Thrombosis and cancerThrombosis and cancer

Dr Galila ZaherDr Galila ZaherConsultant Hematologist Consultant Hematologist

MRCPath MRCPath Oct 2003Oct 2003

Venous thrombosis and cancer are two Venous thrombosis and cancer are two way clinical association. way clinical association.

Pathgenisis of thrombosis is Pathgenisis of thrombosis is different .different .

The frequency is greater.The frequency is greater. The management required is more The management required is more

complex.complex.

PathogenesisPathogenesis Tumor cells express pro-coagulant TF.Tumor cells express pro-coagulant TF. TF :receptor &cofactor for FVIIa.TF :receptor &cofactor for FVIIa. TF expressed in pancreatic adeno-carcemona.TF expressed in pancreatic adeno-carcemona. TF: correlates with the degree of differentiation .TF: correlates with the degree of differentiation . TF: associated with switch in angiogenic balance TF: associated with switch in angiogenic balance

& up regulation of vascular endothelial growth & up regulation of vascular endothelial growth factor .factor .

TF-VII up-regulates palsminogen activator TF-VII up-regulates palsminogen activator receptor promoting tumor cell invasion. receptor promoting tumor cell invasion.

FXa :over expression of the angiogenesis.FXa :over expression of the angiogenesis. Thrombin binding to its receptors upregulates TF Thrombin binding to its receptors upregulates TF

expression. expression.

VTE and occult cancerVTE and occult cancer

Idiopathic VTE have an increased Idiopathic VTE have an increased incidence of subsequently developed incidence of subsequently developed cancer .cancer .

The standardized incidence ratio for The standardized incidence ratio for cancer in patients with VTE is 4.4.cancer in patients with VTE is 4.4.

The SIRs are highest in the first 6m & drop The SIRs are highest in the first 6m & drop to 1 beyond 12m.to 1 beyond 12m.

The cumulative probability of cancer over The cumulative probability of cancer over 6Y FU in idiopathic VTE is 17% Vs 5% in 6Y FU in idiopathic VTE is 17% Vs 5% in secondary VTE. secondary VTE.

Extensive Investigations for Extensive Investigations for underlying cancerunderlying cancer

The potential benefit of screening must be The potential benefit of screening must be weighed against potential harms.weighed against potential harms.

Procedure related morbidity.Procedure related morbidity. The psychological burden of false positive test.The psychological burden of false positive test. The cost of screening.The cost of screening. Small randomized trail :no statistically Small randomized trail :no statistically

significant difference in cancer related significant difference in cancer related mortality .mortality .

It is premature to recommend extensive It is premature to recommend extensive screening in patients who present with screening in patients who present with idiopathic VTE.idiopathic VTE.

Prevention of thrombosis Prevention of thrombosis Surgical prophylaxis: meta-analysis of Surgical prophylaxis: meta-analysis of

trials comparing LMWH &UFH in high –risk trials comparing LMWH &UFH in high –risk surgery included cancer patients :surgery included cancer patients :

Evidence that once daily LMWH is as safe Evidence that once daily LMWH is as safe &effective as UFH.&effective as UFH.

Incidence of venographic DVT can be Incidence of venographic DVT can be reduced with extended out of hospital reduced with extended out of hospital prophylaxis.prophylaxis.

Extended prophylaxis in cancer surgery Extended prophylaxis in cancer surgery there is a significant reduction in DVT from there is a significant reduction in DVT from 12% with placebo Vs 4% with extended 12% with placebo Vs 4% with extended prophylaxis .”Enoxacan II”prophylaxis .”Enoxacan II”

Prevention of thrombosisPrevention of thrombosis

Medical cancer patients:Medical cancer patients: Fewer data are available on prophylaxis Fewer data are available on prophylaxis

in ambulatory cancer patients.in ambulatory cancer patients. PMH of VTE with breast PMH of VTE with breast

cancer ,aromatase inhibitor has much cancer ,aromatase inhibitor has much lower risk of thrombosis than tamoxifen lower risk of thrombosis than tamoxifen . .

Low dose warfarin for the prevention of Low dose warfarin for the prevention of thrombo-embolism in cancer patients. thrombo-embolism in cancer patients. ” Levine” ” Levine”

Prevention of thrombosisPrevention of thrombosis

Central vein catheter thrombosis:Central vein catheter thrombosis:Small trials Low dose warfarin or Small trials Low dose warfarin or

LMWH :LMWH :

demonstrated significant reduction in demonstrated significant reduction in catheter thrombosis.catheter thrombosis.

Randomized trials :no difference .Randomized trials :no difference .Routine prophylaxis is not practiced . Routine prophylaxis is not practiced .

Treatment of VTETreatment of VTE

Difficult :Difficult : Increased risk of recurrence(27%/y Vs Increased risk of recurrence(27%/y Vs

9) .9) . Increased anticoagulant induced Increased anticoagulant induced

bleeding x6.bleeding x6.Both occur predominantly during the Both occur predominantly during the

first month of anticoagulationfirst month of anticoagulation Increased mortality compared to Increased mortality compared to

cancer without VTE. cancer without VTE.

Initial Treatment of DVTInitial Treatment of DVT Meta-analysis:LMWH is as safe & more effective Meta-analysis:LMWH is as safe & more effective

than UFH .than UFH . 20% were cancer patients.20% were cancer patients. it is reasonable to generalize the resuls to cancer it is reasonable to generalize the resuls to cancer

patients.patients. LMWH :SC ,no need for monitoring LMWH :SC ,no need for monitoring improve the improve the

quality of life.quality of life. Home treatment :comparable.Home treatment :comparable. LMWH at home in cancer patient is LMWH at home in cancer patient is

recommended recommended positive impact on the quality of positive impact on the quality of life.life.

Compliance ,reliability &good support system.Compliance ,reliability &good support system.

Initial Treatment of PEInitial Treatment of PE

Few trials comparing LMWH&UFH.Few trials comparing LMWH&UFH.

Case PresentationCase Presentation

24 Dec: 199824 Dec: 199846 Years old Egyptian patient46 Years old Egyptian patientE.R. admission.E.R. admission.Bilateral leg pain.Bilateral leg pain.Red discoloration.Red discoloration.

Risk factorRisk factor No surgery, No immobilizationNo surgery, No immobilization

No bedridden, No trauma. No bedridden, No trauma. FH : diabetics mother.FH : diabetics mother. HT: On Renetic- Adalat .HT: On Renetic- Adalat . No symptoms of PE.No symptoms of PE. Non-smoker TeacherNon-smoker Teacher

Upon ExaminationUpon Examination

Leg Swollen.Leg Swollen. Lf : 45cm Rt : 38 cmLf : 45cm Rt : 38 cm Warm tender.Warm tender. Heart rate 70/m RR 20/m BP-145/90Heart rate 70/m RR 20/m BP-145/90

InvestigationsInvestigations

Duplex U/S. Duplex U/S. Sub acute thrombosis involving DVT Sub acute thrombosis involving DVT Superficial Femoral vein – popliteal veinSuperficial Femoral vein – popliteal veinAnterior & post tibial veins.Anterior & post tibial veins.

Management Management

Standard Heparin started 24/12/02 Standard Heparin started 24/12/02 5000 IVI.5000 IVI. 1.5 x APTT control : 26/12.1.5 x APTT control : 26/12. Thrombophilia Screen :26/1201.Thrombophilia Screen :26/1201. LFT , U&E Normal .LFT , U&E Normal . Hepatitis Screen NegativeHepatitis Screen Negative

Follow up Follow up

OAC for 6m.OAC for 6m. Thrombophilia Screen :Thrombophilia Screen :

Unprovoked DVT, Obesity.Unprovoked DVT, Obesity. Off Wanferin x 6 wOff Wanferin x 6 w PC ,PS ,AT,APCR,ACA IgG - IgM :Negative PC ,PS ,AT,APCR,ACA IgG - IgM :Negative

ANA , DNA CRP, Rhd Factor :Neg.ANA , DNA CRP, Rhd Factor :Neg. LA. Screen & Confirmatory + ve LA. Screen & Confirmatory + ve

April 2001April 2001

Abd US : Rt upper pole renal mass. Abd US : Rt upper pole renal mass. CT & biopsy are recommendedCT & biopsy are recommended

Cortical lesion confined to the organCortical lesion confined to the organ Renal cell adeno-carcinoma.Renal cell adeno-carcinoma.

APL SECONARY TO CANCERAPL SECONARY TO CANCER

Lupus type anticoagulant in a patient with Lupus type anticoagulant in a patient with renal cell carcinomarenal cell carcinoma

An autoimmune paraneoplastic syndrome.An autoimmune paraneoplastic syndrome. J Urol 2002 May;167(5):2129 Ather MH, Mithani S, Bhutto S, Adil J Urol 2002 May;167(5):2129 Ather MH, Mithani S, Bhutto S, Adil S.S.

woman with pulmonary embolism and woman with pulmonary embolism and positive lupus anticoagulant before the positive lupus anticoagulant before the diagnosis of renal cell carcinoma.diagnosis of renal cell carcinoma.

J Urol 1994 Sep;152(3):941-2 Papagiannis A, Cooper A, Banks J Urol 1994 Sep;152(3):941-2 Papagiannis A, Cooper A, Banks J.J.

ovarian cancer.ovarian cancer.

APS before ovarian endometrial APS before ovarian endometrial adenocarcinoma. adenocarcinoma.

widespread thromboembolism .widespread thromboembolism . No respond to anticoagulant treatment.No respond to anticoagulant treatment. The paraneoplastic nature is suggested by The paraneoplastic nature is suggested by

the disappearance of both the disappearance of both thromboembolism and APL only after thromboembolism and APL only after surgical removal of the cancer.surgical removal of the cancer.

CLL& Lung cancerCLL& Lung cancer

Autoimmune complications of CLL:Autoimmune complications of CLL:APL (LA,ACA).APL (LA,ACA).Anti-factor VIII inhibitors.Anti-factor VIII inhibitors. Ann Ital Med Int 1999 Jan-Mar;14(1):46-50 Ann Ital Med Int 1999 Jan-Mar;14(1):46-50

The lung cancer may trigger catastrophic APS.The lung cancer may trigger catastrophic APS. Occlusion of the superior mesenteric artery.Occlusion of the superior mesenteric artery. Nippon Geka Gakkai Zasshi 1999 Nippon Geka Gakkai Zasshi 1999

Feb;100(2):228-30Feb;100(2):228-30