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