Livedoid Vasculopathy Associated With Plasminogen Activator Inhibitor-1 Promoter Homozygosity (4G/4G) Treated Successfully With Tissue Plasminogen Activator

Abstract

Background: Livedoid vasculopathy (LV) is an occlusive thrombotic disease that affects primarily the small blood vessels of the lower extremities and often is associated with recurrent painful ulcerations. The pathogenesis of LV is unclear, but the disease is largely attributed to a hypercoagulable state. Factor V Leiden mutation, heterozygous protein C deficiency, homozygous hyperhomocysteinemia, and other inherited thrombophilias have been associated with LV. Plasminogen activator inhibitor-1 (PAI-1) is an important inhibitor of the fibrinolytic system. Elevated levels of PAI-1 are found in some patients with thrombotic diseases. Some of these patients are homozygous for an allele of PAI-1 containing a stretch of 4 guanines at base −675 in the promoter region. This variant is associated with elevated PAI-1 protein levels, impaired fibrinolysis, and increased risk of thrombosis.Observations: A 33-year-old white woman had a 3-month history of painful enlarging ulcers on both ankles. Various therapies, including administration of oral antibiotic agents and prednisone up to 100 mg/d, to treat presumed vasculitis, were unsuccessful. Skin biopsy specimens revealed numerous thick-walled small blood ves-

Livedoid vasculopathy associated with combined prothrombin G20210A and factor V (Leiden) heterozygosity and MTHFR C677T homozygosity

“…This suggests inter-play between inflammatory and coagulation mechanisms in LV pathogenesis in our patient. Our findings were comparable to those of others [15,20], and in agreement with the finding of Deng et al, who failed to get any noticeable improvements with highdose (100 mg/day) prednisone monotherapy [13].…”

“…Clinical improvement were also reported using novel treatments, including tissue plasminogen activator [13,22], intravenous immunoglobulin [23], and the prostacyclin analogue, iloprost [24]. Our patient was refractory to the initial dapsone and hydroxychloroquine treatment, and prednisone inclusion did not show any improvement.…”

Enhanced functional stability of plasminogen activator inhibitor-1 in patients with livedoid vasculopathy

“…Homozygosity for 4G in the 4G/5G polymorphism of PAI-1 promoter at the -675 bp region has been associated with elevated PAI-1 protein levels [24], impaired fibrinolysis, and increased risk of thrombosis. Livedoid vasculopathy lesions responded to t-PA infusion in a patient with 4G/4G genotype [11]. We observed that genotype frequencies were similar among LV patients compared to prior observations from Turkish subjects [18] without any significant difference in PAI-1 Ag and activity between genotype groups.…”

Livedoid Vasculopathy: A French Observational Study Including Therapeutic Options

“…PAI-1 has a central role in the inhibition of fibrinolysis through the inhibition of the activators of plasminogen (tissue plasminogen activator tPA and urokinase uPA). PAI-1 has been implicated in LV in 3 previous studies (5)(6)(7). In our study, only one patient had an elevated PAI-1 antigen and he also presented with severe hypertriglyceridemia.…”

“…Studies have been discordant about the exact thrombotic risk associated with 4G/5G polymorphism but a recent meta-analysis by Wang et al (25) has concluded that there was a significantly higher risk of thrombosis with the 4G homozygosity in venous thrombosis. In LV, one patient has been reported with 4G/4G homozygous genotype (7). In our LV population, we found that the distribution of the 4G/4G; 4G/5G and 5G/5G genotypes (respectively 22%, 45%, 33%) was not different to the control samples in the same laboratory or other studies (respectively 30%, 50%, 20%) (26,27).…”