Venous thrombosis and prothrombotic factors in inflammatory bowel disease

Table 1 Risk of venous thrombosis in inflammatory bowel disease patients relative to non-inflammatory bowel disease patients

Ref.	Design	Population		Risk measure (95%CI)	Controlled variables
		IBD	Controls
Grip et al[6], 2000 Sweden	Retrospective cohort study Inpatients Records from 2 university hospitals	1253 patients	387 (significant age differences between the IBD cohort and controls)	Incidence rate of VTE 1.5/1000 IBD per year (comparable to the background population)
Bernstein et al[8], 2001 Canada	Retrospective cohort study Inpatients Manitoba Health administrative 1984-1997	5529 patients	Approximately 55000 year, age, gender and postal area of residence matched members of the general population	DVT RR 4.7 (3.5-6.3) CD RR 2.8 (2.1-3.7) UC PE RR 2.9 (1.8-4.7) CD RR 3.6 (2.5-5.2) UC
Miehsler et al[9], 2004 Austria	Retrospective cohort study Outpatients and inpatients Three outpatient clinics of Division of Gastroenterology and Hepatology	618 patients	707 age and gender matched controls	Incidence rate of VTE 6.2% IBD 1.6% Controls VTE aOR 3.6 (1.7-7.8) IBD	Operation, injuries, oral contraceptive use, pregnancy, body mass index and smoking
Bernstein et al[20], 2007 Canada	Retrospective cohort study Inpatients The Statistics Canada’s Health Person Oriented Information database 1994-2004	About 22000 to 25000 patients	About 2.5 to 3.2 million age and gender matched controls	VTE ≥ 50 yr old RR 1.3 (1.23-1.37) IBD < 50 yr old RR 1.57 (1.42-1.72) IBD
Huerta et al[10], 2007 United Kingdom	Prospective cohort study with nested case-control analysis Outpatients and inpatients General Practice Research Database - GPRD 1994-2000	6550 patients	10000 age, gender and year matched controls	VTE OR 1.84 (1.29-2.63) IBD
Nguyen et al[12], 2008 United States	Retrospective cohort study Inpatients Nationwide Inpatient Sample 1998-2004	116842 patients (73197 CD and 43645 UC patients)	522703 controls	VTE aOR 1.48 (1.35-1.62) DC aOR 1.85 (1.70-2.01) UC	Age, gender, calendar year, health insurance payer, comorbidity, presence of IBD related surgery, geographic location, and hospital characteristics
Ha et al[148], 2009 United States	Retrospective cohort study Outpatients and inpatients MarketScan Commercial Claims and Encounters database - Thomson Reuters 2001-2006	17487 patients (7480 CD and 9 968 UC patients)	69948 age, gender and index date matched controls	PVT aHR 6.2 (P < 0.05) IBD DVT aHR 2.3 (P < 0.0001) IBD PE aHR 1.7 (P < 0.001) IBD	Hypertension, diabetes, hyperlipidemia, and, in women, the use of contraceptives
Nguyen et al[14], 2009 United States	Retrospective cohort study Pregnant hospitalized women Nationwide Inpatient Sample 2005	3740 patients (2372 CD and 1368 UC patients)	4.21 million pregnant women	VTE aOR 6.12 (2.91-12.9) CD aOR 8.44 (3.71-19.2) UC	Maternal age, race/ethnicity, median neighbourhood income, comorbidity, health insurance, geographical region, hospital location and teaching status and caesarean delivery
Grainge et al[19], 2010 United Kingdom	Retrospective cohort study Outpatients and inpatients General Practice Research Database 1987-2001	13 756 patients (4835 CD and 6765 UC patients)	71672 age, gender, and general practice matched controls	VTE aHR 3.4 (2.7-4.3) IBD	Age, sex, body-mass index, smoking, cancer diagnosis and history of pulmonary embolism or deep vein thrombosis
Novacek et al[16], 2010 Austria	Retrospective cohort study Outpatients IBD patients from 14 Austrian centers specializing in the treatment of patients with IBD (2006-2008) and controls patients from 4 centers in Austria (1992-2008) 2006-2008	86 patients with history of unprovoked VTE	1255 controls with unprovoked VTE	Recurrence 5 yr after discontinuation of anticoagulation therapy aRR 2.5 (1.4-4.2) IBD	Age, gender, factor V Leiden, prothrombin G20210A mutation, high factor VIII (> 234 IU/dL), duration of anticoagulation and body mass index
Scarpa et al[147], 2010 Italy	Prospective case-control study Hospitalized patients who had major colo-rectal surgery Patients admitted for colorectal surgery in the institute of Clinica Chirurgica I of the University of Padova (Italy) 2004-2006	323 patients	432 controls	Incidence rate of VTE in surgical IBD patients vs surgical non IBD patients (both with prophylactic therapy) 1.9% vs 0% VTE with prophylactic therapy OR 5.9 (0.9-39.7) UC
Kappelman et al[13], 2011 Denmark	Retrospective cohort study and nested case-control study Danish National Patient Registry 1980-2007	49799 patients (14211 CD and 35 229 UC patients)	477504 age and gender matched members of the general population	All VTE HR 2.0 (1.8-2.1) IBD HR 2.2 (2.0-2.5) CD HR 1.9 (1.8-2.0) UC Unprovoked VTE HR 1.6 (1.5-1.8) IBD HR 2.0 (1.6-2.5) CD	Comorbidities and medications
Merrill et al[23], 2011 United States	Retrospective cohort study Surgical patients National Surgical Quality Improvement Program 2008	2249 patients	269119 patients without IBD who were hospitalized and underwent surgery	HR 1.5 (1.4-1.7) UC aOR 1.7 (1.3-2.2) IBD VTE aOR 2.03 (1.52-2.70) IBD	Age, gender, race/ethnicity, admitted from home, smoker, BMI > 30, medical history, clinical factor
Rothberg et al[22], 2011 United States	Retrospective cohort study Inpatients 374 US hospitals 2004-2005	814 patients	241924 controls	VTE aOR 3.11 (1.59-6.08) IBD	Age, gender, VTE prophylaxis, length of stay ≥ 6 d, primary diagnosis, comorbidities, cancer and treatments
Saleh et al[11], 2011 United States	Retrospective cohort study Inpatients National Hospital Discharge Survey 1979-2005	2932000 patients (1803000 CD and 1129000 UC patients)	918570000 age, gender matched controls	VTE HR 1.08 (1.06-1.09) CD HR 1.64 (1.62-1.66) UC
Sridhar et al[21], 2011 United States	Cross-sectional study Inpatients Nationwide Inpatient Sample 2010	148229 patients	17261952 controls	VTE (DVT, PE and/or PVT) aOR 1.38 (1.25-1.53) IBD	Hypertension, diabetes mellitus and hyperlipidemia
Bröms et al[15], 2012 Sweden	Retrospective cohort study Pregnant women Medical, Patient, and Prescribed Drug Registers of all residents in Sweden 2006-2009	1996 patients (787 CD and 1209 UC patients) who gave birth to a single infant	10773 women without IBD who gave birth to a single infant	VTE aRR 2.65 (0.65-10.1) CD (with inactive disease) aRR 3.78 (1.52-9.38) UC	Age, parity, smoking, body mass index and comorbidities

IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; VTE: Venous thrombosis; DVT: Deep venous thrombosis; PE: Pulmonary emboli; PVT: Portal vein thrombosis; aRR: Adjusted relative risk; aOR: Adjusted odds ratio; aHR: Adjusted hazard ratio.

Table 2 Prothrombotic risk factors and abnormalities associated with inflammatory bowel disease

Acquired prothrombotic risk factors

Infection or inflammation, previous thromboembolism, age, smoking, malignancy, central venous catheter, surgery, trauma, immobilization, Pregnancy, drugs (oral contraceptives, steroids), antiphospholipid antibody syndrome, hyperhomocysteinemia, fluid depletion

Genetic prothrombotic risk factors

Factor V Leiden, prothrombin mutation, deficiency of protein C, deficiency of protein S, deficiency of antithrombin, PAI-1 mutation, factor XII mutation and MTHFR mutation

Abnormalities of coagulation

↑ TF, factors VII, FXII, FXI, FX and FV, prothrombin and fibrinogen

↓ AT, protein C, protein S, EPCR, TM and TFPI

↑ Prothrombin fragment 1+2, TAT complexes, fibrinopeptide A and fibrinopeptide B

↓ Factor XIII

Abnormalities of fibrinolysis

↓ t-PA

↑ PAI-1 and TAFI

↑ D-dimer

Abnormalities of platelets

↑ Number, activation (CD40L and P-selectin) and aggregation

Abnormalities of endothelium

↓ NO

↑ vWF

PAI-1: Plasminogen activator inhibitor 1; MTHFR: Methylenetetrahydrofolate reductase; TF: Tissue factor; AT: Antithrombin; EPCR: Endothelial cell protein C receptor; TM: Thrombomodulin; TFPI: Tissue factor-pathway inhibitor; TAT: Thrombin-antithrombin; t-PA: Tissue plasminogen activator; TAFI: Thrombin-activatable fibrinolysis inhibitor; CD40L: CD40 ligand; vWF: von Willebrand factor.

Table 3 Controlled studies on the prevalence of inherited thrombophilias in inflammatory bowel disease

Ref.	Compared groups	Results
		Mutation1	CD	UC	IBD	IBD-VTE	HC	C-VTE	Significance
Liebman et al[101], 1998 United States	11 IBD-VTE patients and 51 IBD patients without VTE	Factor V Leiden			4%	36%			Significant difference (OR = 14.00, 95%CI: 1.55-169.25)
Over et al[107], 1998 Turkey	63 IBD patients (20 CD and 43 UC patients) and 36 HC	Factor V Leiden	50%	20%			11%		Significant difference for CD vs HC (OR = 6.5, 95%CI: 1.3-18.0)
Haslam et al[112], 1999 United Kingdom	54 IBD patients (30 CD and 24 UC patients) and 55 HC	Factor V Leiden			9.3%		3.6%		Difference not significant
Heliö et al[111], 1999 Finland	563 IBD patients (235 CD and 328 UC patients) and 142 HC	Factor V Leiden	3.4%	5.2%	4.5%		2.1%		Differences not significant
		Factor XIII mutation	5.0%	6.1%	5.7%		3.3%		Differences not significant
Grip et al[6], 2000 Sweden	16 IBD-VTE patients, 99 C-VTE and 288 HC	Factor V Leiden				27%	11%	28%	Significant difference for IBD-VTE vs HC (OR = 3.0, 95%CI: 0.8-11.9)
		Prothrombin mutation				0%	1.8%	7.10%	Differences not significant
Koutroubakis et al[61], 2000 Greece	84 IBD patients (36 CD and 48 UC patients) and 61 HC	Factor V Leiden			8.3%		4.9%		Difference not significant
Papa et al[113], 2000 Italy	52 IBD patients (19 CD and 33 UC patients) and 156 HC	Factor V Leiden			1.9%		1.9%		Difference not significant
		Prothrombin mutation			1.9%		2.6%		Difference not significant
Vecchi et al[110], 2000 Italy	102 IBD (51 CD and 51 UC patients) and 204 HC	Factor V Leiden			1.5%		1.2%		Difference not significant
		Prothrombin mutation			1.1%		0.7%		Difference not significant
		MTHFR mutation			41.1%		47.4%		Difference not significant
Guédon et al[102], 2001 France	15 IBD-VTE, 58 IBD patients without VTE, 110 C- VTE and 84 HC	Factor V Leiden			0%	14.3%	3.6%	15.50%	Significant difference for IBD-VTE vs IBD (P < 0.05)
		Prothrombin mutation			1.7%	14.3%	3.6%	11.80%	Differences not significant
		MTHFR mutation			0%	0%	1.2%	0.90%	Differences not significant
Mózsik et al[106], 2001 Hungary	84 IBD patients (49 CD and 35 UC patients) and 57 HC	Factor V Leiden	14.3%	27.5%			5.3%		Significant difference for CD and UC vs HC (P < 0.05)
Nagy et al[108], 2001 Hungary	78 IBD patients (49 CD and 29 UC patients) and 57 HC	Factor V Leiden	14.3%	27.6%			5.3%		Significant difference for CD and UC vs HC (P < 0.05)
Turri et al[103], 2001 Italy	18 IBD patients with arterial or venous thrombosis, 45 IBD patients without thromboembolic events and 100 HC	Factor V Leiden			2.2%	0%	5%		Differences not significant
		Prothrombin mutation			0%	0%	2%		Differences not significant
Bjerregaard et al[120], 2002 Denmark	106 IBD patients and 4188 HC	Factor V Leiden			5.7%		6.7%		Difference not significant
		Prothrombin mutation							Difference not significant
Magro et al[119], 2003 Portugal	116 IBD patients (74 CD and 42 UC) and 141 healthy controls	Factor V Leiden	7%	2%			1%		Differences not significant
		G20210A Prothrombin	4%	0%			3%		Differences not significant
		MTHFR mutation	14%	12%			10%		Differences not significant
		PAI-1 mutation	11%	14%			24%		Differences not significant
Saibeni et al[121], 2003 Italy	152 IBD patients (62 CD and 90 UC patients) and 130 HC	Factor XIII mutation			5.3%		5.4%		Difference not significant
Törüner et al[118], 2004 Turkey	62 IBD patients (28 CD and 32 UC patients) and 80 HC	Factor V Leiden			3.2%		6.3%		Difference not significant
		Prothrombin mutation			0%		2.5%		Difference not significant
		MTHFR mutation			11.3%		6.3%		Difference not significant
Mahmood et al[117], 2005 United Kingdom	68 IBD patients (31 CD and 37 UC patients) and 30 HC	Factor V Leiden	0%	1.5%	1.5%		0%		Differences not significant
		Prothrombin mutation	0%	1.5%	1.5%		0%		Differences not significant
Oldenburg et al[98], 2005 Netherlands	22 IBD-VTE patients and 23 IBD patients without VTE	Factor V Leiden			0%	20%			Difference not significant
		Prothrombin mutation			8.7%	4.5%			Difference not significant
Spina et al[105], 2005 Italy	47 IBD-VTE patients and 94 C-VTE	Factor V Leiden				2.1%		13.8%	Significant difference for C-VTE vs IBD-VTE (P < 0.05)
		Prothrombin mutation				8.5%		12.8%	Difference not significant
Yilmaz et al[116], 2006 Turkey	27 IBD patients and 27 HC	Factor V Leiden			6.7%		5%		Difference not significant
		Prothrombin mutation			3.3%		6.7%		Difference not significant
		Factor XIII mutation			5%		0%		Difference not significant
		MTHFR mutation			3.3%		0%		Difference not significant
		PAI-1 mutation			11.7%		8.3%		Difference not significant
Bernstein et al[109], 2007 Canada	492 IBD patients (327 CD and 165 UC) and 412 HC	Factor V Leiden	6.4%	4.2%			6.1%		Differences not significant
		Prothrombin mutation	1.8%	1.2%			1.2%		Differences not significant
		Factor XIII mutation	8.7%	7.1%			4.3%		Significant difference for CD vs HC (P < 0.05)
		MTHFR mutation	12.5%	9.9%			11.7%		Differences not significant
Koutroubakis et al[104], 2007 Greece	30 IBD patients with vascular complications, 60 IBD patients without vascular complications, 30 controls with vascular complications and 54 HC	Factor V Leiden			6.7%	20.0%	3.7%	16.7%	Significant difference for IBD-VTE vs HC (P < 0.05)
		Prothrombin mutation			5.0%	10.0%	1.9%	13.3%	Differences not significant
		Factor XIII mutation			3.3%	0%	1.90%	0%	Differences not significant
		MTHFR mutation			11.6%	6.6%	7.5%	13.3%	Differences not significant
		PAI-1 mutation			20%		13.0%		Significant difference for IBD-VTE vs HC (P < 0.05)
Yasa et al[115], 2007 Turkey	27 IBD patients and 47 HC	Factor V Leiden			11.1%	43.3%	4.3%	36.7%	Difference not significant
		Prothrombin mutation			7.4%		0%		Difference not significant
		MTHFR mutation			14.9%		6.3%		Difference not significant
Maher et al[114], 2010 Saudi Arabia	26 IBD patients (7 CD and 19 UC patients) and 40 HC	Factor V Leiden			3.8%		2.5%		Difference not significant
Novacek et al[16], 2010 Austria	102 IBD patients (77 CD and 25 UC) and 102 HC	Factor V Leiden			16.1%		26.1%		Difference not significant
		Prothrombin mutation			1.7%		6%		Difference not significant

VTE: Venous thrombosis; CD: Crohn’s disease; UC: Ulcerative colitis; IBD: Inflammatory bowel disease; IBD-VTE: Inflammatory bowel disease with venous thrombosis; HC: Healthy controls; C-VTE: Controls with venous thrombosis; OR: Odds ratio.

¹Presented prevalence data refer to heterozygous and homozygous carrier for FV Leiden and prothrombin mutation and to homozygous carrier for the other mutations.