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

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

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

Arterial vs. venous thromboembolism 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)

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

www.ecc-book.com

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

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

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

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

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

IBD Clot rates – Boston Children’s All kids IBD kids VTE risk 1/10,000/y ~3x higher VTE in Inpatients 0.58% (58/10,000) 1.5% (8/532) (1.7% incl. arterial) CVL 4.5% @ CHB* 3.8% (4/104) *3.82 symptomatic events per 1000 catheter days Zitomersky et al, JPGN 2013; 57:343-7

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

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. Clin Gastroenterol 2013

Prophylactic Anticoagulation for High Risk Colitis patients 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 Continue anticoagulation until either: Discharge Resolution of colitis, or Baseline mobility, if post-op

The “ouch” factor

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

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 Inpatient colitis OR Major surgery High Risk *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

Evaluation of DVT High index of suspicion Labs Imaging 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

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

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

Is heparin safe in IBD? Severe bleeding on anticoagulation is rare Treatment Prophylaxis All adults 2% 3% All kids 4.3% (trauma) CHB 2.5% (4/162) 4.1% HR (2/49) ??? CHB IBD 11.1% (1/9)

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