enewsletter Trombosis Matters nr 2 2016 beeld bij abstract 1 NOG AANKOPENDespite advances in identification, prophylaxis and treatment, the prevalence of recurrent venous thromboembolism (VTE) remains a concern after an acute episode. The population-based Worcester Venous Thromboembolism study aimed to identify the magnitude, identify predictors and develop a risk score calculator of recurrence after a first episode of acute VTE. This calculator may assist clinicians at the time of the index encounter to determine the frequency of clinical surveillance and the appropriate outpatient treatment of VTE.

In this study 2,989 patients were followed for 5,836 person-years (mean follow-up: 23.4 months with a median of 30 months). The study population consisted of residents of central Massachusetts (MA), USA, diagnosed with an acute first-time pulmonary embolism and/or lower-extremity deep vein thrombosis. Patients characteristics were as follows: mean age: 64.3 years, 44% men and 94% white. There were 3 etiology categories of VTE defined: cancer-associated VTE (17%), provoked VTE, occurring within 3 months of surgery, pregnancy, trauma, fracture or hospitalization, but not in the presence of active malignancy (43%) and unprovoked episodes of VTE (40%). The cumulative incidence rates (CIR) of recurrent VTE were 5.1% within 3 months and 15% within 3 years after the index event among all patients. The CIRs for VTE recurrence were 8.7%, 5.2% and 3.8% within 3 months and 25%, 13% and 13% within 3 years among patients with active cancer, provoked, or unprovoked VTE, respectively.

Within this study, 3 independent factors of recurrence were identified during both the acute (3-month) treatment phase and the long-term (3-year) follow-up window among patients diagnosed with a first confirmed episode of VTE: active cancer, varicose vein stripping and inferior vena cava (IVC) filter replacement. The risk score calculator was developed based on the 5 independent predictors of VTE recurrence during the first 3 months after the index event among all patients, e.g. active cancer, previous major trauma, varicose vein stripping, anticoagulant therapy at admission and IVC filter placement. The risk score points of these predictors were 16, 21, 21, 19 and 23, respectively. The predicted rate versus the observed rate of VTE recurrence during the first 3 months after the index event among all patients within different risk score categories were: risk score category 0 (1,890 patients): 2.9% versus 3.1%, risk score category >0 to

To conclude, the risk calculator includes variables that are readily available to clinicians and uses a simple point system to estimate the risk of VTE recurrence. This may enable clinicians at the index encounter to tailor individual patient management practices during acute VTE treatment.


Huang W, Goldberg RJ, Aderson FA, et al. Occurrence and predictors of recurrence after a first episode of acute venous thromboembolism: population-based Worcester Venous Thromboembolism Study. J Thromb Thrombolysis 2016;41:525-38.

enewsletter Trombosis Matters nr 2 2016 beeld bij abstract 2Results from the TROPIQUE study showed that the treatment duration with low-molecular-weight heparins (LMWH) was adequate showing substantial progress in the management of patients with cancer-associated thrombosis (CAT). Moreover, patients’ satisfaction with LMWH treatment was high in spite of their high expectations. In the TROPIQUE study the prescription and use of treatment doses of LMWH in cancer patients with venous thromboembolism (VTE) was prospectively evaluated. The aim was to assess whether LMWH treatment follow-up was consistent with established clinical practice guidelines in terms of treatment doses, duration and administration schedule in order to improve knowledge on management of patients with CAT. In an ancillary study, patients’ perception of long-term treatment with LMWH was assessed.

Recent studies have shown that long-term treatment with LMWH is well accepted by patients and physicians. However, data from prospective studies on the long-term prescription of treatment with LWMH and the follow-up of patients’ experience with the treatment are scarce. The TROPIQUE study was a 6-month prospective observational study in patients receiving anticancer treatment or palliative care and LMWH for symptomatic CAT. A total of 409 patients were included from November 2012 to August 2013 in 65 French centres managing at least 1,000 cancer patients each year. The mean age was 65 years; 21.8% was >75 years old, 68.9% was between 50 and 75 years old, and 9.3% was younger than 50. The majority of patients (88%) had an ECOG performance score 0-2. A proportion of 13.2% of patients had a history of VTE, 24.4% of surgery or trauma, and 74.1% had a central venous catheter. LMWH prescription included dalteparin (10.3%), enoxaparin (14.9%), nadroparin (1.2%), and tinzaparin (73.6%). Four patients received LMWH despite severe renal insufficiency.

The overall adherence to clinical practice guidelines was 55.3% (n=226). The mean treatment duration prescribed at baseline was 5.28 ± 2.07 months, while, during follow-up, the researchers observed an actual mean treatment duration of 6.27 ± 0.15 months. A total of 274 patients (67.1%) received the recommended treatment dose. For patients receiving tinzaparin, the rate of adherence to clinical practice guidelines was 72.8%, and for patients treated with other LMWH, the adherence rate was 6.5%. The low rate of adherence to other LMWH (dalteparin 16.7%, enoxaparin 0%, nadroparin 0%) was mainly due to inappropriate dosing schedule. The rate of adherence was higher in younger patients compared to the elderly. Patients with breast cancer were associated with the highest adherence rate (70.8%) and with appropriate dosing. Conversely, prescription in patients with prostate or bladder cancer was associated with low adherence. Other factors associated with non-adherence to guidelines included male gender, ECOG performance status 3-4, and a bleeding event within a month before VTE, while recent surgery was associated with a high adherence. The clinical outcome incidences in this study were consistent with previous observations in this cancer patient population, except for VTE recurrence which cumulative incidence of 6.1% was rather low compared to previous randomized controlled trials.

The patients’ perception of long-term treatment with LMWH was assessed with the validated Perception Anti-Coagulant Treatment Questionnaire (PACT-Q; Q1 at the start of the study and Q2 after 6 months). A total of 273 PACT-Q1 and 141 PACT-Q2 questionnaires were completed of which 269 and 139 were evaluable, respectively. At the end of the study, 69.1% of patients were overall satisfied or very satisfied with their LMWH treatment. ‘Convenience’ and ‘Anticoagulant Treatment Satisfaction’ scores were 79.7 ± 17.1 and 62.9 ± 16.7, respectively. A strong feeling of reassurance was reported by 67.2% of patients, whereas 48.5% of patients were satisfied with the decrease of their symptoms. The experience with treatment side effects was ‘as expected’ for 41.7%, and ‘better or much better than expected’ for 45.5%.

This prospective observational study showed an overall adherence of 55.3% to LMWH treatment in patients with CAT. However, patients treated with tinzaparin showed an adherence of 72.8% to practice guidelines. This group of tinzaparin treated patients represented a proportion of 73.6% of the study population, which reflects user-patterns in France. The good patient perception in this study is encouraging in view of improving health professional’s compliance with established treatment guidelines for CAT.


Cajfinger F, Debourdeau P, Lamblin A, et al. Low-molecular-weight heparins for cancer-associated thrombosis: adherence to clinical practice guidelines and patient perception in TROPIQUE, a 409-patient prospective observational study. Thromb Res 2016;144:85-92.

enewsletter Trombosis Matters nr 2 2016 beeld bij abstract 3Results from a single arm phase II study showed that baseline D-dimer levels above the median value are predictive of VTE recurrence at 6 months in patients with active cancer and VTE. D-dimer is the degradation product of cross-linked fibrin. The concentration of D-dimer is a possible marker of thromboembolitic events. The reference concentration of D-dimer is less than 0.5 µg/mL fibrinogen-equivalent units (FEU), or less than 250 ng/mL D-dimer units (D-DU). VTE is a major complication of cancer, occurring in 4-20% of cancer patients. Even after LWMH treatment, cancer patients with VTE have a high risk for recurrent VTE.

Researchers from the Keck School of Medicine University of Southern California, Los Angeles, and Weill Medical College of Cornell University, New York, conducted a phase II study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis of VTE in cancer patients. To evaluate whether D-dimer and IL-6 levels are predictive of recurrent VTE or OS, plasma levels of these potential biomarkers were assessed.

Patients with active cancer and pulmonary embolism (PE) and/or proximal deep venous thrombosis (DVT) from one of the two centres were eligible for inclusion in this study. They had to be older than 18 years, with an ECOG performance score ≤2, adequate organ function, and ≥6 month estimated survival. All patients were treated with tinzaparin (once daily 175 U/kg subcutaneous for 6 months). D-dimer and IL-6 levels were measured at baseline, after 7 days, 1 month and 6 months after treatment initiation. Patients who received one or more doses of tinzaparin, and had baseline and 1 week or 1 month samples collected were evaluable and included in the biomarker analysis. The primary endpoints were recurrent VTE or major bleeding, while secondary endpoints included overall survival (OS) and plasma biomarkers.

A total of 97 patients were included in the study, of whom 87 were included in the analysis. One third of patients completed tinzaparin treatment for 6 months or longer. Eleven patients had recurrent VTE at 6 months (3 PE, 7 DVT, 1 central venous thrombosis not associated with a catheter), and 2 patients had a major bleeding. The median baseline D-dimer level was 2,759 ng/mL D-DU, and the median IL-6 level 9.4 pg/mL. The analysis revealed that a baseline D-dimer level above the median was predictive of VTE recurrence at 6 months (p=0.006). Baseline IL-6 level above the median was not predictive of recurrent VTE at 6 months; neither were D-dimer level at 1 month or IL-6 level at 1 month. Moreover, D-dimer and Il-6 levels at baseline and at 1 month were not predictive of OS.


Piatek C, Tagawa ST, Wie-tsi D, et al. Baseline D-dimer levels are predictive of recurrent venous thromboembolism (VTE) at 6 months in cancer patients with VTE treated with tinzaparin. Thromb Res 2016;140 Suppl 1: S174.

enewsletter Trombosis Matters nr 2 2016 beeld bij abstract 4In a recent publication in Thrombosis Research, Dr. Bleker and collegues present the rationale and design of a new study on the optimal dosing of LMWH during pregnancy.

The so-called Highlow study is an investigator-initiated, multicentre, international, open-label, randomized trial with pregnant women with a history of VTE.

The primary efficacy endpoint is symptomatic recurrent VTE during pregnancy and 6 weeks postpartum, while the primary safety endpoints include clinically relevant bleeding, blood transfusions before 6 weeks postpartum and mortality.


Pregnant women have a 5-fold higher chance of VTE compared to non-pregnant women of the same age. Moreover, women with a history of VTE have a 2-10% absolute risk of developing recurrent VTE during a subsequent pregnancy in the absence of pharmacologic thromboprophylaxis. Current guidelines thus recommend pharmacologic thromboprophylaxis for all pregnant women with a history of VTE. LMWH are the preferred anticoagulants for VTE prophylaxis in pregnant women. However, the optimal dose of LMWH during pregnancy is still unknown, as no randomized trials have been performed. There is a need for evidence regarding the optimal strategy for thromboprophylaxis in pregnant women.

To investigate the optimal dose of LMWH, the Highlow study has been designed. In the Highlow study a fixed low dose of LMWH is compared with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. Pregnant women of 18 years and older with a history of VTE and an indication for ante- and postpartum thromboprophylaxis are eligible. Once included, the patient will be randomly assigned to either the fixed low dose or intermediate dose of LMWH. Between 24 April 2013 and 1 June 2016, 210 patients have been randomized in 40 centres in 5 countries.

All patients have 6 moments of contact, 2 weeks after randomization, at 20 and 30 weeks pregnancy, and 1 week, 6 weeks and 3 months postpartum.LMWH is injected subcutaneously once daily. Nadroparin is the preferred type of LMWH, but different types of LMWH are allowed. The fixed low dose is based on the weight of the patient at randomization and will not be changed during the treatment period. Patients in the intermediate dosing regimen will be monitored at every visit, and the dose will be changed if necessary. LMWH dosing will be stopped 24 hours prior to delivery, when contractions start or membranes rupture. During follow-up visits, efficacy and safety of LMWH will be evaluated. There is some debate about prolonging prophylaxis beyond the sixth week postpartum. Current guidelines, however, recommend prophylaxis until the sixth week postpartum, based on the fact that the risk for VTE is highest during the first 6 weeks after delivery.

The Highlow study is the first large randomized controlled trial in pregnant women that is likely to provide high-quality evidence on the optimal dosing of LMWH for the prevention of recurrent VTE in pregnant women with a history of VTE. The authors conclude that this study is likely to impact patient care and modify current guideline recommendations. The estimated last inclusion date is April 2018. Results will be expected after that.


Bleker SM, Buchmüller A, Chauleur C, et al. Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: rationale and design of the Highlow study, a randomised trial of two doses. Thrombosis Research 2016;144:62-8.

The Wells Score Calculator app has been developed to easily calculate the Wells Score of your patient.

The Wells Score is a clinical scoring system that aids in the management of deep vein thrombosis (DVT) and pulmonary embolism (PE). The calculator uses the guidelines from the National Institute for Health and Care Excellence (NICE, CG144) for the management of venous thromboembolism and associated medical literature. NICE has issued guidance on the use of this score and created some associated flow charts to help in the decision pathway. The app then shows the relevant flow chart from the NICE guidelines.

The NICE guidance documents can be found on: http://guidance.nice.org.uk/CG144

This app is released as an Open Source project and is available for Apple and Android.



















Logo world thrombosis day


In 2014, October 13th was officially declared as World Thrombosis Day, to increase the awareness of thrombosis among the general public, medical professionals and policy makers.

This year on October 13th, 2016 the World Thrombosis Day took place with hundreds of educational events in countries around the world.

Learn more at http://www.worldthrombosisday.org