Thromboembolic complications in IBD

1. Thromboembolic complications in IBD Athos Bousvaros MD, MPH Associate Director, IBD Center

2. With gratitude Naamah Zitomersky Cameron Trenor Menno Verhave Thrombosis and IBD: A call for improved awareness and prevention. IBD Journal 2011 17:458

3. Overview • Pathophysiology • Risks of venous thromboembolism • Relative • Absolute • Risk factors • Workup of thromboembolic event • Prophylaxis • Treatment

4. Arterial vs. venous thromboembolism • Arterial • Clot in an artery (carotid, coronary, SMA) • Rare in younger patients (under 40 years) • Preventable with antiplatelet drugs (ASA) • Venous • Clot in venous system • Deep venous thrombosis (usually in leg or arm) • Preventable with anticoagulation (heparin, coumadin)

5. Coagulation cascade PROTEIN S PROTEIN C ANTI- THROMBIN www.ecc-book.com

6. www.ecc-book.com

7. Risk factors in the general population • Hereditary thrombophilias • Factor V Leiden mutation • 5% of Caucasians, 2% Hispanics, 1% African Americans • Prothrombin gene mutation (G20210A) • 2% of Caucasians • Protein C, Protein S, Antithrombin 3 deficiencies • Environmental causes • Smoking, oral contraceptives • Surgery, immobility

8. Why are IBD patients especially at risk? • Inflammation and disease activity • Increased fibrinogen • Increased D-dimer • Increased factors V, VIII, IX • Prothrombotic antibodies (antiphospholipid) • Endothelial damage • Increased homocysteine • Prothrombotic medications • thalidomide

9. No Risk Factor Inflammationis the Most Common Risk Factor; DVT without a Risk Factor is Rare in Children (n=82) Infl Lupus Anticoag Infec CVL NEJM 2004;351:1081-8.

10. Venous thromboembolism (VTE) in inflammatory bowel disease • Relative risk is high • Six fold greater hazard ratio in < 20 years old* • Mainly in patients with flares** • Absolute risk is low • 2811 IBD patients recruited over 2.5 yrs*** • 116 (4%) of patients developed de novo VTE • Mean age 42 years • Risk of recurrence high if anticoagulation stopped *Kappelman et al; Gut 2011 Nylund et al; JPGN 2013 ** Grainge et al, Lancet 2010 *** Novacek, Gastro 2010

11. What complications occur with increased frequency in adults? • Meta analysis of over 200,000 patients – increased risk of venous, but not arterial events. • Deep venous thrombosis RR 2.4 • Pulmonary embolism RR 2.5 • Ischemic heart disease RR 1.3 • Mesenteric ischemia RR 3.4 Fumery et al, J. Crohn’s Colitis 2013

12. IBD Clot rates – Boston Children’s *3.82 symptomatic events per 1000 catheter days Zitomersky et al, JPGN 2013; 57:343-7

13. A major source of morbidity IVC clot needing filter in severe UC

14. Is heparin prophylaxis indicated? • Not in outpatients, unless another reason • “Prophylaxis would be needed for 312 person-years of IBD flares to prevent one person developing venous thromboembolism” – G. Nguyen, Lancet • Yes in inpatients • Included in AGA physician performance measure set, but only 35% of gastroenterologists use it.* • “…heparin has an important role in prophylaxis against thromboembolism in patients admitted to hospital with severe colitis” – Kornbluth and Sachar, ACG Guideline 2010 *Tinsley, J. ClinGastroenterol 2013

15. Prophylactic Anticoagulation for High Risk Colitis patients • Continue anticoagulation until either: • Discharge • Resolution of colitis, or • Baseline mobility, if post-op No personal or strong family history of bleeding Pre-pubertal or < 40kg Enoxaparin 0.5 mg/kg BID Post-pubertal or > 40kg Enoxaparin 40 mg daily

16. The “ouch” factor

17. Colitis: New diagnosis or Admission • Review family history for thrombosis AND bleeding • Address dehydration • Address immobility (PT consultation, plan for ambulation) • Alternatives to combined oral contraception • Counsel about smoking, inactivity, long travel • Consider • factor VIII • D-dimer • lupus anticoagulant • anti-cardiolipin and anti-2 glycoprotein 1 antibodies

18. Proposed High Risk Definition Personal history thrombosis, 1st degree family history, Known thrombophilia,# OCPs, Smoking > 1ppd, BMI > 35 OR PICC/Broviac/Port-a-Cath (especially if ASD) thalidomide High Risk Inpatient colitis OR Major surgery *awareness if elevated factor VIII, D-dimer, isolated APLA #Known thrombophilia = factor V Leiden, prothrombin gene mutation, low protein C/S or antithrombin function, persistent APLA >40 for >12 weeks

19. Evaluation of DVT • High index of suspicion • Headache, vomiting • Extremity swelling • Labs • D-dimer excellent negative predictive value • Imaging • Ultrasound of extremity and femoral veins • MR or MR venography preferred for CNS • Spiral CT for pulmonary embolism • Cardiac echocardiogram for patent foramen

20. Therapy of clots (adult and pediatric) • Unfractionated heparin • 75 U/kg bolus • 18 U/kg/hour • Goal anti-Xa level, 0.3-0.5 U/ml • Low molecular weight heparin (enoxaparin) • 1mg/kg sc bid • Goal anti-Xa level 0.5-1 U/ml • Warfarin for long term management? • Colectomy may be life-saving • Timing of colectomy is tricky

21. Additional therapy • Catheter directed thrombolysis • Inferior vena cava filter • Protect against pulmonary emboli • Surgical thrombectomy • When thrombolysis contraindicated • Is a large clot complicating severe colitis an indication for colectomy? • What is optimal timing for the colectomy? • Control colitis medically, treat clot, then operate

22. Is heparin safe in IBD?Severe bleeding on anticoagulation is rare

23. Conclusions • All patients with IBD are probably at an increased risk of clots during disease flares • Absolute risk is low • The highest risk group appears to be inpatients with severe colitis • Inflammation • Immobility • Prophylaxis with LMWH is indicated in patients hospitalized for severe colitis or post-op • Enoxaparin, 40 mg SQ daily in adults