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 :458

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

4. 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)

5. Coagulation cascade PROTEIN S PROTEIN C ANTI- THROMBIN

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. 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: 9

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
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
CHB*
3.8% (4/104)
*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. Clin Gastroenterol 2013

15. 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

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
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

19. 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

20. Therapy of clots (adult and pediatric)
Unfractionated heparin
75 U/kg bolus
18 U/kg/hour
Goal anti-Xa level, U/ml
Low molecular weight heparin (enoxaparin)
1mg/kg sc bid
Goal anti-Xa level 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
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)

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