1. Obesity and Venous Thromboembolic Disease Angel Galvez MD PhD Oncology Specialists SC Lutheran General Hospital

2. VTE: Epidemiology 5 million DVT’s 900,000 PE’s 290,000 fatalities Heit J. Blood. 2005;106:910.

3. Venous Stasis Small thrombi not washed away Viscosity increased Immobilization Virchow’s Triad Vessel wall damage Accidental trauma Surgical trauma - Hip surgery - Knee surgery - CNS surgery - Cancer Blood Hypercoagulability Increase in fibrinogen activated coagulation factors, platelets Decrease in natural coagulation inhibitors Impaired fibrinolysis Important Factors in Thrombogenesis

4. Examples of medical conditions with increased risk of thrombosis Trauma Malignancies Surgery Congestive heart failure Chemotherapy administration Pregnancy Acquired coagulation abnormalities (APS) Inherited coagulation abnormalities O ral contraceptives N ephrotic syndrome M yeloproliferative disorders P lasma cell dyscrasias I nflammatory bowel disease H eparin induced thrombocytopenia. P NH O besity

5. From: Prevalence of Overweight and Obesity in the United States, 1999-2004 JAMA. 2006;295(13):1549-1555. doi:10.1001/jama.295.13.1549

6. Relative risks of pulmonary embolism and deep venous thrombosis according to age among obese and non-obese patients Age groups Pulmonary embolismDeep venous thrombosis Obese vs non-obese Relative risk(95% CI)Relative risk(95% CI) <40 y5.19(5.11–5.28)5.20(5.15–5.25) 40–49 y1.94(1.91–1.97)2.13(2.11–2.15) 50–59 y1.25(1.23–1.27)1.67(1.65–1.68) 60–69 y1.42(1.40–1.44)1.88(1.87–1.90) 70–79 y2.07(2.04–2.10)1.89(1.87–1.91) >80 y3.15(3.08–3.22)2.16(2.12–2.20) All ages2.18(2.16–2.19)2.50(2.49–2.51) CI = confidence interval. Paul Stein et al. The American Journal of Medicine. September 2005. Volume 118, Issue 9,

7. Mechanism for the observed association between obesity and VTE More body fat (specially abdominal fat) might limit venous return Leptin Levels elevated in obesity Associated with increased ADP induced platelet aggregation It correlates with low tPA and high levels of PAI 1 inhibitor TNF-  and TGF-  produced  in visceral fat Elevated concentrations of PAI 1 inhibitor High Factor VII, Factor VIIIa, Fibrinogen and von Willebrand F. Chronic condition associated to obesity are associated to increase risk of VTE disease Life style factors: decreased physical activity

8. Endothelium Subendothelium Blood flow through a normal blood vessel.

9. Von Willebrand Factor Fibronectin Collagen Vitronectin Laminin Thrombospondin Tissue Factor Primary hemostasis I

10. Serotonin TxA 2 ADP Von Willebrand Factor Fibronectin Collagen Vitronectin Laminin Thrombospondin PGG2, PGH2 Tissue Factor Primary hemostasis II Obesity

11. Von Willebrand Factor Collagen Thrombospondin Tissue Factor Primary hemostasis III

12. Subendothelium FVIIa XaX IXa FVII Thrombin II Platelets F VIIIa F Va Fibrinogen Fibrin IX Tissue Factor Platelets Plasminogen tPA PAI 1 Alpha-2 antiplasmin Natural anticoagulants: Fibrinolysis Obesity

13. Thrombus formation Collagen Tissue Factor Thrombin Platelet activation Prothrombin ADP TXA 2 Plasma Clotting cascade THROMBUS FibrinogenFibrin Platelet aggregation

14. How can we reduce risk of thrombosis in obesity? Weight loss Diet and exercise Thromboprophylaxis

15. Effect of weight loss (by diet and exercise) on hemostatic profile and recurrence of VTE disease Folsom et al (loss of 9.5Kg average) FVII, tPA, PAI-1. No changes in Fibrinogen Marckmann et al (loss of 13.6 Kg average) F VII 12%, Fibrinogen 6%, PAI 1 35% Rissanen et al (loss of 10 Kg average) FVII, PAI 1, No changes in Fibrinogen

16. How can we reduce risk of thrombosis in obesity? Weight loss Diet and exercise Thromboprophylaxis

17. Challenges of chemical thromboprophylaxis in obese patients. High risk (Caprini score of 4 or higher) Different volume of distribution of anticoagulants Morbidly obese patients excluded in most of clinical trials In some cases, there is a need to check PTT, heparin anti Xa or LMWH anti Xa Not enough data on use of novel anticoagulants in morbidly obese patients.

18. Venous thromboembolism prevention in bariatric surgery Risk stratification Mechanical thromboprophylaxis Early ambulation Chemical thromboprophylaxis

19. VTE ThromboprophylaxisVTE treatment Enoxaparin BMI 30-39 Use standard regimen:30 mg/12 hours or 40 mg daily BMI >40 40 mg /12 hours High VTE risk (bariatric surgery with BMI >50 60 mg/12 hours 1 mg/Kg every 12 hours Once daily dose not recommended BMI >40 consider checking anti Xa Dalteparin BMI 30-39 Use standard regimen: 5000 u/day BMI >40 30% increase to 6500 u/day Extended treatment of VTE in cancer patients 200u/Kg/day first month 150u/Kg/day subsequent months

20. Meta-analysis of VTE thromboprophylaxis in obese patients with orthopedic surgery in different novel anticoagulants.

21. Novel anticoagulant use in treatment of VTE disease in morbidly obese patient Although obese patients were not excluded from clinical trials of novel anticoagulants, there is not enough data at this time to support the use of a fix dose of a novel anticoagulant in the treatment of VTE disease in morbidly obese patients.

22. Obesity and Cancer Cancer is a major risk factor for VTE disease Obesity increases the likelihood of suffering cancer Cancer associated to high BMI Endometrial cancer Ovarian cancer Postmenopausal breast cancer Cervical cancer Esophageal cancer Gallbladder cancer Colon cancer Liver cancer Leukemia Thyroid cancer

23. Summary slide Obesity increases risk of venous thromboembolic disease. The increased risk of VTE events in obesity is multifactorial. Weight loss leads to reversal of some of the changes in coagulation parameters seeing in obese patients. Pharmacological thromboprophylaxis in obese patient is effective and safe but might requires adjustment in the dose of the anticoagulant in use. The efficacy and safety of using fix dose anticoagulants in patients with morbidly obese patients is not clearly established and requires further study. Obese patients have a higher risk of suffering certain malignancies that when concurrent with obesity lead to a even much higher risk of suffering VTE events.