Livedoid vasculopathy

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Livedoid vasculopathy

Bethany R. Hairston and Mark D.P. Davis

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

(From Lebwohl, M.G., 2003. The Skin and Systemic Disease: A Color Atlas, second ed. Churchill Livingstone, with permission of Elsevier.)

Livedoid vasculopathy, or livedoid vasculitis, is a painful ulcerative condition of the lower extremities with characteristic clinical and histopathologic features. The lesions of atrophie blanche, a term once synonymous with the disease, are typically present on the lower extremities and are characterized by smooth, porcelain-white lesions surrounded by punctate telangiectasia and hyperpigmentation. Central, shallow ulceration is often present. This condition is difficult to treat and often recalcitrant to therapy.

Management strategy

Appropriate diagnosis of livedoid vasculopathy is necessary before treatment options can be considered. Histologic identification of the characteristic segmental hyalinized appearance of the dermal blood vessels is important to exclude other causes of lower extremity ulcerative disease. Increasing numbers of reports suggest that the disease has a procoagulant predisposition, with both hereditary and acquired hypercoagulable states.

Typically shallow and numerous, the ulcerations in livedoid vasculopathy are painful and slow healing. Wound care is an important facet of treatment. Excellent dressings and topical products are available to treat chronic ulcerative diseases, and selection depends on the moisture content of the wound and the possibility of superinfection. Topical and oral antibiotics may be beneficial, and wounds should be cultured to determine appropriate sensitivity to medications. Pain management is also essential.

Because of the potential procoagulant mechanisms involved in disease etiology, medical therapy has traditionally centered on prevention and treatment of dermal vessel thrombosis and improvement of vascular perfusion. Medical management has included aspirin (acetylsalicylic acid), niacin (nicotinic acid), pentoxifylline, dipyridamole, warfarin, and danazol. Systemic corticosteroids are not considered a primary therapy; however, some patients’ conditions have improved with immunosuppressants in combination therapy. Psoralen with UVA (PUVA) has also been used. Patients with livedoid vasculitis recalcitrant to traditional management have been treated with minidose heparin, subcutaneous low-molecular-weight heparin injections, intravenous iloprost (a prostacyclin analog), intravenous immunoglobulin (IVIG), and a tissue-type plasminogen activator (tPA).

Specific investigations

Skin biopsy, including routine histology and direct immunofluorescence

Wound and tissue cultures

Laboratory studies: hemogram, determination of serum homocysteine, cryoglobulin, anticardiolipin antibody, anti-β₂-glycoprotein I antibodies, factor V Leiden R506Q and prothrombin G20210A mutations, biological activity and antigen levels of protein C and S, functional and immunologic levels of antithrombin III protein, detection of lupus anticoagulant, lipoprotein(a), and fibrinopeptide A levels

Non-invasive venous and arterial function testing: continuous-wave Doppler, venous duplex imaging, plethysmography, and transcutaneous oximetry

Association between peripheral vascular endothelial dysfunction and livedoid vasculopathy.

Yang CH, Shen SC, Hui RC, Huang YH, Chu PH, Ho WJ. J Am Acad Dermatol 2012; 67: 107–12.

Sixteen patients diagnosed with livedoid vasculopathy were compared with 16 matched control subjects in this prospective study using flow-mediated vasodilation of the brachial artery, an indicator of vascular endothelial function, using high-resolution two-dimensional ultrasonic imaging. Peripheral vascular endothelial dysfunction was demonstrated in patients, providing some evidence of endothelial dysfunction in the development of the disease. Decreased nitric oxide bioavailability may be the main reason for this dysfunction; however, the authors noted that more studies are needed to clarify the mechanism.

Livedoid vasculopathy: an intriguing cutaneous disease.

Criado PR, Rivitti EA, Sotto MN, Valente NYS, Aoki V, de Carvalho JF, Vasconcellos C. An Bras Dermatol 2011; 86: 961–77.

Livedoid vasculopathy was originally described as a clinical expression of vasculitis; however, current understanding of the main pathogenetic mechanism suggests a vaso-occlusive phenomenon due to intraluminal thrombosis of dermal vessels. The authors review etiologic associations, publications on livedoid vasculopathy associated with hypercoagulable conditions, and options for treatment.

Livedoid vasculopathy: further evidence for procoagulant pathogenesis.

Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Arch Dermatol 2006; 142: 1413–18.

This retrospective study of 45 patients with biopsy-proven livedoid vasculopathy analyzed the presence of coagulation abnormalities. The laboratory results revealed numerous heterogeneous coagulation abnormalities, including factor V Leiden mutations, protein C or S abnormalities, prothrombin G20210A gene mutations, lupus anticoagulant, anticardiolipin antibodies, and elevated homocysteine, thus providing further evidence of procoagulant mechanisms for this disease.

Livedoid vasculopathy: what is it and how the patient should be evaluated and treated.

Callen JP. Arch Dermatol 2006; 142: 1481–2.

This editorial reviews nomenclature changes with this disease. An illustrative approach to diagnosis and review of treatments are well presented, including a ‘therapeutic ladder’.

Livedoid vasculopathy: the role of hyperhomocysteinemia and its simple therapeutic consequences.

Meiss F, Marsch WC, Fischer M. Eur J Dermatol 2006; 16: 159–62.

Hypercoagulability due to hyperhomocysteinemia was recognized as a potentially contributing factor to livedoid vasculopathy in a 49-year-old woman.

Livedo (livedoid) vasculitis and the factor V Leiden mutation: additional evidence for abnormal coagulation.

Calamia KT, Balabanova M, Perniciaro C, Walsh JS. J Am Acad Dermatol 2002; 46: 133–7.

A case of livedo vasculitis with the factor V Leiden mutation is described.

Livedoid vasculopathy associated with heterozygous protein C deficiency.

Boyvat A, Kundakci N, Babikir MO, Gurgey E. Br J Dermatol 2000; 143: 840–2.

Livedoid vasculitis in association with protein C deficiency is described in one patient.

Livedoid vasculitis: a manifestation of the antiphospholipid syndrome?

Acland KM, Darvay A, Wakelin SH, Russell-Jones R. Br J Dermatol 1999; 140: 131–5.

Four patients with ulcerative livedoid vasculitis are described, all of whom had associated elevated anticardiolipin antibody levels but no other evidence of systemic disease.

Atrophie blanche: a disorder associated with defective release of tissue plasminogen activator.

Pizzo SV, Murray JC, Gonias SL. Arch Pathol Lab Med 1986; 110: 517–19.

Plasma from eight patients with atrophie blanche was analyzed for release of vascular tPA before and after venous occlusion. The average plasma level of releasable tPA was only 0.03 IU/mL compared with 0.70 IU/mL for 118 healthy controls.

First-line therapies

Wound care (including bed rest and leg elevation)	C
Aspirin	C
Dipyridamole	C
Pentoxifylline	D

Atrophie blanche: a clinicopathological study of 27 patients.

Yang LJ, Chan HL, Chen SY, Kuan YZ, Chen MJ, Wang CN, et al. Changgeng Yi Xue Za Zhi 1991; 14: 237–45.

Twenty-seven patients were reviewed with respect to mean age at onset, disease duration, natural course, and clinical morphology. Thirteen patients responded to local wound care, bed rest, and low-dose aspirin plus dipyridamole as treatment for the first attack or recurrent episodes.

Livedoid vasculopathy associated with sickle cell trait: significant improvement on aspirin treatment.

El Khoury J, Taher A, Kurban M, Kibbi AG, Abbas O. Int Wound J 2012; 9: 344–7.

Authors describe a patient with sickle cell trait diagnosed with livedoid vasculopathy; treatment with aspirin led to significant improvement in the cutaneous ulcerations.

Livedo vasculitis: therapy with pentoxifylline.

Sams WM Jr. Arch Dermatol 1988; 124: 684–7.

Eight patients with disease unresponsive to a variety of medications were treated with pentoxifylline. Three experienced complete healing, four were much improved, while only one was unchanged after treatment.

Second-line therapies

Low-molecular-weight heparin	C
Warfarin	D
Hyperbaric oxygen	D
Danazol	D

Frequency of thrombophilia determinant factors in patients with livedoid vasculopathy and treatment with anticoagulant drugs – a prospective study.

Di Giacomo TB, Hussein TP, Souza DG, Criado PR. J Eur Acad Dermatol Venereol 2010; 24: 1340–6.

Thirty-four patients diagnosed with livedoid vasculopathy were tested for prothrombin time, activated partial thromboplastin time, antithrombin activity, protein C and S activity, anticardiolipin antibodies, lupus anticoagulant, prothrombin gene mutation, factor V Leiden mutation, methylenetetrahydrofolate reductase mutation, plasma homocysteine and fibrinogen; 18 (52%) presented laboratory abnormalities of procoagulant conditions. Thirteen of the 34 patients were treated with anticoagulant drugs (either warfarin or heparin) with clinical improvement in 11 patients.

Livedoid vasculopathy in a pediatric patient with elevated lipoprotein(a) levels: prompt response to continuous low-molecular-weight heparin.

Goerge T, Weishaupt C, Metze D, Nowak-Göttl U, Sunderkötter C, Steinhoff M, Schneider SW. Arch Dermatol 2010; 146: 927–8.

The authors describe a pediatric patient with livedoid vasculopathy who had elevated levels of lipoprotein(a). Treatment with low-molecular-weight heparin (enoxaparin) showed remission of the ulcerations and pain.

Treatment of livedoid vasculopathy with low-molecular-weight heparin: report of 2 cases.

Hairston BR, Davis MD, Gibson LE, Drage LA. Arch Dermatol 2003; 139: 987–90.

Two patients with livedoid vasculitis recalcitrant to conventional first- and second-line therapies had a beneficial response to subcutaneous injections of low-molecular-weight heparin.

Difficult management of livedoid vasculopathy.

Frances C, Barete S. Arch Dermatol 2004; 140: 1011.

Fourteen of 16 patients treated with either low-molecular-weight heparin or a vitamin K antagonist (fluindione) had more effective results than with antiplatelet drugs. One patient responded partially to aspirin and dipyridamole; the remaining patient responded to no treatments.

The authors recommend that the benefit–risk ratio, cost, and quality of life be considered when prescribing either low-molecular-weight heparin or vitamin K antagonists.

Ulcerations caused by livedoid vasculopathy associated with a prothrombotic state: response to warfarin.

Davis MD, Wysokinski WE. J Am Acad Dermatol 2008; 58: 512–15.

Warfarin therapy healed ulcerations in a 50-year-old woman who had a lifelong history of painful ulcerations; the patient was a heterozygous carrier of factor V Leiden and prothrombin gene mutations.

A case of livedoid vasculopathy associated with factor V Leiden mutation: successful treatment with oral warfarin.

Kavala M, Kocaturk E, Zindanci I, Turkoglu Z, Altintas S. J Dermatol Treat 2008; 19: 121–3.

A 19-year-old man with a 4-year history of recurrent leg ulcerations had rapid improvement with oral warfarin therapy after laboratory diagnosis of protein C and factor V Leiden mutations.

Warfarin therapy for livedoid vasculopathy associated with cryofibrinogenemia and hyperhomocysteinemia.

Browning CE, Callen JP. Arch Dermatol 2006; 142: 75–8.

A 50-year-old man with abnormal cryofibrinogen and homocysteine levels had a dramatic response to oral warfarin therapy after being refractory to treatment with multiple other medications.

Livedoid vasculopathy: long-term follow-up results following hyperbaric oxygen therapy.

Juan WH, Chan YS, Lee JC, Yang LC, Hong HS, Yang CH. Br J Dermatol 2006; 154: 251–5.

Eight patients completed a prospective study evaluating the efficacy of hyperbaric oxygen on healing the ulcers of livedoid vasculopathy. Leg ulcers in all eight patients healed completely at a mean of 3.4 weeks; however, six patients had relapses of ulceration but responded to additional hyperbaric oxygen therapy.

Low-dose danazol in the treatment of livedoid vasculitis.

Hsiao GH, Chiu HC. Dermatology 1997; 194: 251–5.

Six of seven patients treated with low-dose danazol (200 mg daily orally) had rapid cessation of new lesion formation, prompt reduction in pain, and healing of active ulceration.

Livedoid vasculitis with anticardiolipin antibodies: improvement with danazol.

Wakelin SH, Ellis JP, Black MM. Br J Dermatol 1998; 139: 935–7.

A patient with livedoid vasculitis had anticardiolipin antibodies. The ulcerations were recalcitrant to conventional first- and second-line therapies. She responded to treatment with danazol in combination with initially high-dose systemic corticosteroids.

Third-line therapies

Tissue plasminogen activator	C
Intravenous immunoglobulin	C
PUVA	C
Sulfapyridine	D
Iloprost	E

Livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity (4G/4G) treated successfully with tissue plasminogen activator.

Deng A, Gocke CD, Hess J, Heyman M, Paltiel M, Gaspari A. Arch Dermatol 2006; 142: 1466–9.

Plasminogen activator inhibitor-1, an important inhibitor of the fibrinolytic system, was elevated in a 33-year-old woman with livedoid vasculopathy. Treatment with heparin sodium and tPA dramatically improved her skin lesions, resulting in complete healing of her lower extremity ulcerations.

Tissue plasminogen activator for treatment of livedoid vasculitis.

Klein KL, Pittelkow MR. Mayo Clin Proc 1992; 67: 923–33.

In a prospective study, six patients who had non-healing ulcers caused by livedoid vasculitis and in whom numerous conventional therapies had failed were treated with low-dose tPA. In five of the six patients, dramatic improvement with almost complete healing of the ulcers occurred during hospitalization. Several were maintained with warfarin therapy after their inpatient treatment.

Successful long-term use of intravenous immunoglobulin to treat livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity.

Tuchinda P, Tammaro A, Gaspari AA. Arch Dermatol 2011; 127: 1224–5.

A 33-year-old patient diagnosed with livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity was treated with IVIG after failing anti-inflammatory, antiplatelet, and tissue plasminogen activator (tPA) therapies. She was successfully treated for over 4 years without complications with immunoglobulin, 0.5 g/kg every 2 weeks, given intravenously by an implanted portacatheter. The authors also describe several preventative regimens which may help to decrease the risk of thromboembolic events related to IVIG infusion.

Pulsed intravenous immunoglobulin therapy in livedoid vasculitis: an open trial evaluating 9 consecutive patients.

Kreuter A, Gambichler T, Breuckmann F, Bechara FB, Rotterdam S, Stucker M, et al. J Am Acad Dermatol 2004; 51: 574–9.

The efficacy and safety of IVIG were investigated in nine patients with livedoid vasculitis; seven of these patients had not responded to other treatment modalities. Vast improvement in erythema, healing of ulcerations, and reduction in pain was noted in all patients.

Livedoid vasculitis responding to PUVA therapy.

Lee JH, Choi HJ, Kim SM, Hann SK, Park YK. Int J Dermatol 2001; 40: 153–7.

Eight patients treated with systemic PUVA had rapid cessation of new lesion formation, notable symptom relief, and complete healing of primary lesions without unacceptable adverse effects.

Clinical studies of livedoid vasculitis (segmental hyalinizing vasculitis).

Winkelmann RK, Schroeter AL, Kierland RR, Ryan TM. Mayo Clin Proc 1974; 49: 746–50.

Clinical, laboratory, and histologic studies of 37 patients with livedoid vasculitis were presented. Treatment options included niacin (nicotinic acid), which was effective because of the inhibiting effect of nicotinate on contraction of vascular smooth muscle of the skin. Nine of 12 patients had sustained remission of their livedoid vasculopathy. Rest and wet-dressing therapy produced short remissions. Six of 11 patients responded to sulfapyridine, and three of eight responded to guanethidine. Corticosteroids, sympathectomy, and other forms of chemotherapy were not successful.

Livedoid vasculopathy with combined thrombophilia: efficacy of iloprost (French).

Magy N, Algros MP, Racadot E, Gil H, Kantelip B, Dupond JL. Rev Med Interne 2002; 23: 554–7.

A patient with lupus anticoagulant and factor V Leiden gene mutation had a dramatic and effective response to intravenous iloprost after unsuccessful anticoagulant therapy.

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