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Widespread occlusive vascular disease in a Crohn's disease patient with profound thrombocytosis.

To the Editor: A 47-year-old woman with a history of Crohn’s disease presented with arterial thromboembolic disease of her lower extremities and a gangrenous left foot. The patient was found to have profound thrombocytosis with a platelet count of 1237 10/mm, venous occlusive disease of her portal system and developed a cerebral infarct during her admission. Her hypercoagulable state was believed to be caused by reactive thrombocytosis, confirmed with a bone biopsy, secondary to her inflammatory bowel disease (IBD). The patient underwent plateletphoresis with antiplatelet therapy before a left transmetatarsal amputation followed by a subtotal colectomy due to her refractory Crohn’s colitis. The incidence of thromboembolic events in IBD varies between 1.2% and 6.7% in clinical series and up to 39% in autopsy studies. Most thromboembolic events involve deep venous thrombosis and pulmonary embolism, and IBD patients have approximately a 3-fold increased risk of these complications. Portal vein thrombosis has been reported in 9% of IBD patients with up to a 50% mortality rate secondary to gastrointestinal bleeding. Cerebral vascular accidents are associated with 10% of thromboembolic events in IBD patients and approximately 80% of those patients develop permanent neurologic defects. Arterial thromboembolic events in IBD are rarely described. Multiple risk factors for thromboembolic have been identified in patients with IBD. Various hypercoagulable states such as decreased protein S, elevated anticardiolipin antibodies, antiphospholipid antibodies, factor V Leiden, activated protein C resistance, and hyperhomocysteinemia. Other findings include plasminogen activator inhibitor 1 polymorphism, elevated lipoprotein (a), and elevated tumor necrosis factor a. Reactive thrombocytosis (platelet count >450 10/mm) related to elevated thrombopoietin level or elevated interleukin-6 have also been described as to have other contributing conditions such as immobilization and surgery. Of the risk factors mentioned above, antiphospholipid antibodies and activated protein C resistance have been noted to increase the risk of thromboembolism when present, although they do not seem to be associated with an increased risk in IBD per se. It is believed that subclinical processes concurrently contribute to the development of an environment in the vasculature favorable to the genesis of thrombosis, ischemia, and ultimately infarct. Van Bodegraven described the interaction between the inflammatory process and the coagulation system as IBD stimulates the production of cytokines IL-1, IL-6, and tumor necrosis factor-a, which increase thrombocytosis and coagulation and decrease fibrinolysis through their action on tissue factor, prothrombin, thrombopoietin, and plasminogen activator inhibitor 1. An increase in the contact activating system in the intrinsic coagulation cascade induced by the inflammatory process of IBD occurs as well. These mechanisms with reactive thrombocytosis are presumed responsible for the thromboembolic events. Similarly, Solem et al reported reactive thrombocytosis present in 8% of Crohn’s disease and 15% of ulcerative colitis patients. Although there are multiple etiologies, in IBD it is believed to be caused by elevated interleukin-6 level, an acute-phase inflammatory marker which increases hepatic thrombopoietin production resulting in increased megakaryocytopoiesis and resultant thrombocytosis. Reactive thrombocytosis rarely results in vascular or thrombotic events. This is due to an underlying ‘‘normal’’ interaction between platelets and the endothelial vessel wall, which may be absent in IBD. No single mechanism for the development of a thrombogenic event has been identified in IBD. Various pathways that inhibit fibrinolysis while increasing inflammation, thrombocytosis, and coagulation, seem to act synergistically to create multiple thromboses. This is, to our knowledge, the first reported case of multiple simultaneous arterial and venous thromboembloic events in a patient with IBD. It highlights the complex multifactorial relationship between IBD and the genesis of vascular thrombosis. As such, it presents new considerations and challenges in identifying IBD patients at risk for thromboembolic events and designing appropriate therapy.