biomarkers of thrombosis in cancer patients · 2 potential cat biomarkers : microparticles...
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BIOMARKERS OF THROMBOSIS
IN CANCER PATIENTS Pr. Dominique Farge-Bancel
Internal Medicine and Vascular Disease Unit UF 04, Hôpital St-Louis Hospital Paris Diderot University
for the Groupe Francophone Thrombose et Cancer (GFTC ) / International Thrombosis and Cancer- Continuos Medical Education (ITAC-CME )
www.thrombose-cancer.com / www.itac-cme.com
WHY$BIOMARKERS$for$VTE$in$cancer$pa9ents$?$$
Treatment(of(VTE(:(an(interna/onal(health(priority(in(countries(with(cancer(plan(($Thrombophylaxis$:$a$major$challenge$$
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2.#Farge#et#al.#Thromb#Res#2010;125(Suppl2):S108.#2.#Falanga##&#Zacharski.#Ann#Oncol#2005;16:696.#3.#Monreal#et#al.#J#Thromb#Haemost#2006;4:1950L1956.#4#Pabinger#I#et#al#Blood#2013;#122:2011#5#Hanna#D#et#al#Clin#Rev#Oncol#Hematol#2013;#88:#19#
Cancer$• $Venous$Thromboembolism$$
(VTE=$VT,$PE$or$CAT)$$in$$4$N$20%$cancer$pts$$$
• $VTE$at$autopsy$in$50%$of$cancer$pts$$
VTE$• $20%$of$VTE$pts$
• $have$ac9ve$cancer$$
• $4N12%$of$pts$with$idiopathic$VTE$have$an$underlying$cancer,$$
VENOUS$THROMBOEMBOLISM$AND$CANCER$Copyright$©$1093790$(OPIC$28/02/2012)$(
THE RISK of VTE and THE RISK OF BLEEDING vary according to cancer ⇒ A need for adequate biomarkers to identify patients at risk of VTE
⇒ => primary VTE prevention based on risk stratification
BIOMARKERS OF THROMBOSIS IN CANCER PATIENTS
1. Pathophysiology$of$Cancer$Associated$Thrombosis:$• Pa/ent�s(characteris/cs,(tumor(histology/stage,(treatment(related(
factors(• Hypercoagulability(in(cancer((
2. Poten9al$predic9ve$biomarkers:$• Blood(count(parameters(• Platelets(and(cloAng(ac/va/on(markers(• Micropar/cles(and(Tissue(Factor(• CloAng(factors(Fibrinogen,(Factor(XIII,(factor(VIII(• C(Reac/ve(Protein((CRP)((
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1$Pathophysiology$of$Cancer$Associated$Thrombosis$CANCER = INDEPENDANT RISK FACTOR for VTE CANCER
case control study 625 pts Olmsted county 1 épisode VTE 1975-1990
Heit Arch Int Med 2000; 160: 809-815
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Standardized International Ratio (SIR) adjusted for age, race, sex incidence rates during the year immediately preceeding the diagnosis of cancer
White Arch Intern Med 2005; 165: 1782
1$Pathophysiology$of$Cancer$Associated$Thrombosis$THE$RISK$IS$NOT$EQUAL$according$to$cancer$type$:$OVERALL$INCIDENCE$
California Registry Cancer : 528,693 cancer pts (1993 to 1995)
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$1(Pathophysiology(of(Cancer(Associated(Thrombosis(
THE(RISK(IS(NOT(EQUAL(ACCORDING(TO(CANCER(DISSEMINATION(
6"Timp(Blood(2013(
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Armaud Trousseau (1801–1867)
« Clinique Médicale de L’Hôtel-Dieu de Paris » 1865
Jean-Baptiste Bouillaud (1796-1881)
« De l’oblitération des veines » 1823
1(Pathophysiology(of(Cancer(Associated(Thrombosis(HYPERCOAGULABILITY IN CANCER
Trousseau#A.#Phlegmasia#alba#dolens.#Clinique#médicale#de#l’HôtelLDieu#de#Paris,#Paris:#Ballière:1865;654#Pabinger#I#et#al#Blood#2013;#122:2011# # #Hanna#D#et#al#Clin#Rev#Oncol#Hematol#2013;#88:#19#Copyright © 1093790 (OPIC 28/02/2012
Virchow triad
3 HYPERCOAGULABILITY
• Intinsic factors • Extrinsic factors
(antitumour treatment)
1$Pathophysiology$of$Cancer$Associated$Thrombosis$Acquired hypercoagulability and cancer:
2 ENDOTHELIAL LESIONS
. Tumor cells effraction
• Surgery • Central Venous Catheter
• Chemotherapy • Surgery
• Radiotherapy
1 VENOUS BLOOD STASIS
• Hospitalization, • Immobilization (surgery)
• Extrinsic compression(tumour)
1821-1902
Combination : blood stasis or skeletal immobility + vessel wall insult + blood hypercoagulabilty Copyright © 1093790 (OPIC 28/02/2012
PHYSIOLOGIC COAGULATION PATHWAY - initiated when TF and F VII mediate FX activation
Introduction à l’étude de l’hémostase et de la thrombose,B. Boneu et J.P Cazenave Copyright © 1093790 (OPIC 28/02/2012
Rodger L. Bick, M.D., Ph.D. Cancer-Associated Thrombosis NEJM ; 2003: 349;2
HYPERCOAGULABILITY IN CANCER : inflammation + thrombosis + cancer
! Inflammation: ! fF VIII, Fibrinogen, CRPa ! ↑ Cytokines ! ↑ Adhesion molecules
! VTE associated with: ! TNF-α, IL-8, IL-6, CRP (Fox, 2005) ! ↑ F VIII and VWF (Tsai, 2002) ! ↓ activity ADAMTS 13 (Mannucci, 2003)
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2. POTENTIAL PREDICTIVE BIOMARKERS ! Blood count parameters : particular interest since assessed regularly
! Leukocytosis ! Khorana et al Cancer 2005 : ANC study risk CAT VTE: x 2 fold ! RIETE study 380r cancer pts: risk CAT VTE: x 1.6 fold
! High platelet count risk CAT supported by several studies ! Not(to(be(used(as(a(single(parameter(for(risk(predic/on,(rather(within(RAMs
Cancer type N pt Cut off HR/OR for VTE during follow-up
95% CI
Khorana 2005 Various 3003 ≥ 350G/L 2.8 (HR) 1.1-3.2
Simanek 2010 Various 665 > 443G/LL 3.5 (HR) 1.5-8.1
•
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! CD62P, member of the selectin family of cell adhesion moelcules: ! Expressed on platelets and endothelial cells ! Mediates heterotypic cell-cell interactions ! Interact with PSGL-1 on the surface of monocytes ⇒ TF expression = release of TF bearing MP ⇒ Fibrin + thrombus formation
" sP-selectin ↑ in pts with acute VTE + associated with risk of VTE in pts without cancer.
Bann JTH 2000; Gremmel . J Vasc Surg. 2011 Ay Clin Chem 2007 " CATS prospective study cancer pts, biomarker CAT:
! 6.4%pts (n+44) with VTE within 415 days FU ! Adjusted for age, sex, chemotherapy, surgery,
radiotherapy, palteletts, tumor type, cancer types ! Predictor VTE : HR 2.3 (p=0.009) ↑ risk of VTE.
Ay et al. Blood 2008
2 POTENTIAL CAT BIOMARKERS : P-selectin Inflammation, Thrombosis and Cancer
Andre et al. PNAS 2000 Chen et al.Arch Immunol Ther Exp 2005
Prandoni Lancet Oncol 2007 Copyright © 1093790 (OPIC 28/02/2012
DNDimers$Cancer Entity
n Cutoff HR/OR for VTE during Follow- Up
95% CI
Ay 2008 Various 821 ≥ 1.44 µg/mL 2.2 (HR) 1.3-3.6
Arpaia 2009 Various 124 > 0.65µg/mL 4 (HR) 1.2-13.3
Stender 2009 Colorectal 176 > 0.3µg/mL 6.5 (HR)
1.6-27
Kodarma 2010 Gynecologic 291 > 5µg/mL
1.2 (OR)
1.0-1.4
Ferroni2012 Lung 108 > 1.5µg/mL
11 (HR)
2.6-46
Ay et al 2008
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Thrombin$Genera9on$poten9al$
HR, 2.0; 95% CI, 1.3 to 3.2 P .003
Rickles et al. Chest 2003
2. POTENTIAL PREDICTIVE BIOMARKERS MARKERS OF PLATELETS and CLOTTING ACTIVATION
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Possible Effects of Low-Molecular-Weight Heparins on Tumor Biology.
Journal of Pathophysiology of Haemostasis and Thrombosis. 2006; 103-110
2 POTENTIAL PREDICTIVE BIOMARKERS for CAT : CLOTTING FACTORS: Fibrinogen, F XIII and F VIII
• Fibrinogen with arterial thrombosis but not with VTE • ↑ Polymorphims F XIII associated with VTE in non cancer pts but not in CAT • ↑ F VIII levels established risk factor for VTE in non cancer pt and also in CATS study • CRP : acute phase reactant protein
• Induces TF on monocytes, SMSC and endothelial cells • CTAS study predictive on univariate but not in multivariate
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$2.$POTENTIAL$PREDICTIVE$BIOMARKERS$
Regula/on(of(tumor(cell(and(endothelial(cell(procoagulant(func/ons(
Rickles FR, Falanga A. Thrombosis Research 2001;102: 215-224
TUMOR CELL : = > Cys protease = CP = > cleaves FX = FFX a FXa + FVa : a complex on platelet surface Prothrombin => Thrombin 2 forms of TISSUE FACTOR: - 1 associated with Microparticles MP - 1 non MP, expressed on platelets, leucocytes and enothtelial cells
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PLASMA COAGULATION
Fibrine Fibrinogen
Thrombine (IIa)
Ca++
Sous-endothélium
TISSUE FACTOR
Ca++ FT FT VIIa VII
PL X Ca++ VIIIa
IX IXa PL PL
Va II
X Xa PL
Fibrinolyse (Plasmine)
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Plasma levels of TF bearing MP in cancer patients …MP as a cancer biomarkers?
Panc1 SOJ-6 BxPC-3 MiaPaCa-2
Panc02 LLC1
Contrôle- (Irrelevant)
FT
Contrôle- (Irrelevant)
FT
Human cell lines
Murine cell lines
2. TF expression on cancer cells
Dubois$,$Frere,$Marseille$;$Copyright$©$1093790$(OPIC$28/02/2012)$(
2 POTENTIAL CAT BIOMARKERS : Microparticles subµmvesicles (0.1-1µm); proteins + phospholipids
! Derived from membrane vesiculation during cell maturation Jimenez et al. 2003
! Surface express Phosphatidylserine PL (-), AG originating cell AG Langer et al. 2008, TF Hron"et"al."Tromb"Haemost2007","Tilley"et"al."Tromb"Res,"2008""Del"Conde"et"al."J"Thromb"Haemost"2007"
! MP expressing TF then express platelet-selectin (P selectin) glycoprotein ligand (PSGL-1), which binds P-selectin on the surface of activated endothelial cells (= catalytic surface for TF expression)
! Prothrombo9c$phenotype$in$cancer$mouse$Thomas et al. J Exp Med 2009
2µm
Panc02-GFP
2 POTENTIAL CAT BIOMARKERS
TF activity expressed by cancer cells and cancer MP
TF activity per surface unit X 100 on cancer MPs ⇒ ? MP traverse from tumor to blood stream through leaky vessels ⇒ ? Cancer indirectly stimulate host cells to produce more vesicles
Thomas et al. J Exp Med 2009 Copyright © 1093790 (OPIC 28/02/2012
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Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Copyright © 1093790 (OPIC 28/02/2012
NUMEROUS PATHWAYS involved in Trousseau Syndrome…
Tissue Factor microparticles
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3. RAMs: 2 DIFFERENT RISK ASSESSMENT MODELS for indentification of Cancer patients at risk for VTE
Khorana#AA##et#al##Blood#2008#;#11:#4902##low (score 0), intermediate, (score 1-2), and high risk (score 3) CATS study AY 2008 ; Pabinger et al Blood 2013; 122:: 2011 ##
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Relations ship between tumor growth and biomarkers
# Tissu factor (TF): triiger coagulation , blood clotting // metastasis evolutio,
# Microparticules (MP): All dosage tecnhiques: MP + onset VTE in cancer The best biomarkers for CAT biomarqueurs ?
LIMITS: Detection des MPs par FACS, Sampling (stability), MPs life duration in vivo
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Continuing Medical Education Grant Request
Submitted on behalf of: ITAC-CME 1 Av Claude Vellefaux Hôpital St Louis Médecine interne et vasculaire 75010 Paris www.thrombose-cancer.com / www.itac-cme.com
Program Administrator: Lynn Heywood-McLean [email protected]
Venous Thromboembolism and Cancer: A New Focus for Better Patient Outcomes
This proposal is submitted in the strictest of confidence by ITAC-CME for the purpose of developing continuing medical education programs. VENOUS THROMBOEMBOLISM AND CANCER Copyright © 1093790 (OPIC 28/02/2012)