A. Kleinjan

Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study

In ambulatory patients with solid cancer, routine thromboprophylaxis to prevent venous thromboembolism is not recommended. Several risk prediction scores to identify cancer patients at high risk of venous thromboembolism have been proposed, but their clinical usefulness remains a matter of debate. We evaluated and directly compared the performance of the Khorana, Vienna, PROTECHT, and CONKO scores in a multinational, prospective cohort study. Patients with advanced cancer were eligible if they were due to undergo chemotherapy or had started chemotherapy in the previous three months. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month follow-up period. A total of 876 patients were enrolled, of whom 260 (30%) had not yet received chemotherapy. Fifty-three patients (6.1%) developed venous thromboembolism. The c-statistics of the scores ranged from 0.50 to 0.57. At the conventional positivity threshold of 3 points, the scores classified 13–34% of patients as high-risk; the 6-month incidence of venous thromboembolism in these patients ranged from 6.5% (95%CI: 2.8–12) for the Khorana score to 9.6% (95%CI: 6.6–13) for the PROTECHT score. High-risk patients had a significantly increased risk of venous thromboembolism when using the Vienna (subhazard ratio 1.7; 95%CI: 1.0–3.1) or PROTECHT (subhazard ratio 2.1; 95%CI: 1.2–3.6) scores. In conclusion, the prediction scores performed poorly in predicting venous thromboembolism in cancer patients. The Vienna CATS and PROTECHT scores appear to discriminate better between low- and high-risk patients, but further improvements are needed before they can be considered for introduction into clinical practice.

ADAMTS‐13 and von Willebrand factor predict venous thromboembolism in patients with cancer

Essentials Cancer patients are at high risk of venous thromboembolism (VTE). In this study, cases and controls were cancer patients who did or did not develop VTE. von Willebrand factor (VWF) levels were higher if compared with controls and correlated with cancer stage. VWF and ADAMTS‐13 are associated with the occurrence of VTE in cancer.

Clinical course of upper extremity deep vein thrombosis in patients with or without cancer: a systematic review

BACKGROUND The incidence of upper extremity deep vein thrombosis (UEDVT) is increasing. Information on the clinical course of UEDVT is scarce, especially in cancer patients. AIM To summarize the clinical evidence regarding long-term clinical outcomes of UEDVT, in terms of recurrent venous thromboembolism (VTE), mortality, and anticoagulant-related bleeding, in patients with or without concomitant cancer. METHODS A systematic search of the literature was conducted in MEDLINE, EMBASE and BIOSIS Previews. Incidence rates for all outcome variables were calculated. RESULTS In total, 45 studies comprising 4580 patients were included. No randomized controlled trials were identified. In most studies, patients were treated solely with anticoagulants. Among the prospective studies, the incidences of recurrent VTE and bleeding complications averaged 5.1% and 3.1% respectively, during 3 to 59months of follow-up. In the retrospective studies these figures were 9.8% and 6.7% respectively. Among the prospective studies, the mortality rate was 24% after one year. In the retrospective studies this rate was 35%. Cancer patients were found to have a 2- to 3-fold higher risk of recurrent VTE, an 8-fold increased risk of mortality, and a 4-fold increased risk of bleeding during anticoagulant therapy, compared to non-cancer patients. CONCLUSIONS Studies were very heterogeneous in terms of study design, study populations and treatment approaches. Follow-up durations varied greatly, hampering combined analyses of average incidence rates. There is a need for large prospective studies to provide information on the best management of this disease, especially in high risk groups such as those with cancer.

Current management strategies and long-term clinical outcomes of upper extremity venous thrombosis.

Essentials Few data exist on outcome of upper extremity deep and superficial vein thrombosis (UEDVT and UESVT). We followed 102 and 55 patients with UEDVT or UESVT, respectively, for a median of 3.5 years. Risk of recurrent venous thromboembolism was low in both diseases, and the mortality high. Postthrombotic symptoms were infrequent and cancer patients had a higher risk of recurrent VTE.

Improving the diagnostic management of upper extremity deep vein thrombosis.

Essentials The Constans score and D‐dimer can rule out upper extremity deep vein thrombosis without imaging. We evaluated the performance of an extended Constans score and an age‐adjusted D‐dimer threshold. The extended Constans score did not increase the efficiency compared to the original score. Age‐adjusted D‐dimer testing safely increased the efficiency by 4%, but this needs validation.

Extracellular vesicles exposing tissue factor for the prediction of venous thromboembolism in patients with cancer: A prospective cohort study

INTRODUCTION The procoagulant activity of extracellular vesicles (EV) exposing tissue factor (TF) is a promising biomarker for venous thromboembolism (VTE) in cancer patients. We evaluated an in-house EV-TF activity assay (the fibrin generation test) for the prediction of cancer-associated VTE. We also compared the results with the fibrin generation tests to an EV-TF-dependent factor Xa generation assay in samples from pancreatic cancer patients. MATERIALS AND METHODS Data collected in a multinational, prospective cohort study were used. Patients with various types of advanced cancer were enrolled if chemotherapy was scheduled or started in the previous 3 months. Patients were followed for 6 months for the occurrence of VTE. The fibrin generation test was performed at baseline to measure EV-TF procoagulant activity. RESULTS The fibrin generation test was performed in 648 patients with advanced cancer. The mean age was 62 years; 58% had distant metastasis. Forty patients (6.1%) developed VTE. Overall, a high fibrin generation test result was associated with a two-fold increased risk for VTE (HR 2.0; 95%-CI, 1.1-3.6). The association was stronger in patients with pancreatic cancer (HR 4.1; 95%-CI, 0.91-19) than in those with other tumor types (HR 1.5; 95%-CI, 0.72-3.1). Correlation between the FGT and the TF-dependent factor Xa generation assay in patients with pancreatic cancer was poor (Spearmans R = 0.35). CONCLUSION This study shows that a high EV-TF procoagulant activity as measured by the fibrin generation test is associated with an increased risk of VTE in cancer patients, in particular in those with pancreatic cancer. Future studies should aim to further improve the feasibility and accuracy of EV-TF activity assays.

A worldwide survey to assess the treatment approach of cancer associated venous thromboembolism (CAT)

A1 The valuable influence of pharmacists in the anticoagulation clinic at the Veterans Affairs Medical Center of Washington, DC Zemzem Adem A2 A worldwide survey to assess the treatment approach of Cancer associated venous thromboembolism (CAT) Anita Aggarwal A3 Bridging for an Unintentional Subtherapeutic INR with Lowmolecular-weight heparin (LMWH): A Cost Analysis Tiffany W Chang A4 Patient satisfaction in an urban outpatient anticoagulation clinic after transitioning from a point-of-care device to venipuncture Christopher Malabanan A5 Contemporary Model for Clinical Thrombosis Management Christine P Rash

A worldwide survey to assess the current approach to the treatment of patients with cancer and venous thromboembolism

Introduction: Since the results of the CLOT trial were published in 2003, low-molecular-weight heparin (LWMH) has been recommended as the preferred anticoagulant treatment over vitamin K antagonists (VKAs) for venous thromboembolism (VTE) in patients with cancer. However, there is uncertainty about the duration and dose of LMWH treatment. We assessed the current practice of anticoagulant treatment of patients with cancer and VTE in various countries. Methods: An electronic survey tool was used to build a survey containing 49 questions on different aspects of the treatment of patients with cancer and VTE, and personal links were sent to both thrombosis and non-thrombosis specialists. Results: For this analysis, 123 completed surveys were available, which represented 53% of all invitations to date. Respondents specialties varied from haematology (26%), oncology (17%), haemato-oncology (4.1%), pulmonology (14%), general internal medicine (13%), surgery (4.9%) and other (1.6%). The majority (85%) of respondents generally use LMWH for longterm anticoagulant treatment. The application of LMWH is significantly higher (p=0.031) among European respondents (69/75; 92%) compared to respondents from the United States or Canada (30/40, 75%). Of all specialists who give LMWH for long-term treatment, 55% use fully therapeutic doses, while the remainder chooses for a dose reduction after a certain period of time. When continuing anticoagulants after the long-term treatment period, 45% of respondents prefer LMWH, 9.0% VKA, while the others choose per individual patient for either LMWH or VKA. In patients on LMWH who develop recurrent VTE during treatment, 42% of the respondents continue LWMH with a higher dose, 8.2% give double therapy with LMWH and VKA and 30% would insert a vena caval filter. Discussion: In this pre-final assessment, we observed a relatively high observance rate of the guidelines, with respect to the type of anticoagulant used for the long-term treatment of VTE in cancer patients. In contrast, the dose of LMWH and the continuation of treatment after 6 months are examples of areas in which heterogeneous responses may reflect the limited available clinical evidence. Interestingly, a lower percentage of the specialists in the US routinely use LMWH in patients with cancer compared to European specialists.

Cellular origin and procoagulant activity of tissue factor-exposing microparticles in cancer patients

Background: In patients with cancer, tissue factor-exposing microparticles (TF-exposing MP) have been associated with disease progression and thrombosis. The cellular origin and coagulant activity of TF-exposing MP, however, remain disputed. Therefore, we investigated the cellular origin of the TF-exposing MP and the procoagulant activity in cancer patients. Methods: The cellular origin of TF-exposing MP was investigated by flow cytometry in a cohort of 209 cancer patients (59 pancreatic, 97 gastrointestinal, 23 breast, 15 lung, 5 prostate cancer and 10 other types), and 22 healthy controls. We first determined the numbers of TF-exposing MP in plasma from all patients and measured TF-exposing MP coagulant activity in a fibrin generation test. Based on previous results, a prolongation of the clotting time in the presence of an inhibitory antibody against factor VIIa above 13% was considered abnormal. Second, we selected those patients with numbers of TF-exposing MP above the 95th percentile, and determined the cellular origin of TF-exposing MP in these patients. Results: The numbers of TF-exposing MP were increased in the cancer patients compared to the healthy subjects (median: 2.0 vs 0.40×105/mL; p=0.01). 30% of the cancer patients had an abnormal FGT test, indicating TF-exposing MP coagulant activity. There was no correlation between the number and coagulant activity of TF-exposing MP (r=0.029, p=0.685). 13 patients had TF-exposing MP above the 95th percentile. Of these TF-exposing MP, 5.9% (median; interquartile range (IQR) 0.69-54) double stained with CD227 (MUC-1) and 19% (0.62-41) with CD24, both markers of cancer cells (Fig. 1). Furthermore, 28% (11-63) of the TF-exposing MP stained for CD61, platelet glycoprotein IIIa, 3.9% (0.39-55) for the monocyte LPS-receptor (CD14), while 3.0% (1.4-3.5) of TF-MP stained for the erythrocyte marker CD235, and 0.97% (0.53-4.5) for the granulocyte marker CD66b. (Figure presented) Discussion: Levels of TF-exposing MP in cancer patients are higher than in healthy subjects. Strikingly, but not unexpectedly, we could not demonstrate a relationship between levels of TF-exposing MP and coagulant activity. Therefore, at least part of the TF exposed on circulating MP may be involved in other TF-dependent functions, such as angiogenesis or signal transduction. Most TF-exposing MP seem to originate from cancer cells, as they stained double positive with typical tumour cell markers such as CD227 and CD24. However, most TF-exposing MP also labelled positive for typical blood cell CD antigens, therefore these microparticles might be of mixed cellular origin, being shed after a tumour cell has incorporated blood cell characteristics. This phenomenon is specific rather than an artefact, since no double-labelling was observed with some markers such as CD235.

International registry on the treatment of unsuspected pulmonary embolism in cancer patients

Background: In cancer patients, clinically unsuspected pulmonary embolism (PE) represents a relatively common finding on computed tomography scans performed as part of the oncological follow-up. Patients with unsuspected PE may be at risk to develop symptomatic venous thromboembolism (VTE) and appear to have an increased mortality rate compared to patients without VTE. Current guidelines suggest the same initial and longterm anticoagulation for unsuspected VTE as for patients with symptomatic thrombosis. Based on these indications, cancer patients with unsuspected PE would be anticoagulated for at least 6 months or until the disease is active, which in most cases would mean indefinite treatment. In fact, dedicated studies on the treatment of unsuspected PE are missing, leaving doubts over the need for (indefinite) anticoagulation which exposes these patients to an increased risk of major bleeding events. Objectives: to evaluate the current treatment approaches for unsuspected PE and to assess their efficacy and safety in a large prospective cohort of cancer patients. Design and study population: Multicenter, international, prospective registry. All ambulatory or hospitalized cancer patients with a first diagnosis of unsuspected PE will be eligible for the study. Both solid and hematological cancers at any stage of disease will be considered for inclusion. Patients will be excluded in case of: 1) age