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Livedoid Vasculopathy

  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: William D James, MD  more...
 
Updated: Jan 25, 2016
 

Background

Livedoid vasculopathy (LV), or livedoid vasculitis, is a hyalinizing vascular disease characterized by thrombosis and ulceration of the lower extremities. Livedoid vasculopathy can evolve into a dermatologic finding termed atrophie blanche (AB). Livedoid vasculopathy is a distinct condition that is not usually the result of other diseases, as Jorizzo elegantly noted in 1998.[1]

A recent consensus document has determined AB is related to venous insufficiency. AB has 2 forms: the LV-AB complex and AB with chronic venous insufficiency. Those separate forms require different approaches to treatment.[2]

Biopsy specimens of livedoid vasculopathy aid in diagnosing this condition, but they are not pathognomonic. The skin manifests with segmental hyalinizing vascular involvement of thickened dermal blood vessels, endothelial proliferation, and focal thrombosis without nuclear dust. No true vasculitis is evident. While direct immunofluorescence study reveals immunoglobulin and complement components in the superficial, mid-dermal, and deep dermal vessels, this is merely the result of spongelike absorption of immune components in the thickened vessels. They do not appear to be pathogenic. Pathogenesis involves hyalinization and thrombosis rather than leukocytoclastic vasculitis.

In 1955, Feldaker et al[3] described what is now termed livedoid vasculopathy as livedo reticularis with summer ulcerations. In 1967, Bard and Winkelmann[4] used the terms segmental hyalinizing vasculitis and livedo vasculitis to describe livedoid vasculopathy.

In 1998, Papi et al[5] noted that platelet and lymphocyte activation was present in livedoid vasculopathy, whereas the levels of inflammatory mediators were in the reference range; in particular, they noted increased expression of platelet P-selectin.

Hairston et al[6] reviewed the records of 42 patients with proven livedoid vasculopathy. The following is a summary of the epidemiological and testing data:

  • Approximately 71% were women
  • Mean age of 45 years
  • Age range of 10-85 years
  • Bilateral lower extremity disease in 80.8%
  • Ulceration in 68.9%
  • Atrophie blanche in 71.1%
  • Decreased transcutaneous oximetry measurements in 74.1% of patients tested
  • Mutated factor V Leiden mutation (heterozygous) in 22.2%
  • Decreased activity for protein C or protein in 13.3%
  • Prothrombin G20210A gene mutation in 8.3%
  • Lupus anticoagulant in 17.9%
  • Anticardiolipin antibodies in 28.6%
  • Increased homocysteine levels in 14.3%
  • Biopsy specimens showing intraluminal thrombosis in 97.8%
  • Biopsy specimens with direct immunofluorescence test results showing multiple vascular conjugates in 86.1%

Note the image below.

Preferred sites of vascular involvement by selecte Preferred sites of vascular involvement by selected vasculitides.
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Pathophysiology

While the etiology of livedoid vasculopathy is not yet fully defined, it likely has a procoagulant pathogenesis.[6] Factor V Leiden mutation,[7] heterozygous protein C deficiency,[8] and other inherited hypercoagulable states have been linked to livedoid vasculopathy.[9] In particular, states such as hyperhomocysteinemia, which results in increased clotting, plays a role in livedoid vasculopathy.[10] Plasminogen activator inhibitor (PAI)–1 is an important inhibitor of the fibrinolytic system, and the PAI-1 promoter 4G/4G genotype, in which PAI-1 is increased, has been liked to livedoid vasculopathy.[9]

The histology of livedoid vasculopathy evolves according to the temporal stage of the lesion. Atrophie blanche is a scarring condition of white stellate scars that is an end stage of livedoid vasculopathy.

Most commonly, livedoid vasculopathy shows fibrin deposition within both the wall and the lumen of affected vessels. The absence of a substantial perivascular infiltrate or leukocytoclasia argues against a vasculitis, being more in keeping with a thrombo-occlusive process.

The underlying mechanism of the development of livedoid vasculopathy may be related to (1) the development of a fibrin cuff, (2) white-cell trapping, (3) microthrombi, (4) a defect of endothelial cell plasminogen activator, (5) platelet dysfunction, and (6) enhanced fibrin formation. The following is a summary of the excellent discussion of these mechanisms by Maessen-Visch et al[11] in 1999.

Browse and Burnand[12] posited the fibrin cuff theory. The fibrin cuff theory postulates that because of chronic venous compromise, fibrinogen leaks from the capillaries. This fibrinogen coagulates and hardens to form a fibrin cuff. This cuff surrounds the capillaries. The cuff establishes a barrier that prevents oxygen and nutrients from reaching the skin. However, Maessen-Visch et al[11] note that fibrin is an effective barrier to prevent the diffusion of oxygen to tissue. The cuffs then are an artifact rather than a seal. The fibrin cuffs are more an indication of disturbed microcirculation rather than an etiologic factor in chronic venous insufficiency; therefore, this theory is of uncertain accuracy.

In 1988, Coleridge Smith et al[13] suggested the white-cell trapping theory. In this schema, white cells adhere (trap) to the endothelium of the capillaries as a result of venous hypertension. This results in the induction of proteolytic enzymes and superoxide metabolites. These enzymes and metabolites cause tissue destruction. This molecular degrading effect on tissue appears to be a nonimmunologic phenomenon. Its etiology is due to the low flow in the wide capillaries. No up-regulation of binding molecules, such as intercellular adhesion molecule, vascular cellular adhesion molecule, and endothelial leucocyte adhesion molecule, occurs. A defect of endothelial cell plasminogen activator exists in some patients with livedoid vasculopathy. However, at least 20% of the 118 control subjects showed the same values as patients with livedoid vasculopathy.

Tissue-type plasminogen activator (tPA) levels appear to be lower in patients with livedoid vasculopathy. The average plasma level of releasable tPA was only 0.03 IU/mL in one study, versus an average tPA level of 0.70 IU/mL in 118 healthy controls.[14] Furthermore, Klein and Pittelkow[15] reported a high incidence of defective release of tPA and increased levels of PAI and a high incidence of antiphospholipid antibodies in patients with livedoid vasculopathy. levels of tPA in the reference range were found in patients with chronic venous insufficiency and atrophie blanche or lipodermatosclerosis.

Other evidence has implicated platelet dysfunction; one study noted that 7 patients with atrophie blanche and livedoid vasculopathy had increased platelet aggregation. These 7 patients were treated successfully with antiplatelet therapy.[16] The value of this study is limited because it was not controlled or designed to evaluate these factors and enzyme levels.

Enhanced fibrin formation, as evidenced by elevated levels of total fibrin-related antigen and D-dimer, has also been suggested as the cause for livedoid vasculopathy. This theory also needs to be tested via double-blinded studies. As of yet, well-crafted and adequate studies have not been performed.

Irani-Hakime et al noted livedoid vasculopathy associated with combined prothrombin G20210A and factor V (Leiden) heterozygosity and MTHFR C677T homozygosity, showing a range of thrombotic states can cause livedoid vasculopathy.[17]

Livedoid vasculopathy seems to be primarily an occlusive condition rather than an inflammatory condition.

Livedoid vasculopathy related to elevated levels of lipoprotein(a) has been noted.[18]

Livedoid vasculopathy was correlated with increased activity of plasminogen activator inhibitor (PAI-1) pathology and sticky platelets syndrome type III (also referred to as SPS type III).[19]

In 2014, Criado noted 3 patients with high plasma levels of factor VIII:C activity and other associated thrombophilic factors in patients with chronic leg ulcers and livedoid vasculopathy.[20]

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Epidemiology

Frequency

United States

Livedoid vasculopathy is an uncommon disorder in the United States.

International

Livedoid vasculopathy is an uncommon condition worldwide. In China, a study of 21 patients was performed. The female to male ratio was 3:1. The peak age at beginning of disease was 14-20 years. This was a younger age of onset than in previous studies. More than 85% demonstrated exacerbation in the summer with ulcer formation; 58.33% demonstrated antiphospholipid antibodies; and 71.43% demonstrated multivalent insect antigens hypersensitivity.[21]

In Brazil, livedoid vasculopathy linked with peripheral neuropathy was noted in 2 cases.[22]

Sex

Women are affected by livedoid vasculopathy more often than men. Livedoid vasculopathy can occur during pregnancy when levels of protein C and S drop.[23]

Age

Livedoid vasculopathy lesions can occur at any age, but livedoid vasculopathy is most commonly a disease of adulthood. An interesting case of LV occurred in a child in an area on the leg where a cutaneous hemangioma had been present. The body coagulation suffered from pathology that included prothrombin pathologic mutations, proteins C and S activity reductions, and elevated lipoprotein(a).

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Contributor Information and Disclosures
Author

Noah S Scheinfeld, JD, MD, FAAD Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Noah S Scheinfeld, JD, MD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Abbvie<br/>Received income in an amount equal to or greater than $250 from: Optigenex<br/>Received salary from Optigenex for employment.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD Associate Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Timothy McCalmont, MD Director, UCSF Dermatopathology Service, Professor of Clinical Pathology and Dermatology, Departments of Pathology and Dermatology, University of California at San Francisco; Editor-in-Chief, Journal of Cutaneous Pathology

Timothy McCalmont, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society of Dermatopathology, California Medical Association, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Received consulting fee from Apsara for independent contractor.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Richard H. Musgnug, MD, to the development and writing of this article.

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