1. THROMBOTIC COMPLICATIONS OF PANREATIC CANCER: A CLASSICAL KNOWLEDGE REVISITED D. L. DUMITRASCU, O. SUCIU, C. GRAD, D. GHEBAN 2 ND MEDICAL DEPT. UMPh IULIU HATIEGANU CLUJ ROMANIA

2. Cluj, Romania

3. Armand Trousseau (1801­1867)

4. Looking for this association and its consequences for clinical practice

5.  “In conditions of cachexia, a special state of the blood occurs which predispose to spontaneous coagulation” Trousseau 1865

6. Thrombosis of aorta Jaundice Pancreas CC

7. Pancreatic CC Thrombosis Pancreas

8. longitudinal and transversal section of popliteal vein: recent thrombosis, complete obstruction of popliteal vein

9. transversal section of common femural vein at femural bifurcation: recent thrombosis, complet obstruction (duplex color)

10. Epidemiology  Incidence of thrombosis: in cancer: 5-60%  2x higher in cancer pts vs general population  20% pts DVT have dg cancer

11. 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

12. Localisation of cancer

13. 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

14. 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

15. 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

16. Pathogenesis  The prothrombin 20210A mutation found to be associated with elevated prothrombin levels  2% population, RR 2.0

17.  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

18. Other mechanisms  Extrinsec compression  Vascular invasion

19. Trousseau Syndrome

20. 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

21. CANCER IN 1383 CASES OF PHLEBITIS VENOGRAPHY + Nordstrom et al BMJ 1994 6 mo  ALL CANCER 66 84  Oesophagus + stomac: 3 4  Intestinal 7 10  Liver 5 3  Gallbladder 5 1  PANCREAS 6 2

22. 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.

23. 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)

24. 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.

25. Prognosis  Poorer in pts with cancer (incl. pancreatic cancer + DVT) vs cancer (including pancreatic cancer without DVT (Alcalay et al J Clin Oncol 2006)

26. 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)

27. 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

29. QUESTIONS  Is pancreatic cancer associated with DVT?  YES  NO

30. Shall we screen pts with DVT (recurrent) for occult malignancy including pancreatic cc?  YES  NO