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Neuroblastoma survivors have an increased risk of unfavorable long-term health outcomes, of which developing subsequent neoplasms is one of the most serious. We aimed to provide an overview of the current knowledge on the risk of subsequent neoplasms in neuroblastoma survivors. We conducted a systematic literature search in Medline/Pubmed (01-01-1945-13-01-2022) to identify studies that reported on ≥ 100 neuroblastoma survivors and assessed subsequent neoplasms as an outcome. We identified 410 potentially eligible articles, of which we eventually included 13 reports. All articles described retrospective cohorts with sizes varying from 145 to 5,987 neuroblastoma survivors. Within these cohorts 0.7% - 17.2% of the survivors developed a subsequent neoplasm. A wide variety of types of subsequent malignant and non-malignant neoplasms were observed, of which thyroid carcinoma and acute myeloid leukemia were most frequently reported. The risk of developing a subsequent neoplasm was 2.8 to 10.4 times higher in neuroblastoma survivors than in the general population. Although no statistically significant risk factors for subsequent neoplasms were observed in multivariable analyses, high-risk group survivors, women and those treated with radiotherapy seemed to have a higher risk. In conclusion, the studies in this systematic review consistently show that neuroblastoma survivors are at elevated risk of developing subsequent neoplasms. Future research should further explore risk factors for subsequent neoplasms in neuroblastoma survivors, so future treatment protocols and follow-up care can be improved.

Loan R van Hoeven,1,2 Maria MW Koopman,3 Hendrik Koffijberg,4 Kit CB Roes,1Mart P Janssen1,2 1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, 2Transfusion Technology Assessment Department, Sanquin Research, 3Department of Transfusion Medicine, Sanquin Blood Bank, Amsterdam, 4Department of Health Technology and Services Research, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands Background: While the number of hospitalized patients in Dutch hospitals has increased since 1997, the demand for red blood cell units (RBCs) has simultaneously decreased. This implies a dramatic change in transfusion practice toward fewer blood transfusions on average per patient.Objectives: In order to explain the RBC reduction, different patient groups (surgical, medical, obstetrical, and specific age groups) were studied retrospectively in relation to RBC use. In addition, the use of combinations of RBCs, fresh frozen plasma, and platelets during a transfusion episode was examined for trends over time.Materials and methods: Data from the PROTON database, containing information on all transfusions in twelve Dutch hospitals in the period 1996–2005, including corresponding patient data (age, diagnosis, treatment, and hospitalizations) and blood unit data (type, amount, and date) were analyzed.Results: The proportion of RBCs used for surgical patients declined from 50% in 1996 to 40% in 2005, whereas medical use increased from 47% to 58% (the remaining 2%–3% went to obstetrical patients). Changes were more marked in the higher age groups. Also, a trend was observed toward the use of only one or two RBCs during a transfusion episode rather than three or more. Among surgical patients who received blood, the use of combinations of blood units, as compared to RBCs only, increased from 32% to 39%.Conclusion: The results suggest a more restrictive transfusion policy for surgical patients as well as an increase in medical indications for transfusion. This fits well with the current focus on more cost-effective transfusion policies. Keywords: red blood cell usage, combinations of blood units, trends in blood use, medical and surgical patients

Apheresis donation using citrate causes acute decrease in serum calcium and increase in serum parathyroid hormone. Long-term consequences, such as decrease in bone mineral density (BMD), are not known. In this study, we compared the BMD of 20 postmenopausal apheresis donors (mean donation number 115 times in up to 15 years) with that of 20 whole blood donors (for 15 years or more) aged 55-70. BMD in the lumbar spine was not lower in apheresis donors than in blood donors (mean ± SD 1·00 ± 0·18 vs. 0·92 ± 0·12, P = 0·09). In the hip, BMD was not different between the groups.

Background Although data from electronic health records (EHR) are often used for research purposes, systematic validation of these data prior to their use is not standard practice. Existing validation frameworks discuss validity concepts without translating these into practical implementation steps or addressing the potential influence of linking multiple sources. Therefore we developed a practical approach for validating routinely collected data from multiple sources and to apply it to a blood transfusion data warehouse to evaluate the usability in practice. Methods The approach consists of identifying existing validation frameworks for EHR data or linked data, selecting validity concepts from these frameworks and establishing quantifiable validity outcomes for each concept. The approach distinguishes external validation concepts (e.g. concordance with external reports, previous literature and expert feedback) and internal consistency concepts which use expected associations within the dataset itself (e.g. completeness, uniformity and plausibility). In an example case, the selected concepts were applied to a transfusion dataset and specified in more detail. Results Application of the approach to a transfusion dataset resulted in a structured overview of data validity aspects. This allowed improvement of these aspects through further processing of the data and in some cases adjustment of the data extraction. For example, the proportion of transfused products that could not be linked to the corresponding issued products initially was 2.2% but could be improved by adjusting data extraction criteria to 0.17%. Conclusions This stepwise approach for validating linked multisource data provides a basis for evaluating data quality and enhancing interpretation. When the process of data validation is adopted more broadly, this contributes to increased transparency and greater reliability of research based on routinely collected electronic health records. Electronic supplementary material The online version of this article (doi:10.1186/s12911-017-0504-7) contains supplementary material, which is available to authorized users.

Neurological injuries can be divided into those with traumatic and nontraumatic causes. The largest groups are traumatic brain injury (TBI) and nontraumatic stroke. TBI patients may present with intracranial hemorrhages (contusions, or subdural or epidural hematomas). Strokes are ischemic or hemorrhagic. In all these disorders, thrombosis and hemostasis play a major role. Treatment aims to either cease bleeding and/or restore perfusion. We reviewed hemostatic and thrombolytic therapies in patients with neurological injuries by MEDLINE and EMBASE search using various key words for neurological disorders and hemostatic therapies restricted to English language and human adults. Review of articles fulfilling inclusion criteria and relevant references revealed that, in patients with ischemic stroke, intravenous thrombolytic therapy with recombinant tissue plasminogen activator within 4.5-5 hours after onset of symptoms improves clinical outcome. In contrast, there are no hemostatic therapies that are proven to improve clinical outcome of patients with hemorrhagic stroke or TBI. In patients with hemorrhagic stroke who use vitamin K antagonist or direct oral anticoagulants, there is evidence that specific reversal therapies improve hemostatic laboratory parameters but without an effect on clinical recovery. In patients with hemorrhagic stroke or TBI who use concomitant antiplatelet therapy, there is evidence for harm of platelet transfusion. In patients with aneurysmal subarachnoid hemorrhage, tranexamic acid was shown to reduce rebleeding rate without improving cinical outcome. The effects of tranexamic acid in patients with TBI are still under investigation. We conclude that, in patients with ischemic stroke, thrombolytic therapy improves outcome when given within 45-5 hours. In hemorrhagic stroke and TB!, most hemostatic therapies improved or corrected laboratory parameters but not clinical outcome. Currently, in several trials, the effects of tranexamic acid are being studied of which the results are eagerly awaited. Because improving clinical outcome should be the goal of new therapies, we encourage to use clinical outcome scales as the primary outcome measure in trials that investigate effects of hemostatic therapies in patients with neurological injury. (C) 2017 Elsevier Inc. All rights reserved

INTRODUCTION: Blood transfusion has health-related, economical and safety implications. In order to optimise the transfusion chain, comprehensive research data are needed. The Dutch Transfusion Data warehouse (DTD) project aims to establish a data warehouse where data from donors and transfusion recipients are linked. This paper describes the design of the data warehouse, challenges and illustrative applications. STUDY DESIGN AND METHODS: Quantitative data on blood donors (eg, age, blood group, antibodies) and products (type of product, processing, storage time) are obtained from the national blood bank. These are linked to data on the transfusion recipients (eg, transfusions administered, patient diagnosis, surgical procedures, laboratory parameters), which are extracted from hospital electronic health records. APPLICATIONS: Expected scientific contributions are illustrated for 4 applications: determine risk factors, predict blood use, benchmark blood use and optimise process efficiency. For each application, examples of research questions are given and analyses planned. CONCLUSIONS: The DTD project aims to build a national, continuously updated transfusion data warehouse. These data have a wide range of applications, on the donor/production side, recipient studies on blood usage and benchmarking and donor-recipient studies, which ultimately can contribute to the efficiency and safety of blood transfusion.

SummaryAcquired and hereditary thrombophilias are associated with obstetric complications such as (pre-)eclampsia, HELLP syndrome and fetal loss. Our objective was to assess the risk of obstetric complications in women with elevated levels of FVIII:C or hyperhomocysteinemia, as compared with their relatives who had normal FVIII:C or homocysteine levels. From a large family study of patients with venous thromboembolism or premature atherosclerosis and elevated levels of FVIII:C or hyperhomocysteinemia (propositi), the obstetric histories of female first degree relatives, who had been pregnant at least once, were studied. Levels of FVIII:C and homocysteine (both fasting and post-methionine loading) were determined. The number of obstetric complications was calculated and compared in women with normal and elevated levels of FVIII:C, and normal and elevated levels of homocysteine. Women with elevated levels of FVIII:C had a 15.4% risk for toxicosis, preeclampsia, or HELLP syndrome and a 23.9% for fetal loss. This was not statistically different from women with normal levels of FVIII:C. Women with hyperhomocysteinemia tended to have a lower risk for toxicosis, pre-eclampsia, or HELLP syndrome (8.0%, RR 0.6, 95% CI 0.2-1.7) and fetal loss (22.0%, RR 0.8, 95% CI 0.5-1.5) as compared to relatives with normal levels, although these differences did not reach statistical significance. If the analysis was limited to comparing extremes, the results did not materially differ. Unselected women with elevated plasma levels of FVIII:C or hyperhomocysteinemia are not at increased risk for obstetric complications as compared to their relatives with normal levels.

SummaryWhether long-distance travel and symptomatic venous thromboembolism (VTE) are associated is debated. On the basis of the available literature a fair risk estimate cannot be obtained. We estimated an accurate odds ratio for the relationship between recent travelling and symptomatic VTE.From three case-control studies consisting of 788 and 170 patients with clinically suspected deep vein thrombosis (DVT) and 989 patients with clinically suspected pulmonary embolism (PE) referred for diagnostic work-up, a pooled odds ratio for the relation between travel and symptomatic VTE was calculated. Cases were patients in whom the diagnosis was confirmed according to a diagnostic management strategy, whereas controls were patients in whom the diagnosis was excluded and who had an uneventful clinical follow-up. Patients were seen in the period April 1997 to September 2000. Travel history was recorded prior to diagnostic work-up.The pooled odds ratio for the association between any travel and symptomatic venous thromboembolism was 0.9 (95% CI: 0.6-1.4). The median travel time was 7 h (quartile range 4 to 10 h). Separate analyses performed for different types of transport (plane, car, bus or train) yielded comparable odds ratios. The analysis for duration of travelling showed an increased odds ratio of 2.5 (95% CI: 1.0-6.2) in the category of 10-15 h of travelling.This study shows that the average traveller does not have an increased risk for symptomatic venous thromboembolism. Only very long travelling (more than 10 h) may be associated with venous thromboembolic disease.

Background: To simplify the diagnostic strategy of patients suspected for venous thromboembolism, the use of D-dimer tests has been advocated. Very important for the safety of such diagnostic strategies would be the capacity to recognise false-normal D-dimer results, in order to prevent inadequately withholding anticoagulant treatment in patients who actually have the disease. Insight in the causes of false-normal D-dimer results would therefore be necessary. We hypothesised that certain patient characteristics are associated with relatively low plasma D-dimer levels and, therefore, could increase the risk of false-normal results. Methods: Consecutive patients with an objectively confirmed venous thromboembolic event and an independently obtained false-normal SimpliRED D-dimer test result were included in the study. For each patient, two controls with objectively confirmed venous thromboembolism and an adequate abnormal D-dimer result were selected. Baseline patient characteristics, obtained by standardised questionnaires, were compared between the two groups of patients. Results: In total, 686 patients had a venous thromboembolic event and 47 of these patients had a false-normal SimpliRED result. Therefore, the overall sensitivity of the SimpliRED test for venous thromboembolism was 94% (95% CI: 92–95%). Although the prevalence of certain clinical characteristics was significantly higher in patients with a false-normal D-dimer result than in the controls [odds ratios for (LMW)heparin treatment and symptoms lasting more than 10 days: 5.1 (95% CI: 1.5–18.7) and 3.2 (95% CI:1.4–7.4), respectively], the prevalence of these characteristics was also high in the control group with an adequate abnormal D-dimer. Combining two or more of these characteristics had a low prevalence and did not further improve the ability to identify those patients with a false-normal D-dimer test at presentation. Conclusions: Although these findings clearly indicate an association between certain baseline clinical characteristics and the occurrence of a false-normal SimpliRED test, the clinical utility for these characteristics is limited.

Summary. We characterized anti-factor VIII antibodies in a mild haemophilia A patient with an Arg593Cys mutation in the A2 domain, using V gene phage-display technology. All isolated single-chain variable-domain antibody fragments were directed against residues Arg484-Ile508, a binding site for factor VIII inhibitors in the A2 domain. After a further period of replacement therapy, a transient rise in inhibitor titre was observed. These antibodies were directed against the A2 domain. Activation of a pre-existing pool of B cells, which express antibodies against residues Arg484-Ile508, could explain the rapid anamnestic response.

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.

IntroductionAfter an initial 5- to 10-day course of treatment with either unfractionated or low molecular weight heparin, secondary prophylaxis is usually prescribed to patients with venous thromboembolic disease for a variable period of time. The primary aim of both initial and secondary treatment is to prevent recurrent thrombotic events, including deep vein thrombosis and fatal pulmonary embolism. This objective has to be achieved at a minimal risk of bleeding. There is general consensus that the initial treatment should be with low molecular weight or unfractionated heparin. For secondary prophylaxis, however, there are currently several options. Among these are continued unfractionated heparin or low molecular weight heparin and oral vitamin K-antagonists. In addition, compression stockings and caval vein filters are available.In this chapter, we will first examine the available evidence for each of these options, then discuss the results of randomized trials that have studied the duration of secondary prophylaxis. Finally, we will attempt to synthesize this information using decision analytic techniques.

Low-molecular-weight heparin therapy is administered subcutaneously, not intravenously. This has made possible the management of selected patients who have acute deep venous thrombosis as outpatients. Others can be treated with an abbreviated several day hospitalization rather than the conventional 5 or more hospital days needed for administration of continuous intravenous unfractionated heparin. Two large studies, Tasman and a Canadian trial, have demonstrated the efficacy and safety of low-molecular-weight heparin in this setting. Now, the task is to develop guidelines for widespread application of these findings to daily clinical practice. However, successful home treatment will require intensive patient education as well as an extensive infrastructure of supportive nursing and physician services. Careful patient follow-up will be crucially important.

Objective: To evaluate the safety of withholding anticoagulant treatment from patients with clinically suspected deep vein thrombosis but normal findings on compression ultrasonography. Design: Compression ultrasonography was done with a simplified diagnostic procedure limited to the common femoral vein in the groin and the popliteal vein extending down to the trifurcation of the calf veins. Patients with normal ultrasonography findings at presentation were retested 1 week later. Main outcome measure: The incidence of venous thromboembolic complications during follow up for 6 months in patients in whom anticoagulant treatment was withheld on the basis of normal results on two ultrasonography tests 1 week apart. Setting: University research centres in four hospitals. Results: A total of 1702 patients were included in the study. Abnormal results on compression ultrasonography at presentation or at 1 week were found in 400 and 12 patients, respectively, for a prevalence of deep vein thrombosis of 24%. None of the patients were lost to follow up. Venous thromboembolic complications during the week of serial testing occurred in a single patient and in eight patients during 6 months9 follow up, resulting in a cumulative rate of venous thromboembolic complications of 0.7% (95% confidence interval 0.3% to 1.2%). The mean number of extra hospital visits and additional tests required per initially referred patient was 0.8. Conclusion: It is safe to withhold anticoagulant treatment from patients with clinically suspected deep vein thrombosis who have a normal result on compression ultrasonography at the time of presentation and at 1 week. Key messages Clinical diagnosis of suspected deep vein thrombosis is notoriously unreliable and objective diagnostic tests are indicated to confirm or refute the presence of this condition Ultrasonography with vein compressibility of the common femoral and popliteal vein is the non-invasive test of choice for the diagnostic management of patients with suspected deep vein thrombosis It is safe to withhold anticoagulant treatment from patients with suspected deep vein thrombosis who have normal results on compression ultrasonography on presentation and on a single repeat test 1 week later With the simplified compression ultrasound strategy the number of repeat tests can be safely reduced to a single test performed a week after presentation Most patients with deep vein thrombosis can be identified at presentation, making this strategy convenient to patients and less costly

After a first episode of deep vein thrombosis (DVT), 30-50% of the patients will develop complaints suspect of recurrent DVT. Of these patients, only 20-30% do indeed have a recurrent episode of DVT. To identify patients with a true recurrent DVT, objective testing is mandatory in every patients. However, all the available tests have their limitations in patients with recurrent DVT. In this review, diagnostic strategies using venography, impedance plethysmography, 125I-fibrinogen leg scanning and ultrasonography in patients with recurrent DVT will be discussed. Furthermore, some epidemiologic data and pathophysiologic mechanisms concerning DVT will be considered.

It is unknown whether the use of volumetric infusion pumps for the transfusion of red blood cells (RBCs) or platelet (PLT) concentrates (PCs) affects the quality of the blood components. We therefore investigated the in vitro quality of these components after use of infusion pumps.Ten different volumetric infusion pumps were used to simulate transfusion with RBCs and PCs. To prevent donor-dependent differences multiple units were pooled and divided into equal portions. The storage time of RBCs was 30 to 35 days (n=10 experiments), and for PCs, either 2 (n=5) or 7 days (n=5). For RBCs an infusion rate of 100 or 300mL/hr was used, and for PCs, 600mL/hr. Transfusions without an infusion pump served as a reference.None of the infusion pumps induced an increase of free hemoglobin, annexin A5 binding, or formation of echinocytes in RBCs compared to reference units. In 2- and 7-day-old PCs no effect was shown on PLT concentration, annexin A5 binding, mean PLT volume, and morphology score compared to the reference. The CD62P expression of 2-day-old PCs was significantly lower after transfusion compared to the reference, that is, 11.7±2.1% versus 8.1±1.3% (p0.01).There was no adverse effect on the in vitro quality of RBCs or PCs after simulated transfusion using volumetric infusion pumps. A decrease in PLT activation was observed, which can probably be explained by capturing of activated or damaged PLTs in the 200-µm filter present in the infusion system.

BACKGROUND: The outcome of upper extremity thrombosis in terms of morbidity, mortality and arm functionality is virtually unknown. We investigated mortality, risk factors, recurrent thrombosis and post-thrombotic syndrome (PTS) in patients with suspected upper extremity thrombosis. METHODS: Consecutive patients suspected of having deep vein thrombosis (DVT) of the upper extremity were followed for up to 53 months (mean 21 months). Venography and/or ultrasonography was used for diagnosis. Risk factors were identified from history and thrombophilia laboratory screening. PTS was assessed using a scoring system. Death, recurrent thrombosis and PTS were primary outcome measures. RESULTS: DVT of the upper extremity was diagnosed in 50 of 116 consecutive patients (43%). Malignancy and/or central venous lines were present in 37 of 50 (74%) patients with thrombosis. Inherited thrombophilia was diagnosed in 6 of 30 (20%) and 4 of 33 (12%) of the investigated patients with and without thrombosis, respectively (not significant). Twenty-five patients (50%) with thrombosis died during the follow-up period; this was associated with cancer in 84% of the deaths. Recurrent thrombosis was observed in four patients (8%) during follow-up. Symptoms of PTS were present in 4 of 22 patients (18%) with thrombosis and in 14 of 36 patients (39%) in whom thrombosis was excluded. CONCLUSIONS: Malignancy and central venous lines are major risk factors of upper extremity thrombosis. Thrombophilia seems to be unrelated to the presence or absence of upper extremity thrombosis. Thrombosis in combination with malignancy predicts poor survival. A scoring system can be used to assess the severity of PTS, but it does not discriminate PTS from other causes of arm complaints.

Whether long-distance travel and symptomatic venous thromboembolism (VTE) are associated is debated. On the basis of the available literature a fair risk estimate cannot be obtained. We estimated an accurate odds ratio for the relationship between recent travelling and symptomatic VTE. From three case-control studies consisting of 788 and 170 patients with clinically suspected deep vein thrombosis (DVT) and 989 patients with clinically suspected pulmonary embolism (PE) referred for diagnostic work-up, a pooled odds ratio for the relation between travel and symptomatic VTE was calculated. Cases were patients in whom the diagnosis was confirmed according to a diagnostic management strategy, whereas controls were patients in whom the diagnosis was excluded and who had an uneventful clinical follow-up. Patients were seen in the period April 1997 to September 2000. Travel history was recorded prior to diagnostic work-up. The pooled odds ratio for the association between any travel and symptomatic venous thromboembolism was 0.9 (95% CI: 0.6-1.4). The median travel time was 7 h (quartile range 4 to 10 h). Separate analyses performed for different types of transport (plane, car, bus or train) yielded comparable odds ratios. The analysis for duration of travelling showed an increased odds ratio of 2.5 (95% CI: 1.0-6.2) in the category of 10-15 h of travelling. This study shows that the average traveller does not have an increased risk for symptomatic venous thromboembolism. Only very long travelling (more than 10 h) may be associated with venous thromboembolic disease.

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.

We characterized anti-factor VIII antibodies in a mild haemophilia A patient with an Arg593--Cys mutation in the A2 domain, using V gene phage-display technology. All isolated single-chain variable-domain antibody fragments were directed against residues Arg484-Ile508, a binding site for factor VIII inhibitors in the A2 domain. After a further period of replacement therapy, a transient rise in inhibitor titre was observed. These antibodies were directed against the A2 domain. Activation of a pre-existing pool of B cells, which express antibodies against residues Arg484-Ile508, could explain the rapid anamnestic response.

The clinical expression of factor V Leiden varies widely within and between families and only a minority of carriers will ever develop venous thromboembolism. Co-segregation of thrombophilic disorders is a possible explanation. Our aim was to assess the contributions of high levels of factor VIII:C, factor XI:C, thrombin activatable fibrinolysis inhibitor (TAFI) and lipoprotein (a) (Lp(a)) to the risk of venous thromboembolism in factor V Leiden carriers.Levels of the four proteins were measured, in addition to tests of deficiencies for antithrombin, protein C and protein S, and the prothrombin G20210A mutation, in 153 factor V Leiden carriers, derived from a family cohort study. The (adjusted) relative risk and absolute risk of venous thromboembolism for high levels of each protein were calculated.Of carriers, 60% had one or more concomitant thrombophilic disorders. Crude odds ratios (95% CI) of venous thromboembolism for high protein levels were: 3.2 (1.1-9.3) (factor VIII:C); 1.7 (0.6-4.9) (factor XI:C); 3.0 (1.1-8.2) (TAFI); and 1.9 (0.7-5.7) (Lp(a)). Adjusted for age, sex, other concomitant thrombophilic disorders and exogenous risk factors, the odds ratio for venous thromboembolism were 2.7 (0.8-8.7) for high factor VIII:C levels and 1.8 (0.6-5.3) for high TAFI levels. Annual incidences in subgroups of carriers were 0.35% (0.09-0.89), 0.44% (0.05-1.57) and 0.94% (0.35-2.05) for concomitance of high levels of factor VIII:C, TAFI and both, respectively, as compared to 0.09% (0.00-0.48) in single factor V Leiden carriers and 1.11% (0.30-2.82) for other concomitant disorders.High levels of factor VIII:C and TAFI, in contrast with factor XI:C and Lp(a), are mild risk factors for venous thromboembolism, and substantially contribute to the risk of venous thromboembolism in factor V Leiden carriers. Our data support the hypothesis that the clinical expression of factor V Leiden depends on co-segregation of thrombophilic disorders.

Background: The optimal strategy for diagnosis of deep venous thrombosis (DVT) is less well established for the upper extremities than for the lower extremities. Duplex color ultrasonography can be difficult to perform in the upper extremities because of their anatomy, and contrast venography is often indicated. Moreover, limited data exist on the use of duplex color ultrasonography in this setting. Objective: To determine the accuracy of duplex ultrasonography for diagnosis of DVT of the upper extremities. Design: Prospective study of duplex ultrasonography compared with venography. Setting: A teaching hospital in Amsterdam, the Netherlands. Patients: 126 consecutive inpatients and outpatients with suspected DVT of the upper extremities. Measurements: Contrast venography was obtained after duplex ultrasonography and was judged independently. A three-step protocol, involving compression ultmonography, color ultrasonography, and color Doppler ultrasonography, was used. Sensitivity, specificity, and likelihood ratios for ultrasonography as a whole were calculated. The independent value of each step was assessed. Results: Venography and ultrasonography were not feasible in 23 of 126 patients (18%) and 1 of 126 patients (0.8%), respectively. Results of ultrasonography were inconclusive in 3 patients. Venography demonstrated thrombosis in 44 of 99 patients (44%); in 36 patients (36%), thrombosis was related to intravenous catheters or malignant disease, Sensitivity and specificity of duplex ultrasonography were 82% (95% Cl, 70% to 93%) and 82% (Cl, 72% to 92%), respectively. Venous incompressibility correlated well with thrombosis, whereas only 50% of isolated flow abnormalities proved to be thrombosis-related. Conclusions: Duplex ultrasonography may be the method of choice for initial diagnosis of patients with suspected thrombosis of the upper extremities. However, in patients with isolated flow abnormalities, contrast venography should be performed

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) levels122%; 5.4 (1.6-18.6) for fasting homocysteine levels15.2 micromol/l; and 4.4 (1.0-18.7) for loading homocysteine levels45.8 micromol/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.

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.

The initial treatment of venous thrombosis has long involved the administration of unfractionated heparin by continuous intravenous infusion for at least 5 days, followed by oral vitamin K antagonists for 3 to 6 months. This treatment strategy aims at preventing recurrences of the disease while keeping the risk of bleeding at an acceptable level (1–3). However, because of the unpredictable pharmacokinetic response of unfractionated heparin, frequent laboratory monitoring for dose adjustments is necessary, and hospital admission for the treatment of acute venous thromboembolic disease is often not preventable. The development of low molecular weight heparins, which are manufactured by depolymerization of unfractionated heparin, has changed clinical management of venous thromboembolism. Low molecular weight heparins are characterized by less binding with plasma proteins, platelets, and the endothelium; have a longer halflife; and have a more predictable anticoagulant response as compared with unfractionated heparin (4). This allows once or twice daily, weight-adjusted subcutaneous administration, without the need for laboratory monitoring (5). To date, 14 randomized clinical trials have compared low molecular weight heparin with unfractionated heparin in the initial treatment of venous thromboembolism. A meta-analysis of these studies has shown that low molecular weight heparin is at least as effective as unfractionated heparin in decreasing the incidence of recurrent symptomatic venous thromboembolism (odds ratio [OR] 0.76; 95% confidence interval [CI]: 0.57 to 1.01), but is associated with significant reductions in the likelihood of major bleeding (OR 0.60; 95% CI: 0.39 to 0.93) and mortality (OR 0.78; 95% CI: 0.62 to 0.99) (6). Consequently, low molecular weight heparins are now generally accepted as standard therapy for venous thrombosis. Furthermore, because their administration requires no laboratory monitoring, out-of-hospital treatment has become an attractive option. Two large randomized controlled trials have compared the use of unfractionated heparin treatment in hospital with low molecular weight heparin at home, whereas one smaller trial has studied the use of low molecular weight heparin therapy at home and in the hospital (7–9). There were no differences in the 3to 6-month rates of recurrent venous thromboembolism, major bleeding, and mortality between patients treated in hospital and those treated at home. In addition, the pooled efficacy and safety data did not reveal any differences between in-hospital and at-home treatments (10). However, there were substantial differences in quality of life between both patient groups, with better physical activity and social functioning reported in patients treated at home (7). A costminimization analysis of that study showed that home treatment with low molecular weight heparin would lead to a 64% reduction in costs compared with in-hospital treatment with unfractionated heparin (11). In this issue of The American Journal of Medicine, Segal et al (12) report the results of a systematic review of the efficacy, safety, and costs of outpatient therapy with low molecular weight heparin for the treatment of venous thromboembolism. They searched the literature through March 2002 for studies comparing inpatient versus outpatient treatment with either low molecular weight heparin or unfractionated heparin. They also reviewed studies that addressed costs either through direct comparison or by decision analysis. A total of 19 studies were included. As expected, the authors found no difference in clinical outcome measurements. Although there was moderate evidence showing that at-home treatment with low molecular weight heparin is comparable with unfractionated heparin in hospital, the authors concluded that outpatient treatment is likely to be as efficacious and safe. Indeed, the cost-effectiveness analysis showed a median cost saving of 57% with low molecular weight heparin. What can we learn from this analysis and what will be the consequences for clinical practice? There was already sufficient evidence that low molecular weight heparin is at least as effective and safe as unfractionated heparin for the treatment of venous thromboembolism either in hospital or at home (6,10). The findings of Segal et al confirm this, in particular for out-of-hospital treatment (12). The moderate level of evidence concerning efficacy and safety of home treatment with low molecular weight heparin may be explained by the study samples, most of which were too small and underpowered to detect small differAm J Med. 2003;115:324 –325. From the Departments of Vascular Medicine (MMWK) and Clinical Epidemiology and Biostatistics (PMMB), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Requests for reprints should be addressed to Maria M. W. Koopman, MD, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, F4-245, P.O. Box 22660, Amsterdam 1100 DD, The Netherlands, or m.m.koopman@amc.uva.nl.

Background: The factor V Leiden mutation is a common genetic defect associated with an increased risk for venous thromboembolism. The clinical implications for asymptomatic carriers of this mutation and, consequently, the usefulness of screening families in which a proband has both the mutation and venous thrombo embolism are unclear. Objective: To determine the incidence of venous thromboembolism in asymptomatic carriers of the factor V Leiden mutation. Design: Prospective cohort study. Setting: University hospitals in the Netherlands. Participants: 470 asymptomatic carriers of the factor V Leiden mutation (234 men, 236 women; mean age, 43 years [range, 15 to 88 years]), 12 of whom were homozygous. Carriers were identified by screening the first-degree relatives (>15 years of age) of 247 symptomatic probands. Measurements: Objectively diagnosed episodes of venous thromboembolism and the relationship between incidence and exposure to high-risk situations. Results: Nine venous thromboembolic events were observed in 1564 observation-years, resulting in an annual incidence of 0.58% (95% CI, 0.26% to 1.10%). The incidence of spontaneous venous thromboembolism was 0.26% (CI, 0.07% to 0.65%) per year; 3.5% (CI, 0.1% to 17.8%) per episode of surgery, trauma, or immobilization; 0.0% (CI, 0.0% to 19.5%) per pregnancy; 1.8% (CI, 0.4% to 5.2%) per year of oral contraceptive use; and 2.9% (CI, 0.8% to 15.3%) per year of use of hormone replacement therapy. Conclusions: The absolute annual incidence of spontaneous venous thromboembolism in asymptomatic carriers of the factor V Leiden mutation is low and does not justify routine screening of the families of symptomatic patients.