Small Vessel Vasculitis / Venulitis, Related to Trazodone Therapy
Allen P. Burke
University of Maryland School of Medicine
A 50-year-old woman was taking trazodone for fibromyalgia. She developed bowel symptoms with right
lower quadrant mass. There was a vague recent history of a rash, but the physical examination on
admission did not note any skin lesions. Peripheral eosinophil count was mildly elevated at 3%. Imaging
demonstrates markedly thickened wall of the cecum and ascending colon. A right hemicolectomy was
There was edema of the submucosal layer (figure 1) and inflammation of the veins, with sparing of the
accompanying arteries (figure 2). The venous inflammation destroyed the wall and resulted, in many
segments, in luminal thrombosis (figure 3). A higher magnification of the vein showed eosinophils in a
chronic inflammatory infiltrate (figure 4). There was less striking involvement of smaller venules and
Low magnification of the bowel showing submucosal edema.
Submucosa demonstrating inflammation of veins with sparing of arteries.
Normal artery (above) with inflamed vein (below) with luminal thrombosis.
Numerous eosinophils are present in the venous inflammation.
Small vessel vasculitis / venulitis, related to trazodone therapy.
Small vessel vasculitis involves arterioles, capillaries, and venules, and is associated with immune
complex deposition or may be pauci-immune. The histologic hallmark is fibrinoid necrosis with
leukocytoclasia, or apoptotic degeneration of neutrophils, especially in the acute phase. Pauci-immune
small vessel vasculitis is frequently associated with anti-neutrophil cytoplasmic antibodies and is
loosely synonymous with microscopic polyangiitis. Immune small vessel vasculitis may be idiopathic,
drug-related and short-lived, or a manifestation of systemic autoimmune disease. Small vessel
vasculitis, either pauci-immune or immune complex-related, may be associated with necrotizing muscular
arteritis in Wegener's granulomatosis and rheumatoid arthritis and other autoimmune disorders,
An antigen-antibody complex mediated small vessel vasculitis may be induced by drugs, especially
penicillins, aminopenicillins, D-penicillamine, sulfonamides, allopurinol, hydralazine,
colony-stimulating factors, allopurinol, cefaclor, minocycline, phenytoin, isotretinoin, methotrexate,
thiazides, pyrazolones, retinoids, quinolones, hydantoins, and propylthiouracil. Some drugs, such as
penicillins, cause vasculitis by conjugating to serum proteins and mediating immune-complex vasculitis
that is similar to serum-sickness vasculitis. Other vasculitis-inducing drugs that cause immune-complex
formation are foreign proteins, such as streptokinase, cytokines, and monoclonal antibodies. In
addition, such drugs as propylthiouracil and hydralazine appear to cause vasculitis by inducing ANCA.
Trazodone has been associated with small vessel vasculitis in the skin. 
The interval between the first exposure and appearance of symptoms is variable. Although typically
benign and self-limiting, patients with severe manifestations have required corticosteroids,
plasmapheresis, hemodialysis, or cyclophosphamide.
Bowel involvement is not uncommon in systemic immune-related vasculitis, such as Henoch Schonlein
purpura, and ANCA-related microscopic polyangiitis. However, small vessel vasculitis localized to the
gastrointestinal tract is rare. Among cases of isolated vasculitis of the bowel, small vessel vasculitis
accounts for about 10%, the others consisting primarily of polyarteritis, phlebitis, and Churg-Strauss
It is and often associated with reaction to drugs or a manifestation of lupus.
Giant cell phlebitis is a rare form of vasculitis that occurs most commonly in the right colon and
omentum.  The symptoms are generally those related to a mass, and intestinal strictures and even
perforation may occur. The etiology is unknown, but there may be an association with reactions to
medications, and eosinophils are often present within the lesions. Histologically, giant cell phlebitis
is characterized by granulomatous destruction of muscular veins. It is possible that giant cell
phlebitis, limited Churg-Strauss syndrome, and small vessel vasculitis are part of a spectrum
representing differing expressions of a form of allergic or hypersensitivity phenomenon.
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