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Mechanisms of Cancer-Induced Thrombosis: The Interface

Pathogenesis?

Biological significance?

Potential importance for cancer therapy?


Pathogenesis of Thrombosis in Cancer – A Modification of Virchow’s Triad

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?

„ Potential importance for cancer therapy?


Interface of Biology and Cancer

FVII/FVIIa
Tumor Blood Coagulation
TF Activation
Cell

VEGF
THROMBIN

FIBRIN
Angiogenesis
IL-8
PAR-2 TF

Endothelial cells
Angiogenesis

Falanga and Rickles, New Oncology:Thrombosis, 2005


Activation of Blood Coagulation in Cancer Biological Significance?

„ 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?

3. Potential importance for cancer therapy?


VTE and Cancer: Epidemiology

„ Of all cases of VTE:


‹ About 20% occur in cancer patients
‹ Annual incidence of VTE in cancer
patients ≈ 1/250

„ Of all cancer patients:


‹ 15% will have symptomatic VTE
‹ As many as 50% have VTE at autopsy

„ Compared to patients without cancer:


‹ Higher risk of first and recurrent VTE
‹ Higher risk of bleeding on anticoagulants
‹ Higher risk of dying

Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21


Clinical Features of VTE in Cancer

„ VTE has significant negative impact on quality of life


„ VTE may be the presenting sign of occult malignancy
• 10% with idiopathic VTE develop cancer within 2 years
• 20% have recurrent idiopathic VTE
• 25% have bilateral DVT

Bura et. al., J Thromb Haemost 2004;2:445-51


The rate of recurrent venous thromboembolism (VTE) during
well-conducted anticoagulation in patients with deep vein Rate of recurrent
thrombosis (DVT) or pulmonary embolism (PE) is consistently
3–5% pts in the first 3 months
around 3–5% of patients in the first 3 months following the
thrombotic episode. The conditions that have mainly been
found to be associated with the risk of recurrent VTE during
Main causes
anticoagulation are active cancer and antiphospholipid
syndrome.
active cancer
AP syndrome.

Prandoni et al; J Thromb Haemost 2007


The rate of recurrent VTE during Rate of recurrent
well-conducted anticoagulation in patients with DVT or PE is
consistently around 3–5% of patients in the first 3 months
3–5% pts in the first 3 months
following the thrombotic episode.

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).

Prandoni et al; J Thromb Haemost 2007


DVT and PE in Cancer Facts, Findings, and Natural History

„ VTE is the second leading cause of


death in hospitalized cancer patients1,2
„ The risk of VTE in cancer patients
undergoing surgery is 3- to 5-fold higher It has been estimated
than those without cancer2 that 1 in every 7
„ Up to 50% of cancer patients may have hospitalized cancer
evidence of asymptomatic DVT/PE3
patients who die, do so
„ Cancer patients with symptomatic DVT
exhibit a high risk for recurrent DVT/PE from pulmonary
that persists for many years4 embolism (PE).
1. Ambrus JL et al. J Med. 1975;6:61-64
2. Donati MB. Haemostasis. 1994;24:128-131
3. Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
4. Prandoni P et al. Ann Intern Med. 1996;125:1-7
Risk Factors for Cancer-Associated VTE

„ 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

A total of 2119 patients were enrolled, of MASTER multicenter


whom 424 (20%) had cancer. registry
The incidence of bilateral lower limb DVT was
significantly higher in patients with cancer 8.5% versus 4.6%;
than in patients without cancer (8.5% versus p<0.01
4.6%; p<0.01),
as were the rates of iliocaval thombosis
(22.6% versus 14%; p<0.001), and upper limb
deep vein thrombosis (9.9% versus 4.8%;
p<0.001). Imberti et al 2008
consequently

Venous thromboembolism (VTE) is a frequent


complication in cancer patients and represents an
important cause of morbidity and mortality.
During the 3-month period, immobilization
Major bleeding complications Rate of major bleeding
developed in twice as many patients
7,3 % pts in the first 3 months
with (four of the 55, 7.3%)
than without (11 of the 322, 3.4%) prior immobilization,
No immobilization 3.4%

but the adjusted relative risk was not RR =2,1


statistically significant (2.1; 95% CI 0.7–6.5).

Prandoni et al; J Thromb Haemost 2007


Bleeding Events in CLOT

Dalteparin OAC
P-value*
N=338 N=335
Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27

Any bleed 46 (13.6%) 62 (18.5%) 0.093

* Fisher’s exact test

Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146


Treatment of Cancer-Associated VTE
Study Design Length of N Recurrent Major Death
Therapy VTE (%) Bleeding (%)
(Months) (%)
CLOT Trial Dalteparin 6 336 9 6 NS
39
0.002 NS
(Lee 2003) OAC 336 17 4 41

CANTHENOX Enoxaparin 3 67 11 7 0.09


11
0.09 0.03
(Meyer 2002) OAC 71 21 16 23

LITE Tinzaparin 3 80 6 6 NS
23
0.03 NS
(Hull ISTH 2003) OAC 87 11 8 22

ONCENOX Enox (Low) 6 32 3.4 NS NS NR


(Deitcher ISTH Enox (High) 36 3.1
2003) OAC 34 6.7
MASTER multicenter registry

Major bleeding (3.3% versus 1.1%; p=0.001), in-


hospital treatment (73.3% versus 66.6%; p=0.02)
and inferior vena cava filter implantation (7.3%
versus 4.1%; p=0.005) were significantly more
frequent in patients with cancer, in whom oral
anticoagulants were less often used (64.2% versus
Imberti et al 2008
82%; p<0.0001).
consequently

Major bleedings is a frequent complication in cancer


patients (than in patient without cancer) and represents
an important cause of morbidity and mortality.
1.00
DVT/PE and Malignant Disease
0.80
Probability of
Death

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

Levitan N, et al. Medicine 1999;78:285


As Number Of Cancer Survivors Increases, VTE Rates Increase

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

Stein PD, et al. Am J Med 2006; 119: 60-68


Relative Risk of VTE in
Cancer Patients

1
2
3
4

0.5
1.5
2.5
3.5
4.5

Pancreas

Stein PD, et al. Am J Med 2006; 119: 60-68


Brain
Myeloprol
Stomach
Lymphoma
Uterus
Lung
Esophagus
Prostate
Rectal
Kidney
Colon
Ovary
Liver
VTE Risk And Cancer Type: “Solid And Liquid”

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.

The incidence of VTE in cancer


patients has been described to be
approximately 15%, with reported
incidence rates ranging from 3.8%
to 30.7%.
„ Probability of death within 183 days of initial
hospital admission in patients with cancer with or
without concurrent VTE
However, it is likely to be much higher, because
VTE is often asymptomatic or minimally
symptomatic and, even when symptoms are
present; they are often nonspecific or mistakenly
attributed to the underlying malignancy.
Especially in patients who have a poor life
expectancy, preventing death from pulmonary
embolism is the mainstay of treatment.
Some patients with DVT develop recurrent VTE
or bleeding complications mainly during
anticoagulant treatment.
These complications may occur more frequently
if these patients have concomitant cancer.
From a prospective follow-up study arise that in ANTICOAGULANTS
thrombosis patients those with cancer have a ACTION AND MONITORING
higher risk (was 20.7% or a hazard ratio of 3.2 HEPARIN-AT LMWH WARFARIN
for recurrent venous thromboembolism or
bleeding during anticoagulant treatment than
F XIIa F VII
those without cancer (6.8%).
F XIa F IX
In the same study, the cumulative incidence of F IXa F Xa
F X
major bleeding was 12.4% in patients with F Xa F II
cancer and 4.9% in patients without cancer, with THROMBIN (IIa)
PT/INR
a risk ratio of 2.2. PTT Anti Xa levels

Fig 1. Cumulative incidence of recurrent


VTE during anticoagulant therapy.
Fig 2. Cumulative
incidence of clinically
important bleeding
during anticoagulant
therapy in DVT
patients with and
without cancer.

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

Probability of survival (%)


Probability of survival (%)

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

Days after randomization Days after randomization

Lee, et.al. N Engl J Med, 2003;349:146


Landmark CLOT Cancer Trial
Reduction in Recurrent VTE

Probability of Recurrent VTE, % 25 Risk reduction = 52%


Recurrent VTE
p-value = 0.0017
20

15 OAC

10
Dalteparin
5

0 30 60 90 120 150 180 210


Lee, Levine, Kakkar, Rickles et.al. N
Engl J Med, 2003;349:146 Days Post Randomization
Famous: Trial Design
Kaplan–Meier survival curves for all patients in dalteparin and placebo groups
distribution function estimate

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)

No. at risk: 190 85 30 22 12 5 4 Dalteparin


184 72 15 9 8 5 2 Placebo
Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
Survival Analysis: Good Prognosis Patients In an analysis not specified a priori, survival
was examined in a subgroup of patients
(dalteparin, n = 55; and placebo, n = 47) who
had a better prognosis and who were alive 17
months after randomization. In these
1.0 patients, Kaplan-Meier survival estimates at 2
Dalteparin
and 3 years from randomization were
Kaplan–Meier survival

0.9
distribution estimate

Placebo significantly improved for patients receiving


0.8 dalteparin versus placebo (78% v 55% and
0.7 60% v 36%, respectively, P = .03). The rates
0.6 of symptomatic venous thromboembolism
were 2.4% and 3.3% for dalteparin and
0.5 placebo, respectively, with bleeding rates of
0.4 4.7% and 2.7%, respectively.
0.3
0.2
0.0
17 23 29 35 41 47 53 59 65 71 77 83
Time from randomisation (months)

No. at risk: 47 17 10 9 9 8 8 5 3 2 0 Placebo


55 31 26 22 20 13 8 5 5 5 3 Dalteparin

Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.


LMWH and Survival: Further Studies (2003)
CLOT Dalteparin
1 month 200 IU/kg od
Solid tumor malignancy and 5 months ≅160 IU/kg od
acute VTE R
All patients received dalteparin Oral anticoagulant
200 IU/kg od 5–7 days 6 months

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

0.4 Dalteparin 0.4 Dalteparin

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

Months after randomization Months after randomization

Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.


MALT Survival Curves
Overall population Good prognosis population
1.0 1.0 >6 months survival

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

Months after randomization Months after randomization

Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.


Anti-Tumor Effects of LMWH
CLOT 12-month Mortality
Patients Without Metastases (N=150)

100
90 Dalteparin
Probability of Survival, %

80
70
60 OAC
50
40
30
20
10
0
HR = 0.50 P-value = 0.03

0 30 60 90 120 150 180 240 300 360

Days Post Randomization


Lee A, et al. ASCO. 2003
A model for the prediction of symptomatic venous
thrombosis after the initiation of chemotherapy, among
outpatients with different types of malignancies
schedulated by Khorana et al in 2008.
Primary site of cancer, platelet count, leukocyte count,
hemoglobin level, use of erythropoiesis-stimulating
agents, and body mass index were found to be
predictive factors.
Symptomatic venous thrombotic events were recorded
when reported by physicians. Due to this design, the
occurrence of asymptomatic thrombotic events could
not be assessed.
Based on the predictive factors, patients were classified into
‰ low-risk (27%),
‰ intermediate-risk (61%), and
‰ high-risk (12%) groups.

Most thrombotic events (75%) occurred during the first 2 cycles of


chemotherapy.
In the low-risk group, only 0.6% developed symptomatic venous
thrombosis, compared with 1.9% in the intermediate-risk group.
These findings suggest that the 88% of the patients in the low- and
intermediate-risk groups are unlikely to benefit from prophylactic
anticoagulation.
Patients in the high-risk group had a nearly 7% risk of developing
venous thrombosis during a median follow-up period of 73 days. One
may argue whether a 7% risk warrants thromboprophylaxis; 93% of
patients in this high-risk group would be treated without any
apparent benefit, and moreover, patients with a malignancy have an
increased risk of major bleeding during thromboprophylaxis.
To make a balanced decision, the risks and benefits need to
be assessed.
Unfortunately, data regarding bleeding risk were unavailable
in the study by Khorana et al. Similarly, data on prophylactic
anticoagulation use was lacking.
If one of the investigated factors instigated the use of
anticoagulation, and thereby indirectly decreased the risk of
venous thrombosis, this would influence the model.
This was a very large study consisting of more than
4000 patients with different types of malignancies.
Most patients had an excellent performance status.
Only a few patients with less prevalent malignancies
strongly associated with venous thrombotic events,
such as brain tumors, were included. One has to be
careful in generalizing the results to patients with a
poor performance status and patients with these less
prevalent malignancies, as other predictive models
may more closely fit those cases.

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

40 VTE vs. n=2131 control subjects


• CA patients = 7x OR for VTE vs. non-CA
patients
30 28
22.2
20.3 19.8
20
14.3

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

Type of cancer Time since cancer diagnosis


Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
VTE is a major cause of morbidity and mortality in patients with cancer.
Hence, it is essential that oncologists and other health providers are
able to diagnose DVT and PE accurately and administer effective
treatment for these common vascular complications

Falanga et all 2008


Cancer patients with venous thrombosis
are more likely to develop recurrent
thromboembolic complications and These risks correlate
major bleeding during anticoagulant with the extent of
treatment than those without cancer.
malignancy.
The clinical presentation
of acute VTE is different
The most common and often more extensive
situations that increase in cancer patients than in
the thromboembolic risk patients free from
in cancer patients malignancy. Moreover,
include immobilization, the management of the
surgery, chemotherapy acute phase of VTE is
with or without adjuvant more problematic in
hormone therapy, and cancer patients,
the insertion of central
especially because of a
venous catheters
higher rate of major
bleeding and the need for
implantation of inferior
vena cava filters.
Imberti et al 2008
During anticoagulant therapy, Possibilities for improvement
cancer patients have a 2- to 4- using the current paradigms of
fold higher risk of recurrent anticoagulation seem limited
VTE and major bleeding and new treatment strategies
complications when compared should be developed.
with non cancer patients
The long-term administration of LMWH should be considered as an
alternative to anti-vitamin K drugs in patients with advanced
disease and in those with conditions limiting the use of oral
anticoagulants.

Prolongation of anticoagulation should be considered for as long


as the malignant disorder is active.

The evidence of lowered cancer mortality in patients on LMWH


has stimulated renewed interest in these agents as
antineoplastic drugs and raises the distinct possibility that
cancer and thrombosis share common mechanisms.
Thromboprophylaxis may prevent the occurrence of venous thrombosis,
an important cause of morbidity and mortality among patients with cancer,
especially those on active antitumor therapy. Identifying cancer patients at
high risk for thrombosis who might benefit from prophylaxis is still a
major challenge.
The only well-defined high-risk group for which thromboprophylaxis
appears to be effective and relatively safe is surgical patients, although
prophylaxis is also recommended for acutely ill medical patients.
However, a high-risk group of outpatients with cancer remains to be
determined, and is a necessary piece of information to obtain before the
appropriateness of thromboprophylaxis can be assessed.
Doggen 2008
Interface of Biology and Cancer
Tumor cells

Angiogenesis, Fibrinolytic activities: Procoagulant Activities


Basement matrix t-PA, u-PA, u-PAR,
degradation. PAI-1, PAI-2

IL-1, Activation of
TNF-α, coagulation
VEGF

PMN leukocyte FIBRIN

Platelets

Monocyte Endothelial cells

Falanga and Rickles, New Oncology:Thrombosis, 2005