Sabina Villalta

The Long-Term Clinical Course of Acute Deep Venous Thrombosis

Deep venous thrombosis of the lower extremity is a serious disorder; the estimated incidence is 1 per 1000 persons per year [1-3]. The disease can occur after surgical procedures and trauma and in the presence of cancer or inherited coagulation disorders; it can also develop without any of these factors [3]. The clinical course of deep venous thrombosis might be complicated by pulmonary embolism, recurrent episodes of deep venous thrombosis, and the development of serious post-thrombotic sequelae, such as venous ulceration, debilitating pain, and intractable edema [3]. Patients with deep venous thrombosis are usually treated with an initial course of heparin (5 to 10 days) followed by 3 to 6 months of oral anticoagulant therapy. This treatment regimen reduces the risk for short-term thromboembolic complications to approximately 5% [4, 5]. The long-term risk for recurrent venous thromboembolism and the incidence and severity of post-thrombotic sequelae in patients with symptomatic deep venous thrombosis have not been well documented. In a recent large randomized, clinical trial comparing 6 weeks of oral anticoagulant therapy with 6 months of therapy [6], patients with symptomatic deep venous thrombosis were followed for 2 years for recurrences and death. This trial showed a substantial reduction in the risk for recurrent venous thromboembolism among patients in the 6-month oral anticoagulant group, but the investigators did not report on the occurrence of the post-thrombotic syndrome. Another recent study [7] reported the 8-year incidence of recurrences and post-thrombotic manifestations in patients with confirmed symptomatic deep venous thrombosis. However, only a few patients were included in this study, and data were collected retrospectively. We assessed the clinical course of a first episode of symptomatic deep venous thrombosis in a large consecutive series of patients who had long-term follow-up. We assessed mortality and the long-term incidences of recurrent venous thromboembolism and the post-thrombotic syndrome. We also evaluated the potential risk factors for these three outcomes. Methods Identification of Inception Cohort The Department of Internal Medicine of the University of Padua, Padua, Italy, is a diagnostic facility for outpatients with clinically suspected venous thromboembolism in a community of approximately 350 000 persons. All consecutive outpatients with a first episode of clinically suspected deep venous thrombosis who were referred by their general practitioners between January 1986 and December 1991 had noninvasive testing [8]. Patients were potentially eligible for the study if confirmatory venography showed deep venous thrombosis. Patients were excluded from the study if they had been referred because of recurrent venous thrombosis, were geographically inaccessible for follow-up, or refused to give informed consent. The Institutional Review Board of the hospital of the University of Padua approved the study. Baseline Assessment At the time of referral, demographic characteristics were recorded and a medical history was taken; information was elicited on the period between the onset of symptoms and presentation to the thrombosis service (patientphysician delay), the presence of risk factors for thrombosis (that is, cancer, surgery, trauma or fracture, immobilization for more than 7 days, pregnancy or childbirth, or estrogen use), and symptoms of pulmonary embolism. Information was also obtained on the history of venous thromboembolism in first-degree relatives. Antithrombin, protein C and S, and lupus-like anticoagulant levels were subsequently measured. Assays were done, and previously described criteria for abnormality and deficiency were used [9]. The venograms obtained at baseline were divided into those representing proximal venous thrombosis (with or without concurrent venous thrombosis of the calf) and those indicating isolated venous thrombosis of the calf. Proximal venous thrombosis was defined as thrombosis located above the trifurcation of the calf veins that involved at least the popliteal vein, superficial femoral vein, common femoral vein, or iliac vein. The location and occlusiveness of proximal thrombi were also determined. A patient was considered to have nonocclusive deep venous thrombosis if contrast material was seen between the thrombus and the vessel wall along the entire thrombus. Treatment Patients were admitted to the hospital and treated with an initial course of high-dose intravenous standard heparin (a bolus of 5000 U followed by continuous infusion of 30 000 U/d, subsequently adjusted to maintain an activated partial thromboplastin time between 1.5 and 2.5 times the normal value) or subcutaneous low-molecular-weight heparin (90 U of anti-factor Xa/kg of body weight twice daily). Therapy with oral anticoagulant agents (warfarin) was started on day 5 to 7 of treatment and was continued for 3 months. The oral anticoagulant dose was adjusted daily to maintain an international normalized ratio between 2.0 and 3.0. Treatment with low-molecular-weight heparin was discontinued on day 10 or later if the international normalized ratio was less than 2.0. This treatment strategy deviated in the following groups of patients: those with cancer, protein deficiencies, or lupus anticoagulant, in whom oral anticoagulation therapy was prolonged; those with small isolated venous thrombosis of the calf, who received oral anticoagulation alone; those with contraindications to anticoagulant treatment, who received no treatment or an inferior caval-vein filter; those who refused to be hospitalized, who received low-dose heparin and oral anticoagulant agents; and those with threatened viability of the leg, who received thrombolytic therapy. The actual type and duration of treatments were recorded. All patients were instructed to wear elastic graduated compression stockings (providing 40 mm Hg of pressure at the ankle) for at least 2 years. Follow-up All patients were seen 3 and 6 months after the initial referral and thereafter returned to the study center every 6 months for follow-up assessments. Patients were asked to return to the thrombosis center immediately if symptoms suggestive of recurrent venous thromboembolism developed. Follow-up was continued for as long as 8 years or until July 1995. To avoid diagnostic suspicion bias, the medical history on general health, symptoms of recurrent venous thromboembolism, and the post-thrombotic syndrome was obtained by using a standardized form. Patients who could not attend the follow-up sessions were visited at home. For all patients who died during follow-up, the date and cause of death were documented. Diagnosis of Recurrent Venous Thromboembolism and Hemorrhage Contrast venography of the symptomatic leg or legs was done as described previously [10]. The criteria for deep venous thrombosis were a constant intraluminal filling defect confirmed in at least two different projections or nonvisualization of a vein or a segment thereof, despite adequate technique and repeated injections with contrast material. The presence or absence of venous thrombosis was assessed by a panel of independent observers who were unaware of the patients other clinical features or previous test results. If a patient presented with clinically suspected recurrent venous thrombosis of the leg, venography was done. The criterion for recurrent venous thrombosis of the leg was a new intraluminal filling defect on the venogram. If the venogram was not diagnostic, recurrent venous thrombosis was diagnosed on the basis of an abnormal 125I-fibrinogen leg scan or results of noninvasive tests that had changed from normal to abnormal [11, 12]. Patients with suspected pulmonary embolism had venography if they had concurrent leg symptoms or perfusion lung scanning in the absence of leg symptoms. Pulmonary embolism was excluded if the perfusion scan was normal. Because ventilation lung scanning was not available during the first years of the study and because pulmonary angiography could not routinely be done, we could not definitively diagnose pulmonary embolism in some patients. If a definitive diagnosis could not be made, patients were classified as not having recurrent venous thromboembolism. Perfusion lung scanning and pulmonary angiography were done and their results were interpreted according to standard procedures [13]. Hemorrhagic episodes were classified as major or minor, as reported previously [14]. The documentation of all patients suspected of having a recurrent venous thromboembolic or bleeding event was reviewed by a three-member adjudication committee that was unaware of further clinical details of the patient. Criteria for the Post-Thrombotic Syndrome Presence of the post-thrombotic syndrome was assessed by investigators who were unaware of previous post-thrombotic manifestations and further clinical details of the patient. The presence of leg symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (pretibial edema, induration of the skin, hyperpigmentation, new venous ectasia, redness, and pain during calf compression) was scored. For each item, the investigators assigned a score of 0 (not present or minimal) to 3 (severe). The presence of a venous ulcer of the lower limb was recorded. In patients with bilateral thrombosis, the higher score was used. A total score of 15 or more on two consecutive visits or the presence of a venous ulcer indicated severe post-thrombotic syndrome, and a total score of 5 to 14 on two consecutive visits indicated mild post-thrombotic syndrome. This score has been shown to have good reproducibility, and it correlates well with the patients perception of the interference of leg symptoms with daily life [15]. Statistical Analysis We calculated Kaplan-Meier estimates and 95% CIs for a visual assessment of survival and calculated the risk for recurrent venous thromboembolism and mild and severe post-thrombotic

The Risk of Recurrent Venous Thromboembolism in Patients with an Arg506→Gln Mutation in the Gene for Factor V (Factor V Leiden)

BACKGROUND A recently discovered mutation in coagulation factor V (Arg506-->Gln, referred to as factor V Leiden), which results in resistance to activated protein C, is found in approximately one fifth of patients with venous thromboembolism. However, the risk of recurrent thromboembolism in heterozygous carriers of this genetic abnormality is unknown. METHODS We searched for factor V Leiden in 251 unselected patients with a first episode of symptomatic deep-vein thrombosis diagnosed by venography. The patients were followed prospectively for a mean of 3.9 years to determine the frequency of recurrent venous thrombosis and pulmonary embolism. RESULTS Factor V Leiden was found in 41 of the patients (16.3 percent; 95 percent confidence interval, 11.8 to 20.9 percent). The cumulative incidence of recurrent venous thromboembolism after follow-up of up to eight years was 39.7 percent (95 percent confidence interval, 22.8 to 56.5 percent) among carriers of the mutation, as compared with 18.3 percent (95 percent confidence interval, 12.3 to 24.3 percent) among patients without the mutation (hazard ratio, 2.4; 95 percent confidence interval, 1.3 to 4.5; P<0.01). CONCLUSIONS The risk of recurrent thromboembolic events is significantly higher in carriers of factor V Leiden than in patients without this abnormality. Large trials assessing the risk-benefit ratio of long-term anticoagulation in carriers of the mutation who have had a first episode of venous thromboembolism are indicated.

A simple ultrasound approach for detection of recurrent proximal-vein thrombosis.

BackgroundThe objective of this study was to develop a simple ultrasound method for measuring thrombus regression in patients with proximal deep-vein thrombosis (DVT) and to test its utility for the detection of DVT recurrence.Methods and Resuls. The study comprised a cross-sectional survey and a prospective investigation (149 and 145 patients, respectively). In both phases, the normalization rate of a previously abnormal ultrasound test, applying the criterion of full compressibility of the common femoral and popliteal veins (C-US method), was assessed. In the prospective study, the vein diameter under maximum compression (thrombus thickness) was measured in the abnormal venous segments at scheduled times (1, 3, 6, and 12 months). In patients presenting with suspected DVT recurrence, the procedure was repeated and results were compared with those available from the previous examination. Noncompressibility of a previously normal(ized) venous segment and enlargement of thrombus thickness (.

Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial

2 mm) were considered diagnostic of proximal DVT recurrence. The diagnostic accuracy of the C-US method alone, as well as of the combined ultrasound methods (C-US + thrombus thickness), was assessed against contrast phlebography. C-US test normalization occurred in only 301% of patients within 1 year. A significant reduction of the thrombus mass (P<.0001) was recorded throughout the entire study period. However, a major decrease in thrombus mass (>50%o) was recorded within the first 3 months. Of 29 patients who developed a suspected recurrent DVT, phlebography confirmed diagnosis in 11. The C-US method alone showed an excellent accuracy (100%) but was applicable in only 6 patients (21%). Both the sensitivity and the specificity for proximal DVT recurrence of the combined ultrasound methods were 100%o (95% confidence interval, 69% to 100% and 81% to 100%, respectively) and were applicable in all patients. ConclusionsThe serial ultrasound measurement of thrombus mass after an acute episode of DVT may allow the correct identification of patients who develop a recurrent proximal-vein thrombosis.

The postthrombotic syndrome

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation.

Following deep vein thrombosis (DVT), one of every two patients will develop postthrombotic syndrome (PTS), which causes remarkable consequences on the socioeconomic level. Residual thrombosis is an important predictor of PTS, and severe early symptoms, old age, obesity, improper anticoagulation, recurrent thrombosis and varicose veins are major risk factors. Diagnosis of PTS is mainly based on the clinical findings for patients with a history of DVT, while in those without it, instrumental diagnosis might help in detecting a previous DVT. Prompt administration of adequate compression elastic stockings (ECS) in patients with symptomatic DVT reduces the frequency of PTS by half. Usually, the management of an established PTS is demanding, and often discouraging. However, when carefully supervised and instructed to wear proper ECS, more than 50% of patients either remain quiescent or improve during long-term follow-up.

Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis A post-hoc analysis

The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed.

Thrombophilia and the risk of post-thrombotic syndrome: retrospective cohort observation

Post-thrombotic syndrome (PTS) is a common complication of deep-vein thrombosis (DVT). Poor quality treatment with vitamin K antagonists (VKA) is a risk factor for PTS. We hypothesised that treatment with the direct oral anticoagulant (DOAC) rivaroxaban may lower PTS incidence as compared to enoxaparin/VKA, as DOACs have a more stable pharmacologic profile than VKA. We performed a post-hoc subgroup analysis of the Einstein DVT trial (n=3449). Kaplan-Meier survival analysis was performed to compare the cumulative incidence of PTS between the rivaroxaban and enoxaparin/VKA groups. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models. We included 336 patients with a mean age of 58 ± 16 years and a median follow-up after index DVT of 57 months (interquartile range 48-64). Of these, 162 (48 %) had been treated with rivaroxaban and 174 (52 %) with enoxaparin/VKA. The cumulative PTS incidence at 60 months follow-up was 29 % in the rivaroxaban group and 40 % in the enoxaparin/VKA group. After adjusting for age, gender, body mass index, previous VTE, ipsilateral recurrent DVT, extent of DVT, idiopathic DVT, duration of anticoagulant treatment, compliance to assigned study medication, elastic compression stocking use and active malignancy, the HR of PTS development for rivaroxaban was 0.76 (95 % CI: 0.51-1.13). In conclusion, treatment of acute DVT with rivaroxaban was associated with a numerically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment. The potential effect on reducing PTS deserves evaluation in a large randomised trial.

Unexpectedly High Recanalization Rate in Patients with Pulmonary Embolism Treated with Anticoagulants Alone

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Immobilization resulting from chronic medical diseases: a new risk factor for recurrent venous thromboembolism in anticoagulated patients.

The rate of residual thrombosis, defined as the long-term persistence of thrombotic material in the pulmonary artery tree after pulmonary embolism (PE), is uncertain. Although a systematic review reported low recanalization rates (43% at 6 mo) (1), most studies used perfusion or ventilation–perfusion lung scanning or older generation computed tomography (CT) scanners. In a prospective study we determined the rate of residual thrombosis in a cohort of consecutive patients with acute PE as detected by 64-row multidetector CT (MDCT), treated with anticoagulants alone and reassessed 6 months later with the same high-technology procedure.