Homocysteinemia and livedoid vasculitis

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Homocystinuria is a rare autosomal recessive genetic abnormality associated with significantly increased levels of homocysteine in the blood.1 The disorder is associated with arterial and venous thromboembolic events at an early age. Patients may have a marfanoid habitus, mental retardation, and psychiatric disorders. Skin manifestations include skin and hair hypopigmentation, a malar rash, livedo reticularis, and leg ulcers. Deficiencies of several enzymes involved in homocysteine metabolism, including cystathionine β-synthase and 5,10-methylenetetrahydrofolate reductase, are associated with homocystinuria. In the general population, an association between total plasma homocysteine levels and coronary artery disease, peripheral artery disease, stroke, and venous thrombosis has been shown in more than 75 clinical and epidemiologic studies.2,3 Livedoid vasculitis is a cutaneous occlusive vasculopathy characterized by recurrent painful ulcers of the lower extremities in association with a persistent livedo reticularis (Fig 1). Histologic examination reveals segmental hyalinization and primarily noninflammatory thrombotic occlusion of dermal arterioles. Some patients with livedoid vasculitis have enhanced procoagulant or deficient fibrinolytic activity of plasma.4 Treatment with tissue plasminogen activator (t-PA) has promoted healing of chronic leg ulcers caused by livedoid vasculitis.5 No studies to date have addressed the possible contribution of increased blood homocysteine levels to the pathogenesis of small-vessel occlusive vasculopathy. It is possible that increased homocysteine levels alone or in combination with other defects of inherited thrombophilia (the “doublehit” effect) may be associated with an increased risk of small-vessel thrombosis. Klein and Pittelkow5 found a high incidence of anticardiolipin antibodies, lupus anticoagulant, increased levels of t-PA inhibitor, and low levels of endogenous t-PA activity in patients with livedoid vasculitis. An increased risk of large vessel thrombosis was also demonstrated in patients with homocystinuria who in addition had factor V Leiden.6 The aim of this study was to determine whether homocysteine levels are increased in patients with livedoid vasculitis and, if so, whether this is an isolated phenomenon or occurs in association with other inherited or acquired defects leading to thrombophilia.