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THROMBOTIC COMPLICATIONS OF PANREATIC CANCER: A CLASSICAL KNOWLEDGE REVISITED
D. L. DUMITRASCU,O. SUCIU, C. GRAD, D. GHEBAN2ND MEDICAL DEPT.UMPh IULIU HATIEGANU CLUJROMANIA
Cluj, RomaniaCluj, Romania
Armand Trousseau (1801 1867)
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
Thrombosis of aorta
Jaundice
Pancreas CC
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
PathogenesisVirchow’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
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).
Pathogenesis
Other mechanisms
Extrinsec compression
Vascular invasion
Trousseau Syndrome
24%
20%13%
12%
9%5%
pancreaslungprostatestomachac leukemiacolon
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 2005Type 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
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