D. P. M. Brandjes

Acenocoumarol and Heparin Compared with Acenocoumarol Alone in the Initial Treatment of Proximal-Vein Thrombosis

BACKGROUNDnIn most countries, heparin is used in the initial treatment of patients with deep-vein thrombosis. Well-designed studies establishing the efficacy of heparin therapy are lacking, however. Treatment with acenocoumarol alone, according to the hypothesis that high dosages of oral anticoagulants obviate the need for heparin, is considered an effective alternative in some countries.nnnMETHODSnIn a randomized, double-blind study we compared the efficacy and safety of continuous intravenous heparin plus acenocoumarol with the efficacy and safety of acenocoumarol alone in the initial treatment of outpatients with proximal-vein thrombosis. The principal study end point was a confirmed symptomatic extension or recurrence of venous thromboembolism during six months of follow-up. In addition, we assessed asymptomatic extension or pulmonary embolism by repeating venography and lung scanning after the first week of treatment. The incidence of major bleeding was determined during three months of follow-up.nnnRESULTSnThe study was terminated early by the Data Safety and Monitoring Committee because of an excess of symptomatic events in the group that received acenocoumarol alone (in 12 of 60 patients [20 percent], as compared with 4 of 60 patients [6.7 percent] in the combined-therapy group by intention-to-treat analysis; P = 0.058). Asymptomatic extension of venous thrombosis was observed in 39.6 percent of the patients in the acenocoumarol group and in 8.2 percent of patients treated with heparin plus acenocoumarol (P < 0.001). Major bleeding complications were infrequent and comparable in the two groups.nnnCONCLUSIONSnPatients with proximal-vein thrombosis require initial treatment with full-dose heparin, which can safely be combined with acenocoumarol therapy.

Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis.

BACKGROUNDnIsolated deficiencies of antithrombin III, protein C, protein S, and plasminogen have been implicated as a cause of deep-vein thrombosis. It is assumed that patients with recurrent, familial, or juvenile thrombosis are very likely to have such a deficiency.nnnMETHODSnWe studied the prevalence of isolated deficiencies of these proteins in 277 consecutive outpatients with venographically proved acute deep-vein thrombosis, as compared with 138 age-matched and sex-matched controls without deep-vein thrombosis, and calculated the positive predictive value of a history of recurrent, familial, or juvenile venous thromboembolism for the presence of such a deficiency.nnnRESULTSnThe overall prevalence of deficiencies of any of these proteins in the patients with venous thrombosis was 8.3 percent (23 of 277 patients) (95 percent confidence interval, 5.4 to 12.4), as compared with 2.2 percent in the controls (3 of 138 subjects) (95 percent confidence interval, 0.5 to 6.1; P less than 0.05 for the comparison between groups). The positive predictive values for the presence of an isolated protein deficiency in patients with recurrent, familial, or juvenile deep-vein thrombosis, defined as the proportion of patients with the clinical finding who had a deficiency of one or more of the proteins, were 9, 16, and 12 percent, respectively.nnnCONCLUSIONSnThe cause of acute venous thrombosis in most outpatients (91.7 percent) cannot be explained by abnormalities of coagulation-inhibiting and fibrinolytic proteins. The information obtained from the medical history concerning recurrent or familial venous thrombosis or the onset of the disease at a young age is not useful for the identification of patients with protein deficiencies.

Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism

The clinical diagnosis of pulmonary embolism is an insufficient basis for initiating long-term anticoagulant therapy [1, 2]. When objective tests are used, the diagnosis of pulmonary embolus is confirmed in only about 30% of patients in whom the condition is suspected [1, 2]. It is important to identify patients with pulmonary embolism because adequate anticoagulant treatment reduces morbidity and mortality from recurrent thromboembolic disease [3]. However, anticoagulant therapy carries a substantial risk for major bleeding [4]. Thus, it is equally important to identify patients without pulmonary embolism from whom anticoagulant therapy can be safely withheld. Lung scintigraphy remains the test of first choice for the diagnostic work-up of patients suspected of having pulmonary embolism. It has been conclusively shown that anticoagulant agents can be safely withheld from patients who have normal scans [5, 6]. In patients with segmental or larger perfusion defects and locally normal ventilation (that is, patients with high-probability lung scans), the diagnosis is sufficiently proven to warrant long-term anticoagulant therapy [1, 2, 7]. Unfortunately, the lung scan is neither normal nor high-probability in 40% to 60% of patients [1, 2, 7-9]. Further investigation is required because the prevalence of pulmonary embolism in this group is still approximately 20% to 40% [1, 2, 9, 10]. Pulmonary angiography is generally considered the definitive test, but this method is invasive and requires substantial technical resources and expertise for proper execution [9, 11]. Therefore, several alternate noninvasive methods that reduce the need for pulmonary angiography have been advocated; these include tests for the measurement of coagulation activation [12, 13], clinical decision rules [14, 15], and spiral computed tomography [16]. On the basis of the concept that pulmonary embolism and deep venous thrombosis are manifestations of the same disease, some investigators have evaluated the use of tests for the detection of venous thrombosis of the leg in the diagnostic work-up of patients suspected of having pulmonary embolism [17, 18]. To be clinically useful, such a test should be simple, readily available, and highly accurate. Compression ultrasonography has been shown to be reliable for detecting and excluding thrombosis in patients in whom deep venous thrombosis is clinically suspected [19-21]. However, in nonsymptomatic persons with a high risk for thrombosis (for example, patients who have recently undergone hip surgery), this test did not prove clinically useful, primarily because of an insufficient sensitivity [22-24]. We sought to determine the diagnostic value of compression ultrasonography in consecutive patients suspected of having pulmonary embolism. We then used our findings to assess the potential contribution of compression ultrasonography to the diagnostic management of symptomatic patients. Methods Patients Patients were eligible for the study if they were 18 years of age or older and underwent perfusion-ventilation lung scanning for a diagnostic work-up of pulmonary embolism at the Academic Medical Center in Amsterdam, the Netherlands. All patients were primarily referred because pulmonary embolism was clinically suspected (outpatients) or because they developed signs or symptoms of pulmonary embolism during hospitalization for another illness (inpatients). All patients were scheduled to undergo ultrasonography as soon as possible; this test was done independently of the other tests. All patients were prospectively followed for 6 months. The study protocol was approved by the institutional review board, and informed consent was obtained for all patients. Diagnostic Methods Perfusion lung scanning was done in all patients after the administration of 100 MBq of 99mTechnetium-labeled macroaggregates of albumin. Six views were routinely obtained: anterior, posterior, left and right lateral, and left and right posterior oblique. Lung scans were interpreted by using an anatomic-segment lung chart [25] and were considered normal if no perfusion defects were seen in any of the six projections. If segmental or larger defects were seen, ventilation lung scanning was done using 81mKrypton gas. Pulmonary embolism was considered to be excluded if the lung scan was normal and was considered to be proven if a high-probability scan (that is, a scan showing at least one segmental perfusion defect with locally normal ventilation [1, 7]) was obtained. Selective pulmonary angiography was attempted in all patients who had a nondiagnostic lung scan. Angiography involved a modified Seldinger approach with a 6.7F-braded, multiple side-holed, Grollman-type pig-tail catheter. The angiogram was classified according to standard definitions as normal, indicative of pulmonary embolism, or inadequate for interpretation [1, 2, 9]. B-mode gray-scale compression ultrasonography was done with a 7.5-MHz linear-array sonographic scanner. While the patient was in the supine position, the common femoral vein was visualized at the inguinal ligament; the adjacent artery was used as a reference point. The popliteal vein was scanned while the patient was in the prone or lateral decubitus position, and the transducer was placed posteriorly in the mid-popliteal fossa. For evaluation of the distal popliteal vein, the transducer was moved slowly from the popliteal fossa along the calf until the trifurcation of the calf veins was visualized. No attempt was made to visualize the calf veins. Ultrasonographic results were considered abnormal (that is, consistent with the presence of deep venous thrombosis) if a venous segment could not be completely compressed [19-21]. All patients underwent bilateral compression ultrasonography, which was done by an independent investigator who was not aware of the results of lung scanning or pulmonary angiography. Results of compression ultrasonography were not forwarded to the referring physician, and decisions about anticoagulant treatment were based on the results of lung scanning or pulmonary angiography. Statistical Analysis The rate of abnormal compression ultrasonography in patients in whom pulmonary embolism was proven (sensitivity) was calculated for all patients and for patients with the diagnosis of pulmonary embolism by using as a conjoint gold standard a high-probability lung scan or a non-high-probability lung scan plus a subsequent abnormal angiogram. We also determined the rate of abnormal ultrasonographic results in patients in whom pulmonary embolism was excluded by either a normal lung scan or a normal angiogram (1 specificity). Finally, the rate of abnormal results on compression ultrasonography was calculated for patients whose diagnosis of pulmonary embolism was uncertain because angiography could not be performed or because the result could not be interpreted. The possible contribution of compression ultrasonography to the diagnostic management of symptomatic patients was assessed by 1) calculating the number of lung scans and angiograms that could be avoided if compression ultrasonography yielded abnormal results and 2) determining the number of patients who would be inappropriately treated with anticoagulation because of false-positive ultrasonographic results. These calculations were done by applying the sensitivity and specificity of compression ultrasonography obtained in our study to a hypothetical population of 1000 patients suspected of having pulmonary embolism; the proportional distribution of lung scanning and angiography results were the same as those seen in our study. To minimize bias, all 397 patients (including the 40 patients in whom ultrasonography was not done) were used to calculate the necessary figures. We assumed that the prevalence of pulmonary embolism in the 30 patients without a diagnosis (those whose lung scan was nondiagnostic but who did not undergo pulmonary angiography) was 27%, as was seen in the remaining patients who had a nondiagnostic lung scan. Furthermore, the sensitivity and specificity of ultrasonography in these 30 patients were assumed to be similar to those obtained in the cohort of patients with a nondiagnostic lung scan in whom angiography was done. This resulted in an overall calculated prevalence of pulmonary embolism of 41.1%, with a high-probability lung scan in 30.2% of these patients and a nondiagnostic lung scan in 40.6%. Pulmonary embolism was considered to be present in 27% of patients who had a nondiagnostic lung scan (if angiography had been performed). Finally, we assumed that all patients with abnormal ultrasonographic results would be treated with anticoagulant agents without further testing. Results A total of 397 consecutive patients who were clinically suspected of having pulmonary embolism were enrolled (Figure 1). The mean age was 56 years (range, 18 to 92 years); 223 patients (56%) were women, and 206 (52%) were outpatients. Twenty-four percent of patients had cancer, 21% had recently had surgery, 12% had congestive heart failure, and 12% had a history of venous thromboembolism. No risk factor was seen in 26% of patients. The median interval between the onset of symptoms and diagnostic investigations was 2 days. Compression ultrasonography could not be done in 40 patients. Thirty of these patients had a normal perfusion lung scan; 22 of the 30 were outpatients for whom compression ultrasonography could not be arranged before they left. Compression ultrasonography was not performed in 4 patients who had a high-probability lung scan and 6 patients who had a nondiagnostic lung scan (angiography results were abnormal in 1 patient and normal in 2; angiography was not done in 3 patients). Treatment decisions in these 40 patients were made on the basis of lung scans and angiography results, as was done for the 357 patients in whom ultrasonography was performed. Figure 1. Flow diagram of test outcomes of 397 patients suspected of having pul

The clinical course of patients with suspected pulmonary embolism.

BACKGROUNDnThe outcome of patients with suspected pulmonary embolism is known to a limited extent only.nnnOBJECTIVEnTo address this limited knowledge in a cohort in whom pulmonary embolism was proved or ruled out.nnnMETHODSnConsecutive patients with clinically suspected pulmonary embolism underwent lung scintigraphy and angiography if required. Pulmonary embolism was excluded by normal results of a lung scan or angiogram, and, if so, anticoagulant therapy was withheld. Pulmonary embolism was proved with a high-probability perfusion-ventilation lung scan or a confirmatory angiogram if a nondiagnostic lung scan was obtained. These patients were treated with heparin intravenously and anticoagulants orally on a long-term basis. All patients were followed up for 6 months, with a special focus on recurrent thromboembolism, bleeding complications, and mortality.nnnRESULTSnA total of 487 consecutive inpatients and outpatients were included. Pulmonary embolism was excluded or proved in 243 and 193 patients, respectively. In 51 patients a definite diagnosis could not be established. The overall prevalence of pulmonary embolism was 39%. In patients in whom pulmonary embolism was proved, excluded, or uncertain, recurrent venous thromboembolism was observed in 2.6%, 0.9%, and 2%, respectively. Serious bleeding complications occurred in 7 patients (3.3%; 95% confidence interval [CI], 1.8%-6.3%), 2 cases of which were fatal. The total mortality after 6 months in patients with proved or excluded pulmonary embolism was 17% (95% CI, 12%-23%) and 11% (95% CI, 7%-15%), respectively. Death was related to (recurrent) pulmonary embolism in 5% and 0% of these cases, respectively.nnnCONCLUSIONSnDuring a 6-month period, recurrent pulmonary embolism occurred in approximately 5 patients (2.5%) who were treated for a previous episode. Fatal bleeding complications attributable to the use of anticoagulants were encountered in 1%. The mortality among patients with suspected pulmonary embolism was considerable. However, most deaths were unrelated to pulmonary embolism, but were the result of serious underlying illnesses.

Reduction of contact activation related fibrinolytic activity in factor XII deficient patients. Further evidence for the role of the contact system in fibrinolysis in vivo.

In this study the contribution of activation of the contact system to activation of the fibrinolytic system in vivo was investigated in healthy volunteers and in factor XII deficient patients. The plasminogen activating activity in plasma from healthy volunteers after infusion of desamino D-arginine vasopressin (DDAVP) was only partially blocked (for 77%) with specific antibodies to tissue-type plasminogen activator and urokinase type plasminogen activator. The residual activity could be quenched by a monoclonal antibody that inhibits factor XII activity and was not present in patients with a factor XII deficiency. The formation of plasmin upon the DDAVP stimulus as reflected by circulating plasmin-alpha 2-antiplasmin complexes was lower in factor XII deficient patients than in healthy volunteers. Activation of the contact system occurred after DDAVP infusion in healthy volunteers and was absent in factor XII deficient patients. These results indicate that DDAVP induces a plasminogen activating activity that is partially dependent on activation of the contact system and that contributes to the overall fibrinolytic activity as indicated by the formation of plasmin-alpha 2-antiplasmin complexes. This fibrinolytic activity is impaired in factor XII deficient patients which may explain the occurrence of thromboembolic complications in these patients.

Feasibility, safety and clinical utility of angiography in patients with suspected pulmonary embolism

The purpose of our study was to assess feasibility, safety and clinical utility of selective pulmonary angiography in patients with suspected pulmonary embolism and a nondiagnostic lung scan. The design was a prospective, descriptive study. The subjects were consecutive patients with clinically suspected pulmonary embolism and a nondiagnostic lung scintigram in whom pulmonary angiography was considered. Angiography was withheld in cases of manifest heart failure, renal failure, mean pulmonary artery pressure above 40 mmHg, or if there were compelling clinical reasons. All patients were followed-up for 6 months. The outcome measures were successful angiography, morbidity, mortality and recurrent pulmonary embolism in patients with normal angiogram in whom anticoagulants were withheld during 6 months of follow-up. Of 487 patients, 196 (40 %) had nondiagnostic lung scan findings. In 46 patients (23 %) pulmonary angiography was withheld. Pulmonary embolism was excluded in 105 patients (70 %), and proven in 40 (27 %) patients. In 5 (3 %) patients the angiogram was inadequate for interpretation. No fatal complications were encountered [95% confidence interval (CI) 0–2.4%]. Nonfatal complications occured in 3 patients (2%; 95% CI 0–3.4%). Pulmonary angiography is safe, rules out pulmonary embolism in two thirds of patients with a nondiagnostic lung scan and can be performed in almost 80% of these patients. It is safe to withhold long-term anticoagulants if a normal angiogram is obtained in this subgroup of patients with clinically suspected pulmonary embolism.

Non-invasive diagnostic work-up of patients with clinically suspected pulmonary embolism; results of a management study

Summary.u2002 Background :u2003Clinicians often deviate from the recommended algorithm for the diagnosis of pulmonary embolism consisting of ventilation‐perfusion scintigraphy and pulmonary angiography.

The role of plasma D-dimer concentration in the exclusion of pulmonary embolism

Objective. To determine the role of four ELISA D‐dimer assays in the exclusion of pulmonary embolism.

Pulmonary embolism as a first clinical sign of occult malignancy: A prospective follow-up study

Pulmonary embolism as a first clinical sign of occult malignancy: A prospective follow-up study -

Non-Invasive Diagnostic Techniques in Deep Vein Thrombosis

Patients presenting with clinical signs and symptoms of deep venous thrombosis of the lower extremities represent a diagnostic problem. In the general population approx. 1 out of 1000 subjects will develop deep vein thrombosis each year. In more than 50 percent of these patients, the diagnosis of venous thrombosis is not confirmed by objective testing (Haeger 1969, Cranley, Canos, Sull 1976). Therefore the reliance on clinical signs and symptoms, i.e. calf muscle tenderness, leg swelling, increased skin temperature, redness, and Homan’s sign will inevitably result in overtreatment of more than half of the symptomatic patient group. Moreover, treating these patients unnecessarily will expose them to the risks of anticoagulant therapy. For this reason, the use of objective diagnostic methods in each patient with clinically suspected deep vein thrombosis is mandatory (Hoek, Lensing, ten Cate et al 1989).