A New Microparticle Coagulant Activity Assay to Predict Venous Thromboembolism in Patients with Pancreatic Cancer
Authors: van Es Nick , Bleker Suzanne , Kleinjan Ankie , Berckmans Rene , Wilmink J W , Nieuwland Rienk , Middeldorp Saskia , Büller Harry R 
Published: October 2019

Introduction: Patients with pancreatic cancer are at very high risk of venous thromboembolism (VTE). While the etiology of the prothrombotic state of these patients is not fully understood, emerging evidence suggests a causal role for circulating tumor-derived, tissue factor bearing microparticles (TFMP). We aim to assess whether a new, practical TFMP coagulant activity assay – the fibrin generation test (FGT) – is able to identify pancreatic cancer patients at the highest risk of VTE as they would benefit most from pharmaceutical thromboprophylaxis.

Methods: In this ongoing prospective cohort study, patients with pancreatic cancer who have recently started neoadjuvant or palliative chemotherapy are enrolled after informed consent. Exclusion criteria are VTE within 3 months prior to inclusion and current anticoagulant use. Within 30 minutes from standardized blood withdrawal, the FGT is performed on fresh, essentially cell-free, citrated plasma. The time to fibrin formation is measured by optical densitometry after incubation of the samples with either saline or anti-factor VIIa, both in duplicate. The prolongation in the time to fibrin formation in the presence of anti-factor VIIa compared to saline reflects the contribution of the TFMP to coagulation. A predefined cut-off of 13% was used to indicate high TFMP coagulant activity. The primary outcome is objectively confirmed symptomatic or asymptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) during 6 months follow-up. We use multiple imputation techniques to avoid bias from excluding patients in whom the FGT result is unavailable due to non-adherence to the standardized blood withdrawal. We perform competing risk regression analysis to deal with death as competing event for the occurrence of VTE.

Results: At present, 88 patients with pancreatic cancer have been enrolled. Baseline characteristics and follow-up data are presented in the Table. The TFMP coagulant activity as assessed with the FGT was high in 43 patients (48.9%). Fourteen percent (6/43) of patients with a high FGT result developed VTE, as compared to 2.6% (1/39) in patients with a low FGT result (OR 6.0; 95%CI 0.74-48.99). In the multivariate competing risk model including sex, age, tumor extent, and histology the adjusted OR was 6.04 (95%CI 0.75-48.8).

Conclusion: Our preliminary results suggest that the FGT, a practical TFMP coagulant activity assay, has predictive value for VTE in patients with pancreatic cancer. Although the number of events at present is too low to draw definite conclusions, the FGT is a promising biomarker that could easily be implemented in clinical practice. If these results will be confirmed, the FGT may be used as a risk stratification tool to identify pancreatic cancer patients at high-risk for VTE and install thrombosis prophylaxis in these patients.

Table. Baseline characteristics and follow-up data Characteristic All patients (N=88) Median age, years (IQR) 62.6 (55.1-68.0) Mean BMI, kg/m2 (SD) 26.3 (20) Male 49 (55.7%) Performance status WHO 0 50 (56.8%) WHO 1 32 (36.4%) WHO 2 6 (6.8%) Antiplatelet therapy 12 (13.6%) Cancer details Extent Local disease 36 (40.9%) Resectable 2 (2.3%) Borderline resectable 8 (9.1%) Irresectable 26 (29.5%) Distant metastasis 52 (59.1%) Recurrent cancer 8 (9.1%) Adenocarcinoma 80 (90.9%) Median time from cancer diagnosis to inclusion, days (IQR) 70 (47-103.5) Chemotherapy Gemcitabin 68 (77%) Neoadjuvant chemotherapy 10 (11.4%) Median time from start chemotherapy to inclusion, days (IQR) 14 (7-45) Median FGT, % (IQR) 14.9 (0-42.9) FGT result unavailable 6 (6.8%) Median follow-up, days (IQR) 123 (4-180) Follow-up status Withdrawn alive 57 (64.8%) Death 24 (27.3%) DVT or PE 7 (8.0%)

Disclosures

No relevant conflicts of interest to declare.