Obesity and Venous Thromboembolic

Disease

Angel Galvez MD PhD

Oncology Specialists SC

Lutheran General Hospital

VTE: Epidemiology

5 million DVT’s

900,000 PE’s

290,000 fatalities

Heit J. Blood. 2005;106:910.

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

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

• Oral contraceptives• Nephrotic syndrome• Myeloproliferative disorders• Plasma cell dyscrasias• Inflammatory bowel disease• Heparin induced

thrombocytopenia.• PNH• Obesity

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

Relative risks of pulmonary embolism and deep venous thrombosis according to age among obese and non-obese patients

Age groups

Pulmonary embolism Deep venous thrombosis

Obese vs non-obese Obese vs non-obese

Relative risk (95% CI) Relative risk (95% CI)

<40 y 5.19 (5.11–5.28) 5.20 (5.15–5.25)

40–49 y 1.94 (1.91–1.97) 2.13 (2.11–2.15)

50–59 y 1.25 (1.23–1.27) 1.67 (1.65–1.68)

60–69 y 1.42 (1.40–1.44) 1.88 (1.87–1.90)

70–79 y 2.07 (2.04–2.10) 1.89 (1.87–1.91)

>80 y 3.15 (3.08–3.22) 2.16 (2.12–2.20)

All ages 2.18 (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,

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- a and TGF- b 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

Endothelium

Subendothelium

Blood flow through a normal blood vessel.

Von Willebrand Factor

Fibronectin Collagen

Vitronectin

Laminin

Thrombospondin

Tissue Factor

Primary hemostasis I

Serotonin

TxA2ADP

Von Willebrand Factor

FibronectinCollagen

Vitronectin

Laminin

Thrombospondin

PGG2, PGH2

Tissue Factor

Primary hemostasis II

Obesity

Von Willebrand Factor

Collagen

Thrombospondin

Tissue Factor

Primary hemostasis III

Subendothelium

FVIIa

XaX

IXa

FVII

Thrombin

II

Platelets

F VIIIa

F Va

FibrinogenFibrin

IX

Tissue Factor

Platelets

Plasminogen

tPA

PAI 1

Alpha-2 antiplasmin

Natural anticoagulants: Fibrinolysis

Obesity

Obesity

Thrombus formation

Collagen

TissueFactor

Thrombin

Plateletactivation

Prothrombin

ADP

TXA2

PlasmaClottingcascade

THROMBUS

Fibrinogen Fibrin

Plateletaggregation

• How can we reduce risk of thrombosis in obesity?

• Weight loss• Diet and exercise

• Thromboprophylaxis

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

• How can we reduce risk of thrombosis in obesity?• Weight loss

• Diet and exercise

• Thromboprophylaxis

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.

Venous thromboembolism prevention in bariatric surgery

• Risk stratification• Mechanical thromboprophylaxis• Early ambulation• Chemical thromboprophylaxis

VTE Thromboprophylaxis VTE treatment

Enoxaparin

BMI 30-39 Use standard regimen:30 mg/12 hours or 40 mg dailyBMI >40 40 mg /12 hoursHigh VTE risk (bariatric surgery with BMI >5060 mg/12 hours

1 mg/Kg every 12 hoursOnce daily dose not recommendedBMI >40 consider checking anti Xa

Dalteparin

BMI 30-39 Use standard regimen: 5000 u/dayBMI >40 30% increase to 6500 u/day

Extended treatment of VTE in cancer patients200u/Kg/day first month150u/Kg/day subsequent months

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

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.

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

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.