Livedoid vasculopathy; favorable clinical response with low dose warfarin

ARTICLE

ejd.2011.1529

Auteur(s) : Satoshi Nakamura^1,2 namu@asahikawa-med.ac.jp, Mari Kishibe², Kaoru Nishi¹, Yoshio Hashimoto¹, Keiko Takeda², Toshihiro Mizumoto¹, Hajime Iizuka²

¹ Asahikawa Kousei Hospital, Department of Dermatology, 1-joudori 24-chome 111, Asahikawa Hokkaido, Japan

² Asahikawa Medical University, Department of Dermatology, Asahikawa Hokkaido, Japan

Livedoid vasculopathy (LV) is a chronic, recurrent, painful skin disorder involving distal lower extremities. LV is induced by coagulation abnormalities or by fibrinolysis alterations such as anti-phospholipid syndrome, decreased protein C activity, Factor V Leiden gene mutation, and hyper-homocysteinemia [1-3]. Warfarin-potassium (warfarin) for thrombotic dissolution has been applied for LV [1-3]. We describe 3 cases showing favorable clinical responses with low-dose warfarin (2.5-5mg). We detected C677T heterozygous methylene-tetrahydrofolate reductase (MTHFR) gene mutations in 2/3 cases, the significance of which remains to be determined.

A 27-year-old man had painful ulcers on bilateral legs of 10-years duration. He had no traumatic episode, but had a smoking history for 4 years. Physical examination revealed irregular-shaped skin ulcers, sized up to 4.5 × 2.5cm, on bilateral legs. Complete blood count, liver function test, and serum electrolytes were normal. Hepatitis B and C virus antibodies, rheumatoid factor, and cryoglobulin were negative. Anti-cardiolipin IgG antibody, anti-cardiolipin β2GP1 complex IgG, perinuclear anti-neutrophil cytoplasmic antibody, cytoplasmic anti-neutrophil antibody, and antinuclear antibodies were also negative. Prothrombin time, prothrombin time-international normalization ratio (PT-INR), activated partial thromboplastin time; protein C and S activities were within normal limits. Antiphosphatydylserine-dependent anti-prothrombin (aPS/PT) IgG was not detected. MTHFR analysis disclosed heterozygous C677T allele. Histopathology disclosed small vessels with mild endothelial proliferation, perivascular lymphoid cell infiltration, hyalinization, and thrombosis. We started 5mg/day warfarin with PT-INR monitoring between 1-2. The ulcers re-epithelized within 3 weeks.

A 41-year-old woman had painful ulcers on bilateral legs, of 14-years duration. She had been treated by corticosteroid ointment, systemic corticosteroid, prostaglandin-F2 (PG-F2), and aspirin. She had no smoking history. Physical examination revealed 2-3cm sized irregular-shaped ulcers on bilateral legs. Her laboratory and histopathological findings were essentially like the previous case. No alteration of MTHFR gene was detected. We started 4 mg warfarin with PT-INR monitoring between 1-2. The ulcers were completely epithelized within 3 weeks.

A 40-year-old woman had painful ulcers on bilateral legs of 2-years duration. She had been treated by corticosteroid ointment, systemic corticosteroid, PG-F2, aspirin, and sarpogrelate hydrochloride. She was a taxi-driver with a smoking history. Physical examination revealed up to 3cm-sized irregular shaped deep ulcers on her bilateral legs (figure 1A). Her hemoglobin A1c level was 6.4%. The other laboratory findings were normal. MTHFR analysis disclosed a heterozygous C667T allele. Histopathology disclosed endothelial cell proliferation, marked perivascular lymphoid cell infiltration, hyalinization, and thrombosis (figure 1B). We started 3mg warfarin (figure 1C) with PT-INR monitoring between 1-2. A favorable clinical response with complete re-epithelization was detected within 5 weeks (figure 1D).

LV is induced by various coagulation or fibrinolysis abnormalities. However, only 41% cases show notable coagulation abnormalities [1]. Intra-luminal thrombosis is usually detected. We tried low dose warfarin for 3 patients and their ulcers re-epithelized within 3 to 5 weeks. PT-INR was adjusted to be less than 2 [2, 3]. Our patients did not show abnormalities by standard laboratory tests or aPS/PT IgG. We detected, however, heterozygous mutation of C667T of the MTFHR gene in 2/3. Hyper-homocysteinemia induced by the mutation of MTFHR, which catalyses 5,10 methylenetetrahydrofolate (MTFH) formation from 5MTFH as well as methionine formation from homocysteine has been documented [4]. This may result in abnormal homocysteine metabolism and an elevated risk of vascular disease [5]. Meta-analysis of MTHFR gene polymorphism of C667T disclosed that homozygous (TT) and heterozygous (CT) mutation of MTHFR results in higher plasma homocysteine concentration than CC genotype. This mutation may be related to the increased risk of thrombosis [6]. Although cutaneous vascular embolization of LV may be related to the MTHFR genotype, the precise relation to LV remains to be determined. Further study is required to clarify the nature of LV, especially in terms of MTHFR gene polymorphism.

Disclosure

Financial support: none. Conflicts of interest: none.

References

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