Stroke Snapshot: Ulcerative Colitis & Stroke

Discussion

Ulcerative colitis is an idiopathic chronic inflammatory condition affecting the mucosa of the colon. Ulcerative colitis is characterized by a relapsing and remitting pattern, and recognized as a part of inflammatory bowel disease (IBD).¹ Hypercoagulability, iron deficiency, chronic vascular endothelial changes, and possibly chronic intestinal loss of essential factors in the clotting cascade due to an underlying inflammatory process are suspected to be the cause of rare but known cerebrovascular complications of ulcerative colitis.^1-4

Manifestation and Pathophysiology

Individuals with ulcerative colitis have an increased risk of cerebrovascular disease compared with the general population, with a frequency up to 4.7%.² The reported hazard ratio for cerebrovascular disease among people with ulcerative colitis over age 50 is 2.045.⁵ Arterial ischemic strokes with multiple mechanisms have been reported, including vasculitis and cardioembolic stroke due to left ventricular thrombus formation.^1,6 Rare cases of intracerebral hemorrhage, suspected to be related to therapies targeting tumor necrosis factor (TNF) for IBD, have also been reported.¹

The incidence of cerebral venous sinus thrombosis in IBD is estimated at 6.4%, and this is reported to be almost twice as high in people with ulcerative colitis vs Crohn disease.⁴ Other neurologic manifestations unrelated to cerebrovascular disease are reported elsewhere and are beyond the scope of this review.¹ Multiple causes of hypercoagulability have been reported but overall, no single cause have been defined as the main culprit.² Increased levels of homocysteine, platelets, factor VIII, fibrinogen, and fibrinopeptide A have been reported in people with ulcerative colitis who have had a stroke.² Experimental studies suggest potential activation of the coagulation system with elevated inflammatory markers shifting the balance toward a prothrombotic state.⁷ Despite decreased levels of thrombin, platelet activation occurs via interleukin 6 (IL-6) or the CD40 ligand.⁸

Although factor V is the most identifiable risk factor for thrombophilia—found in 33% of persons with ulcerative colitis—the significance of this finding is expected to resemble that of individuals with thrombotic conditions.^2,9 Similarly, decreased levels of protein S, antithrombin, and impaired fibrinolysis have also been reported. Transient decreased in protein S levels have been documented in cases of cerebral venous thrombosis and active bowel inflammation in ulcerative colitis.⁴ Similar cases of temporary protein C and factor II deficiency havebeen reported as well.¹⁰ Increased procoagulation factors, including von Willebrand factor; factors V, VII, X, XI, and XII; and fibrinogen have also been noted during active bowel inflammation.¹¹

Chronic intestinal inflammation leading to intestinal loss of necessary clotting cascade factors is also suspected to play a role in the association of ulcerative colitis and stroke.^3,12 Vitamin K malabsorption during active inflammation occurs due to the harmful effect of inflammation on the intestinal bacterial microbiome. Vitamin D deficiency is also seen in ulcerative colitis and thought to play a role in the proinflammatory process.¹² Severe iron deficiency anemia is more common in cerebral venous sinus thrombosis among those with ulcerative colitis and is thought to be a predisposing factor.⁴

Thrombophlebitis is mainly thought to be caused by impaired hemostasis, hypercoagulability, vessel wall changes, and alterations to gut microbes and endotoxins in people with venous thrombosis who have ulcerative colitis.^8,13 Clinical studies suggest a role for elevated levels of trimethylamine N-oxide (TMAO) in thromboembolism through endothelial cell activations, vessel wall inflammation, and platelet hyperactivity. Other endotoxins produced by gut bacteria are thought to play a role.¹³ Venous sinus thrombosis is more commonly seen during an active flare of inflammatory disease; however, it can also occur during remission periods.^4,14

Prevention and Treatment

To date, there are no specific evidence-based guidelines for the treatment and prevention of cerebrovascular disease in the context of ulcerative colitis. In the absence of active gastrointestinal bleeding, antiplatelets and anticoagulants are considered safe in this population.^2,4 There are no reports of anticoagulation use in those with active gastrointestinal bleeding, and involvement of a gastroenterologist is recommended for such cases. Ulcerative colitis is not a contraindication for the use of acute intravenous thrombolysis, unless there has been active gastrointestinal bleeding in the prior 21 days.¹⁵ Mechanical thrombectomy is not contraindicated either.

Conclusion

Although rare, ulcerative colitis can increase the risk of potential cerebrovascular complications, which can have potentially fatal complications. Multiple etiologies are suspected as predisposing factors. No specific treatment or prevention is currently available, with current treatments considered safe in the setting of ulcerative colitis.