Maria M. W. Koopman

Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions

Abstract Objective: To investigate whether users of oral contraceptives who are carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis. Design: Comparison of a prospective series of cases of cerebral sinus thrombosis with population data. Setting: Neurological teaching hospitals from different regions in the Netherlands (cases) and a representative sample of the non-institutionalised Dutch population (controls). Subjects: 40 women aged 18-54 years with cerebral sinus thrombosis (cases) and 2248 women aged 18-49 years (controls). Main outcome measure: Current use of oral contraceptives at the time of the thrombosis (cases) or at the time of the questionnaire (controls). Prevalences of a hereditary prothrombotic condition in patients and in the population with odds ratios. Results: 34 of 40 (85%) women with cerebral sinus thrombosis used oral contraceptives, versus 1007 of 2248 (45%) of the control women; the age adjusted odds ratio was 13 (95% confidence interval 5 to 37). Seven of 36 patients (19%) had a prothrombotic deficiency, versus 7% expected in the population; this corresponds to a threefold to fourfold increase in risk. In women who used oral contraceptives and also carried a prothrombotic defect, the odds ratio for cerebral sinus thrombosis was about 30 relative to women who had neither risk factor. Conclusion: The use of oral contraceptives and being a carrier of a hereditary prothrombotic condition increase the risk of and interact in a multiplicative way in the development of cerebral sinus thrombosis. Key messages The use of oral contraceptives is associated with an increased risk of cerebral venous sinus thrombosis This risk of cerebral venous sinus thrombosis in women who use oral contraceptives is larger if there is an additional hereditary prothombotic factor (protein C, S, or antithrombin deficiency, factor V Leiden mutation) The association between oral contraceptives, thrombophilia, and deep vein thrombosis is also valid for cerebral sinus thrombosis Women do not need to stop using oral contraceptives as the absolute risk of cerebral sinus thrombosis is very small

High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia

OBJECTIVE In patients with a history of severe preeclampsia, an increased frequency of hemostatic abnormalities has recently been suggested in small studies without control groups. Our purpose was to investigate the prevalence of such abnormalities in a large patient group with a history of severe hypertensive disorder in pregnancy, in comparison with an appropriate control group. STUDY DESIGN A total of 345 patients with a history of severe preeclampsia were investigated at a minimum of 10 weeks post partum for the presence of activated protein C resistance, the associated factor V mutation, hyperhomocysteinemia and anticardiolipin antibodies. The control group consisted of 67 healthy women with a history of uncomplicated pregnancies only. Blood was obtained during the second half of a normal menstrual cycle, and none of the patients or control subjects used oral contraceptives. RESULTS Of all patients, 11.3% had activated protein C resistance (control subjects 1.5%, P =.025). Only half of these patients had the factor V mutation. Hyperhomocysteinemia was present in 12.1% of all patients, in comparison with 4.5% in the control group (P =.115). Anticardiolipin antibodies were observed in 20.9% of the patients, whereas these antibodies were found in 7.5% of the control subjects (P =.016). In general, the prevalence of these abnormalities was 1.5 to 2 times higher in patients who were delivered before 28 weeks, in comparison with patients who were delivered after 28 weeks. CONCLUSIONS Hemostatic abnormalities, associated with an increased risk of thrombosis, are present in approximately 40% of patients with a history of severe preeclampsia, which is almost 4 times higher than in control subjects. These findings might suggest a cause of preeclampsia and could have implications in subsequent pregnancies and general health.

Travel and risk of venous thrombosis.

Summary In 1998 the term economy class syndrome was coined to describe the association between travel and thrombosis. A fair risk estimate, however, has not been done. We report the results of a prospective study, in which we kept the effect of bias to a minimum. We compared travel history in 788 patients with venous thrombosis with that of controls with similar symptoms but in whom the disease had been excluded. For air travel alone, the odds ratio was 1·0 (95% CI 0·3–3·0); also, no association was recorded for other methods of transportation. We have shown that, there is no increased risk of deep vein thrombosis among travellers.

Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis

Summary.  Elevated levels of coagulation factor VIII:C (FVIII:C) are associated with an increased risk for venous and arterial thromboembolism. Whether relatives of patients with elevated levels of FVIII:C are also at increased risk for thrombotic disease is unknown. The objective was to determine the annual incidences of both venous and arterial thrombotic events in first‐degree relatives of patients with elevated levels of FVIII:C and venous thromboembolism (VTE) or premature atherosclerosis. A retrospective study with 584 first‐degree relatives of 177 patients with elevated levels of FVIII:C was performed. The level of FVIII:C was determined and relatives with elevated and normal levels of FVIII:C were compared. Of the participants, 40% had elevated levels of FVIII:C. The annual incidence of a first episode of VTE was 0.34% and 0.13% in relatives with elevated levels of FVIII:C and those with normal levels, respectively [OR 3.7 (95% CI 1.9–7.5)]. The absolute annual incidence in the youngest age group with elevated levels of FVIII:C was 0.16% (0.05–0.37) and gradually increased to 0.99% (0.40–2.04) in those older than 60 years of age, although the odds ratios were not statistically significant. The annual incidences of a first arterial thrombotic event were 0.29% and 0.14% in relatives with and without elevated levels of FVIII:C, respectively [OR 3.1 (1.4–6.6)]. In particular the risks for a first myocardial infarction [OR 4.3 (1.0–18.1); P =0.046] and a first peripheral arterial thrombosis [OR 8.6 (1.6–47.6)] were increased. Within families of patients with elevated levels of FVIII:C and VTE or premature atherosclerosis, 40% of their first‐degree relatives has elevated levels of FVIII:C as well, and they are at increased risk for both VTE and arterial thrombosis as compared with their relatives with normal levels.

Prospective Study of Color Duplex Ultrasonography Compared with Contrast Venography in Patients Suspected of Having Deep Venous Thrombosis of the Upper Extremities

Context Venography is the standard test for diagnosing deep venous thrombosis of the upper extremities. It is not an ideal test because it requires intravenous access and contrast media. Ultrasonography is a widely available alternative test, but how feasible and accurate is it? Contribution In 126 consecutive patients with suspected upper-extremity thrombosis, venography and ultrasonography were not feasible in 18% and fewer than 1%, respectively. When venography was used as the reference standard, the likelihood ratio for a positive result on ultrasonography was 4.5 (95% CI, 2.53 to 8.02). The likelihood ratio for a negative result was 0.2 (CI, 0.12 to 5.57). Implications Positive findings on ultrasonography are reasonably accurate for diagnosing deep venous thrombosis of the upper extremities. The Editors The exact incidence of deep venous thrombosis (DVT) of the upper extremities is unknown. A prevalence of 2 cases per 1000 hospital admissions has been reported (1). Deep venous thrombosis of the upper extremities is increasingly recognized as causing high mortality and morbidity, similar to DVT of the leg (2, 3). Deep venous thrombosis of the upper extremities is closely associated with malignant disease and the use of central venous access lines (3-11). Nevertheless, few prospective studies on diagnosis and management of DVT of the upper extremities have been published. Contrast venography is generally considered the reference method for diagnosis of DVT of the upper extremities (2, 3). However, because of its inherent problems, such as availability, use of ionizing radiation, necessity of iodinated contrast media, and technical difficulties in obtaining intravenous access, researchers have searched for more appropriate, noninvasive methods. Ultrasonography is widely available and has been used extensively for diagnosis of DVT of the lower extremities (12-18). However, only a few prospective studies have been done in limited numbers of patients to establish its role in the diagnosis of DVT of the upper extremities (3, 19-22). In addition, ultrasonography is problematic because of the anatomy of the upper extremities. The overlying bony structures and the inability to visualize the central intrathoracic venous system limit the value of compression ultrasonography. Therefore, duplex color ultrasonography has been proposed for diagnosis of DVT of the upper extremities (3, 19-24). We sought to assess the diagnostic accuracy of duplex color ultrasonography compared with contrast venography in patients suspected of having DVT of the upper extremities. Methods Study Sample From August 1996 to March 2001, 126 consecutive outpatients and inpatients with clinically suspected DVT of the upper extremities were referred for diagnostic work-up. Three of these patients were referred twice, and 2 patients were referred three times. Patients were excluded if they were pregnant, were younger than 18 years of age, had renal failure prohibiting contrast venography, had a known allergy to iodinated contrast agents, or were unable to provide informed consent. Informed consent for duplex color ultrasonography and venography was obtained at referral from all but 2 patients, and the Institutional Review Board of the Academic Medical Center, Amsterdam, approved the study. Contrast Venography Contrast venography of the symptomatic extremity was performed by using digital subtraction angiography equipment (Polytron, Siemens, Erlangen, Germany). Standardized protocol consisted of a 30-mL contrast injection in the antecubital vein or, if this was not possible, in a more distal forearm vein in the affected arm. No tourniquet was applied. Patients were studied with the examined arm extended and with little abduction of the upper arm to prevent compression of the axillary vein by soft tissues. Low osmolar nonionic contrast was used at a concentration of 300 mg of iodine per liter (Omnipaque, Nycomed-Amersham, Oslo, Norway). All injections were performed by hand. Digital subtraction images of the brachial, axillary, subclavian, and superior caval veins were obtained at a rate of one frame per second. We defined DVT of the upper extremities as the presence of an intraluminal thrombus or persistent nonfilling of a venous segment in the presence of filling of collateral vessels, as demonstrated by contrast venography. All other findings were considered inadequate for interpretation. Duplex Color Ultrasonography Duplex color ultrasonography of the affected extremity was performed with assessment of the basilic, cephalic, axillary, and subclavian veins. The jugular and innominate veins were not included; because the first is visible only on ultrasonography and the second is visible only on venography, comparison is not possible. After identification of the relevant vessels, a three-step procedure was performed. This involved compression ultrasonography of the venous segments that could be reached, assessment of intravascular thrombus by using color ultrasonography, and flow measurements during respiration to determine the outflow of the venous system by using color Doppler ultrasonography. Patients were asked to perform the Valsalva maneuver to allow assessment of changes in flow pattern. Flow patterns of the unaffected veins in the upper extremities were used only in cases of doubt. All tests were performed by senior residents and staff radiologists who had adequate experience in duplex color ultrasonography, using normal departmental practice. We used three qualified ultrasonography machines that were updated but were not changed during the study (Sonos 2000, Hewlett Packard, Andover, Massachusetts; Aloka 1700 and 2000, Aloka, Tokyo, Japan); probes ranged from 4.5 to 7.5 MHz. Duplex color ultrasonography was considered to demonstrate DVT if it showed noncompressibility of a venous segment, a visible intraluminal thrombus, or an abnormal flow pattern (absent flow or absence of phasic flow pattern indicating outflow obstruction) (3). If none of these findings were present, the results were considered normal. All other findings, lack of visualization, and performance of flow measurements were considered inadequate for interpretation. Study Design We performed a prospective comparative study in consecutive patients with clinically suspected DVT of the upper extremities. All patients underwent duplex color ultrasonography as the first test. Results were reported independently and within 4 hours before performance of the reference method, contrast digital venography. Because we followed departmental routine in our teaching hospital, a variety of qualified residents and staff personnel performed the ultrasonography and venography studies at any time during the day or evening. At all times, the radiologist who performed venography was blinded to the initial results on color duplex ultrasonography. Findings on duplex color ultrasonography were compared with those on contrast venography (the reference method). We also assessed potential factors associated with the cause of DVT of the upper extremities, such as the presence of malignant disease, indwelling catheters, or a hypercoagulable state. Statistical Analysis We calculated diagnostic accuracy (sensitivity and specificity), likelihood ratios (25), and 95% CIs for all findings except indeterminate findings on duplex color ultrasonography (because comparison with contrast venography was not possible). Patient groups in which DVT of the upper extremities was confirmed, excluded, or remained uncertain were compared by using the chi-square test. A P value less than 0.05 indicated statistical significance. Results During the inclusion period, 126 patients were eligible for study enrollment. A total of 27 patients was excluded from the analysis. Contrast venography could not be performed in 16 patients because of medical or technical reasons (failure to obtain venous access, n = 10; renal failure, n = 3; pregnancy, n = 2; and iodinated contrast allergy, n = 1). Another 5 patients were excluded because of logistic reasons, and 2 patients declined to provide informed consent. Therefore, venography could not be performed in 23 of 126 patients (18%). In 1 patient, duplex color ultrasonography was not performed because of logistic reasons. Finally, results of duplex color ultrasonography were indeterminate in 3 patients, resulting in a conclusive rate of 98%. A flow diagram of patients is provided in Figure 1. Figure 1. Flow of patients through the study. A total of 99 patients was available for evaluation after undergoing both duplex color ultrasonography and contrast venography. Forty-four patients were men, and 55 were women; the mean age of all patients was 54 years (range, 18 to 92 years). Deep venous thrombosis was demonstrated by contrast venography in 44 patients (44%). The distribution of thrombi in the veins of the right or left upper extremity on venography is shown in Figure 2. Eight patients had primary thrombosis of unknown cause, while an underlying cause could be shown in 36 patients (Table 1). Malignant disease was present in 63% of patients with proven DVT of the upper extremities and in 19 of 55 patients (35%) in whom DVT was excluded (P < 0.01). Figure 2. Distribution of 29 thrombi in the right upper-extremity veins and 33 thrombi in the left upper-extremity veins on digital subtraction venography. Table 1. Identified Causes of Proven Deep Venous Thrombosis of the Upper Extremities in 44 Patients Results on duplex color ultrasonography were compared with results on contrast venography (Table 2). Eight studies were false negative and 10 were false positive, resulting in a sensitivity and specificity of 82% (95% CI, 70% to 93%) and 82% (CI, 72% to 92%), respectively. The likelihood ratio was 4.5 (CI, 2.53 to 8.02) for a true-positive test result and 0.22 (CI, 0.12 to 0.42) for a true-negative test result. Table 2. Duplex Color Ultrasonography Compared with Contrast Venography in 99 Patients

Limitations of compression ultrasound for the detection of symptomless postoperative deep vein thrombosis

Compression ultrasonography is regarded as the non-invasive gold-standard to detect deep vein thrombosis (DVT) in patients presenting with symptoms. However, its use as a screening method in symptom-free postoperative patients at high risk of developing DVT remains controversial. In 100 consecutive patients who had undergone craniotomy, we compared the results of bilateral compression ultrasonic measurements of the results of bilateral compression ultrasonic measurements of the entire legs with the outcomes of contrast venography. Proximal DVT was detected in 13 patients, 5 of whom also had an abnormal ultrasonic result (sensitivity 38%, 95% CI 8-69%). Only 5 of the 9 patients with an abnormal ultrasound result for the proximal veins had proximal DVT (positive predictive value, 56%, 18-94%). Calf sonograms were evaluable in 71 of the 91 patients with bilaterally normal ultrasound results for the proximal veins. Of the 16 patients with calf DVT, ultrasound was abnormal in 8 (sensitivity 50%, 25-75%). Overall, ultrasound detected 13 of the 26 patients with proximal or isolated calf DVT (sensitivity 50%, 29-71%). The positive predictive value for the whole leg examination was 41% (24-60%). Most thrombi missed by ultrasound were non-occlusive and smaller than 5 cm. We conclude that compression ultrasound is not useful for screening for DVT in symptom-free postoperative high-risk patients.

The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders

Summary. The duration of anticoagulant treatment after a first episode of venous thromboembolism primarily depends on the risk of recurrence. Variability of recurrence rates in factor (F) V Leiden carriers may be due to concomitant thrombophilic disorders. A retrospective study was performed in 329 FV Leiden carriers with a history of venous thromboembolism (262 probands, 67 relatives). The annual rate of first recurrence was estimated in relatives. The contribution of concomitant thrombophilic disorders to the recurrence rate was evaluated in probands and relatives by a nested case–control analysis in 105 matched pairs of carriers either with or without recurrence. The overall annual recurrence rate was 2·3 per 100 patient–years. The adjusted risk of recurrence for concomitant thrombophilic disorders was: 9·1 (1·3–62·8) for the FII mutation; 1·0 (0·2–4·9) for homozygosity for FV Leiden; 1·5 (0·2–9·5) for inherited deficiencies of protein C or S; 1·8 (0·7–4·9) for FVIII coagulant activity (FVIII:C) levels > 122%; 5·4 (1·6–18·6) for fasting homocysteine levels > 15·2 µmol/l; and 4·4 (1·0–18·7) for loading homocysteine levels > 45·8 µmol/l. Of these disorders, only the FII mutation and hyperhomocysteinaemia significantly increased the risk of recurrence in FV Leiden carriers. The estimated recurrence rate ranged from 0·45 per 100 patient–years after a secondary first event in the absence of concomitant disorders to 4·8 per 100 patient–years when a spontaneous first event was combined with concomitant disorders. Our study provides supportive evidence that the incidence of recurrent venous thromboembolism in heterozygous FV Leiden carriers depends on the concomitance of other thrombophilic disorders, in addition to whether the first thrombotic event occurred spontaneously.

Low-Molecular-Weight Heparins in the Treatment of Venous Thromboembolism

For many decades, the conventional wisdom has been that patients with a diagnosis of acute venous thromboembolic disease confirmed by objective techniques should receive an initial continuous intravenous course of unfractionated heparin for at least 5 days to prevent early and late recurrences [1, 2]. Oral anticoagulant therapy can be started simultaneously and should be continued for at least 3 months [3]. Because the pharmacokinetic response of unfractionated heparin is unpredictable, daily laboratory monitoring and dose adjustments are required; therefore, hospital admission for treatment of acute thromboembolic disease is usually unavoidable [4]. This standard practice is now being challenged by the development of low-molecular-weight heparins, which are manufactured by depolymerization of unfractionated heparin. The concept behind the development of these refined compounds is that inhibition of activated coagulation factor X (Xa) is crucial for the antithrombotic activity of heparins. Unlike unfractionated heparin, which has equivalent activity against both factor Xa and thrombin, low-molecular-weight heparins have greater activity against factor Xa. Therefore, it is expected that low-molecular-weight heparins will be associated with anti-thrombotic activity at least equal to that of unfractionated heparin, whereas the risk for hemorrhage is smaller. However, the most important advantages of low-molecular-weight heparins are their superior pharmacokinetic properties. Compared with unfractionated heparin, they bind less to plasma proteins, blood cells, and the endothelium, resulting in nearly complete bioavailability, longer half-life, and more predictable anticoagulant response [5, 6]. This allows once- or twice-daily subcutaneous administration of low-molecular-weight heparins adjusted for body weight without the need for laboratory monitoring. Evidence also suggests that the risk for heparin-induced thrombocytopenia is smaller with low-molecular-weight heparins [7]. We briefly review the research evidence on the clinical use of low-molecular-weight heparin in patients with deep venous thrombosis and pulmonary embolism. We then explore the pragmatic question of the proper clinical indications for use of low-molecular-weight heparin therapy today, and we look at clinical situations in which one should be more cautious in the use of these compounds. The role of low-molecular-weight heparins in the treatment of acute deep venous thrombosis has been assessed in at least nine clinically similar randomized studies of high methodologic quality. In a pooled analysis of these trials, which included a total of about 3500 patients, fixed-dose subcutaneous low-molecular-weight heparin was similar to or better than continuous, intravenous, dose-adjusted unfractionated heparin for reducing the incidence of symptomatic recurrent venous thromboembolism during 3 to 6 months of follow-up (odds ratio, 0.75 [95% CI, 0.55 to 1.01]; P = 0.06) [8-10]. Two randomized studies with clinical follow-up compared initial therapy with unmonitored low-molecular-weight heparin with unfractionated heparin in patients with acute symptomatic pulmonary embolism. Almost 900 patients were studied, and the pooled odds ratio for symptomatic recurrent venous thromboembolism over 3 months was 0.91 (CI, 0.42 to 1.97; P = 0.81) [9, 10]. In these studies, low-molecular-weight heparin was also administered subcutaneously in a dose identical to that used in the treatment of patients with deep venous thrombosis. When all studies of patients with deep venous thrombosis or pulmonary embolism were combined, the occurrence of clinically important hemorrhage was reduced significantly in the low-molecular-weight heparin recipients (odds ratio, 0.55 [CI, 0.34 to 0.89]; P = 0.02) [8-10]. Because low-molecular-weight heparins are administered by subcutaneous injection in unmonitored, weight-adjusted dosing, two randomized studies and one cohort study evaluated the potential of self-treatment with low-molecular-weight heparin out of hospital. These studies in patients with symptomatic, usually proximal deep venous thrombosis revealed that self-treatment with low-molecular-weight heparin had an efficacy and safety similar to those of intravenous unfractionated heparin administered in the hospital. Approximately 30% to 50% of the patients who received low-molecular-weight heparin were fully treated at home, 10% to 25% were admitted to the hospital for the entire treatment period, and the remainder were discharged after 1 to 3 days in the hospital [11-13]. The potential for out-of-hospital treatment with low-molecular-weight heparins makes strategies that use these compounds potentially cost-effective, despite the higher costs of fractionated heparins. Most studies of low-molecular-weight heparin in patients with venous thromboembolism have used two subcutaneous injections of the agent daily. However, studies comparing a once-daily with a twice-daily regimen indicate that the two regimens have similar efficacy and safety [13, 14]. What are the implications of these findings for the practicing clinician? For most patients with acute deep venous thrombosis, including those with proximal venous thrombosis and those with risk factors for recurrent disease or cancer, there is sufficient evidence that low-molecular-weight heparins are an effective and safe alternative to intravenous unfractionated heparin. However, it should be recognized that in the above-mentioned studies, about 15% of the eligible patients with deep venous thrombosis were excluded because they had clinically suspected pulmonary embolism, previous deep venous thrombosis, or an expected high risk for bleeding. Although the results of the randomized studies can probably be extrapolated to these patients, it is uncertain whether low-molecular-weight heparin treatment is the most appropriate option for these patients. The efficacy and safety of home treatment in patients with deep venous thrombosis who do not have clinically overt pulmonary embolism have been shown to be similar to those of treatment with unfractionated heparin in the hospital. Therefore, treatment at home throughout the entire course of therapy or after a few days in the hospital should be considered in patients who understand the implications of such treatment. Most patients are able to inject themselves; alternatively, a family member or a visiting nurse can give the injections. It must be emphasized that care outside the hospital increases pressure on community agencies to provide proper anticoagulant therapy and that these agencies must be prepared for this task. For patients with proven pulmonary embolism, it is less clear whether low-molecular-weight heparins can be recommended as a replacement for unfractionated heparin. Findings in patients with pulmonary embolism will probably not differ much from those in patients with deep venous thrombosis. As of now, only two studies have been performed, and more data are needed to justify a change in clinical practice. In conclusion, for patients with symptomatic deep venous thrombosis, low-molecular-weight heparin seems to be the preferred therapy on the basis of its demonstrated efficacy coupled with ease of administration, lack of need for laboratory monitoring, and decreased risk for bleeding. Out-of-hospital treatment is appropriate for most of these patients. For patients with symptomatic pulmonary embolism, growing evidence shows that low-molecular-weight heparin may be the best option, but more data are needed. Although unfractionated heparin has dominated the treatment of venous thromboembolism for more than 80 years, it seems increasingly likely that the fractionated preparations of this classic drug will take over this role.

Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis

Resistance to activated protein C (APC), caused by a mutation at amino acid position Arg506 of the factor V gene, has recently been identified as the most prevalent genetic defect associated with venous thrombosis. Similarly to factor V, mutations at the cleavage sites of factor VIII for APC may occur in patients with venous thrombosis. Here we have analysed 125 consecutive patients with incidental or recurrent venous thromboembolism for the presence of mutations at the cleavage sites for APC at amino acid positions Arg336 and Arg562 of factor VIII. Our findings indicate that mutations at these amino acid positions of factor VIII do not occur in the patient group analysed.

Diagnosis of deep vein thrombosis

In this chapter, various tests have been discussed in the diagnosis of DVT and have been classified according to various patient categories. To summarize, the following guidelines may be of clinical use in the management of patients with suspected DVT. Acute, First Event of Suspected DVT These patients often suffer from occluding, proximal thrombi. Therefore, noninvasive tests such as CUS or IPG are most suitable for these patients. If an abnormal CUS or IPG result is found, the diagnosis is virtually proven, and this may serve as a basis to treat the patient with anticoagulants. If a normal CUS or IPG result is obtained, serial testing is indicated to detect extending calf vein thrombi or nonoccluding DVT, which becomes occlusive at follow up. Anticoagulants may be withheld safely if the test remains normal within 1 week. Acute, Recurrent Suspected DVT These patients may have residual thrombi present, which makes the noninvasive tests (CUS/IPG) less useful. However, if a normal noninvasive test was documented previous to the acute recurrent event, this test may be used. If an abnormal test result is found in the presence of a documented, normal previous-test outcome, this may serve as a basis for anticoagulant therapy. Although no formal studies have been performed to evaluate the safety of withholding anticoagulants if a normal CUS or IPG result is obtained, serial testing is likely to be adequate in these circumstances. Phlebography is the only truly evaluated approach, and this could be considered in all suspected recurrent DVT. Furthermore, contrast venography is the test of choice to discern acute from old thrombi. Asymptomatic DVT in High-Risk Patients The majority of these thrombi are mostly localized in the calf veins only and are often nonocclusive. This makes noninvasive tests unreliable for their detection. Therefore, only contrast venography should be used in this patient category.