.At 5 day after thrombosis,the thrombi became tough,and no significant adhesion to vessel wall.The vessel wall showed edema.At 14 day after thrombosis,the thrombi became hard and adhered to the vessel wall,there was organization in the thrombi.The vessel wall is thickened and the luminal is stenotic.At 28 day after thrombosis,the thrombi became harder, the organization is obvious,and the adhesion to the vessel wall was tightly.The vessel wall was significantly thickened.In thrombolytic group,at 1 day after thrombosis,the thrombi looked fresh,soft,and did not adhere to the vessel wall, there was no changes of the vessel wall.At 5 day after thrombosis,the thrombi were softer than which in control group,and no adhesion to vessel wall.The vessel wall showed slight edema.At 14 day after thrombosis,the thrombi were more fresh and softer than which in control group and slightly adhered to the vessel wall and could be easily separated,there was little organization in the thrombi.The vessel wall is thickened and the luminal is stenotic.At 28 day after thrombosis,the thrombi became harder and adhered to the vessel wall,the organization is obvious, the vessel wall was thickened in 4 rabbits.The thrombi were disappear and the vessel wall were slightly thickened and stiff in 2 rabbits.②Microscopic examination:In the control group,at 1 day after thrombosis, the thrombi were erthyrocytic,there were hemorrhage in adventitia.At 5 day after thrombosis,the thrombi were still erythrocytic mainly,the endothelium denuded and the proliferation of fibroblast and inflammation cells infiltration were observed.At 14 day after thrombosis,the organization of the thrombi were appear, the proliferation of smooth muscle cells were obvious,and there were neovascularization in the thrombi.At 28 day after thrombosis,the thrombi organization was obvious and there were calcification in the thrombi.The thickness of the vascular wall was increased.In thrombolytic group,at 1 day after thrombosis,the thrombi were erythrocytic and there were endothelium denudation and inflammation cells infiltration.At 5 day after thrombosis,the thrombi were still erythrocytic mainly,the denuded endothelium began to be repaired,and the proliferation of smooth muscle cells and the inflammation cells infiltration were less than that in the control group.At 14 day after thrombosis,the organization of the thrombi appeared,the proliferation of smooth muscle cells were obvious,and the endothelium was resumed.At 28 day after thrombosis,the thrombi organization was obvious and the thickness of the vascular wall was increased. The endothelium was resumed completely.2.The scan electromicroscopic examinationThe normal endothelium showed that the endothelial cells were cobble-shaped and lined up tightly and regularly.In the control group,at 1 day after thrombosis,the endothelial cells were swollen,and lined up irregularly,the subendothelial collagen exposed,the endothelium injury degree wereⅡdegree. At 5 day after thrombosis,the thrombi adhered to the endothelium,there were infiltration of inflammatory cells and exposion of subendothelail collagen.At 14 and 28 day after thrombosis,the injury of endothelium was aggrevated further,and there was no endothelium repair.3.the expression of theα-actinAt 1 day after thrombosis,there were no significant difference among the three groups;In the control group,the expression ofα-actin was increased at 5 day after thrombosis,was highest at 14 day,and was in a higher level at 28 day.At 5, 14,28 day after thrombosis,the expression ofα-actin in the control group were higher than that in thrombolytic group.ConclusionBy using the catheter directed local thrombolysis to cure DVT of low extremities in non-acute stage,indications of the thrombolytic therapy can be expanded and the time window of the thrombolysis can be increased,and the incidence of hemorrhage can be reduced.The thrombolytic therapy can protect the vascular endothelium and reduce the cell proliferation of smooth muscle,reducing the adhesion between the thrombus and vascular wall.Using endovenous comprehensive techniques to cure the DVT of low extremities in non-acute stage can significantly improve the recanalization rate and thrombus dissolving rate for the thrombus affected veins.The thrombus dissolving rate is high when the patient has short disease duration and is treated in high daily administration frequency of drug.The thrombus dissolving rate can be improved when the duration for local thrombolysis is properly expanded.By using the endovenous comprehensive techniques to cure the DVT of low extremities in non-acute stage,incidence of PTS can be reduced and the clinical symptoms of PTS can be eased.The endovenous comprehensive techniques can be utilized to cure DVT of low extremities in non-acute stage and treat the iliac vein compression at the same time.
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