By Puskas, A Balogh, Z; Hadadi, L; Imre, M; Et al
Aim. The aim of this study was to evaluate the dynamics of the recanalization process (spontaneous fibrinolysis) in completely occlusive deep venous thrombosis (DVT) using duplex ultrasound examination and to investigate the influence of different factors on the evolution of thrombus regression. Methods. This longitudinal prospective study was done with 74 consecutive patients with completely occlusive acute multilevel DVT, confirmed by echo duplex scan after 1, 3, 6, and 12 months. At each re-evaluation, the degree and the type of recanalization were determined. Efficacy of tinzaparin (175 IU/kg, s.c., q.d. for 7-14 days) and continued with warfarin (12 months at INR 2-3) as well as patients’ compliance with compressive elastic hosiery wearing were carefully followed. Relationship between the degree and pattern of recanalization and patients’ age, gender, as well as thrombosis etiology and location were determined.
Results. Sixty-four patients completed the study. The mean recanalization rate was 39.7% at 1, 64.8% at 3, 82% at 6, and 90.3% at 12 months. Marginal recanalization was more frequently observed, but recanalization pattern was changing during follow-up.
Conclusion. In the case of efficient anticoagulant and compressive therapy, the spontaneous recanalization process of DVT is important from the very first month of evolution, but an almost complete re-permeabilization is observed only after 12 months of treatment. The unilocular, marginal pattern of thrombus lysis is often observed and has better evolution than the multilocular cavernous one. The dynamics of recanalization are characterized by distal-to-proximal extension and in the first 6 months are significantly influenced by patient’s gender and thrombosis etiology.
[Int Angiol 2007;26:53-63]
Key words: Venous thrombosis – Thromboembolism – Low molecular weight heparins – Anticoagulants – Ultrasonography – Risk factors.
After the acute onset of deep vein thrombosis (DVT), the natural history of the disease is characterized by a dynamic process that could also involve physiologic lysis of the clot and thrombus extension.1,2 Understanding these competitive mechanisms is crucial, because delayed thrombus regression could be involved in the development of late complications, such as postthrombotic syndrome or chronic venous insufficiency.3-6 About 2/3 of patients with DVT may develop secondary valvular insufficiency with consecutive post- thrombotic syndrome.7 The factors that influence this process are mainly unclear.
In the last few years, low molecular weight heparins (LMWHs) have been widely validated as an initial treatment option in DVT. The metaanalyses of the clinical studies suggest their superiority over unfractionated heparin in the prevention of recurrent venous thromboembolismA9 The optimal duration of following oral anticoagulant therapy, however, still remains controversial. Six- month oral anticoagulation therapy is more effective in recurrence prevention than 6week or 3-month treatment,10,11 although a recent study demonstrated that 1 year of oral anticoagulation therapy could not satisfactory prevent the recurrent events in patients with idiopathic DVT.12
There is a close relationship between failure of thrombus recanalization and episodes of recurrence.13 Thus, the normalization rate of compression ultrasonography in patients with a first episode of DVT could serve as an objective indicator to individualize the optimal duration of anticoagulants. It is still unclear which factors may influence the normalization of venous wall and lumen after the acute phase of thrombus formation.
Although venography was considered the gold standard in phlebology, duplex scan ultrasonography is the most appropriate method to monitor the thrombus regression, because it is noninvasive, repeatable, and reproducible. The modified Marder score is used as a semi-quantitative duplex ultrasonographic scoring system to follow up the recanalization process. 14,15 However, neither this scoring system nor other noninvasive methods are able to describe in a precise, quantitative way venous recanalization.
In the present study, self-devised software was applied to quantify the venous recanalization. With the use of statistical analysis, the dynamics of clot regression and its possible influencing factors were evaluated.
Materials and methods
Study design
This is a prospective longitudinal clinical study that evaluates the dynamics of spontaneous recanalization process in subjects diagnosed with completely occlusive, multi-segment, acute DVT. Patients received efficient oral anticoagulant and compressive therapy and were followed for 1 year via serial duplex ultrasonography examinations. At each scheduled visit, the exact size of thrombus regression (in percentage) was calculated using a standard program included in the duplex scanner or special software developed by our team, depending on the recanalization pattern found. The obtained values were processed with the help of statistical analysis in order to study the influence of different factors such as age, gender, etiology, and location of thrombosis on the recanalization rate. Events like recurrent venous thromboembolism, major hemorrhagic complications, and mortality occurring throughout the study period were considered as secondary endpoints.
The study protocol is in accordance with the principles of the Helsinki-Tokyo declaration and was approved by the local scientific and ethics committee. The patients included in the study were provided with an information letter, and written consent was obtained.
Patients
Seventy-four consecutive symptomatic adult patients who had been assigned to the Angiology Department of the second Medical Clinic, Targu Mures, Romania, presenting fully occlusive acute multi-level DVT of the lower limbs (onset of symptoms less than 10 days) were eligible for entering the study. The location and extent of thrombotic process was objectively documented by color duplex ultrasonography. A homogenous patient group was recruited with regard to the onset of thrombosis (acute, first episode), degree of occlusion (fully occlusive), total thrombus “load”7 (total number of affected segments; all patients had more than one segment involved), and efficiency of anticoagulant and compressive therapy. Table I lists the requirements for those patients enrolled in the study.
Assessment of patients and diagnosis of deep vein thrombosis
The assessment of each patient included registration of detailed medical history, clinical examination, blood tests, and color duplex scan. To obtain a detailed personal and familial medical history, a special protocol form was filled in by each patient. Based on the questionnaires and physical examination, the Wells Pretest Probability Score16 (PTP score), which includes the most specific symptoms and signs as well as the main risk factors of DVT, was calculated for each subject in order to define low, medium, or high probability of thrombosis. Clinical signs of pulmonary embolism or any complications were also assessed.
Laboratory investigations included complete blood count, electrolytes, glycemia, urea, creatinine, liver function tests, erythrocyte sedimentation rate, and coagulation profile. The active tumor screening in patients older than 50 years was routinely performed using abdominal ultrasound, chest X-ray, and tumor markers, as well as upper gastrointestinal endoscopy, colonoscopy, CT, or MR imaging in several cases. After the acute phase, patients younger than 40 years were screened for primary thrombophilia (acenocoumarol was replaced with tinzaparin 10 days before the test).
Venous ultrasonography of the lower extremity is accepted to be a sensitive and accurate noninvasive test for confirming the presence of acute DVT.17 For diagnosis (and also follow-up), a GE Agilent Image Point HXB.1, Sonos 4500/5500B.1 duplex scanner has been used with a 5-10 MHz linear probe and/or a 2.5-5 MHz convex transducer, depending on the depth at which the examined veins were situated. The examination of the lower limb veins is started with the patient lying in the prone position, with the sonographer holding the transducer at the anterior and inner aspect of the thigh to visualize the common femoral, profound femoral, and superBcial femoral veins. The transducer was displaced down toward the leg, moving slowly along the anterior and medial side of the thigh, with the arteries and veins kept in image. At the level of the knee, the transducer was held at the back of the externally rotated and slightly bent leg in order to evaluate the popliteal vein. The calf veins (anterior tibial, posterior tibial, peroneal) and the popliteal vein were examined in the sitting position. In transverse section, the compression ultrasonography method was used, transmitting pressure with the transducer to the soft tissues, as well as to the vessels of the limb. Holding the transducer over the adductor canal, just above the knee, the examiner used the free hand to compress the soft tissues along the inner back aspect of the thigh, lifting them toward the transducer. Duplex sonography and color Doppler imaging have been used intermittently during the examination. We used the convex probe to scan the iliac veins. After the transverse B-mode and color flow visualization of the inferior vena cava, the common iliac and external iliac veins were visualized in longitudinal view. The presence of color flow within the lumen excluded the possibility of completely occlusive thrombi. The ultrasonographic diagnostic features of fully occlusive, acute DVT are summarized in Table II.17 In these ways, the diagnosis of DVT and its most probable etiology were determined. All objective diagnostic tests were interpreted by experienced specialists. The ultrasonography was done by the first author (A. P.), who has much experience in this field (over 2 000 scans/year).
Therapeutic regimens
The therapeutic protocol was identical in the case of each enrolled patient. After the definitive diagnosis of completely obstructive acute DVT, a subcutaneous injection of LMWH tinzaparin sodium (Innohep; Leo Pharmaceutical Products Ltd., Ballerup, Denmark) was administered once daily in a weight-adjusted dose of 175 anti Xa ID/kg bodyweight for 7-14 days. Oral anticoagulation therapy with low dose (2 mg) acenocoumarol (Sintroni; Novartis Pharma AG, Basle, Switzerland) was started on the 3rd day following the initiation of LMWH therapy. During the follow-up, the dosage of acenocoumarol was adjusted to keep the INR values between 2 and 3. These values were determined weekly during the 1st month and monthly thereafter. LMWH treatment was stopped as soon as the INR value reached the 2-3 interval. The acenocoumarol therapy was given for 12 months.
At the same time, all the patients were encouraged to ambulate in the daytime. Wearing of elastic support stockings was prescribed from the very 1st day of treatment until the end of study period (1 year). Grade I compression stockings were first applied with the size corresponding to the ankle, calf, and thigh diameters. Later, the size of hosiery was adjusted according to the volume reduction of the affected leg.
Patterns and measurements of venous recanalization, primary outcomes
To evaluate the healing process after the acute phase of DVT, 4 visits were scheduled for re-evaluation at 1, 3, 6, and 12 months. At each occasion the above-described ultrasonographic protocol was utilized.
We found two main patterns of thrombus regression. The first one was characterized by the presence of small multiple channels inside the thrombus, marked by low pulse repetition frequency (PRF)-color flow mapping. It was named by us the “cavernous” type, which might correspond either to a partially reopened native venous segment or to small parallel collateral channels that have developed in response to the adjacent obstruction. These channels may be hard to visualize and differentiate if the patient is in the supine position; sitting or standing distends them slightly and makes them easier to perceive.17 The second one is characterized by the presence of wall thickening with lumen diameter reduction, which we called the “marginal” type of reopening. It is easier observed on longitudinal plane image, holding the transducer parallel to the axis of the vein. The thickening most likely represents a mixture of hyperplasic response of the endothelium and some residual thrombus that becomes incorporated into the wall during the scarring (fibroblastic) response.17 Finally, in most patients an almost normal ultrasonographic venous appearance was seen at the end of the follow-up period. The type of venous recanalization (cavernous or marginal) was determined in transversal and longitudinal plane with color Doppler examination. To obtain an image of the recanalized territory as complete as possible, the venous circulation was augmented by applying simultaneous compression to the distal musculature.
The next step was the calculation of percentage of recanalization rate in transverse section, by proportioning the total area of the examined vein to the area filled with color signal. In each case, the re-examination of involved venous segments was repeated and video-recorded three times consecutively. The measurements were averaged.
When a marginal recanalization pattern was found, the quantitative determination was performed by proper software of the scanner, originally used for the measurement of carotid artery stenosis, but also serviceable in case of the venous system (Figure 1). The recordings were transformed in digital format, and the frames were saved as bitmap images and processed with software (Vein) created for the present study (Figure 2).
The Vein software was written in Delphi programming language and used the same principles as the proper software of the scanner. Marking the area of the whole vena and the color-filled areas on the transverse section image, we obtained two types of territories, which appear respectively in blue and red. The computer calculates the ratio between the sum of the red areas and the blue one, with the result representing the actual size of venous recanalization.
Evaluation of secondary outcomes
Recurrence of venous thromboembolism was assessed by duplex scan at scheduled visits or at any time considered necessary during the follow-up period. Patients with clinically suspected pulmonary embolism underwent a spiral CT examination or MR angiography. Subjects with recurrence of venous thromboembolism have been excluded from the follow-up. The incidence of major hemorrhagic events was also recorded and evaluated. Bleeding was considered major if it was clinically important and associated with a fall of hemoglobin that required transfusion or if it is associated with intracranial, intraocular, pericardial, or retroperitoneal hemorrhage.
Thrombocytopenia was defined as a platelet count below 150 000/ mm^sup 3^, or at least a 50% decrease compared with the baseline value.
Every fatal event was recorded and the cause of each fatality was documented.
Follow-up
Patients were asked to attend the angiology department at fixed intervals: at 1 month, 3 months, 6 months, and 1 year after the acute phase. At each occasion, a physical examination as well as a duplex scan was performed and recorded for each patient. The INR value was determined weekly in the 1st month and at least monthly thereafter, or at any time considered necessary. Subjects were instructed to appeal to the personnel of the department in any case of suspicion of recurrence or bleeding tendency. At unscheduled presentations for bleeding tendency or in case of other complaints, blood samples were collected for the measurement of full blood count, liver function test, coagulation tests, INR values, and renal function test.
Statistical analysis
A software package (Microsoft Office Excel 2001 and GraphPad InStat(R) version 3.06, 32 bit for Windows) was used for data collection and statistical analysis.
Different groups of patients were distinguished by age, gender, thrombosis etiology, and thrombus location. The venous recanalization was followed in every anatomical segment separately; every subject included in the present study had more than one segment involved. The mean, the standard deviation, and the standard error of the mean were calculated from the values of venous recanalization measured in different venous segments.
The Kolmogorov-Smirnov test was used to test data for normal distribution. The Mann-Whitney U-test (for nonparametric distributions) and Student’s t-test with Welch correction (in case of Gaussian distributions) were used to compare the means of recanalization rates of different patient groups. The statistical significance between different groups was reached if P
Results
Patients
In the period April 2003-March 2005, 74 patients who corresponded to the criteria of the protocol were studied. The diagnosis in every case was acute, fully occlusive multi-level deep venous thrombosis of the lower limb(s), confirmed by color-duplex scan. The follow-up was completed by 64 of the 74 patients: 4 of them were excluded because of low compliance (more than 2 absences from scheduled visits), 4 because of poor INR control, 1 because the underlying disease (hepatocarcinoma) had a fatal evolution, and 1 because of recurrence of a thromboembolic event. The baseline characteristics of the patients enrolled in the study and the location of DVT are shown in Table III.
Regarding the thrombus location, the most frequently affected vessels were the superficial femoral vein (divided into proximal, middle, and distal segments), together with the popliteal vein (Figure 3).
Recanalization of proximal (proximal end of the thrombus situated above popliteal vein) and distal thrombosis (proximal parts of clot in and below popliteal vein) has been followed separately. To determine the direction of thrombus regression, the size of repermeabilization was compared at the upper and the lower ends of the clot by measuring the recanalization in the most proximally and the most distally situated venous segments, respectively. In spite of detailed medical history, physical examination, paraclinical investigations, and laboratory investigations, the etiological diagnosis was stabilized in only 65.6% of the enrolled cases; the rest of patients were considered as having idiopathic DVT. In 36 of the 42 cases with a confirmed etiological diagnosis, one or more thrombogenic factors have been identified (Table IV; the numbers indicated exceed the number of subjects, because some of them had more than 1 risk factor). In 6 cases, the diagnosis of primary thrombophilia was confirmed by specific tests; 2 patients presented the association of factor V Leiden mutation, oral contraceptive therapy, and smoking.
However, not all of the patients were present at each re- evaluation during the 12 months (Table V). In statistical analysis, those subjects attending their scheduled re-evaluation were assumed to be representative of all patients eligible to be re-examined at those points in time.
Evolution of thrombus regression
At every re-examination, the presence, rate, and type of venous recanalization were determined. Using the recanalization rates determined by the two software programs, the mean thrombus regression of the venous segments was calculated for each re- examination period (Table V). These values, represented as a function of time, convey the quantitative change of recanalization (Figure 4). Recanalization was fastest during the 1st month, reaching 39.7% on the average. After 6 months, the process became slower; at the end of the follow-up period, however, an average of 90.3% thrombus regression was found.
As exemplified in Figure 5, thrombus regression visualized by color duplex examination had started either in one place, near the wall of the examined vessel (marginal recanalization), or in multiple points in the same time (multilocular or cavernous pattern). However, marginal recanalization was more frequently observed; the patterns of thrombus regression changed during the follow-up period, with the cavernous type being found in 37.3% of the examined venous segments at 1 month but only in 24.1% of the partially recanalized segments at 1 year (Figure 6).
The venous segments were followed separately, according to the type of thrombus regression found at the 1st month’s re-evaluation (Figure 7A). Even if later evolution changed to the opposite pattern, a statistically significant difference between the 2 groups’ outcome persisted during the whole follow-up period (months 1 and 3: P
Different recanalization rates have been found in male and female patients. Six-month thrombus regression was faster in women than in men (months 1, 3, and 6: P=0.004), but no statistically significant difference was present at 12 months (Figure 7B).
The relationship between recanalization and patients’ age has been studied with the help of correlation analysis. A closer association expressed by a weak negative correlation was observed only in proximal DVT cases, at the 1st and the 2nd reevaluations (month 1: r=-0.5876, P=0.001; month 3:r=0 -0.4971,P
The dynamics of venous recanalization was compared in idiopathic and secondary DVT. In the first 6 months after the acute phase, a significant difference had been found in the evolution of the process (Figure 7C).
Proximal (above-knee) and distal (below-knee) thrombosis had different evolution at one point of the follow-up (month 3: P=0.009) (Figure 7D). DVT localization on the right or left lower limb did not show statistically significant difference at any moment.
Regarding the direction of the venous reopening process, the average regressions of the most proximally and most distally situated thrombus parts were statistically compared (every enrolled subject had multilevel thrombosis). Generally higher values of average recanalization were found in distal venous segments (Figure 8). In the 3rd and the 6th months of the follow-up, this difference was statistically significant (P
Efficacy of anticoagulant therapy
The present study investigated the process of spontaneous fibrinolysis that appears with efficient anticoagulation. After a short fluctuation in the 1st month, the INR of the enrolled subjects stabilized between 2 and 3 (Figure 9).
Discussion
The late complication of acute DVT, the post-thrombotic syndrome, is considered by many physicians as unavoidable. The post- thrombotic sequelae are most frequently attributed to the patient’s poor compliance rather than to inadequate treatment of the acute DVT. After the acute phase of DVT, recanalization of thrombosed venous segments can occur, restoring at least partial patency.
The healing process after an episode of acute DVT involves two major pathologic mechanisms. The first one is represented by spontaneous lysis of the thrombus. The rate of lysis is affected by the size (thrombus “load”), the totally or partially obstructive nature of the thrombus, and the amount of regional blood flow.17 An incompletely obstructive thrombus in a venous channel with high flow is more likely exposed to quick resorption through normal lytic pathways, while a fully occlusive thrombus in a duplicated superficial femoral vein probably persists for a much longer period.’8 Exposure of clot matrix to the local lytic agents also influences the thrombus regression process, its rate being directly proportional to the clot surface exposed. The second mechanism responsible for clot regression is a cellular response, including migration of monocytes and fibroblast proliferation. The monocytes help to dissolve the thrombus by local release of plasminogen activator. Finally, the thrombus will be replaced with smooth muscle cells, fibroblasts, and connective tissue matrix.17 A neovascular and a monocytic response are also present in the vein wall, and the adherent clot undergoes a fibrous transformation. If both residual venous obstruction and subsequently developed valvular insufficiency are minimized or avoided, the severity of the post-thrombotic syndrome can be reduced. In a large prospective study evaluating the natural history of acute DVT under anticoagulation, it was found that 17% of patients had valvular reflux at the end of the 1st week; this progressed to 66% at 1 year. Reflux was more common in patients suffering from fully occlusive DVT compared to those with a partly obstructive clot. Subjects who tended to have early and complete recanalization mostly did not develop valvular incompetence. Therefore, the timing of lysis may also have clinical implications.19 It is also demonstrated that valvular function is maintained more frequently when lysis occurs within 3 months after the diagnosis.20 These findings erase previous concepts that valves are irrevocably destroyed within the first 3-5 days of the acute thrombosis. The effect of residual obstruction is superimposed on reflux. Following acute DVT, combined reflux and obstruction are 3 times more likely to be found in limbs with post-thrombotic syndrome than in those without clinical evidence of sequelae.21 Therefore, successfully clearing the deep vein thrombus maintains valvular function and reduces symptoms.22
Because of the availability of sequential duplex scan follow-up, the outcome of an acute DVT episode has become more understandable. The term “recanalization” used in the literature is rather confusing. In some studies, it means the reopening of the occluded venous lumen without any specification as to the degree of this process. Thus, recanalization is defined as the presence of flow in a previously obstructed segment, whether or not residual thrombus can be seen.1,7 In other works, ultrasound findings are arbitrarily scored as normalized if, at maximum compressibility, the residual thrombus occupies less than 40% of the vein area calculated in the absence of compression.13 The semi-quantitative scoring system (modified Marder score) is useful to follow up patients, but it cannot describe the dynamic status and the type of recanalization in a precise way.15
In the last few years, LMWHs have been widely validated as initial treatment option in DVT. However, the optimal duration of oral anticoagulant therapy remains controversial. Leg compression with easy-to-use elastic stockings is accepted nowadays as a better alternative than bed rest for mobile patients with symptomatic proximal DVT. It is also believed that immediate leg compression combined with walking accelerates lysis.23
In this study, we had a homogenous patient group with regard to the onset of thrombosis, degree of initial occlusion (fully occlusive), total thrombus “load,” and efficiency of anticoagulant and compressive therapy. Self-devised software was applied to quantify the venous recanalization. Using statistical analysis, the dynamics of clot regression and its possible influencing factors were evaluated.
The results of the present study confirm the recently described observation that, after the acute phase of thrombosis, the deep venous clot suffers a recanalization process and the obstructed vein becomes more or less permeable.1,2,7 In case of efficient anticoagulant and compressive therapy, the spontaneous recanalization process of DVT is important from the very 1st month but complete lumen normalization appears only after 12 months of treatment. This may indicate a need for a longer than 6-month period of anticoagulation. The normalization rate of compression ultrasonography in patients with a first episode of DVT could serve as an objective indicator to individualize the optimal duration of anticoagulants.7 Ultrasonographic follow-up of DVT patients, therefore, is mandatory.
Analogous to the thrombus extension process, clot regression gradually progresses from the distal venous segments to the proximal ones. Marginal recanalization pattern is more frequently observed, even at the 1st month after the acute phase, and it has a better prognosis for complete lumen reopening at 1 year than the cavernous pattern.
Conclusions
Our results suggest that during 6 months after the formation of thrombus, clot regression is faster in female patients, as well as in cases of idiopathic thromboses. However, at 12 months, the evolution is no longer influenced by patient s gender or thrombosis etiology. Patients’ age and thrombus location have a minor effect on the recanalization process, with younger patients and those with clots formed in the veins below the knee presenting better venous repermeabilization only in the first 3 months.
Received April 20, 2006; acknowledged May 10, 2006; accepted for publication October 10, 2006.
References
1. Killewich LA, Bedford GR, Beach KW, Strandness DE Jr. Spontaneous lysis of deep venous thrombi: rate and outcome. J Vase Surg 1989;9:89-97.
2. Krupski WC, Bass A, Dilley RB, Bernstein EF, Otis SM. Propagation of deep venous thrombosis identified by duplex ultrasonography. J Vase Surg 1990; 12:467-74; discussion 474-5. 3. Eichlisberger R, Frauchiger B, Widmer MT, Widmer LK, Jager K. [Late sequelae of deep venous thrombosis: a 13year follow-up of 223 patients]. Vasa 1994;23:234-43.
4. Haenen JH, Janssen MC, van Langen H. Duplex ultrasound in the hemodynamic evaluation of the late sequelae of deep venous thrombosis. J Vase Surg 1998;3:472-8.
5. LeSiege CJ1 McKean SC, Persson AV. Importance of valvular incompetence after acute deep venous thrombosis. J Cardiovasc Surg 1992;33:710-4.
6. van Haarst EP, Liasis N, van Rarnshorst B, Moll FL. The development of valvular incompetence after deep vein thrombosis: a 7 year follow-up study with duplex scanning. Eur J Vase Endovasc Surg 1996; 12:295-9.
7. Markel A, Meissner M, Manzo RA, Bergelin RO, Strandness DE Jr. Deep venous thrombosis: rate of spontaneous lysis and thrombus extension. IntAngiol2003;22:376-82.
8. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparin: a meta- analysis. Arch Intern Med 1995; 155:601-7.
9. Siragusa S, Cosmi B, Piovella F, Hirsch J, Ginsberg GS. Low- rnolecular-weight heparins and unfractionated heparin in the treatment of patients of acute venous thromboernbolism: results of meta-analysis. Am J Med 1996; 100: 269-77.
10. Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995;74:606-11.
11. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med 1995;332:1661-5.
12. Agnelli G, Prandoni P, Santamaria MG1 Bagatella P, Iorio A, Bazzan M et al. Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001;345:165-9.
13. Piovella F, Crippa L, Barone M, Vigano D’Angelo S1 Serafini S, Galli L et eu. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002;87;515-22.
14. Marder VJ, Soulen RL1 Atichartakarn V, Budzynski AZ, Parulekar S1 Kim JR et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977;89: 1018-29.
15. Daskalopoulos ME, Daskalopoulou SS, Tzortzis E1 Sfiridis P, Nikolaou A, Dimitroulis D et al. Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): a prospective randomized trial. Eur J Vase Endovasc Surg 2005;29:638- 50.
16. Anand SS, Wells PS, Hunt D, Brill-Edwards P1 Cook D, Ginsberg JS. Does this patient have deep vein thrombosis? JAMA 1998;279:1094- 9. Erratum in: JAMA 1998;280: 328. JAMA 1998;279:1614.
17. Polak FJ. Peripheral vascular sonography: a practical guide. Baltimore: Lippincott Williams & Wilkins; 2004.p.l68-227.
18. Masuda EM, Kessler DM, Kistner RL, Eklof B, Sato DT. The natural history of calf vein thrombosis: lysis of thrombi and development of reflux. J Vase Surg 1998;28:67-73; discussion 73-4.
19. Markel A, Manzo R, Bergelin R, Strandness DE. Valvular reflux after deep vein thrombosis: incidence and time occurrence. J Vase Surg 1992; 15:377-84.
20. Meissner MH, Manzo RA, Bergelin RO, Strandness DE. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vase Surg 1993;18:596-605.
21. Johnson BF, Manzo RA, Bergelin MS, Strandness DE. Relationship between changes in the deep venous system and the development of the post-thrombotic syndrome after an acute episode of lower limb deep vein thrombosis. J Vase Surg 1995;21:307-13.
22. Comerota AJ, Aldridge SC. Thrombolytic therapy for acute deep vein thrombosis. Semin Vase Surg 1992;5:76-84.
23. Blattler W, Partsch H. Leg compression and ambulation is better than bed rest for the treatment of acute deep venous thrombosis. Int Angiol 2003;22:393-400.
A. PUSKAS1, Z. BALOGH1, L. HADADI1, M. IMRE1, E. ORBAN1, K. KOSA1, Z. BRASSAI 1, S. A. MOUSA2
1 Department ofAngiology and second Medical Clinic
University of Medicine and Pharmacy, Targu Mures, Romania
2 Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, NY, USA
Address reprint requests to: Shaker. A. Mousa, PhD, MBA, FACC, FACE, Pharmaceutical Research Institute at Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208, USA. E-mail: [email protected]
Copyright Edizioni Minerva Medica Mar 2007
(c) 2007 International Angiology. Provided by ProQuest Information and Learning. All rights Reserved.
Comments