The Journey Through the Pathogenesis and Treatment of Venous Thromboembolism in Inflammatory Bowel Diseases: A Narrative Review

Keywords

immunothrombosis - hypercoagulability - pulmonary embolism - thromboinflammation - venous thrombosis

Inflammatory bowel diseases (IBDs) are a group of chronic inflammatory conditions of the gastrointestinal tract including Crohn's disease (CD) and ulcerative colitis (UC). In approximately 20 to 30% of cases, IBDs are also associated with severe extraintestinal complications, such as increased risk of venous thromboembolism (VTE), due to the link between systemic inflammation and hypercoagulability,[1] which may ultimately result in higher healthcare costs. Our review endeavors to examine the main correlations between IBD and VTE, the pathophysiology, and currently available therapeutic options.

Epidemiology of VTE in IBD

VTE is one of the most common extraintestinal complications of IBD. Several large population-based cohort studies and meta-analyses have demonstrated an increased risk of VTE in patients with IBD compared with the population without IBD.[1] [2] [3] The prevalence of VTE in IBD patients ranges from 1 to 8% in retrospective studies, though it is remarkably higher (up to 39%) in autopsy studies.[4] In a multicenter study comprising 2,811 IBD patients, the prevalence and incidence rates of all VTEs were 5.6 and 6.3% per 1,000 person-years, respectively.[5] A more recent study reported higher rates of deep vein thrombosis (DVT) (adjusted incidence rate ratio [IRR]: 2.44 [95% confidence interval [CI]: 2.00–2.99; p < 0.01) and pulmonary embolism (PE) (IRR: 1.90 [95% CI: 1.42–2.54]; p < 0.01) in patients with IBD.[6] The DVT risk appears to be similar in CD and UC: the reported incidence rate of DVT was 31.4/10,000 person-years and that of PE was 10.3/10,000 person-years in CD versus 30.0/10,000 person-years and 19.8/10,000 person-years in UC, respectively[4] ([Table 1]).

Table 1 Incidence rate of venous thromboembolism, deep venous thrombosis and pulmonary embolism in patients with IBD, Crohn's disease and ulcerative colitis

VTE risk	Overall IBD	Crohn's disease	Ulcerative colitis	General population
Overall VTE risk	24.0/10,000 person-years	23.3/10,000 person-years	24.4/10,000 person-years	10.4–18.3/10,000 person-years
DVT	30.7/10,000 person-years	31.4/10,000 person-years	30.0/10,000 person-years	4.5–11.7/10,000 person-years
PE	14.9/10,000 person-years	10.3/10,000 person-years	19.8/10,000 person-years	2.9–7.8/10,000 person-years

Abbreviations: DVT, deep venous thrombosis; IBD, inflammatory bowel disease; PE, pulmonary embolism; VTE, venous thromboembolism.

The incidence of VTE increases with age, and it is associated with active disease (defined as corticosteroid use) and hospitalization.[2] Although most studies found no significant sex-related differences in VTE incidence, it was recently reported that male sex may be associated with an increased risk of VTE-related hospitalization[6] [7] [8]; the extent of the disease may also correlate with a higher VTE risk.[9] A retrospective study found pancolonic involvement in 76% of patients with UC and VTE, whereas colonic involvement, complicated disease (i.e., fistulas, stenosis, abscesses), and recent surgery were reported as risk factors for CD.[9]

Regarding VTE location, DVT of the lower extremity and PE are the most common VTE complications in IBD.[7] In the study conducted by Papay and colleagues, 35.7% of VTE cases in IBD patients involved proximal leg veins, whereas approximately 11.5% of patients presented thrombosis in the distal leg veins; most VTE events did not display other provoking risk factors than IBD (77.1%).[7] Another study reported that thrombosis may also occur in splanchnic veins or other unusual sites.[10] In an Austrian multicenter study comprising IBD patients with a history of VTE, 90.4% presented with DVT and/or PE, whereas 9.6% had portal, mesenteric, cerebral, or internal jugular vein thrombosis.[7] [11]

The mortality rate associated with IBD-related VTE is estimated at 8 to 22%.[12] [13] Furthermore, VTE occurrence in patients with IBD increases hospitalization costs.[6]

IBD was shown to be an independent risk factor for VTE recurrence (hazard ratio [HR]: 2.5 [95% CI: 1.4–4.2; p = 0.001).[14] Indeed, the likelihood of recurrence 5 years after discontinuation of anticoagulation therapy was significantly higher among IBD patients (33.4% [95% CI: 21.8–45.0) versus patients without IBD (21.7% [95% CI: 18.8–24.6; p = 0.01).[14] Two studies confirmed that patients with IBD who suffered a first episode of unprovoked VTE had a 33% likelihood of recurrent VTE within 5 years versus 21% in non-IBD patients following a first episode of unprovoked VTE.[12] [15] In case of VTE recurrence, DVT was the main manifestation (40%), followed by PE (23%).[12] Postthrombotic syndrome is a frequent complication of VTE, and together with chronic venous disease and high body mass index may increase the risk of VTE recurrence among IBD patients.[16]

Pathogenesis of Venous Thrombosis in IBD

There is growing evidence of a cross-talk and mutual influence between inflammatory and coagulation systems. Activation of systemic inflammation in IBD seems to be the main risk factor for VTE, and although the specific pathogenetic mechanism is still unclear, the so-called vascular hypothesis has garnered strong support among experts[3] ([Fig. 1]). In particular, vascular endothelial dysregulation due to local gut and systemic inflammation can lead to a prothrombotic state.[3] Several prothrombotic changes have been described, such as the activation of the coagulation system, increased platelet activity, and the dysregulation of fibrinolysis.[3] Furthermore, the dysregulation of the gut microbiome seems to play a relevant role in promoting systemic inflammation and subsequent procoagulant state ([Table 2]). Finally, increased thrombin generation may further amplify the activation of systemic inflammation.

Fig. 1 Main pathophysiological mechanisms inducing high VTE risk in IBD patients. IBD, inflammatory bowel disease; VTE, venous thromboembolism; TF, tissue factor; MPs, microparticles; AT, antithrombin; PC, protein C; PS, protein S; TM, thrombomodulin; EPCR, endothelial protein C receptor; VWF, von Willebrand factor; ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; LPS, lipopolysaccharide; TLR, toll-like receptor; ROS, reactive oxygen species; TX, thromboxane; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1.

Table 2 Molecular mechanisms involved in determining procoagulant state in IBD patients

Molecular pathway	Mechanism of hypercoagulability
Local inflammation	Endothelial dysfunction Cytokines release (TNF-α and IL-6) TF release from monocytes/macrophages, endothelial cells, and platelets
Endothelial dysfunction	Elevated plasma levels of TM and low levels on mucosal and endothelial cells Low expression of EPCR on intestinal endothelial cells ETP ratio Increased circulating levels of VWF and decreased levels of ADAMTS-13
Coagulation activation	High levels of procoagulant factors (V, VII, VIII, X, XI, XII, fibrinogen) and fibrin and thrombin formation products Reduced levels of natural anticoagulant AT, PC, and PS High ETP
Fibrinolysis alteration	Hypofibrinolysis Increased TAFI and PAI-1 concentrations Increased active to total PAI-1 ratio 50% clot lysis time Reduced FXIII levels
Platelets	Abnormal platelet aggregation and activation Increased P-selectin expression on platelets Increased level of PF4 Release of platelet-derived TF-bearing microparticles Increased platelet expression of CD40L and leukocyte recruitment
Gut microbiome	Decrease in commensal anaerobic bacteria and increased gram-negative Enterobacteriaceae LPS overexpression due to a weakening of gut barrier and the increase of Enterobacteriaceae TLR2 and TLR4 promote cells activation and release of procoagulant molecules
Systemic inflammation	Vasoconstrictors release (endothelin-1 and thromboxanes) ROS generation from leukocytes and endothelial cells Ischemia-reperfusion injury of the endothelium after microthrombi formation ROS induce NF-κB factor activation

Abbreviations: ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; AT, antithrombin; CD40L, CD40 ligand; EPCR, endothelial protein C receptor; ETP, endogenous thrombin potential; IBD, inflammatory bowel disease; IL, interleukin; LPS, lipopolysaccharide; PAR, protease-activated receptors; PC, protein C; PF4, platelet factor 4; PS, protein S; ROS, reactive oxygen species; TAFI, thrombin-activatable fibrinolysis inhibitor; TF, tissue factor; TLR, toll-like receptor; TM, thrombomodulin; TNF-α, tumor necrosis factor-α; VWF, von Willebrand factor.

Local Inflammation

Immune-mediated angiogenesis and increased vascular permeability are involved in the pathogenesis of IBD, by enhancing the recruitment of proinflammatory cells from the bloodstream to the intestinal mucosa.[17] Vascular endothelial cells in the gut may be a source of cytokines in a complex cross-talk between innate and adaptive immunity.[17] Proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) may trigger the coagulation cascade by inducing the release of tissue factor (TF) from monocytes/macrophages, endothelial cells, and platelets.[18] Increased TF activity from activated monocytes and TF-bearing microparticles (MPs) was observed in IBD patients.[19] On the other hand, proinflammatory cytokines such as TNF-α and IL-1β downregulate the natural anticoagulant pathway as PC pathway and the heparin–antithrombin pathway.[20] [21]

Furthermore, IL-6 involved in the megakaryocytes maturation process contributes to the prothrombotic state by increasing platelet production.[22]

Endothelial Dysfunction

Activated endothelial cells promote the proinflammatory state by recruiting leukocytes via an increase in several adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.[23] This results in the activation of the hemostatic system and platelet aggregation, ultimately leading to a vicious cycle of increased cytokines and chemokines production, and overexpression of adhesion molecules and TF on endothelial cells.

Protein C (PC) is a natural anticoagulant expressed on endothelial cells of the mucosal microvasculature, but also in intestinal epithelial cells where it maintains and enhances tight junctions, and thus preserves the integrity of the intestinal barrier. The expression of PC and endothelial protein C receptor (EPCR) is downregulated in patients with CD and UC, resulting in increased gut permeability.[24]

The role of thrombomodulin in IBD is still a matter of debate. Some authors have argued that elevated thrombomodulin levels may be a marker of endothelium damage in several chronic inflammatory diseases, and therefore indicative of major disease activity.[25] Thrombomodulin is a glycoprotein expressed on cell surfaces and predominantly synthesized by vascular endothelial cells, and is a main cofactor for thrombin-mediated activation of PC.[18] In isolated human intestinal endothelial cells from CD and UC, there was a downregulation of EPCR and thrombomodulin, which in turn caused impairment of PC activation by the inflamed mucosal microvasculature resulting in a procoagulant state.[26] This finding is in line with the theory of microthrombi formation in bowel capillaries as main determinant in the pathogenesis of IBD.[27] Moreover, Reichman-Warmusz et al performed serial cryostat sections of endoscopic mucosal biopsy specimens from IBD patients.[28] As demonstrated by immunohistochemical staining, in IBD patients there was an upregulation of TF, and a downregulation of thrombomodulin and tissue factor pathway inhibitor (TFPI). In most IBD sections, TF positively stained small microvessels, infiltrating mononuclear cells and fibroblast-shaped cells tightly surrounding the colon crypts; thrombomodulin intensely stained the endothelium of small capillaries in the controls, whereas such staining mainly accompanied infiltrating mononuclear cells in IBD subjects. They also found only weak TFPI staining in endothelial cells of IBD subjects versus healthy individuals.[28]

Some studies found increased circulating levels of von Willebrand factor (VWF) and decreased levels of an ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in patients with IBD.[29] [30] A study by Meucci et al demonstrated significant increases in plasma VWF levels, which correlated with the degree of systemic inflammation.[30] A subsequent study performed by Cibor et al showed that VWF antigen levels were higher in patients with UC and CD versus healthy controls.[29] Patients with active CD had 38% higher VWF ristocetin cofactor activity versus healthy controls.[31] Moreover, decreased ADAMTS-13 activity was demonstrated in CD patients; decreased ADAMTS-13 antigen and activity was found in UC patients, in whom these parameters correlated negatively with disease activity.[29] Low ADAMTS-13 levels may stem from enhanced VWF multimer consumption or greater proteolytic cleavage by activated neutrophils triggered by circulating cytokines (e.g., TNF and IL-6) in IBD.[32] Therefore, IBD patients often present increased VWF levels and VWF/ADAMTS-13 ratio, and these changes are due to cytokine release and increased TF exposure on damaged endothelial cells at inflammation sites.[32]

Prothrombotic Changes

Coagulation factors V, VII, VIII, X, XI, XII, and fibrinogen, as well as products of fibrin and thrombin formation are remarkably higher in IBD patients than in healthy individuals, and they correlate with disease activity—these factors are significantly higher during the acute phase in IBD[30] [33] [34] ([Table 3]).

Table 3 Pathological changes in coagulation and fibrinolysis factors determining VTE in IBD patients

Coagulation factors or inhibitors	Plasma level	Fibrinolysis factor	Plasma level
TF	↑	tPA	↑
Fibrinogen	↑	PAI-1	↑
FVII	↑	Plasminogen	=
FX	↑	D-dimer	↑
Prothrombin	=	TAFI	↓
Thrombin	↑
FV	↑
FXII	↑
FXI	↑
FIX	↑
FVIII	↑
FXIII	↓
TFPI	↓
AT	↓
PS	↓
PC	↑
TM	↑
EPCR	↑

Abbreviations: AT, antithrombin; EPCR, endothelial protein C receptor; PAI-1, plasminogen activator inhibitor-1; PC, protein C; PS, protein S; TAFI, thrombin-activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; tPA, tissue plasminogen activator.

Several studies found high levels of thrombin–antithrombin (TAT) complexes and prothrombin fragments F1 + 2 both in active CD and UC versus absent in inactive diseases.[35] [36] On the other hand, prothrombin levels were normal in IBD patients.[37]

As for coagulation inhibitors, levels of antithrombin were decreased in IBD patients.[38] [39] Levels of protein S—the main cofactor of PC—were markedly reduced despite fluctuating values of serum PC, thus resulting in increased thrombin generation.[30] [38] [39]

Saibeni et al showed that the endogenous thrombin potential (ETP), a measurement of thrombin generation capacity in the presence of thrombomodulin or as a ratio (with/without thrombomodulin), was increased in IBD patients, especially those with higher active disease.[37] A recent study demonstrated that ETP and ETP ratio decreased after treatment with infliximab; in addition, FVIII, fibrinogen, and FVIII/PC ratio decreased at the end of infliximab treatment versus baseline.[33]

Finally, thrombin may mediate and amplify inflammatory cascades in IBD via the activation of protease activated receptors (PARs).[40] Thrombin is an essential mediator of the PAR pathway through the activation of PAR-1, -3, and -4, resulting in detrimental cellular effects such as barrier disruption in endothelial cells.[40]

Hypofibrinolysis

Several findings have suggested alterations of fibrinolysis in IBD patients ([Table 3]). There have been reports of increased D-dimer levels in IBD patients, notably during flares, though other studies were not able to confirm this finding.[35] [41] [42] [43] Decreased levels of FXIII were reported in patients with active IBD and it correlated with disease activity. This may stem from increased consumption due to microthrombi formation.[44] Plasminogen levels were reported to be normal, whereas tissue plasminogen activator (tPA) levels were mildly elevated.[36] [38]

Some authors reported increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) in IBD patients,[45] [46] as well as increased plasminogen activator factor 1 (PAI-1) leading to hypofibrinolysis.[42] A 2015 case–control study compared fibrinolysis profiles of IBD patients with and without prior VTE versus healthy controls and found that increased concentrations of fibrinolysis markers were significantly associated with the presence of IBD.[15] In particular, PAI-1 antigen, active PAI-1, and TAFI concentrations, as well as 50% clot lysis time were significantly associated with the presence of IBD (all p < 0.05).[15] Active to total PAI-1 ratio, 50% clot lysis time and clot amplitude were significantly higher in IBD patients with VTE versus those without VTE, and remained higher after adjustment for age, sex, C-reactive protein, type of disease, the presence of comorbidities, and disease activity.[15]

Platelets

Abnormal platelet aggregation and activation were found in both active and inactive IBD.[15] A study conducted on patients with CD found that platelet aggregation and platelet adhering to monocytes increased after activation with the specific PAR-1 and PAR-4 agonists in patients with active disease versus those in remission and healthy controls.[47] The expression of P-selectin on platelets from CD patients was enhanced only by PAR-1 activation.[47] Platelet activation markers such as platelet factor 4 were increased in IBD patients and it correlated with disease activity.[48] Microparticles were found in the plasma of adult and pediatric IBD patients.[49] [50] [51] In particular, MPs derived from activated platelets express TF on their surface, suggesting a possible role in the activation of coagulation.[52] [53] Platelets may mediate leukocyte recruitment to the inflamed colon via the surface CD40 ligand (CD40L).[52] Danese et al[54] found increased platelet expression of CD40L and increased plasma levels of platelet soluble CD40L in both UC and CD versus healthy controls.[55] Therefore, platelet activation appears to be linked to inflammatory changes in IBD patients, thus inducing a prothrombotic state. Moreover, increased platelet count was described in IBD patients, and it seemed to correlate with disease activity.[27] [56] Mean platelet volume (MPV) was shown to be decreased in IBD patients and linked to disease activity.[57] Megakaryopoiesis induced by inflammation causes enhanced platelet formation and decreased half-life.[58] Large platelets appear to be more active and infiltrate inflammatory sites, thus resulting in lower MPV of blood platelets.[58] Therefore, platelet activation and thrombocytosis play a major role in the pathogenesis of IBD and the development of thrombosis.

Gut Microbiome

The alterations of the gut microbiome in IBD patients also appear to contribute to determining a prothrombotic state. In particular, a decrease in commensal anaerobic bacteria and an increase in gram-negative Enterobacteriaceae may increase the risk of VTE.[59] Lipopolysaccharide overexpression due to a weakening of the gut barrier and the increase of Enterobacteriaceae has been observed in IBD patients.[60] Lipopolysaccharide is a glycolipid that may activate toll-like receptors (TLRs) on monocytes, endothelial cells, and platelets, directly or via cytokines.[61] After being activated by bacterial components, TLR2 and TLR4 promote cell activation and the subsequent release of different procoagulant molecules.[57] [58] Pastorelli et al found increased lipopolysaccharide levels in the circulation of IBD patients which correlated with TLR4 concentrations in both the active and the remission phases of IBD.[60] Serum lipopolysaccharide levels correlated with both D-dimer and prothrombin fragments F1 + 2 levels, thus supporting the hypothesis of impaired gut barrier triggering the activation of the coagulation cascade in IBD patients.[60] Indeed, lipopolysaccharide can act as a link between the microbiome and hypercoagulability.

Systemic Inflammation

In IBD, increased gut permeability results in an inflammatory response in the bowel wall, due to the dysregulated mucosal infiltration of luminal bacteria, toxins, and antigenic molecules. The inflammatory response and the endotoxemia both may induce a procoagulant state.[62] Microthrombi detected in the systemic circulation of IBD patients have been linked to endotoxins from the gut.[49]

Several vasoconstrictors, such as endothelin-1 and thromboxanes, are released from the activated endothelium and play an important role in ischemia-reperfusion injury.[50] There have been reports of increased levels of reactive oxygen species (from leukocytes) in IBD patients, as a result of ischemia-reperfusion injury of the endothelium after microthrombi formation.[51] Reactive oxygen species are also involved in the inflammatory response in IBD via NF-κB factor activation which promotes the release of several proinflammatory cytokines.[52] Therefore, endothelial dysfunction stemming from ischemia-reperfusion injury may result in inflammation, thrombosis, anatomic and functional changes in the vasculature, and tissue damage via a vicious self-propagating cycle.

Risk Factors for VTE in IBD

Age

Young IBD patients had more than sixfold higher risk of developing VTE as compared with age- and sex-matched individuals without IBD (HR: 6.4 [95% CI: 2.5–14.7]).[53] A retrospective study showed that hospitalized children and adolescents with IBD had a 2.4 relative risk of developing VTE as compared with those without IBD.[12] Moreover, several studies demonstrated that VTE risk increased with age (odds ratio [OR]: 2.32; 95% CI: 2.26–2.38).[12] [55] Finally, older age was associated with high risk of developing postdischarge VTE[63] ([Table 4]).

Table 4 Venous thromboembolism risk factors in IBD patients

VTE risk factor	Findings
Age	Patients ≤20 y, DVT HR: 6.0; 95% CI: 2.5–14.7), PE HR: 6.4 95 CI: 2.0–20.3)[53] VTE risk increased with age (OR: 2.32; 95% CI: 2.26–2.38)[55]
Disease activity	IBD flare is linked to VTE HR: 8.4 [95% CI: 5.5–12.8][63]
Disease extent	Pancolonic involvement in 76% of UC patients with VTE; diffuse disease in 79% of CD patients[9]
Surgery	IBD-related surgery VTE HR: 40.81 [95% CI: 10.2–163.9][68]
C. difficile infection	VTE risk in patients with IBD and C. difficile infection: 1.7 [95% CI: 1.4–2.2][70]
IBD treatment	Systemic corticosteroids OR: 1.22 [95% CI: 1.16–1.29][8] JAK inhibitors (tofacitinib) DVT IR: 0.04 [95% CI: 0.00–0.23]; PE IR: 0.21 [95% CI: 0.07–0.48][75]
Thrombophilia	FV Leiden mutation 14.3% of IBD patients with VTE versus 0% of IBD without VTE[80]
Hospitalization	IBD patients hospitalized for reasons other than IBD flare VTE HR: 12.97 [95% CI: 8.68–19.39][65]
Pregnancy	VTE risk during pregnancy almost 2-fold higher in women with IBD[90] In the postpartum period, VTE RR: 2.1 [95% CI: 2.72–3.04][90]

Abbreviations: CD, Crohn's disease; CI, confidence interval; DVT, deep venous thrombosis; HR, hazard ratio; IBD, inflammatory bowel disease; IR, incidence rate; OR, odds ratio; PE, pulmonary embolism; RR, relative risk; UC ulcerative colitis; VTE, venous thromboembolism.

Disease Activity and Extent

The presence of active disease increases the risk of VTE among patients with IBD. In particular, IBD flare was associated with the highest VTE risk (HR: 8.4; 95% CI: 5.5–12.8) versus IBD patients with chronic disease activity or in remission.[64] A retrospective study showed that 71% of IBD patients diagnosed with VTE had active disease at the time of diagnosis.[15]

A study by Solem et al found an association between disease extent and VTE risk in patients with IBD: 76% of UC patients with VTE had pancolonic involvement, whereas 79% of CD patients had diffuse disease (56% ileocolonic disease, 23% colonic disease, and 21% ileal disease).[9] A more recent study demonstrated that 71% of UC patients with a VTE had pancolitis, and all CD patients with VTE had ileocolonic involvement[65] ([Table 4]).

Surgery

Colorectal surgery is a risk factor for VTE in IBD patients. In particular, IBD-related surgery conferred a higher thrombotic risk both during hospitalization and post-discharge, even when compared with non–IBD-related surgery for colorectal cancer.[66] [67] [68] The highest risk of VTE is present within the first 2 weeks of hospital discharge, with 61% of postoperative venous thrombosis occurring within that period[69] ([Table 4]).

Clostridium difficile Infection

A large retrospective cohort study showed that Clostridium difficile infection is an independent risk factor for VTE in IBD patients.[70] In particular, the risk of VTE is twofold greater in patients with IBD and C. difficile infection versus subjects without infection.[70] C. difficile infection could be a risk factor for readmission due to VTE in patients with IBD during a 2-month time period[63] [70] [71] ([Table 4]).

Medications

Corticosteroid treatment can increase VTE risk in IBD patients.[72] [73] Systemic corticosteroids were associated with significantly higher rate of VTE complications in IBD patients compared with IBD patient without steroid medication (OR: 1.22; 95% CI: 1.16–1.29).[8] Corticosteroids can induce hypercoagulability, by increasing plasma fibrinogen level and decreasing tPA activity and prostacyclin synthesis.[74] Furthermore, the use of corticosteroids before hospitalization is an independent risk for VTE.[72]

Tofacitinib, a Janus kinase inhibitor employed for the treatment of moderate and severe UC, can also increase VTE risk in IBD patients[75] ([Table 4]). In the study by Setyawan et al, authors argued that this therapy seems to be associated with an increased risk of thrombosis.[6] A recent post-marketing surveillance trial in patients affected by rheumatoid arthritis showed that tofacitinib treatment (10 mg twice daily) was more significantly correlated with PE than tofacitinib 5 mg or TNF inhibitors.[76] In 2019, the FDA released an updated safety announcement limiting the use of high-dose tofacitinib in UC patients to initial induction therapy.[77] Beyond 8 weeks of therapy, high-dose tofacitinib should be used only in limited situations after a careful evaluation of risks and benefits, especially in patients with previous risk factors for VTE.[78]

Inherited and Acquired Thrombophilia

The prevalence of factor V Leiden mutation in IBD patients with VTE was significantly higher (14.3%) than in IBD patients without thrombosis (0%; p = 0.04).[79] [80] On the other hand, the prevalence of prothrombin G20201A mutation was similar in IBD patients with versus without thrombosis.[81]

A higher frequency of mild hyperhomocysteinemia has been reported in IBD patients[82] and has been linked to genetic factors (a mutation in the methylenetetrahydrofolate reductase gene), IBD drugs (sulfasalazine, methotrexate, corticosteroids), and nutritional deficiencies (e.g., folate, vitamins B6, and B12).[83] Some data demonstrated that homocysteine is increased in the mucosa of patients with UC and CD, thus inducing an inflammatory state in the mucosal endothelium.[83]

A significantly higher prevalence of anticardiolipin and anti β2-glycoprotein I (anti-β2-GPI) antibodies has been found in patients with UC and CD versus healthy controls.[84] However, a clear correlation between antiphospholipid antibodies and thromboembolism has not been established.[80]

A recent study showed that patients with CD had a significantly higher prevalence of both anticardiolipin and anti-phosphatidylserine/prothrombin (anti-PS/PT) antibodies versus UC and healthy controls.[85] The prevalence of anti-β2-GPI, anticardiolipin, and anti-PS/PT antibodies was similar in patients with active versus inactive disease.[85]

Increased levels of lipoprotein (a) have been detected in patients with CD, and appear to correlate with an increased rate of VTE.[86]

Hospitalization

Hospitalization is a relevant predictive factor for VTE, as it reflects periods of increased inflammation.[64] [87] The VTE rate among hospitalized IBD patients increased from 192 to 295 cases per 10,000 between 2000 and 2018.[8] Increasing age, male sex, UC (OR: 1.30 [95% CI: 1.26–1.33]), non-Hispanic Black, and chronic corticosteroid use (OR: 1.22 [95% CI: 1.16–1.29]) were associated with VTE during hospitalization.[8] Other risk factors for VTE events include immobility, the use of a venous catheter for parenteral nutrition, and fluid depletion due to diarrhea. Hospitalized IBD patients present higher rates of VTE, as well as VTE-related mortality versus hospitalized patients without IBD.[87] Moreover, a nationwide Korean study showed that IBD patients hospitalized for reasons other than IBD flare carried greater than 12-fold increased VTE risk (HR: 12.97; 95% CI: 8.68–19.39) versus healthy controls.[65] Furthermore, VTE was observed during clinical remission in one-third of IBD hospitalized patients.[88] [89]

Pregnancy

Physiologic changes during pregnancy increase the risk of VTE. Based on data from a Danish nationwide population-based cohort study, the relative risk for VTE during pregnancy was almost twofold higher in women with IBD as compared with those without IBD.[90] In the postpartum period, women with IBD had a 2.1 (95% CI: 2.72–3.04) higher relative risk of developing VTE versus women without IBD.[90] A recent meta-analysis reinforced the finding that pregnancy conferred greater than twofold increased risk of VTE among patients with IBD, which persisted during the postpartum period.[91] A subgroup analysis revealed that the VTE risk was more relevant in UC patients versus CD both during the pregnancy and postpartum.[91]

Prevention of VTE in IBD

VTE in patients with IBD was associated with a worse prognosis, longer hospital stay (11.7 vs. 6.1 days, p < 0.01) and higher mortality rates.[87] In-hospital mortality for IBD patients presenting with VTE was significantly higher versus IBD patients without VTE, both for CD (17.0 vs. 4.2 per 1,000 hospitalizations, p < 0.01) and UC (37.4 vs. 9.9 per 1,000 hospitalizations, p < 0.01).[87]

North American and European Societies of Gastroenterology and the European ECCO guidelines on extraintestinal complications in IBD recommend pharmacological thromboprophylaxis in all hospitalized IBD patients.[92] [93] [94] [95] Primary pharmacological thromboprophylaxis is recommended in all hospitalized patients with IBD, due to the high VTE risk, regardless of the reason for admission.[93] [96]

Low-molecular-weight heparin (LMWH) is the first drug of choice, though unfractionated heparin may be preferred in case of low estimated glomerular filtration rate.[94] Despite growing evidence of the importance of primary thromboprophylaxis in IBD patients, its in-hospital implementation remains uneven. In a Canadian multicenter retrospective study, IBD patients hospitalized in surgical departments received VTE prophylaxis more frequently than those hospitalized in medical departments (84 vs. 74%).[97] Concerns about major or minor bleeding during hospitalization explain the sparse use of LMWH in everyday clinical practice. Several studies demonstrated that the rate of major and minor bleeding did not increase among patients receiving VTE prophylaxis compared with a control group. Furthermore, hematochezia—passing of red/fresh blood in the stools—appeared to be less frequent among IBD patients receiving VTE prophylaxis.[98] [99] Therefore, all clinicians ought to be aware of the safety and the importance of VTE prophylaxis in hospitalized IBD patients.

Thromboprophylaxis is strongly recommended in patients undergoing general/abdominal surgery or caesarean section.[16] [96] However, univocal data on the duration of treatment postdischarge are not yet available. A 2021 study conducted by Lee et al investigated the use of rivaroxaban as postdischarge VTE prophylaxis in IBD patients.[90] [100] Additional 4 weeks of VTE prophylaxis postdischarge with 10 mg/day of rivaroxaban resulted in higher quality-adjusted life-years versus in-hospital VTE prophylaxis alone.[90] Although postdischarge VTE prophylaxis for all patients with IBD is not cost-effective, it should be considered on a case-by-case scenario by thoroughly assessing the VTE risk profile, costs, and patient's preference.[100]

Mechanical thromboprophylaxis, graduated compression stockings, and/or intermittent pneumatic compression devices are indicated only for temporary use in IBD patients hospitalized with major gastrointestinal bleeding who are hemodynamically unstable.[93] Pharmacological prophylaxis should be resumed once hemodynamic stability has been restored.[93] Mechanical thromboprophylaxis is also recommended for the early mobilization of patients after major surgery or long hospitalization.[93]

Hospitalization is an important VTE risk factor in patients with IBD, both during active disease and in remission. Therefore, VTE prophylaxis should be recommended for all IBD patients hospitalized for an acute flare.[93] [95] Whether prophylaxis should be extended to all outpatients with disease flare is still a matter of debate. A large UK cohort study demonstrated that the absolute VTE risk in hospitalized IBD patients in remission is threefold higher than in nonhospitalized patients with an acute flare.[64] There are little data pertaining to the management of IBD outpatients. According to the Canadian Gastroenterology guidelines, thromboprophylaxis in outpatients is recommended only in case of an acute flare if there is a previous history of VTE,[93] due to the higher intrinsic VTE risk.

There is currently no definitive data regarding the use of combined hormone therapy in women with IBD. Cotton et al demonstrated that women with IBD do not carry an increased risk of VTE compared with healthy controls, even in the presence of concomitant thrombotic risk factors such as cigarette smoking or cancer.[101] Furthermore, a 2015 study did not find an increased thromboembolic risk in women with IBD receiving oral contraceptive therapy versus healthy women.[102] Nevertheless, the U.S. Medical Eligibility Criteria for Contraceptive Use recommends the use of alternative contraceptive methods in patients with IBD where possible and advise against their use altogether in patients with severe forms of IBD, with complications, undergoing surgery, or steroid treatment.[103]

Treatment of VTE in IBD

There are no specific recommendations for the treatment of VTE events in IBD patients. The European ECCO guidelines on extraintestinal manifestations in IBD recommend LMWH as first-line drug if the patient is hemodynamically stable.[95] In the post-acute phase, LMWH is usually switched to oral vitamin K antagonists (VKAs).[95] Some data indicate that the efficacy and the safety of anticoagulation therapy appear to be similar in patients with or without IBD.[104] Moreover, the frequency of major/minor bleeding was not reported to be higher in IBD patients with acute flare or in remission versus patients without IBD.[104]

According to the Canadian Association of Gastroenterology, the duration of anticoagulant treatment depends on the clinical condition of each patient. In case of VTE occurring during IBD acute flare, anticoagulation therapy is recommended for 3 to 6 months for unprovoked VTE, whereas it should be continued for 1 month after resolution of risk factor (for a total of at least 3 months) in case of provoked VTE[93] ([Fig. 2]). Hormonal therapy should be discontinued in female patients presenting a first VTE episode during IBD acute flare.[103]

Fig. 2 Therapeutic indications for venous thromboembolism (VTE) in inflammatory bowel disease (IBD) patients and suggested duration according to clinical characteristics.

In case of VTE occurring during clinical remission, anticoagulation therapy should be continued for 1 month after resolution of risk factor and at least for 3 months for provoked VTE,[93] whereas indefinite anticoagulation therapy is recommended with periodic reviews in case of unprovoked VTE. That recommendation is in line with the current ECCO guidelines[95] ([Fig. 2]).

Indefinite anticoagulation therapy with LMWH or VKA is recommended in case of recurrent VTE (i.e., two or more events), regardless of IBD activity.[93]

In case of massive PE and/or hemodynamic instability, the use of catheter-directed thrombolysis with t-PA, urokinase, or streptokinase is recommended.[105] It should also be taken into consideration in otherwise healthy patients with significant iliofemoral DVT, seeing as it may reduce the incidence and severity of postthrombotic syndrome.[105]

Anticoagulant therapies have evolved greatly in the past 10 years, thanks to the development of non–vitamin K antagonist oral anticoagulants (NOACs). These new drugs have improved patients' quality of live owing to their excellent safety profile and daily manageability.[106] Unfortunately, there are little data in the current literature about the use of NOACs in IBD patients. In a 2018 study based on data retrieved from the RIETE registry—an ongoing international observational registry of patients with VTE—only 2 out of 180 IBD patients in remission with VTE were treated with NOACs, namely, rivaroxaban.[104] Viola et al performed a retrospective analysis on the outcomes of IBD patients treated with NOACs in comparison with IBD patients on antiplatelet therapy and non-IBD patients on NOACs.[107] Authors showed that anemia and hospitalizations were more frequent in IBD patients on NOAC treatment, but there was no difference between the three groups concerning the need for intravenous iron or blood transfusions.[107] However, in this study, only 8 of 14 patients were treated with a NOAC for VTE. Larger studies are needed to evaluate the NOAC indication and safety to treat VTE in IBD patients.

Future anticoagulant therapies may help further reduce the risk of bleeding complications via selective targeting of coagulation factors that play a more relevant role in pathological thrombosis versus physiological hemostasis. In that regard, the inhibition of factors XI and XII in animal models grants protection from arterial and venous thrombosis without provoking bleeding complications.[108] [109] Therapeutic targeting of factor XI may also yield beneficial effects on vascular dysfunction, arterial hypertension, and thrombus formation in atherosclerotic lesions, and in patients with systemic inflammatory conditions.[110] Several experimental drugs targeting intrinsic coagulation factors are currently undergoing preclinical development/study.[111] To date, small-molecule inhibitors, antibodies, and antisense oligonucleotides targeting factor XI have completed only early phase trials in humans.[112]

Conclusions

Patients with IBD have an increased risk of developing thromboembolic events. The pathophysiological changes underlying IBD can induce a prothrombotic state, thus resulting in microthrombi in the intestinal mucosa and an increased risk of systemic VTE. Notably, the interplay among alteration of the gut microbiome, dysregulated activation of immune cells, intestinal microthrombosis, and endothelial dysfunction represents the basis of the so-called vascular hypothesis. Endothelial dysfunction may in turn trigger a systemic inflammatory response mediated by cytokines, activated platelets, and the coagulation cascade with an increase in procoagulant factors and a decrease in the levels of natural anticoagulants. Furthermore, hypofibrinolysis also contributes to the maintenance of a hypercoagulable state. There are growing data on the molecular mechanisms underlying these pathological pathways, which may provide novel therapeutic targets in the treatment of bowel disease and the prevention of thromboembolic complications.

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