Thalidomide use and digital gangrene.

A 60-year-old woman who presented initially with splenomegaly and petechiae underwent evaluation with a bone marrow biopsy, which revealed a diagnosis of chronic idiopathic myelofibrosis (with extramedullary hematopoiesis). She was initiated on therapy with thalidomide (100 mg daily) and prednisone (30 mg daily). Eight weeks into her treatment course, she developed erythema and pain, specifically in the right index distal phalanx (Fig 1) she used to push open the thalidomide blister packs. She subsequently developed gangrene in the involved fingertip. Hypercoagulation diagnostic interpretive studies revealed no abnormalities, the patient had no prior history of thromboembolism, and tests for connective tissue disorders were negative. ECG imaging revealed no evidence of valvular disease or vegetations. Treatment with thalidomide was stopped and the patient underwent successful debridement. There were no recurrences. Thalidomide, a glutamic acid derivative, is US Food and Drug Administration approved for the treatment and maintenance of cutaneous manifestations of multiple myeloma and erythema nodosum leprosum. Its unlabeled applications, which constitute the majority of its use, include the treatment of myelodysplastic syndromes, myeloproliferative disorders, Crohn’s disease, graft-versus-host reactions after bone marrow transplantation, and AIDS-related aphthous stomatitis. The mechanism of action by which thalidomide produces benefits in cancer patients is unclear, but theories include direct inhibition of myeloma cells, oxidative damage to DNA mediated by free radicals, manipulation of adhesion molecules, and alterations in cytokine activity, specifically tumor necrosis factor alpha, interleukin 1 beta, tumor growth factor beta, and cyclooxygenase 2. Thalidomide use has been associated with venous thrombosis; however, to date there have been only a few case reports of arterial thrombosis, and even fewer with development of gangrene. The mechanism by which thalidomide produces this adverse effect may include alterations in von Willebrand factor levels and direct action on previously damaged endothelial cells. Concern for thromboembolic events has been raised, especially for patients concurrently receiving chemotherapy and steroid therapy. In combination therapy series, rates of venous thrombosis were 20% to 30%. Most of these studies involved thalidomide therapy in myeloma and the myelodysplastic syndromes, and in fact, this is the first report describing arterial thrombosis in patients with idiopathic myelofibrosis treated with thalidomide. Idiopathic myelofibrosis is a myeloproliferative process characterized by intramedullary reticulin formation (fibrosis) and extramedullary hematopoiesis. It commonly produces cytopenias, as well as dysfunctional platelets, and a predisposition to bleeding rather than hypercoagulability. Early studies and single institution experiences have shown that thalidomide therapy can improve cytopenias, transfusion dependency, and splenomegaly; although, there are other studies that found the adverse effects outweighed its benefits. This case is a demonstration of the unusual occurrence of arterial thrombosis that occurs with thalidomide use and trauma related to taking the medicine.