Jan W. ten Cate

Detection of Deep-Vein Thrombosis by Real-Time B-Mode Ultrasonography

In 220 consecutive outpatients with clinically suspected deep-vein thrombosis of the leg, we compared contrast venography with real-time B-mode ultrasonography, using the single criterion of vein compressibility with the ultrasound transducer probe. The common femoral and popliteal veins were evaluated for full compressibility (no thrombosis) and noncompressibility (thrombosis). Both veins were fully compressible in 142 of the 143 patients with normal venograms (specificity, 99 percent; 95 percent confidence interval, 97 to 100). All 66 patients with proximal-vein thrombosis had noncompressible femoral veins, popliteal veins, or both (sensitivity, 100 percent; 95 percent confidence interval, 95 to 100). For all patients (including 11 with calf-vein thrombi), sensitivity and specificity were 91 (95 percent confidence interval, 82 to 96) and 99 percent, respectively. The sensitivity for isolated calf-vein thrombosis was only 36 percent. The compression ultrasound test was repeated in a subset of 45 consecutive patients by a second examiner, unaware of the results of the first test, whose results agreed in all patients with those of the first examiner (kappa = 1). We conclude that ultrasonography with the single criterion of vein compressibility is a highly accurate, simple, objective, and reproducible noninvasive method for detecting proximal-vein thrombosis in outpatients with clinically suspected deep-venous thrombosis.

Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis

BACKGROUND Post-thrombotic syndrome varies from mild oedema to incapacitating swelling with pain and ulceration. We investigated the rate of post-thrombotic syndrome after a first episode of deep-vein thrombosis and assessed the preventive effect of direct application of a sized-to-fit graded compression stocking. METHODS Patients with a first episode of venogram-proven proximal deep-vein thrombosis were randomly assigned no stockings (the control group) or made-to-measure graded compression elastic stockings for at least 2 years. Post-thrombotic syndrome was assessed with a standard scoring system that combined clinical characteristics and objective leg measurements. Patients were assessed every 3 months during the first 2 years, and every 6 months thereafter for at least 5 years. The cumulative incidence of mild-to-moderate post-thrombotic syndrome was the primary outcome measure. FINDINGS Of the 315 consecutive outpatients considered for inclusion, 44 were excluded and 77 did not consent to take part. 194 patients were randomly assigned compression stockings (n = 96) or no stockings (n = 98). The median follow-up was 76 months (range 60-96) in both groups. Mild-to-moderate post-thrombotic syndrome (score > or = 3 plus one clinical sign) occurred in 19 (20%) patients in the stocking group and in 46 (47%) control-group patients (p < 0.001). 11 (11%) patients in the stocking group developed severe post-thrombotic syndrome (score > or = 4), compared with 23 (23%) patients in the control group (p < 0.001). In both groups, most cases of post-thrombotic syndrome occurred within 24 months of the acute thrombotic event. INTERPRETATION About 60% of patients with a first episode of proximal deep-vein thrombosis develop post-thrombotic syndrome within 2 years. A sized-to-fit compression stocking reduced this rate by about 50%.

Activation of Coagulation after Administration of Tumor Necrosis Factor to Normal Subjects

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.

A Comparison of Real-Time Compression Ultrasonography with Impedance Plethysmography for the Diagnosis of Deep-Vein Thrombosis in Symptomatic Outpatients

BACKGROUND Impedance plethysmography performed serially over a one-week period has been shown to be an effective diagnostic strategy for patients with clinically suspected acute deep-vein thrombosis. Compression ultrasonography has a high sensitivity and specificity for the detection of proximal-vein thrombosis. The clinical value of repeated ultrasonography in the management of symptomatic deep-vein thrombosis is unknown. METHODS We conducted a randomized trial in 985 consecutive outpatients with clinically suspected deep-vein thrombosis to compare the diagnostic value of serial impedance plethysmography (494 patients) and serial compression ultrasonography (491 patients). We compared the positive predictive values of both tests for the diagnosis of venous thrombosis, using contrast venography as a reference. The frequencies of venous thromboembolism during a six-month follow-up period were also compared in patients with repeatedly normal results in order to evaluate the safety of withholding anticoagulant therapy from such patients. RESULTS The positive predictive value of an abnormal ultrasonogram was 94 percent (95 percent confidence interval, 87 to 98 percent), whereas the predictive value of impedance plethysmography was 83 percent (95 percent confidence interval, 75 to 90 percent) (P = 0.02). In patients with repeatedly normal results, the incidence of venous thromboembolism during the six-month follow-up period was 1.5 percent (95 percent confidence interval, 0.5 to 3.3 percent) for serial compression ultrasonography, as compared with 2.5 percent (95 percent confidence interval, 1.2 to 4.6 percent) for serial impedance plethysmography. CONCLUSIONS In making the diagnosis of deep-vein thrombosis in symptomatic outpatients, serial compression ultrasonography is preferable to impedance plethysmography, in view of its superior performance in detecting venous thrombosis.

Serial impedance plethysmography for suspected deep venous thrombosis in outpatients. The Amsterdam General Practitioner Study

Diagnosis of deep venous thrombosis by clinical signs and symptoms is unreliable, but contrast venography is relatively expensive and invasive. We therefore evaluated the use of impedance plethysmography as a noninvasive alternative in 426 consecutive outpatients with clinically suspected acute deep venous thrombosis. Four sequential impedance plethysmograms were obtained on days 1, 2, 5, and 10 of the study. In 289 patients (68 percent), the results of all four studies were normal, and these patients were not treated with anticoagulants. One of these patients may have had a minor pulmonary embolus during the 10-day study period. During a six-month follow-up of all patients, none of the 289 patients whose plethysmograms were normal died of venous thromboembolism or presented with suspected pulmonary embolism. In 137 patients (32 percent), the impedance plethysmograms were abnormal; 117 (85 percent) had the abnormal results on their first test, and 20 (15 percent) had them on subsequent tests. All patients with abnormal plethysmograms also underwent contrast venography, which confirmed the diagnosis of deep venous thrombosis in 92 percent. We conclude that the diagnostic accuracy of repeated impedance plethysmography compares favorably with that of venography and that the technique is a safe and effective noninvasive approach to the diagnosis and care of outpatients with clinically suspected acute deep venous thrombosis.

Enhanced thrombin generation in normal and hypertensive pregnancy.

We investigated the plasma levels of thrombin-antithrombin III complexes in women with uncomplicated pregnancy, patients with preeclampsia, gestational hypertension, and nonpregnant control subjects. In addition, we measured the coagulation inhibitors antithrombin III, protein C, and protein S. In normal pregnancy we observed a progressive increase in plasma thrombin-antithrombin III levels, and a decrease in protein S levels. In preeclampsia we observed increased thrombin-antithrombin III levels, reduced antithrombin III and protein C levels, and no further reduction of protein S compared with normal pregnancy. These new methods provide solid evidence for a prethrombotic state in normal pregnancy, especially in preeclampsia.

The clinical course of patients with suspected pulmonary embolism.

BACKGROUND The outcome of patients with suspected pulmonary embolism is known to a limited extent only. OBJECTIVE To address this limited knowledge in a cohort in whom pulmonary embolism was proved or ruled out. METHODS Consecutive 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. RESULTS A 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. CONCLUSIONS During 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.

A comparative trial of a low molecular weight heparin (enoxaparin) versus standard heparin for the prophylaxis of postoperative deep vein thrombosis in general surgery

BACKGROUND Various studies have been performed in general surgery patients comparing low molecular weight heparin (LMWH) with standard heparin (SH) for the prevention of postoperative deep vein thrombosis (DVT), revealing contradicting results. Therefore, we have compared the efficacy and safety of a LMWH for the prevention of DVT after major general surgery. PATIENTS AND METHODS Patients received either 20 mg LMWH (enoxaparin) once daily, or 5,000 IU SH TID, starting preoperatively in a prospective, randomized, double-blind international multicenter trial. DVT was diagnosed using fibrinogen I 125 leg scanning. Major and minor bleeding were assessed clinically. RESULTS A total of 718 patients were randomized to LMWH, and 709 patients to SH. DVT was detected in 58 LMWH-treated patients (8.1%, 95% confidence interval [CI] 6.2% to 10.3%) and in 45 patients allocated to SH (6.3%, 95% CI 4.7% to 8.4%, P > 0.05). Major bleeding complications occurred in 11 LMWH-treated patients (1.5%, 95% CI 0.8% to 2.7%) and in 18 patients to whom standard heparin was administered (2.5%, 95% CI 1.5% to 3.9%, P > 0.05). Four LMWH-treated patients (0.6%) required reoperation for bleeding as compared to 13 patients in the SH group (1.8%, P = 0.03). CONCLUSION This LMWH appeared as effective and safe as SH. In view of its more convenient way of administration, this LMWH might be preferred for thromboprophylaxis.

Acquired antithrombin III deficiency: Laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate

Antithrombin III (ATIII) is the predominant naturally occurring inhibitor of serine proteases generated during blood coagulation [Rosenberg RD: Annu Rev Med 1978; 29: 367-378]. Since 1965, several assays have been developed that allow rapid and precise determination of ATIII in plasma. As a consequence, the existence of acquired ATIII deficiency in many pathologic conditions has been described. Acquired ATIII deficiency is based on decreased synthesis, increased loss or increased consumption, or induced by drugs. An inherited ATIII deficiency is associated with a lifelong tendency to venous thromboembolism. In contrast, the clinical significance of acquired ATIII deficiency has been less well defined. A precise estimate of the risk of thromboembolism in the acquired ATIII deficiency state cannot easily be provided, owing to the lack of studies in consecutive patients. In 1978, a purified human ATIII concentrate became available for clinical investigation. Despite numerous small studies, the value of ATIII replacement therapy in patients with acquired deficiency remains to be demonstrated.

Coagulopathy in ruptured or dissecting aortic aneurysms

A consumption coagulopathy was demonstrated in each of four patients with either ruptured aneurysm of the aorta or a dissecting aortic aneurysm. The most prominent features of this disorder were (1) a prolonged prothrombine time due to a decrease of one or more clotting factors, and (2) formation of fibrin and fibrinogen degradation products. Recognition of this coagulation disorder could be a valuable diagnostic tool to differentiate a ruptured or dissecting aortic aneurysm from other conditions with a similar acute onset. The coagulation disorder could be due to liberation of coagulant material from the aortic wall into the circulation or to an accumulation of clotting factors at the site of the lesion, secondary to the local exposition of tissue factors from the torn arterial wall. The probability of the latter mechanism is suggested by the local increase of radioactivity after the injection of 125I-fibrinogen.