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Cancer- Associated Thrombosis CAT

Cancer- Associated Thrombosis CAT. Academic Day - Medical Oncology Jan 28, 2011. Armand Trousseau 1801-1867. 1865: Association of Cancer and Thrombosis.

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Cancer- Associated Thrombosis CAT

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  1. Cancer- Associated ThrombosisCAT Academic Day - Medical Oncology Jan 28, 2011

  2. Armand Trousseau 1801-1867 1865: Association of Cancer and Thrombosis

  3. “…struck by thefrequencywith whichcancerous patients are affected withpainful edema of the…extremities…other cases, in which the absence of appreciable tumour made me hesitateas to the nature of adisease of the stomach, mydoubts were removed … I know the disease to becancerous whenphlegmasia alba dolensappeared in the … limb. There appears to be cachexiae…a particular condition of the blood which predisposes tospontaneous coagulation” Armand Trousseau, New Sydenham Society 1865

  4. “J’ai perdu” “I am lost” “The phlebitis that has just appeared tonight leaves me no doubt as to the nature of my illness” Trousseau 1867

  5. Cancer and Venous Thromboembolism A two way street Cancer causes Thrombosis CANCER THROMBOSIS Thrombosis affects the Biology of Cancer

  6. Cancer and VTE - Introduction Major complication in 4-20% of pts  6x risk Leading cause of death Risk increases with Cancer Therapy VTE Prophylaxis and Treatment - Complex Risk of recurrence & bleeding on treatment VTE in Cancer pts  Reduction in Survival

  7. VTE in Cancer Impact and Implications VTE: • May indicate occult Cancer • May complicate known Cancer • May complicate hospitalization, surgery or systemic Rx for Cancer

  8. VTE in Cancer Impact and Implications VTE: • Second leading cause of death • Interrupts/delays needed Ca treatment • Anticoagulant therapy increases bleeding risk • Reduces survival 2-8x likelihood of death • Increases readmission x4 25% for VTE issues • Economic burden: Hospitalization 11 days $20,000 (U.S. figures - 2002)

  9. Cancer and VTE Topics for Discussion • Pathogenesis of Thrombosis • Epidemiology - Tumour type/stage, ChemoRx • Prognosis of Cancer and VTE • Prophylaxis: Surgery/Medical/Central Catheters Thalidomide and Myeloma • Treatment of VTE – Failure of LMWHs

  10. Cancer and VTE Additional Topics • New anticoagulants ?? For Cancer • Cancer Survival and Anticoagulants ? • Treatment of Portal/Splenic Vein Thrombosis • Treatment of Central Venous Catheter clots • Treatment of Tumour Thrombi eg Renal Cell Ca • Malignancy Workup in Idiopathic VTE

  11. Cancer and VTEPathogenesis

  12. Rudolf Virchow 1821-1902

  13. VIRCHOW’S TRIAD STASIS ENDOTHELIAL INJURY DVT HYPERCOAGULABILITY

  14. Virchow’s Triad & Cancer Venous stasis • Prolonged bedrest • Venous compression by tumor or nodes • Venous invasion by tumor Endothelial Injury • Direct invasion/adhesion by tumor • Surgery • Chemotherapy • Radiation • Venous catheters

  15. Virchow’s Triad & Cancer Activation of coagulation Tumour Cell Activities • Procoagulant • Fibrinolytic • Inflammatory Cytokines • Direct cell interactions - Endothelial - Monocytes/Macrophages - Platelets

  16. Cancer and Thrombosis F X TF- FVIIa Prothrombin FVIIa uPAR Fibrinogen TF uPA FXa CP Thrombin TUMOUR CELL VEGF Fibrin Adhesion Mitogen Mitogen TNF IL-1 Monocyte Platelet ↑TF IL- 8 Plt ↑TF ↑PAI Adhesion TC ↑TF ↑TF ↓TM Endothelial cell Rickles, F. Thrombosis Research 2001

  17. Cancer and Thrombosis - Procoagulant F X TF- FVIIa Prothrombin FVIIa uPAR Fibrinogen TF uPA FXa CP Thrombin TUMOUR CELL VEGF Fibrin Adhesion Mitogen Mitogen TNF IL-1 Monocyte Platelet ↑TF IL- 8 Plt ↑TF ↑PAI Adhesion TC ↑TF ↑TF ↓TM Endothelial cell Rickles, F. Thrombosis Research 2001

  18. Procoagulant Activity • Tissue Factor • Transmembrane glycoprotein forms complex with VIIa • Prime activator of Coagulation • Cancer cells express TF constitutively • Major role in VEGF/angiogenesis • Cancer Procoagulant • Cysteine proteinase • Activates factor X directly • Mostly in malignant tissue (Acute Promyelocytic Leukemia)

  19. Cancer and Thrombosis - Fibrinolysis F X TF- FVIIa Prothrombin FVIIa uPAR Fibrinogen TF uPA FXa CP Thrombin TUMOUR CELL VEGF Fibrin Adhesion Mitogen Mitogen TNF IL-1 Monocyte Platelet ↑TF IL- 8 Plt ↑TF ↑PAI Adhesion TC ↑TF ↑TF ↓TM Endothelial cell Rickles, F. Thrombosis Research 2001

  20. Fibrinolytic Properties • Most tumor cells can express proteins necessary for fibrinolysis: u-PA, t-PA and PAI-1, PAI-2 • May also express receptors to activate fibrinolysis • Likely cause of bleeding problems in leukemia • Plasminogen activators/inhibitors may play role in tumor invasion, proliferation, and metastasis

  21. Cancer and Thrombosis - Cytokines F X TF- FVIIa Prothrombin FVIIa uPAR Fibrinogen TF uPA FXa CP Thrombin TUMOUR CELL VEGF Fibrin Adhesion Mitogen Mitogen TNF IL-1 Monocyte Platelet ↑TF IL- 8 Plt ↑TF ↑PAI Adhesion TC ↑TF ↑TF ↓TM Endothelial cell Rickles, F. Thrombosis Research 2001

  22. Cytokine Release Tumours release inflammatory cytokines: • TNF, IL-1acts on vascular endothelial cells  Tissue Factor and  PAI  Thrombomodulin ( Protein C activation) • VEGF (Vascular endothelial growth factor)  Tissue Factor by endothel. cells and monocytes  adhesion molecules expression by endothel. cells - attracts platelets, WBCs, tumour cells

  23. Cancer and Thrombosis – Cell interactions F X TF- FVIIa Prothrombin FVIIa uPAR Fibrinogen TF uPA FXa CP Thrombin TUMOUR CELL VEGF Fibrin Adhesion Mitogen Mitogen TNF IL-1 Monocyte Platelet ↑TF IL- 8 Plt ↑TF ↑PAI Adhesion TC ↑TF ↑TF ↓TM Endothelial cell Rickles, F. Thrombosis Research 2001

  24. Tumor Cell Interactions with Host Cells Endothelial Cells Indirect: via cytokines (TNF, IL-1, VEGF) Direct: Tumour cells have membrane adhesion molecules • These integrins and selectins bind to tumour adhesion molecules receptors on endothelium cells • Initiates local clotting activation & thrombosis • Attracts and activates platelets and WBC’s • Tumor-tumor and tumor-vascular cell adhesion leads to cell migration, cell invasion, angiogenesis

  25. Tumor Cell Interactions with Blood Cells Platelets • Direct Adhesion of platelets to tumor cells and to vascular endothelial cells • Activation by tumor cells in vitro & in vivo • Release of proaggregation factors (ADP, cathepsin)

  26. Tumor Cell Interactions with Blood Cells Monocyte-Macrophage • Tumors may induce expression of Tissue Factoron mononuclear phagocytes directly or via inflammatory mediators • May be mechanism of localized fibrin deposition within tumor tissue

  27. Cancer and VTEEpidemiology

  28. Cancer and VTE – Epidemiology • 4-20%of Cancer patients will have VTE during thecourse of their disease 15% Symptomatic, 50% asymptomatic, 50% autopsy • Cancer has 4-7xrisk ofVTE • Active Cancer accounts for 20%of New VTEs • VTE is second most common cause of death

  29. Cancer and VTE – Epidemiology AnnualIncidence -Small Cohort (Hospital)studies 6-8% - Epidemiological studies (data bases) 1.1-1.2 - Recent Population studies~ 1% Time course of VTE Odds Ratio Highest Incidence first 3 months 54X 3 -12 months 14X 1 - 3 years 4X

  30. Cancer and Risks of VTE • Cancer - related Factors • Treatment - related Factors • Patient - related Factors • Biomarkers

  31. Cancer and Risks of VTE Cancer-related Factors • Tumour type: pancreas, stomach, gynecologic, renal, lung, primary brain, lymphoma, myeloma • Advanced stage • Initial period after diagnosis (3-6 months) • Histology – adeno Ca >> squamous Ca 2-3x

  32. Cancer and Risks of VTE Treatment-related Factors • Major Surgery RR 2x • Hospitalization RR 2.3x • Cancer Therapy Chemotherapy RR 2 - 6x Hormonal therapy RR 1.6x Anti-angiogenesis drugs RR 1.3 - 2.0 x • Erythropoiesis Stimulating agents RR 1.7x • Transfusions RR 1.6x • Central vein catheters ??? 14%~4% recent data

  33. Cancer and Risks of VTE Patient -related Factors • Older age • Female Sex • Race Black > Caucasian > Asian • Comorbidities: Infection, Renal, Pulmonary, Arterial Thrombosis, Anemia, Obesity RR ~1.5-2.5 • Prothrombotic Mutations – FVL, Prothrombin Gene • Prior VTE RR 6x • Performance status- Immobility RR 2-4x

  34. Cancer and Risks of VTE Candidate Biomarkers  Risk Models • Pre-chemo platelets > 350,000 • Pre-chemo WBC > 11,000 • Hb < 100 gm/l • Elevated Tissue Factor – Hi grade expression in Tumour cells, ↑Systemic TF levels • ↑ D-dimer • ↑ Soluble P-selectin (12%) RR 2.6 • ↑ C-reactive protein

  35. Cancer and Risks of VTE Cancer-related Factors • Tumour type: pancreas, stomach, gynecologic, renal, lung, primary brain, lymphoma, myeloma • Advanced stage • Initial period after diagnosis (3-6 months) • Histology – adeno Ca>> squamous Ca 2-3x

  36. Cancer and VTE Cancers most strongly associated with VTE: • Bone 75 per 1,000/yr • Ovary 65 • Brain 64 • Pancreas 45 Cancers most common in patients with VTE: • Breast 26% 371 of 1426 VTE’s • Colorectal 13% 189 • Prostate 12% 168 • Lung 11% 152 Blom J. J Thromb Haemost 2006; 4:529-535

  37. Frequency, Risk Factors and Trends for VTE in Cancer Pts in Hospital Sites with Highest Risk VTE % Odds Ratio p Pancreas 8.1% 2.46 <.0001 Kidney 5.6% 1.71 Ovary 5.6% 1.57 Lung 5.1% 1.31 Stomach 4.9% Brain 4.7% 1.74 Myeloma 5.0% Non Hodg Lymphoma 4.8% Hodg Lymphoma 4.6% Khorana et al Cancer 2007;110:2339-46

  38. Cancer and VTE - Metastatic Disease Metastatic Disease increases VTE risk 4-13X Incidence of VTE / 100 pt-yr Pancreas 20.0 Stomach 10.7 Bladder 7.9 Renal 6.0 Lung 5.0 Chew et al. Arch Int Med. 2006;166: 458-64

  39. Cancer and VTECancer Therapy

  40. Cancer Therapy VTE odds ratio. • Surgery in Cancer pts 2x • Hospitalization 2.3x • Cancer therapy Chemotherapy 6.5x Hormonal therapy 1.6x Anti-angiogenesis agents 1.3x • Support Rx- Erythropoiesis agents 1.7x • Transfusions - RBCs/Platelets 1.6x • Central Venous Catheters 28%  4%??? • Radiation ???

  41. Cancer and VTEThrombosis and Chemotherapy

  42. VTE and Chemotherapy Chemotherapy - independent risk for VTE Pts on Chemotherapy  VTE 11% /yr VTE during Chemo  Early Mortality RR 2X Cancer pts Cancer pts + Chemo VTE risk 4x 6.5x Recurrent VTE 2x 4x

  43. Rate of VTE in Breast Cancer Stage % VTE * Treatment I 0.1 none 1 tamoxifen 4.5 tamoxifen + CTX II 0 -1.6 tamoxifen 1.3 -10 CTX 3.1-9.6 tamoxifen + CTX III/IV 15-17 CTX *Asymptomatic VTE

  44. Prothrombotic Effects of Chemotherapy • Damage to vascular endothelium • Platelet Activation/Aggregation • Increased Procoagulants • Decreased Anticoagulants (AT III, PC, PS) • Tumour and Endothel. cell Apotosis  increase TF • Tumour cell Cytokine Release  increases TF • Monocyte/Macrophage Expression of TF • Decrease Fibrinolysis Haddad T. Thromb Res 2006 118:555-68

  45. VTE and Chemotherapy Chemotherapy and VTE 10-20% / yr Cisplatin 8 - 18% L-asparaginase 4 - 14% Fluoruracil 15 - 17% Thalidomide + Decadron / ChemoRx 20 - 40% Anti-angiogenesis drugs (Avastin) marginal - 30%? Supportive Rx: EPO, G-CSF, Steroids 3 - 60%?

  46. Risk Model - ChemoRx associated VTE Khorana Patient Characteristic Odds Ratio • Cancer site Very high risk - stomach, pancreas 4.3 High Risk - lung, lymphoma, gyn, blad. testic. 1.5 Low Risk - breast, colorectal, Head & Neck 1.0 • Pre-chemo Platelets >350x109/l1.8 • Hgb <100 g/l or ESAs use 2.4 • Prechemo WBC > 11x109/l2.2 • BMI >35 kg/m22.5 Khorana A. Blood 2008; 111:4902

  47. Risk Model - ChemoRx associated VTE Patient Characteristic Risk Score • Cancer site Very high risk - stomach, pancreas 2 High Risk - lung, lymphoma, gyn, blad. Testic. 1 • Pre-chemo Platelets >350x109/l1 • Hgb <100 g/l or ESAs 1 • Prechemo WBC > 11x109/l 1 • BMI >35kg/m21 Khorana A. Blood 2008; 111:4902

  48. Risk Model - ChemoRx associated VTE Results during 4 cycles of ChemoRx Risk group % of pts Risk of VTE Risk Score 0 Low 27% 0.3 % 1-2 Intermediate 60% 2 % ≥ 3 High 13% 7 % Median time – ChemoRx to VTE 2.5 months Khorana A. Blood 2008; 111:4902

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