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THROMBOTIC COMPLICATIONS OF
PANREATIC CANCER: A CLASSICAL
KNOWLEDGE REVISITED
D. L. DUMITRASCU,
O. SUCIU,
C. GRAD,
D. GHEBAN
2ND MEDICAL DEPT.
UMPh IULIU HATIEGANU CLUJ
ROMANIA
Cluj, Romania
Armand Trousseau
(18011867)
Looking for this association and its
consequences for clinical practice
 “In conditions of cachexia, a special
state of the blood occurs which
predispose to spontaneous
coagulation”
 Trousseau
1865
Jaundice
Pancreas CC
Thrombosis of aorta
Pancreatic CC
Thrombosis
Pancreas
longitudinal and transversal section of popliteal vein: recent
thrombosis, complete obstruction of popliteal vein
transversal section of common femural vein at femural bifurcation: recent
thrombosis, complet obstruction (duplex color)
Epidemiology
 Incidence of thrombosis:
 in cancer: 5-60%
 2x higher in cancer pts vs general
population
 20% pts DVT have dg cancer
Clinical types of thrombosis:
 Superficial migratory thrombophlebitis (Trousseau
syndrome)
 Idiopathic deep venous thrombosis
 Nonbacterial thrombotic endocarditis
 Intravascular disseminated coagulation
 Thrombotic microangiopathy (thrombocitary
thrombocytopenic purpura and the hemolitic-uremic
syndrome)
 Arterial thrombosis
Localisation
of cancer
Pathogenesis
Virchow’s triad
 Alterations in blood flow
 Vascular endothelial injury
 Alterations in the constituents of the
blood
 Patients with cancer : hypercoagulable state >>
substances with procoagulant activity: tissue factor,
cancer procoagulant
Pathogenesis
 Hypercoagulability
 Abnormal coagulation tests
 Thrombine generated in excess
 Tumour cells have direct procoagulant
effect
 Tissue factor activate F IX and FX
initiating coagulation
 Tumoral procoagulant: a Ca-dependent
cistein-protease
Pathogenesis
 The factor V Leiden mutation, a
mutation of the F5 gene (gene ID:
2153), causes partial resistance of
this coagulation factor to the
inactivating effects of activated
protein C, a protein encoded by the
PROC gene (gene ID: 5624)
 5% population RR 3-8
Pathogenesis
 The prothrombin 20210A mutation
found to be associated with elevated
prothrombin levels
 2% population, RR 2.0
Pathogenesis
 The endothelial cells may become
procoagulant under the influence of
proinflammatory cytokinases or other
peptides: TNF & IL-1 increase the
expression of adhesion molecules for
leukocytes, PAF and tissue factor
 TNF decreases the endothelial fibrinolytic
activity, increases endothelial production of
IL-1, increases the expression of
thrombomoduline (which diminishes the
activation of anticoagulant proteine C).
Other mechanisms
 Extrinsec compression
 Vascular invasion
Trousseau Syndrome
5%
9%
24%
12%
13%
20%
pancreas
lung
prostate
stomach
ac leukemia
colon
PANCREATIC CARCINOMA and
DVT
 N=202
 Venous THROMBOSIS: 108.3 PER 1000
PATIENT-YEARS (~11%)
 Thrombosis: 58.6-FOLD INCREASE
 CHEMOTHERAPY: 4.8-FOLD
 RADIOTHERAPY: 1.0
 POSTOPERATIVE: 4.5-FOLD
 METASTASIS: 1.9-FOLD
Blom et al Eur. J. Cancer 410, 2006
CANCER IN 1383 CASES OF
PHLEBITIS VENOGRAPHY + Nordstrom et al
BMJ 1994
<6mo >6 mo
 ALL CANCER
66
84
 Oesophagus + stomac: 3
4
 Intestinal
7
10
 Liver
5
3
 Gallbladder
5
1
 PANCREAS
6
2
Sorensen et al NEJM 1998
 15,348 patients with DVT and 11,305 patients with
pulmonary embolism
 1737 cases cancer in the cohort with deep venous
thrombosis, compared with 1372 expected cases
(standardized incidence ratio, 1.3);
 Among the patients with pulmonary embolism,
standardized incidence ratio was 1.3,
 The risk was substantially elevated only during the
first six months of follow-up and declined rapidly
 40% of patients given a diagnosis of cancer within
one year after hospitalization for thromboembolism
had distant metastases at the time of the diagnosis
 Strong associations with cancers: pancreas, ovary,
liver (primary hepatic cancer), brain.
Risk of Venous Thrombosis per Type of
Malignancy for Patients With a Diagnosis of
Malignancy Within 5 Years Before Diagnosis of
Venous Thrombosis
Bloom et al 2005











Type of Malignancy
No. of Patients/No. of Control
Odds Ratio (95% CI)/Adjusted Odds Ratio(95% CI)
No malignancy 1.00 1.00
Men 1279 /1038
Women 1552/ 1024
Malignancy
All hematological cancer 37/ 1 26.2 (3.6-191.4)/ 28.0 (4.0-199.7)
Gastrointestinal malignancies
Bowel 46/ 2 16.8 (4.1-69.1)/ 16.4 (4.2-63.7)
Pancreas 2/ 0 ND ND
Stomach 2 /0 ND ND
Esophagus 2/ 0 ND ND
All gastrointestinal cancer 52/ 2 18.9 (4.6-77.8)/ 20.3 (4.9-83.0)
Risk factors








Advanced age
Caucasians
Comorbidities
History of DVT
Location of cancer
First 6 months after cc dx
Metastasis
Recent surgery, current hospitalization,
chemotherapy, central venous catheters,
sepsis.
Prognosis
 Poorer in pts with cancer (incl.
pancreatic cancer + DVT) vs cancer
(including pancreatic cancer without
DVT
(Alcalay et al J Clin Oncol 2006)
Prophylaxis
 LMWH 5000 iu once a day
(Bergquist et al Br J Surg 1995)
 LMWH superior to heparin
(Mismetti et al Br J Surg 2001)
 Long-term: 4 weeks postop. superior to 1 week
(Rasmussen et al Blood 2003)
Conclusions
 Pts with pancreatic cancer have higher risk
to develop thrombotic events
 This contribute to their morbitiy nd
mortality
 These complications should be actively
searched in order to improve life
expectancy and qol
 Thromboprofilaxis of pts with pancreatic
cancer refered to surgery or having
catheters is very important
QUESTIONS
 Is pancreatic cancer associated with
DVT?
 YES
 NO
Shall we screen pts with DVT
(recurrent) for occult malignancy
including pancreatic cc?
 YES
 NO