Transcript Diapositive 1

Differential Influence of Lung Cancer Stage, Time from Diagnosis and Chemotherapy
on Plasma and Cellular Biomarkers of Hypercoagulability. The ROADMAP Study
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
OTG
(n=50)
CG
(n = 30)
27±6*
6.2±4.7*
27±7*
6,2±4*
27,6±7,5*
6,6±5,2*
62,8±9
0,26±0.1
PPL-ct (sec)
TFa (ng/ml)
DD (μg/ml)
1,8±2,2*
HPA (ng/ml)
In patients with lung adenocarcinoma, metastasis, advanced stage and chemotherapy (CTx) are factors
1,1±1*
1,4±1,2*
0,23±0,1*
34±16*
34±20*
50,9±11
which increase the risk of venous thromboembolism (VTE). However, routine pharmacological
P-Selectin (ng/ml)
65,4±20
64,8±15
62,6±19
62,6±10
thromboprophylaxis is not recommended but individualized risk assessment for VTE is encouraged
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
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
* p<0,05 versus CG
14
15
10
4
0
0
0
0.5
1
Localised
1.5
Metastatic
2
0
2.5
0.5
1
Localised
FVIIa
1.5
Metastatic
2
2.5
2
2.5
2
2.5
Heparanase
120
12
100
10
80
8
$ p<0,05 versus NG
 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)
identified the most frequent and clinically relevant risk factors for VTE in medical and surgical patients
8
5
U/mL
 A multicenter cross-sectional observational study of the Tenon Thrombosis group (COMPASS - Study),
10
6
Table I. Baseline hypercoagulability markers in patients stratified according to Chemotherapy status
(naive or on-treatment)
patients and prospective clinical validation is necessary
12
2
MRI (nM/min)
 The development of risk assessment models (RAM) to stratify the risk of VTE adapted for cancer
16
0,12±0,02
37±20*
adjusted relative risk (RR) ratio of 22 compared with non cancer patients
18
0,3±0.01
FVIIa (U/ml)
 Lung Adenocarcinoma stands out among the types of cancer with a high risk for VTE, having an
20
25
20
0,32±0.12$*
0,4±1,2*
D-Dimers
TFa
mcg/mL FEU
Introduction
All Patients (n=79)
NG
(n=29)
ng/mL
1Service
Hypercoagulability Biomarkers

Service d’Hématologie Biologique
Hôpital Tenon, APHP, Paris, France
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
ng/mL
Group Thrombosis and Cancer
Cancer Biology and Therapeutics
Centre de Recherche Saint-Antoine
INSERM U938
Université Pierre et Marie Curie
60
6
40
4
20
2
D-Dimers
which can be used to create a RAM model adapted to specific patients’ settings The incorporation of
0
20
0
0
0.5
Localised
1
1.5
Metastatic
2
2.5
0
0.5
Localised
1
1.5
Metastatic
18
biomarkers of blood hypercoagulability int the RAM could improve its sensitivity to identify patients
MRI
Heparanase
1.8
250.00
Mcg/mL FEU
200.00
1.4
Ng/mL
investigate the variability of haematological biomarkers (HB) associated with hypercoagulability, with
Nmol/min
1.2
 To this aim we conducted an observational prospective study, in patients with lung adenocarcinoma, to
Figure 3. Baseline hypercoagulability markers in patients according to cancer stage
14
1.6
1
0.8
150.00
100.00
12
10
0.6
50.00
0.2
4
0
Dead
1
1.5
Living
2
2.5
0
0.5
1
Dead
1.5
2
2
2.5
Living
0
Patients and Methods
0.5
1
1.5
2
2.5
nmol/min
0.5
0
FVIIa
10
0.00
40
1500
1000
0
0.5
1
Poor Diff.
1.5
Moderate Diff.
2
2.5
0.5
200.00
450
180.00
400
160.00
350
100000
1.2
80000
1
0.8
0.6
1.5
Moderate Diff.
2
2.5
0
nM
100.00
80.00
20.00
50
0.00
0
1
Poor Diff.
1.5
Moderate Diff.
2
0.5
1
Poor Diff.
Moderate Diff.
1.5
2
2.5
P-Selectin
100000
80000
pg/mL
0.5
0.4
0.3
60000
0.2
20000
0
0
0
0.5
Poor Diff.
1
1.5
Moderate Diff.
2
2.5
0
0.5
No thrombosis
1
Thrombosis
1.5
2
2.5
No thrombosis
The present study evaluated a wide spectrum of biomarkers of cellular and plasma
hypercoagulability in patients with lung adenocarcinoma
Chemotherapy enhances both cellular and plasma hypercoagulability
40000
0.1
0
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
120000
0.7
2.5
Conclusion
0
2.5
0.8
2
200
100
0.5
1.5
250
40.00
0
1
Figure 4. Baseline hypercoagulability markers in patients according to thrombosis in the 3
month follow-up period
150
60.00
0.5
Thrombosis
300
120.00
ng/mL
1.4
Thrombin Peak
MRI
nmol/min
1
Poor Diff.
0.6
OTG (Table I.)
120000
0
0
Heparanase
the On Treatment Group (OTG). The NG showed significantly higher levels of HPA as compared to the
1.6
0.2
140.00
 The Naive Group of patients (NG) showed significantly shorter lag-time and lower ETP as compared to
1.8
0.4
0
 Thrombin generation (TGT) in citrated PPP was assessed with the Thrombogram-Thrombinoscope®
propagation phase of TGT (MRI) was significantly lower in patients as compared to CG
No thrombosis
20000
0
Results
1.5
Heparanase
40000
500
1
Thrombosis
60000
10
in plasma were measured with ELISA Kit (Cusabio Biotech and R&D Systems respectively). The
0.5
No Thrombosis
ng/mL
50
20
assay using PPP-reagent®5 pm TF by Diagnostica Stago. The levels of P-Selectin and heparanase (HPA)
0
160000
30
before change of therapy line
0
2.5
140000
nmol/L x min
U/mL
up. HB screening took place at baseline and after 3 cycles of CTx and one month after last CTx or
2
2000
70
 Patients were assessed at baseline on the day of their entry in the study, and after 3 months follow-
1.5
P-selectin
2500
60
chronometric parameters of TGT (lag-time, and ttPeak) were significantly prolonged. The velocity of the
1
Thrombosis
pg/mL
individuals.
 P-Selectin levels and endogenous thrombin potential (ETP) did not differ between the two groups. The
0.5
ETP
90
30
50.00
80
compared to the CG. The levels of FVIIa were significantly lower in patients compared to CG
100.00
 The increase of TGT, as well as that of HPA, P-Selectin, FVIIa was associated with the grade of
the disease (Fig. 2)
had already received CTx (n=34). The control group (CG) consisted of 30 healthy age & sex-matched
 Patients showed significantly shortened PPL and significantly higher levels of TFa, D-Dimer and HPA as
40
150.00
0
surgery or hospitalization were included in the study (n=80). Patients were either CTx naive (n=46) or
 Patients’ mortality and symptomatic thrombotic events were recorded
50
20
Figure 1. Baseline hypercoagulability markers in patients (D-Dimers, MRI & Heparanase) according to
mortality in the 3 month follow-up period
 Patients with documented lung adenocarcinoma eligible for CTx at distance of at least 3 months from
activity (TFa) by specific clotting based home test
200.00
Axis Title
Patients and study design
VIIa by Staclot VIIa-rTF®, D-Dimers (DDi) by Liatest D-Di (Diagnostica Stago, France), and Tissue Factor
60
0.00
0
procoagulant phospholipids clotting time (PPL) was measured with STA-Procoag-PPL® ,levels of Factor
250.00
6
0.4
respect to adenocarcinoma-related characteristics
PPL-t
MRI
8
seconds
eligible for thromboprophylaxis.
16
0
0.5
Poor Diff.
1
1.5
Moderate Diff.
2
Figure 2. Baseline hypercoagulability markers in patients according to cancer grade
 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)
2.5
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