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Pathogenesis?
Biological significance?
ty
1. Stasis
b ili
Sta
Prolonged bed rest
ul a
sis
Extrinsic compression of blood vessels by tumor
o ag
2. Vascular Injury
e rc
Direct invasion by tumor
H yp
Prolonged use of central venous catheters
Endothelial damage by chemotherapy drugs
Effect of tumor cytokines on vascular endothelium
3. Hypercoagulability Vascular Injury
Tumor-associated procoagulants and cytokines (tissue factor, CP, TNFα, IL-1β,
VEGF, etc.)
Impaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT,
Protein C and S)
Enhanced selectin/integrin-mediated, adhesive interactions between tumor
cells,vascular endothelial cells, platelets and host macrophages
Mechanisms of Cancer-Induced Thrombosis: Clot and Cancer Interface
Pathogenesis?
Biological significance?
FVII/FVIIa
Tumor Blood Coagulation
TF Activation
Cell
VEGF
THROMBIN
FIBRIN
Angiogenesis
IL-8
PAR-2 TF
Endothelial cells
Angiogenesis
Epiphenomenon?
Is this a generic secondary event
(as in inflammation, where clot formation is an incidental
finding)
Or, is clotting . . .
A Primary Event?
Linked to malignant transformation
Mechanisms of Cancer-Induced Thrombosis: Implications
1. Pathogenesis?
2. Biological significance?
other causes
Recurrent VTE during the 3-month course developed in six
of the 55 patients (10.9%) with immobility,
immobilization 10.9%
as compared with 11 of the 322 (3.4%) ambulant patients,
leading to a relative RR =2,9
risk, adjusted for age, of 2.9 (95% CI: 1.2–7.5).
Cancer
Type
z Men: prostate, colon, brain, lung
z Women: breast, ovary, lung
Stage
Treatments
Surgery
z 10-20% proximal DVT
z 4-10% clinically evident PE
z 0.2-5% fatal PE
Systemic
Central venous catheters (~4% generate clinically relevant VTE)
Comorbid Condition and DVT Risk
► Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar
proportion of the cases, while nursing home residence accounted for 13%.
► The individual attributable risk estimates for malignant neoplasm, trauma, congestive
heart failure, central venous catheter or pacemaker placement, neurological disease
with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%,
and 5%, respectively.
► Together, the 8 risk factors accounted for 74% of disease occurrence
Heit JAet al Arch Intern Med. 2002. Relative impact of risk factors for deep vein
thrombosis and pulmonary embolism: a population-based study
Predicted probability for any venous
thromboembolic events (VTE) based on the
factors inpatient treatment, prior
thrombosis in medical history, thrombosis
in family history, chemotherapy, fever and
C-reactive protein (CRP), showing the rate
of patients with a given number of risk
factors as calculated from the total of 507
patients included
Clinical characteristics and management of acute deep vein thrombosis and pulmonary
embolism (PE) have been reported to be different in patients with and without cancer.
MASTER multicenter registry
Dalteparin OAC
P-value*
N=338 N=335
Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27
LITE Tinzaparin 3 80 6 6 NS
23
0.03 NS
(Hull ISTH 2003) OAC 87 11 8 22
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0 20 40 60 80 100 120140 160 180
Number of Days
4
3,5
And Noncancer Patients (%)
Cancer Patients
VTE in Hospitalized Cancer
3
2,5
2
1,5
1
Noncancer Patients
0,5
0
79
81
83
85
87
89
91
93
95
97
99
YEAR
1
2
3
4
0.5
1.5
2.5
3.5
4.5
Pancreas
Leukemia
Relative Risk of VTE Ranged From 1.02 to 4.34
Breast
Cervix
Bladder
Does VTE in patients with cancer
adversely affect outcome?
60% of cancer patients, have
localized cancer or limited
metastatic disease that would have
allowed for longer survival in the
absence of a fatal PE.
Prandoni et al 2002
OAC vs LMWH
LMWH vs placebo
CLOT Survival Curves
Overall population Good prognosis population
100 100 without metastases
90 90 Dalteparin
80 80
p=0.62
70 70
60 60 OAC
50
Dalteparin 50
40 OAC 40
p=0.03
30 30
20 20
10 10
0 0
0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 30 60 90 120 150 180 210 240 270 300 330 360 390
15 OAC
10
Dalteparin
5
1.0
The Kaplan-Meier survival estimates at 1, 2, and 3 years after
Dalteparin
Kaplan–Meier survival
0.9 randomization for patients receiving dalteparin were 46%, 27%, and
21%, respectively, compared with 41%, 18%, and 12%, respectively,
0.8 Placebo for patients receiving placebo (P = .19).
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 12 24 36 48 60 72 84
Time from randomisation (months)
0.9
distribution estimate
Chemotherapy plus
SCLC study dalteparin 5000 IU od
18 weeks
Small cell lung cancer R
(SCLC)
Chemotherapy (cyclophosphamide,
Patients with responsive limited disease epirubicin, vincristine)
received thoracic radiotherapy 18 weeks
MALT Nadroparin
2 weeks therapeutic dose
Solid tumor 4 weeks 1/2 therapeutic dose
R
malignancy
Placebo
Altinbas M, et al. J Thromb Haemost. 2004;2:1-6. 6 weeks
Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135. Lee, et.al. N Engl J Med, 2003;349:146
SCLC Study Survival Curves
Overall population Good prognosis population
1.0 1.0 limited disease
Probability of survival
0.8
Probability of survival
0.8 p=0.007
p=0.01
0.6 0.6
0.2 0.2
Placebo Placebo
0.0 0.0
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Probability of Survival
Probability of Survival
0.8 0.8
p=0.021 p=0.010
0.6 0.6
0.4 0.4
Nadroparin
0.2 0.2 Nadroparin
Placebo Placebo
0.0 0.0
0 12 24 36 48 60 72 84 96 0 12 24 36 48 60 72 84 96
100
90 Dalteparin
Probability of Survival, %
80
70
60 OAC
50
40
30
20
10
0
HR = 0.50 P-value = 0.03
Khorana et al 2008
Recurrence and bleeding were both related to
cancer severity and occurred predominantly
during the first month of anticoagulant
therapy but could not be explained by sub- or
overanticoagulation.
So, patients with DVT who also have cancer
seem to be at a higher risk for recurrent
venous thromboembolic complications during
anticoagulation.
Effect of Malignancy on Risk of Venous Thromboembolism (VTE)
53.5
50 • Population-based case-control (MEGA)
study
• N=3220 consecutive patients with 1st
Adjusted odds ratio
10 4.9
3.6 2.6
1.1
0
Gastrointestinal
3 to 12 months
0 to 3 months
Hematological
5 to 10 years
metastases
1 to 3 years
> 15 years
Distant
Breast
Lung
IL-1, Activation of
TNF-α, coagulation
VEGF
Platelets