Thromboembolic
complications in IBD
Athos Bousvaros MD, MPH
Associate Director, IBD Center
With gratitude
Naamah Zitomersky
Menno Verhave
Cameron Trenor
Thrombosis and IBD: A call for improved awareness and prevention.
IBD Journal 2011 17:458
Overview
• Pathophysiology
• Risks of venous thromboembolism
– Relative
– Absolute
•
•
•
•
Risk factors
Workup of thromboembolic event
Prophylaxis
Treatment
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)
Coagulation cascade
PROTEIN S
PROTEIN C
ANTITHROMBIN
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
(n=82)
Lupus
anticoag=40%
Central venous
catheter=24%
Lupus
Anticoag
Infl
Acute
infection=13%
Chronic
inflamm=10%
Infec
Other=8%
CVL
Idiopathic=5%
NEJM 2004;351:1081-8.
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
– Pulmonary embolism
– Ischemic heart disease
– Mesenteric ischemia
RR 2.4
RR 2.5
RR 1.3
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)
CVL
4.5% @ CHB*
1.5% (8/532)
(1.7% incl. arterial)
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
Post-pubertal or > 40kg
Enoxaparin 0.5 mg/kg BID
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
Inpatient colitis
OR
Major surgery
Personal history thrombosis,
1st degree family history,
Known thrombophilia,#
OCPs,
Smoking > 1ppd,
BMI > 35
OR
PICC/Broviac/Port-a-Cath
(especially if ASD)
thalidomide
*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
High Risk
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
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
2%
4.3% (trauma)
CHB
2.5% (4/162)
4.1% HR (2/49)
11.1% (1/9)
???
CHB IBD
???
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