Service d’Hématologie Biologique Hôpital Tenon, APHP, Paris, FranceGroup Thrombosis and Cancer

Cancer Biology and TherapeuticsCentre de Recherche Saint-AntoineINSERM U938 Université Pierre et Marie Curie

In patients with lung adenocarcinoma, metastasis, advanced stage and chemotherapy (CTx) are factors

which increase the risk of venous thromboembolism (VTE). However, routine pharmacological

thromboprophylaxis is not recommended but individualized risk assessment for VTE is encouraged

Lung Adenocarcinoma stands out among the types of cancer with a high risk for VTE, having an

adjusted relative risk (RR) ratio of 22 compared with non cancer patients

The development of risk assessment models (RAM) to stratify the risk of VTE adapted for cancer

patients and prospective clinical validation is necessary

A multicenter cross-sectional observational study of the Tenon Thrombosis group (COMPASS - Study),

identified the most frequent and clinically relevant risk factors for VTE in medical and surgical patients

which can be used to create a RAM model adapted to specific patients’ settings The incorporation of

biomarkers of blood hypercoagulability int the RAM could improve its sensitivity to identify patients

eligible for thromboprophylaxis.

To this aim we conducted an observational prospective study, in patients with lung adenocarcinoma,

to investigate the variability of haematological biomarkers (HB) associated with hypercoagulability, with

respect to adenocarcinoma-related characteristics

Introduction

Results

The present study evaluated a wide spectrum of biomarkers of cellular and plasma hypercoagulability in patients with lung adenocarcinoma

We established that the increase of procoagulant phospholipids in plasma, the up-regulation of TF pathway, the enhanced D-Dimers formation and heparanase release is a universal phenomenon in lung cancer

Chemotherapy enhances both cellular and plasma hypercoagulability

Variations of thrombin generation and FVIIa levels allow to identify subgroups of patients who present hypercoagulability

Baseline values of TGT, PPL, HPA were found to be related with 3-month mortality and the incidence of thrombotic episodes

These data allow to propose that the weighted incorporation of biomarkers of cellular and plasma hypercoagulabilty in RAMs for VTE might improve their predictive value. This concept is being studied on an ongoing trial

Conclusion

Differential Influence of Lung Cancer Stage, Time from Diagnosis and Chemotherapy on Plasma and Cellular Biomarkers of Hypercoagulability. The ROADMAP Study

Ilias Evmorfiadis1,2, Paraskevi Boura3, Aurélie Rousseau1,2,4, Ariadni Charpidou2, Giannis Giozos2, Patrick Van Dreden4, Konstantinos Syrigos2, Anastasia Spanoudaki5, Matthieu Grusse4, Ismail Elalamy 1,2 and Grigoris T. Gerotziafas1,2

 1Service d’Hématologie Biologique Hôpital Tenon, Hôpitaux Universitaires Est Parisien, Assistance Publique Hôpitaux de Paris, Paris, France 2INSERM U938, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris, France 3Oncology Unit GPP, 3rd Department of Medicine, Athens School of Medicine, Athens, Greece

4Research and Development, Diagnostica Stago, Gennevilliers, France

Patients and Methods 

Patients and study design

Patients with documented lung adenocarcinoma eligible for CTx at distance of at least 3 months from

surgery or hospitalization were included in the study (n=80). Patients were either CTx naive (n=46) or had

already received CTx (n=34). The control group (CG) consisted of 30 healthy age & sex-matched

individuals.

Patients were assessed at baseline on the day of their entry in the study, and after 3 months follow-

up. HB screening took place at baseline and after 3 cycles of CTx and one month after last CTx or before

change of therapy line

Thrombin generation (TGT) in citrated PPP was assessed with the Thrombogram-Thrombinoscope®

assay using PPP-reagent®5 pm TF by Diagnostica Stago. The levels of P-Selectin and heparanase (HPA) in

plasma were measured with ELISA Kit (Cusabio Biotech and R&D Systems respectively). The

procoagulant phospholipids clotting time (PPL) was measured with STA-Procoag-PPL® ,levels of Factor

VIIa by Staclot VIIa-rTF®, D-Dimers (DDi) by Liatest D-Di (Diagnostica Stago, France), and Tissue Factor

activity (TFa) by specific clotting based home test

Patients’ mortality and symptomatic thrombotic events were recorded

Figure 1. Baseline hypercoagulability markers in patients (D-Dimers, MRI & Heparanase) according to mortality in the 3 month follow-up period

* p<0,05 versus CG $ p<0,05 versus NG

Patients showed significantly shortened PPL and significantly higher levels of TFa, D-Dimer and HPA as

compared to the CG. The levels of FVIIa were significantly lower in patients compared to CG

P-Selectin levels and endogenous thrombin potential (ETP) did not differ between the two groups. The

chronometric parameters of TGT (lag-time, and ttPeak) were significantly prolonged. The velocity of the

propagation phase of TGT (MRI) was significantly lower in patients as compared to CG

The Naive Group of patients (NG) showed significantly shorter lag-time and lower ETP as compared to

the On Treatment Group (OTG). The NG showed significantly higher levels of HPA as compared to the

OTG (Table I.)

Hypercoagulability Biomarkers All Patients (n=79) NG

(n=29) OTG

(n=50) CG

(n = 30)

PPL-ct (sec) 27±6* 27±7* 27,6±7,5* 62,8±9 TFa (ng/ml) 6.2±4.7* 6,2±4* 6,6±5,2* 0,26±0.1

DD (μg/ml) 1,8±2,2* 1,1±1* 1,4±1,2* 0,3±0.01 HPA (ng/ml) 0,4±1,2* 0,32±0.12$* 0,23±0,1* 0,12±0,02

FVIIa (U/ml) 37±20* 34±16* 34±20* 50,9±11

P-Selectin (ng/ml) 65,4±20 64,8±15 62,6±19 62,6±10 Lag-time (min) 4,3±0,8* 3,9±1$ 4,5±0,9* 2,5±0.01 ttPeak (min) 7.7±1.4* 7±1 8,7±1,3* 5±1 MRI (nM/min) 91±40* 94±41 87,3±33* 110±24

Peak (nM) 279±71* 279±76 284±62* 288±36 ETP (nM.min) 1583±328 1567±326 1673±315*$ 1496±191

Table I. Baseline hypercoagulability markers in patients stratified according to Chemotherapy status (naive or on-treatment)

Figure 4. Baseline hypercoagulability markers in patients according to thrombosis in the 3 month follow-up period

Figure 3. Baseline hypercoagulability markers in patients according to cancer stage

Figure 2. Baseline hypercoagulability markers in patients according to cancer grade

Patients who died within the 3-month follow-up (31%) had higher baseline levels of DDi and lower HPA levels as compared to those who were still alive (Fig. 1)

The increase of TGT, as well as that of HPA, P-Selectin, FVIIa was associated with the grade of the disease (Fig. 2)

Patients with metastatic cancer had higher levels of P-Selectin, TFa, DDi, FVIIa, TGT and HPA as compared to patients with localized or advanced disease (Fig. 3)

Patients who experienced a thrombotic episode (5%) had significantly higher baseline levels of TGT, shorter PPL and lower levels of HPA as compared to those who remained without thrombosis (Fig 4)