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Thrombosis in inflammatory bowel disease: Are we tailoring prophylaxis to those most at risk?
Journal of Crohn's and Colitis (2014) 8, 166–171
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Thrombosis in inflammatory bowel disease: Are we tailoring prophylaxis to those most at risk? Robert V. Bryant a,⁎, Vipul Jairath a,b , Nicola Curry c , Simon P.L. Travis a a
Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, United Kingdom NHS Blood and Transplant, Oxford University Hospitals NHS Trust, United Kingdom c Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, United Kingdom b
Received 24 August 2013; accepted 6 September 2013 KEYWORDS Inflammatory bowel disease; Ulcerative colitis; Crohn's disease; Thrombosis; Venous thromboembolic disease
Abstract Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk? © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE).1–6 The reasons are acquired, multifactorial, and ⁎ Corresponding author at: Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford Hospitals NHS Trust, Headley Way, Headington OX3 9DU, United Kingdom. Tel.: +44 1865 741166. E-mail addresses: [email protected] (R.V. Bryant), [email protected] (V. Jairath), [email protected] (N. Curry), [email protected] (S.P.L. Travis).
related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated.7,8 VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis.7 Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD,9–12 practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis.13–15 Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an
1873-9946/$ - see front matter © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.crohns.2013.09.007
Tailoring thromboprophylaxis in IBD Table 1
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Manifestations, risks and mechanisms of thrombosis in patients with IBD.
Manifestations, risks and mechanisms of thrombosis in patients with IBD Manifestations
Risk factors
Mechanisms
Deep venous thrombosis and pulmonary embolus Portomesenteric thrombosis
Active disease state Extent of disease
Cerebral sinus thrombosis Upper limb and jugular thrombosis Intracardiac thrombosis Aortic mural thrombosis Retinal vein thrombosis Cerebrovascular disease Ischaemic heart disease
Surgery Hospitalisation Central line placement Corticosteroids Pregnancy Older age Oral contraceptives Previous history of VTE Family history of VTE
Inflammation Increased procoagulant acute phase reactants Decreased anticoagulant factors Thrombocytosis Increased platelet activation Extracellular vesicles? Hyperhomocysteinaemia?
appreciable risk of VTE.2 Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk?
2. Impact and manifestations of thrombosis in patients with IBD VTE occurs in patients with IBD at a younger age than the general population1,16 and may lead to prolonged hospitalisation, impaired quality of life and increased healthcare utilisation.3,17 IBD has also been shown to be a risk factor for recurrent VTE, with an adjusted recurrence rate 2.5 fold (95% CI 1.4–4.2) that of the general population 5 years after cessation of anticoagulation for a first VTE.18 Mortality rates following VTE amongst patients with IBD are considerable, ranging from 18 to 22%.19,20 Perhaps more striking is evidence that mortality rates in hospitalised patients with IBD and VTE are 2.1 fold-higher (95% CI 1.6–2.9) than those of patients with VTE, but without IBD.3 This study found that IBD-related bowel surgery had the greatest impact on inpatient mortality associated with VTE (OR 4.8; 95% CI 3.97–5.8), which is incongruous with the younger age and low comorbidity of patients with IBD. Although unable to define the type of VTE, the data suggest that VTE in this group may be more severe or carry a higher risk of pulmonary embolism.3 Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common sites of VTE in patients with IBD, representing 90% of events (Table 1).21 The location of VTE in IBD is otherwise diverse and requires astute clinical awareness. Portal vein or superior mesenteric vein thrombosis should be considered if there is disproportionate abdominal pain or clinical deterioration in a hospitalised patient, whether with Crohn's disease (CD) or ulcerative colitis (UC).21,22 Cerebral sinus thrombosis should be considered in the event of headache, altered consciousness, or focal neurology.23 Other reported sites of VTE include subclavian, internal jugular, or superior vena caval thrombosis, commonly associated with central lines or parenteral nutrition. Intracardiac, aortic mural, or retinal vein thrombosis in IBD have been described.7,8,20 Less well recognised is the association between IBD and arterial thrombotic events,
including mesenteric arterial thrombosis, which may lead to catastrophic loss of small bowel, particularly in patients with UC (hazard ratio 12.5 compared to age-matched hospitalised patients, p b 0.0001).24 Debate continues about an increased risk of cerebrovascular or ischaemic heart disease, despite a lower burden of conventional risk factors.25,26
3. When is the risk of VTE in IBD patients highest? Incidence rates of VTE from population-based studies range from 2.4 to 4.6/1000 person years, equating to a relative risk in both ambulatory and hospitalised patients of 1.5 to 3.5 that of the general population.1–3,6,18 A meta-analysis including 11 studies that compared risk of VTE in patients with IBD to control populations, reported a 2.2 fold (95% CI 1.83–2.65) relative risk of VTE.4 Despite conflicting literature, the risk of VTE appears similar between UC and CD.3,4,21 Patients with pancolitis (UC), or colonic involvement in CD appear to be at particular risk.8 Traditional risk factors for VTE also operate in IBD, including immobility, smoking, older age, surgery, pregnancy or oral contraceptives, corticosteroids and central venous lines (Table 1).2,3,7,27,28 Disease activity is closely associated with VTE risk.2,8,21 The UK General Practice Research Database was used to evaluate the association between disease activity and VTE, defining a disease flare as a requirement for corticosteroids.2 Patients with IBD had an 8.4-fold (95% CI 5.5–12.8) increased risk of developing VTE during active disease compared with the general population. When the risk of VTE was stratified into ambulant outpatients versus hospitalised patients with active disease, the risk of VTE was 15.8-fold (95% CI 9.8–25.5) higher in ambulant outpatients compared to controls, but only 3.2-fold (95% CI 1.7–6.3) higher in hospitalised patients compared to hospitalised controls. Although the absolute risk in ambulant outpatients with active IBD is low (and lower than in hospitalised patients), this highlights active disease amongst outpatients with IBD as a greater risk than previously recognised. Thus, another question: for how long does the increased risk of VTE in patients with active IBD persist after hospitalisation?
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4. Mechanisms of increased thrombotic risk in IBD The magnitude of the risk of VTE in IBD is distinct from other chronic inflammatory or bowel disorders, such as rheumatoid arthritis and coeliac disease, implicating disease-specific factors in the pathogenesis of VTE in IBD (Table 1).2,6 There is no evidence that hereditary thrombophilias are more common in patients with IBD.29–31 Acquired haemostatic alterations are likely to play the most significant role, particularly during the active phase of disease.8 Inflammation may drive a hypercoagulable state through activation of the coagulation cascade, coupled with promotion of platelet aggregation and impairment of anticoagulant or fibrinolytic mechanisms.3,8 Neutrophil extracellular traps, which are extracellular DNA fibres produced during inflammation, link inflammation and thrombosis, as they have been shown to stimulate thrombogenesis and are abundant in thrombi in animal models of VTE.32 Although hyperhomocysteinaemia is common in patients with IBD, probably due to nutrient malabsorption or hypercatabolism,8,33,34 several studies have shown no association between hyperhomocysteinaemia and a history of thrombotic events.8,33,34 Inflammation in IBD may promote the release of prothrombotic acute-phase reactants, including Factor VIII, von Willebrand factor, lipoprotein a, and fibrinogen, as well as diminished levels of naturally-occurring anticoagulant factors antithrombin, protein C, protein S and tissue factor pathway inhibitor.8 Platelet function is also likely to contribute to the prothrombotic tendency of IBD patients. Thrombocytosis is common and platelets circulate in an activated state in patients with active IBD, evidenced by surface activation markers P-selectin, GP53, CD40 ligand and CD36, as well as an increased potential to aggregate spontaneously in vitro.35–39 There has also been interest in the role of procoagulant extracellular vesicles (ECVs) released from cells during inflammation, previously known as circulating microparticles, in the pathogenesis of pro-thrombotic states.40 Elevated levels of circulating ECVs have been demonstrated in patients with active IBD but not in those in remission. It has been suggested that they may be a biomarker of response to infliximab in patients with CD, prompting speculation about their role in VTE as well as the pathogenesis of IBD.41,42 This is questionable, since other work suggests that although ECVs may be increased during active disease, they may not significantly influence thrombin generation or hypercoagulability.43,44 More research is required in this area.
5. Management of VTE in IBD: Guidelines, practice and evidence Consensus recommendations from international organisations support VTE prophylaxis for hospitalised patients with active IBD.9,10,45–47 Data from hospitalised general medical inpatients show that the risk of VTE is significantly reduced by prophylaxis with low molecular weight heparin or fondaparinux.47 Thromboprophylaxis is safe in patients with IBD, with no significant difference in rates of major bleeding between those who do and do not receive
R.V. Bryant et al. thromboprophylaxis (0.26 vs. 0 per 1000 person days respectively), even when there is rectal bleeding during a flare.48,49 It is therefore notable that surveys suggest that up to 55% of gastroenterologists are unaware of VTE guidelines for patients with IBD and 65% may not give pharmacological VTE prophylaxis to patients hospitalised with acute severe colitis.13–15 There is particular inconsistency in administration of VTE prophylaxis for patients with quiescent IBD admitted to hospital for other reasons.13 Greater awareness of the risks of VTE in IBD and better adherence to VTE guidelines were associated with IBD specialists (N 50% IBD practice), those affiliated to an academic hospital and those recently qualified (b 5 years).15 Management of established VTE in the IBD population shows similar disparity. Decisions around anticoagulation balance the risks of recurrent or more extensive VTE against the risk of haemorrhage and adherence to therapy.18 The complexity of decision-making is reflected by survey data from gastroenterologists showing that the recommended duration of anticoagulation ranges from 3 months to lifelong.13,14 Markov decision analysis suggests that extended anticoagulation is usually preferable over time-limited anticoagulation for patients with IBD after a first (‘unprovoked’) VTE when outcomes are ascertained over a lifetime.17 For patients who develop VTE during active disease, time-limited anticoagulation during periods of active disease (not necessarily including hospitalisation) may be an alternative strategy.17 There are, however, no randomised trials in the IBD population to confirm the potential benefits of VTE prophylaxis, nor the best approach to treatment of VTE.
6. Tailoring VTE prophylaxis in IBD: What are the issues? Despite the 16-fold increased risk of VTE amongst outpatients with active IBD, there are neither guidelines nor recommendations to guide practice. Although the absolute risk of VTE is low, up to 80% of all VTE in IBD occurs in outpatients.21 This is particularly true of patients recently discharged from hospital following a disease flare, since most outpatients with VTE have been hospitalised within the preceding 3 months.50 Extended anticoagulation after hospitalisation, or thromboprophylaxis for outpatients with active disease and a history of VTE are conceivable strategies to manage this risk. Nevertheless, we lack data on the clinical and cost–effectiveness.7 Thromboprophylaxis need not mean self-injected low molecular weight heparin, since oral agents such as rivaroxaban have proven efficacy in preventing VTE. These may be particularly useful for outpatients due to ease of administration, lack of requirement for monitoring and improved adherence.51 Compounding the lack of evidence around appropriate thromboprophylaxis in patients with IBD, clinicians lack reliable biomarkers to identify those most at risk. Standard tests such at prothrombin and activated partial thromboplastin times (PT and APTT), D-dimer, or platelet count correlate poorly with the risk of thrombosis, which is unsurprising given that they only assess isolated components of the coagulation cascade.8 This is consistent with the lack of value in screening
Tailoring thromboprophylaxis in IBD for VTE in asymptomatic patients with IBD.52 Global assays of coagulation, such as those for thrombin generation, may have a role in monitoring thrombotic risk in IBD.53
7. Tailoring VTE prophylaxis in IBD: Future directions Clinical trials are needed to confirm the effectiveness and safety of thromboprophylaxis in patients with IBD, particularly in ambulatory patients with active disease and in those recently discharged from hospital. Trials would be challenging to conduct because absolute event rates of thrombosis are low, but novel approaches to VTE trial design using composite endpoints will assist planning.54 Surrogate markers of thrombogenic potential, including calibrated automated thrombinography and thromboelastography, might be used in proof of concept studies,53,55 or as secondary endpoints. Better methods of measuring thrombotic risk are crucial to guiding appropriate thromboprophylaxis in patients with IBD. Mechanisms of thrombosis in patients with IBD need to be understood, so that biomarker assays of prothrombotic potential can be evaluated. Incorporating sensitive coagulation assays with thrombotic biomarkers and clinical risk indices into clinical practice should help guide clinicians. VTE is a life-threatening extraintestinal manifestation of IBD mitigated by appropriate thromboprophylaxis. Essential to reducing the risk of VTE in patients with IBD is timely and effective management of disease flares, and clinician awareness and adherence to thromboprophylaxis guidelines. Outpatients with active disease and patients after discharge from hospitalisation deserve particular attention. Prevention of VTE is part of managing the manageable to reduce the burden of IBD.
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Conflict of interest Author declares that there are no conflict of interest.
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Acknowledgements No funding was received for this article.
RVB drafted the manuscript. VJ, NC, and SPLT edited the manuscript. Each of the authors read and approved the final manuscript.
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VIEWPOINT
Thrombosis in inflammatory bowel disease: Are we tailoring prophylaxis to those most at risk? Robert V. Bryant a,⁎, Vipul Jairath a,b , Nicola Curry c , Simon P.L. Travis a a
Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, United Kingdom NHS Blood and Transplant, Oxford University Hospitals NHS Trust, United Kingdom c Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, United Kingdom b
Received 24 August 2013; accepted 6 September 2013 KEYWORDS Inflammatory bowel disease; Ulcerative colitis; Crohn's disease; Thrombosis; Venous thromboembolic disease
Abstract Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk? © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE).1–6 The reasons are acquired, multifactorial, and ⁎ Corresponding author at: Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford Hospitals NHS Trust, Headley Way, Headington OX3 9DU, United Kingdom. Tel.: +44 1865 741166. E-mail addresses: [email protected] (R.V. Bryant), [email protected] (V. Jairath), [email protected] (N. Curry), [email protected] (S.P.L. Travis).
related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated.7,8 VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis.7 Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD,9–12 practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis.13–15 Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an
1873-9946/$ - see front matter © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.crohns.2013.09.007
Tailoring thromboprophylaxis in IBD Table 1
167
Manifestations, risks and mechanisms of thrombosis in patients with IBD.
Manifestations, risks and mechanisms of thrombosis in patients with IBD Manifestations
Risk factors
Mechanisms
Deep venous thrombosis and pulmonary embolus Portomesenteric thrombosis
Active disease state Extent of disease
Cerebral sinus thrombosis Upper limb and jugular thrombosis Intracardiac thrombosis Aortic mural thrombosis Retinal vein thrombosis Cerebrovascular disease Ischaemic heart disease
Surgery Hospitalisation Central line placement Corticosteroids Pregnancy Older age Oral contraceptives Previous history of VTE Family history of VTE
Inflammation Increased procoagulant acute phase reactants Decreased anticoagulant factors Thrombocytosis Increased platelet activation Extracellular vesicles? Hyperhomocysteinaemia?
appreciable risk of VTE.2 Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk?
2. Impact and manifestations of thrombosis in patients with IBD VTE occurs in patients with IBD at a younger age than the general population1,16 and may lead to prolonged hospitalisation, impaired quality of life and increased healthcare utilisation.3,17 IBD has also been shown to be a risk factor for recurrent VTE, with an adjusted recurrence rate 2.5 fold (95% CI 1.4–4.2) that of the general population 5 years after cessation of anticoagulation for a first VTE.18 Mortality rates following VTE amongst patients with IBD are considerable, ranging from 18 to 22%.19,20 Perhaps more striking is evidence that mortality rates in hospitalised patients with IBD and VTE are 2.1 fold-higher (95% CI 1.6–2.9) than those of patients with VTE, but without IBD.3 This study found that IBD-related bowel surgery had the greatest impact on inpatient mortality associated with VTE (OR 4.8; 95% CI 3.97–5.8), which is incongruous with the younger age and low comorbidity of patients with IBD. Although unable to define the type of VTE, the data suggest that VTE in this group may be more severe or carry a higher risk of pulmonary embolism.3 Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common sites of VTE in patients with IBD, representing 90% of events (Table 1).21 The location of VTE in IBD is otherwise diverse and requires astute clinical awareness. Portal vein or superior mesenteric vein thrombosis should be considered if there is disproportionate abdominal pain or clinical deterioration in a hospitalised patient, whether with Crohn's disease (CD) or ulcerative colitis (UC).21,22 Cerebral sinus thrombosis should be considered in the event of headache, altered consciousness, or focal neurology.23 Other reported sites of VTE include subclavian, internal jugular, or superior vena caval thrombosis, commonly associated with central lines or parenteral nutrition. Intracardiac, aortic mural, or retinal vein thrombosis in IBD have been described.7,8,20 Less well recognised is the association between IBD and arterial thrombotic events,
including mesenteric arterial thrombosis, which may lead to catastrophic loss of small bowel, particularly in patients with UC (hazard ratio 12.5 compared to age-matched hospitalised patients, p b 0.0001).24 Debate continues about an increased risk of cerebrovascular or ischaemic heart disease, despite a lower burden of conventional risk factors.25,26
3. When is the risk of VTE in IBD patients highest? Incidence rates of VTE from population-based studies range from 2.4 to 4.6/1000 person years, equating to a relative risk in both ambulatory and hospitalised patients of 1.5 to 3.5 that of the general population.1–3,6,18 A meta-analysis including 11 studies that compared risk of VTE in patients with IBD to control populations, reported a 2.2 fold (95% CI 1.83–2.65) relative risk of VTE.4 Despite conflicting literature, the risk of VTE appears similar between UC and CD.3,4,21 Patients with pancolitis (UC), or colonic involvement in CD appear to be at particular risk.8 Traditional risk factors for VTE also operate in IBD, including immobility, smoking, older age, surgery, pregnancy or oral contraceptives, corticosteroids and central venous lines (Table 1).2,3,7,27,28 Disease activity is closely associated with VTE risk.2,8,21 The UK General Practice Research Database was used to evaluate the association between disease activity and VTE, defining a disease flare as a requirement for corticosteroids.2 Patients with IBD had an 8.4-fold (95% CI 5.5–12.8) increased risk of developing VTE during active disease compared with the general population. When the risk of VTE was stratified into ambulant outpatients versus hospitalised patients with active disease, the risk of VTE was 15.8-fold (95% CI 9.8–25.5) higher in ambulant outpatients compared to controls, but only 3.2-fold (95% CI 1.7–6.3) higher in hospitalised patients compared to hospitalised controls. Although the absolute risk in ambulant outpatients with active IBD is low (and lower than in hospitalised patients), this highlights active disease amongst outpatients with IBD as a greater risk than previously recognised. Thus, another question: for how long does the increased risk of VTE in patients with active IBD persist after hospitalisation?
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4. Mechanisms of increased thrombotic risk in IBD The magnitude of the risk of VTE in IBD is distinct from other chronic inflammatory or bowel disorders, such as rheumatoid arthritis and coeliac disease, implicating disease-specific factors in the pathogenesis of VTE in IBD (Table 1).2,6 There is no evidence that hereditary thrombophilias are more common in patients with IBD.29–31 Acquired haemostatic alterations are likely to play the most significant role, particularly during the active phase of disease.8 Inflammation may drive a hypercoagulable state through activation of the coagulation cascade, coupled with promotion of platelet aggregation and impairment of anticoagulant or fibrinolytic mechanisms.3,8 Neutrophil extracellular traps, which are extracellular DNA fibres produced during inflammation, link inflammation and thrombosis, as they have been shown to stimulate thrombogenesis and are abundant in thrombi in animal models of VTE.32 Although hyperhomocysteinaemia is common in patients with IBD, probably due to nutrient malabsorption or hypercatabolism,8,33,34 several studies have shown no association between hyperhomocysteinaemia and a history of thrombotic events.8,33,34 Inflammation in IBD may promote the release of prothrombotic acute-phase reactants, including Factor VIII, von Willebrand factor, lipoprotein a, and fibrinogen, as well as diminished levels of naturally-occurring anticoagulant factors antithrombin, protein C, protein S and tissue factor pathway inhibitor.8 Platelet function is also likely to contribute to the prothrombotic tendency of IBD patients. Thrombocytosis is common and platelets circulate in an activated state in patients with active IBD, evidenced by surface activation markers P-selectin, GP53, CD40 ligand and CD36, as well as an increased potential to aggregate spontaneously in vitro.35–39 There has also been interest in the role of procoagulant extracellular vesicles (ECVs) released from cells during inflammation, previously known as circulating microparticles, in the pathogenesis of pro-thrombotic states.40 Elevated levels of circulating ECVs have been demonstrated in patients with active IBD but not in those in remission. It has been suggested that they may be a biomarker of response to infliximab in patients with CD, prompting speculation about their role in VTE as well as the pathogenesis of IBD.41,42 This is questionable, since other work suggests that although ECVs may be increased during active disease, they may not significantly influence thrombin generation or hypercoagulability.43,44 More research is required in this area.
5. Management of VTE in IBD: Guidelines, practice and evidence Consensus recommendations from international organisations support VTE prophylaxis for hospitalised patients with active IBD.9,10,45–47 Data from hospitalised general medical inpatients show that the risk of VTE is significantly reduced by prophylaxis with low molecular weight heparin or fondaparinux.47 Thromboprophylaxis is safe in patients with IBD, with no significant difference in rates of major bleeding between those who do and do not receive
R.V. Bryant et al. thromboprophylaxis (0.26 vs. 0 per 1000 person days respectively), even when there is rectal bleeding during a flare.48,49 It is therefore notable that surveys suggest that up to 55% of gastroenterologists are unaware of VTE guidelines for patients with IBD and 65% may not give pharmacological VTE prophylaxis to patients hospitalised with acute severe colitis.13–15 There is particular inconsistency in administration of VTE prophylaxis for patients with quiescent IBD admitted to hospital for other reasons.13 Greater awareness of the risks of VTE in IBD and better adherence to VTE guidelines were associated with IBD specialists (N 50% IBD practice), those affiliated to an academic hospital and those recently qualified (b 5 years).15 Management of established VTE in the IBD population shows similar disparity. Decisions around anticoagulation balance the risks of recurrent or more extensive VTE against the risk of haemorrhage and adherence to therapy.18 The complexity of decision-making is reflected by survey data from gastroenterologists showing that the recommended duration of anticoagulation ranges from 3 months to lifelong.13,14 Markov decision analysis suggests that extended anticoagulation is usually preferable over time-limited anticoagulation for patients with IBD after a first (‘unprovoked’) VTE when outcomes are ascertained over a lifetime.17 For patients who develop VTE during active disease, time-limited anticoagulation during periods of active disease (not necessarily including hospitalisation) may be an alternative strategy.17 There are, however, no randomised trials in the IBD population to confirm the potential benefits of VTE prophylaxis, nor the best approach to treatment of VTE.
6. Tailoring VTE prophylaxis in IBD: What are the issues? Despite the 16-fold increased risk of VTE amongst outpatients with active IBD, there are neither guidelines nor recommendations to guide practice. Although the absolute risk of VTE is low, up to 80% of all VTE in IBD occurs in outpatients.21 This is particularly true of patients recently discharged from hospital following a disease flare, since most outpatients with VTE have been hospitalised within the preceding 3 months.50 Extended anticoagulation after hospitalisation, or thromboprophylaxis for outpatients with active disease and a history of VTE are conceivable strategies to manage this risk. Nevertheless, we lack data on the clinical and cost–effectiveness.7 Thromboprophylaxis need not mean self-injected low molecular weight heparin, since oral agents such as rivaroxaban have proven efficacy in preventing VTE. These may be particularly useful for outpatients due to ease of administration, lack of requirement for monitoring and improved adherence.51 Compounding the lack of evidence around appropriate thromboprophylaxis in patients with IBD, clinicians lack reliable biomarkers to identify those most at risk. Standard tests such at prothrombin and activated partial thromboplastin times (PT and APTT), D-dimer, or platelet count correlate poorly with the risk of thrombosis, which is unsurprising given that they only assess isolated components of the coagulation cascade.8 This is consistent with the lack of value in screening
Tailoring thromboprophylaxis in IBD for VTE in asymptomatic patients with IBD.52 Global assays of coagulation, such as those for thrombin generation, may have a role in monitoring thrombotic risk in IBD.53
7. Tailoring VTE prophylaxis in IBD: Future directions Clinical trials are needed to confirm the effectiveness and safety of thromboprophylaxis in patients with IBD, particularly in ambulatory patients with active disease and in those recently discharged from hospital. Trials would be challenging to conduct because absolute event rates of thrombosis are low, but novel approaches to VTE trial design using composite endpoints will assist planning.54 Surrogate markers of thrombogenic potential, including calibrated automated thrombinography and thromboelastography, might be used in proof of concept studies,53,55 or as secondary endpoints. Better methods of measuring thrombotic risk are crucial to guiding appropriate thromboprophylaxis in patients with IBD. Mechanisms of thrombosis in patients with IBD need to be understood, so that biomarker assays of prothrombotic potential can be evaluated. Incorporating sensitive coagulation assays with thrombotic biomarkers and clinical risk indices into clinical practice should help guide clinicians. VTE is a life-threatening extraintestinal manifestation of IBD mitigated by appropriate thromboprophylaxis. Essential to reducing the risk of VTE in patients with IBD is timely and effective management of disease flares, and clinician awareness and adherence to thromboprophylaxis guidelines. Outpatients with active disease and patients after discharge from hospitalisation deserve particular attention. Prevention of VTE is part of managing the manageable to reduce the burden of IBD.
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Conflict of interest Author declares that there are no conflict of interest.
13.
Acknowledgements No funding was received for this article.
RVB drafted the manuscript. VJ, NC, and SPLT edited the manuscript. Each of the authors read and approved the final manuscript.
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