Alberto Cogo

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

Accuracy of clinical assessment of deep-vein thrombosis

The clinical diagnosis of deep-vein thrombosis is generally thought to be unreliable. From experience, we hypothesised that this widely held view might be incorrect. We developed a clinical model and prospectively tested its ability in three tertiary care centres to stratify symptomatic outpatients with suspected deep-vein thrombosis into groups with high, moderate, or low probability groups of deep-vein thrombosis. We evaluated our clinical model in combination with venous ultrasonography to determine the potential for an improved and simplified diagnostic approach in patients with suspected deep-vein thrombosis. All patients were clinically assessed to determine the probability for deep-vein thrombosis before they had ultrasonography and venography. All tests were performed and interpreted by independent observers. In 529 patients, the clinical model predicted prevalence of deep-vein thrombosis in the three categories: 85% in the high pretest probability category, 33% in the moderate, and 5% in the low category. There was no statistical difference in the performance of the model in the three centres. The model demonstrated excellent interobserver reliability (Kappa = 0.85). There were important differences with ultrasonography between the high and low pretest probability groups for both positive predictive values (100% (95% CI, 94-100%) vs (63% [35-85%], respectively). Thus, use of the clinical model combined with ultrasonography would decrease the number of false positive and negative diagnosis if venography were done when the ultrasound result and pretest probability were discordant. The diagnostic process could be simplified by excluding those patients with low pretest probability and normal ultrasound results from serial testing.

Deep-Vein Thrombosis and the Incidence of Subsequent Symptomatic Cancer

BACKGROUND In contrast to the established relation between overt cancer and subsequent venous thromboembolism, it is unclear whether symptomatic deep-vein thrombosis is associated with a risk of subsequent overt malignant disease. METHODS Two hundred sixty consecutive patients with symptomatic, venographically proved deep-vein thrombosis were enrolled in a study, of whom 250 were followed during a two-year period. Among those assessed during follow-up, the incidence of subsequently detected cancer in the 105 patients with secondary venous thrombosis (i.e., thrombosis associated with a well-recognized risk factor other than cancer) was compared with the incidence of cancer in the 145 patients with idiopathic venous thrombosis. RESULTS Routine examination at the time of diagnosis of the venous thrombosis revealed cancer in 5 of the 153 enrolled patients with idiopathic venous thrombosis (3.3 percent) and in none of the 107 enrolled patients with secondary venous thrombosis. During follow-up, overt cancer developed in 2 of the 105 patients with secondary venous thrombosis (1.9 percent) and in 11 of the 145 patients with idiopathic venous thrombosis (7.6 percent; odds ratio, 2.3; 95 percent confidence interval, 1.0 to 5.2; P = 0.043). Of the 145 patients with idiopathic venous thrombosis, 35 had confirmed recurrent thromboembolism. Overt cancer subsequently developed in 6 of the 35 (17.1 percent). The incidence of cancer in the patients with recurrent idiopathic venous thrombosis was higher than that in the patients with secondary venous thrombosis (P = 0.008; odds ratio, 9.8; 95 percent confidence interval, 1.8 to 52.2) or in the patients with idiopathic venous thrombosis that did not recur (P = 0.024; odds ratio, 4.3; 95 percent confidence interval, 1.2 to 15.3). CONCLUSIONS There is a statistically significant and clinically important association between idiopathic venous thrombosis and the subsequent development of clinically overt cancer, especially among patients in whom venous thromboembolism recurs during follow-up.

Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis

In view of the potential of low-molecular-weight heparins (LMWH) to simplify initial therapy and allow outpatient treatment of proximal deep-vein thrombosis, we undertook a randomised comparison of fixed-dose subcutaneous LMWH with adjusted-dose intravenous standard heparin in the initial treatment of this disorder. Our main objectives were to compare the efficacy of these regimens for 6 months of follow-up and to assess the risk of clinically important bleeding. Of 170 consecutive symptomatic patients with venographically proven proximal deep-venous thrombosis, 85 received standard heparin (to achieve an activated partial thromboplastin time of 1.5 to 2.0 times the pretreatment value) and 85 LMWH (adjusted only for body weight) for 10 days. Oral coumarin was started on day 7 and continued for at least 3 months. The frequency of recurrent venous thromboembolism diagnosed objectively did not differ significantly between the standard-heparin and LMWH groups (12 [14%] vs 6 [7%]; difference 7% [95% confidence interval -3% to 15%]; p = 0.13). Clinically important bleeding was infrequent in both groups (3.5% for standard heparin vs 1.1% for LMWH; p greater than 0.2). We conclude that fixed-dose subcutaneous LMWH is at least as effective and safe as intravenous adjusted-dose heparin in the initial treatment of symptomatic proximal-vein thrombosis. Since there is no need for laboratory monitoring with the LMWH regimen, patients with venous thrombosis can be treated at home.

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 (.

Serial 2-Point Ultrasonography Plus D-Dimer vs Whole-Leg Color-Coded Doppler Ultrasonography for Diagnosing Suspected Symptomatic Deep Vein Thrombosis: A Randomized Controlled 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.

Noninvasive Objective Tests for the Diagnosis of Clinically Suspected Deep-Vein Thrombosis

CONTEXT Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00353093.

Prevalence of Antiphospholipid Antibodies and Lupus Anticoagulant in Juvenile Patients with Objectively Documented Deep-vein Thrombosis

Deep-vein thrombosis of the lower extremity is a frequent disorder associated with morbidity and mortality due to pulmonary embolism and the postthrombotic syndrome. It was not until the introduction of contrast venography that the inaccuracy of the clinical diagnosis became apparent. Since then, management decisions have usually been based on objective diagnostic test. Venography is generally considered the reference method for the diagnosis of deep-vein thrombosis, but it is invasive and associated with serious side effects. Several noninvasive or less invasive objective diagnostic methods have been developed. These diagnostic methods are distinctly different in technology and consequently in their ability to demonstrate or refute deep-vein thrombosis. In this review, a critical analysis is provided on the accuracy of the current noninvasive diagnostic approaches to venous thrombosis in patients with a first episode of clinically suspected deep-vein thrombosis. Results of studies were considered only when their methodology fulfilled the essential criteria for evaluation of a diagnostic test.

Changing features of proximal vein thrombosis over time

The prevalence of lupus anticoagulant (LA) and antiphospholipid antibodies (APA) in young patients (<45 years) with deep-vein thrombosis (DVT) is not clearly defined yet. We studied 93 consecutive patients (36 males, 57 females; aged 15 to 45) with objectively documented DVT. A control group consisting of 100 nor mal, sex- and age-matched individuals was also investi gated. In all subjects, we evaluated prothrombin time (PT), partial thromboplastin time (PTT), AT III antigen and activity, protein C antigen and activity, free and total protein S antigen and protein S activity, fibrinogen, plas minogen, heparin cofactor II, plasminogen activator in hibitor (PAI), lupus anticoagulant (LA), and APA. For the assessment of LA, we used the PTT-LA kit (Boeh ringer Mannheim, Milan, Italy) as a screening test, with mixing studies with the Staclot-PNP kit and the Staclot- LA kit (Boehringer Mannheim, Milan, Italy) as confirma tory procedures. For the detection of APA, we used a commercially available enzyme-linked immunoassay (ELISA) (Asserachrom APA, Boehringer Mannheim, Mi lan, Italy). History was elicited in all patients to deter mine if the thrombotic episode was idiopathic or the re sult of a well-identified risk factor. LA was found in 11 (11.8%) patients. APA were positive in 13 (14%) and bor derline in 19 (20.4%) patients. In the control group, no patients were positive for LA or APA, but five exhibited borderline APA levels. LA was significantly more fre quent (p = 0.05) in patients with idiopathic DVT than in patients with secondary DVT; no difference was found for APA (p > 0.5). An inherited coagulation defect was found in seven (7.5%) patients. Our data suggest that the presence of LA or APA is associated with an increased incidence of thrombotic manifestation in young patients. Moreover LA is more frequent in patients with idiopathic DVT. Because the incidence of recurrent thrombotic manifestations in patients with LA or APA is estimated to be ∼50% within 2 years from the first thrombotic episode, the tests should be performed in all patients with juvenile thrombosis.

Acetylsalicylic acid inhibits platelet PAI-1 antigen release without affecting circulating PAI-1 antigen in plasma

Recently, the sensitivity of impedance plethysmography (IPG) for the diagnosis of acute deep-vein thrombosis (DVT) in symptomatic outpatients has been questioned. In order to verify whether a change in the venographic pattern of DVT has occurred over years, accounting for the decreased sensitivity of IPG, the authors compared two series of consecutive venograms demonstrating proximal DVT, performed between 1984-1988 (166 patients) and 1990-1992 (140 patients). They evaluated both the extension and the occlusiveness of deep-vein thrombi in the two series. Moreover, changes in the referral characteristics of patients were investigated. In the second series of venograms a signif icant decrease in thrombi extension, expressed by a lower prevalence of iliac vein throm bosis (29% versus 43%; P = 0.0074) was observed; moreover, a significant increase in the prevalence of nonocclusive thrombi (22% versus 8%; P = 0.0004) was also recorded in the second series when compared with the first. During the study period, among the referral characteristics of patients, the authors observed both a significant decrease in the prevalence of proximal DVT (from 31% to 24%; P < 0.01) and a slight and not statistically significant decrease in the median time elapsed between onset of symptoms and referral for objective testing (from eight and a half to seven days). In conclusion, proximal deep- vein thrombi are currently less extensive and occlusive than observed in the past. These results might depend on earlier referral of less symptomatic patients and might explain the recently reported decrease in IPG sensitivity for proximal DVT.