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Thrombosis In Cancer:
Gerald A Soff MD
Topics To Cover
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1. History of “First” Paraneoplastic Syndrome
2. Pathophysiology and Clinical Relevance
3. Screening For Occult Malignancy: in patient
presenting with unprovoked thrombosis
4. Management
5. Incidental Thrombosis, Clinical Relevance
6. Coincidental Thrombocytopenia
7. Primary Thrombosis Prophylaxis
8. Role of New Direct Oral Anticoagulants
Armand Trousseau
(1801-1867)
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1. First to associate thrombosis and malignancy.
2. First to suggest screening for malignancy in
recurrent or idiopathic thromboembolic disease.
3. First to suggest that the pathophysiology was
not mechanical obstruction, but a change in the
character in the coagulation system itself.
4. First to suggest the association may be integral
to the cancer growth itself.
– Khorana AA. J. Thrombosis & Haemostasis, 2003
January 1, 1867
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“Peter, I am lost, the
phlebitis that has just
appeared tonight leaves
me no doubt about the
nature of my illness.”
He died six months later of
gastric cancer.
2. Pathophysiology and Clinical
Relevance
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20% of cancer patients develop VTE at some point
during their illness.
20% of VTE occurs in cancer patients
– Heit, 2005; Prandoni et al, 2005; Hillen, 2000.
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1 year survival rate for patients with advanced
cancer:
– Presented with VTE: 12%
– Presented without VTE: 36%
– Sorensen H et al. N Engl J Med, 2000
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Thrombosis in cancer a property of aggressive
disease, not simply manifestation of “late stage.”
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Causes of death in 4466 cancer patients
receiving outpatient chemotherapy
Cause of Death
N (%)
All
141 (100)
Progression of cancer
100 (70.9)
Thromboembolism
13 (9.2)
Arterial
8 (5.6)
Venous
5 (3.5)
Infection
13 (9.2)
Respiratory failure
5 (3.5)
Bleeding
2 (1.4)
Aspiration pneumonitis
2 (1.4)
Other
9 (6.4)
Unknown
5 (3.5)
Khorana AA et al. JTH 5: 632–634, 2007.
Risk of Venous Thrombosis per
Type of Malignancy
Adjusted Odds Ratio (95% CI)
No Malignancy
1.00
Lung
22.2 (3.6-136.1)
All Hematological Cancer
28.0 (4.0-199.7)
GI
20.3 (4.9-83.0)
Breast
4.9 (2.3-10.5)
Brain
6.7 (1.0-45.4)
Skin
3.8 (1.1-12.9)
ENT
1.6 (0.4-6.4)
Blom JW, et al. JAMA 2005;293(6):715-722.
Virchow’s Triad:
Pathophysiology Of Thrombosis
Altered blood
vessel wall
Cancer
Altered blood
flow/venous stasis
Increase in blood
coagulability
Coagulation And Vascular Factors
Contribute to Cancer Associated Thrombosis
 1. Tissue Factor:
– Tumor cells directly produce and release Tissue Factor.
– Tissue Factor circulates in microparticles and may result
in systemic thrombotic risk.
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2. Platelets:
– Early literature suggested role of platelets
adhesion/metastasis of malignant cells.
– Elevated platelet count increases thrombosis rates in
cancer.
• Khorana AA & Connolly GC. JCO. 27:4839-4847,
2009.
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3. Endothelial cell damage.
– Following endothelial cell damage, blood is exposed to a
thrombogenic surface.
– Antiangiogenic agents target endothelial cells.
TF Expression In Pancreatic
Neoplasia and Thrombosis Rates
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Low TF expression, VTE Rate: 4.5%
High TF expression, VTE Rate: 26.3%
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4-fold Risk Ratio, (P = 0.04).
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– (Khorana AA. Clin. Canc. Res. 13, 2870-2875, 2007.)
TF Expression Predicts Poor Survival In
Resected Pancreatic Cancer Patients.
All cancer patients
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With Lymph node
involvement
Few deaths related to VTE.
Poor prognosis associated with increased TF
expression is largely independent of thrombosis.
– Nitori N. et al. Clin. Canc. Res. 11, 2531-2539, 2005
Systemic Effects of Tissue Factor?
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Why do patients experience thrombosis at sites
distant from the underlying cancer?
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If Tissue Factor is cell-surface associated, how does
it influence cancer growth at distant sites?
Tissue Factor Circulates in CellDerived Microparticles.
Boulanger et al. Hypertension, 2006
Hugel et al, Physiology 20: 22-27, 2005
3. Screening For Occult Malignancy: in
patient presenting with unprovoked
thrombosis
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Likelihood of finding an occult malignancy
is much greater after an unprovoked VTE
than a secondary VTE.
Study
Meta-Analysis
of 7 Studies
(1986-1998)
Idiopathic
Thrombosis
50/668
(7.5%)
Secondary
Thrombosis
19/1100
(1.7%)
Odds Ratio
4.3
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Idiopathic thrombosis: 7.5% - 10% diagnosed
with cancer within 1-2 years.
40-60% of patients already have metastatic disease
when their cancer becomes clinically evident,
Likelihood of finding early, curable cancers that
present with thromboembolic disease when cancer
is only detectable by aggressive work-up is small.
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Recommend appropriate routine cancer
screening for age & sex, i.e. colonoscopy,
prostate exam, mammography, pap and
pelvic exam, etc.
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Follow-up/work-up indicated only if initial History,
physical and routine labs suggest specific site.
4. Management of
Thrombosis In Cancer
Patients
Difficulty Using Warfarin For
Anticoagulation in Cancer Patients
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Unpredictable levels of anticoagulation
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Drug interactions
Malnutrition/anorexia
Vomiting
Liver dysfunction.
Need for interruption of therapy
– Invasive procedures
– Chemotherapy-induced thrombocytopenia
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Higher thrombosis recurrence rate with
warfarin in cancer patients.
– Prandoni et al Blood 100:3484-3488, 2002
The CLOT Study
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Patients with cancer and DVT &/or PE.
LMWH, (Dalteparin) compared with warfarin
(vitamin K antagonist).
All got LMWH (Dalteparin 200 IU/kg, SQ, daily
for 5-7 days, then randomized to:
– 6 months of Warfarin (INR target 2.5) or
– 6 months of LMWH:
• 200 IU/kg, SQ, daily for 1 month, then 150 IU/kg for 5
months.
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Lee et al. NEJM 349:146-53, 2003
Dalteparin Resulted in Approximately 50%
Reduction in Thrombosis Recurrences
Lee, A. et al. N Engl J Med 2003;349:146-153
CLOT Study: Death From All Causes
• While VTE complications were reduced by effective anticoagulation
with LMWH this was not associated with improved survival.
• No evidence of an anti-tumor effect.
• Lee, A. Y.Y. et al. N Engl J Med 2003;349:146-153
5. Incidental Thrombosis/
Pulmonary Embolism
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Clinical relevance?
Risks of recurrence, need for anticoagulation?
Retrospective cohort study (2004-2010)
Incidental Pulmonary Embolism (n=51)
Symptomatic Pulmonary Embolism (n=144)
Observed for 1 year
– Den Exter P L et al. JCO 29:2405-2409, 2011.
Cumulative Recurrent VTE
den Exter P L et al. JCO 2011;29:2405-2409
Cumulative Overall Survival
den Exter P L et al. JCO 2011;29:2405-2409
VTE Recurrence (12 Months), By
Initial PE Anatomy
Deng et al, ASH Abstract, 2012 (From MSKCC)
Monthly Death Rate After Cancer
Associated PE
Deng et al, ASH Abstract, 2012 (From MSKCC)
6. Coincidental Thrombocytopenia
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In general population, when thrombocytopenia
develops in patient on heparin or LMWH:
– Stop heparin
– Send test for Heparin-Dependent Antiplatelet Antibody
– Initiate alternative anticoagulant until diagnosis confirmed or
ruled out.
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However, in cancer patients on chemotherapy,
thrombocytopenia is the norm.
Likelihood of HITT a function of timing of
chemotherapy nadir, and duration of heparin
therapy. (Peak time for HITT is 5-15 days after
initial exposure to heparin).
Suggested Dose Reduction of
Therapeutic Anticoagulation For VTE
In Setting Of Thrombocytopenia:
MKCC Guidelines.
Platelet Count (Not bleeding,
and not-dependent on platelet
transfusions)
Enoxaparin
>50,000/ul
Full-dose (1 mg/kg, q 12 hours),
but with close monitoring
Reduced-Dose Enoxaparin
(30-40 mg SQ bid)
25,000-50,000/ul
< 25,000/ul
Hold anticoagulation
7. Primary Thrombosis Prophylaxis
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Is there a role for thrombosis prophylaxis in
outpatient, ambulatory cancer patients prior to
development of a thrombosis.
The hope has been that anticoagulation may exert
a direct antitumor effect as well as prophylaxis
against thrombosis.
No clinical study has shown a direct anticancer
effect.
7. Primary Thrombosis
Prophylaxis (II)
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While increased thrombosis rates are clear, the
absolute rate reduction with primary
anticoagulation is not great enough to justify the
cost and inconvenience.
It is rare that cancer patients with thrombosis die
from the event or develop significant morbidity.
Therefore, one would need to justify a high
number to treat with prophylactic anticoagulation,
to avoid each patient with symptomatic thrombosis
or death.
SAVE-ONCO
Thrombosis
Semuloparin
N=1,608
placebo
N= 1,604
Hazard Ratio
20 (1.2%)
55 (3.4%)
0.36
p<0.0001
(95% CI: 0.21–0.60)
Major
Bleeding
19 (1.2%)
clinically
relevant
bleeding
2.8%
18 (1.1%)
1.05
(95%CI 0.55 to 1.99)
2.0%
HR=1.40
(95%CI 0.89–2.21).
59% risk reduction in PE rate (odds ratio 0.41, 95%CI 0.19–0.85).
8. Role of New Direct Oral
Anticoagulants:
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Should we use the new oral anticoagulants for VTE
treatment in cancer?
Dabigatran (Pradaxa): Direct Thrombin Inhibitor
Rivaroxaban (Xarelto): FXa inhibitor
Apixaban: FXa inhibitor
All 3 approved for non-valvular atrial fibrillation,
Only rivaroxaban approved for DVT/PE
treatment.
New Oral Anticoagulants In
Cancer Patients
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Studies of the new agents did not have adequate
cancer population for subgroup analysis.
VTE treatment studies used warfarin as the
control arm, but warfarin has already been shown
to be unsafe and ineffective for DVT treatment in
cancer patients.
– Warfarin is not the standard of care in cancer.
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No reversal agent,
No established assay to monitor dose/effect
Specific studies will need to be conducted in cancer
patients, with LMWH control.
New Oral Anticoagulants (II)
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LMWH > warfarin
NOAC ~ warfarin,
Therefore cannot conclude NOAC ~LMWH
Questions To Answer
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Does anticoagulation reduce primary or metastatic
tumor growth?
Is there a survival benefit from anticoagulation,
separate from thrombosis prophylaxis?
Is there a role for anti-platelet agents?
In cancer setting, what is optimal anticoagulation
therapy for indications besides venous thrombosis?
(i.e. mechanical valves, atrial fibrillation)?
Will the new oral anticoagulants be proven to be
equivalent to LMWH?