[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.167.149.128. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Observation
January 2006

Warfarin Therapy for Livedoid Vasculopathy Associated With Cryofibrinogenemia and Hyperhomocysteinemia

Author Affiliations

Author Affiliations: Division of Dermatology, Department of Medicine, University of Louisville, Louisville, Ky.

Arch Dermatol. 2006;142(1):75-78. doi:10.1001/archderm.142.1.75
Abstract

Background  Livedoid vasculopathy is an idiopathic, chronic disorder manifested by painful, purpuric macules on the lower extremities that superficially ulcerate, resulting in atrophic, stellate scars with peripheral telangiectasias and hyperpigmentation.

Observations  A 50-year-old man presented with recurrent, painful ulcerations on the medial aspect of his malleoli and calves. The clinical presentation, histologic findings, and results of laboratory evaluation confirmed the diagnosis of livedoid vasculopathy in this case. Despite being refractory to treatment with multiple other medications, the lesions responded dramatically to oral warfarin sodium therapy.

Conclusion  Treatment with warfarin may be a beneficial therapy for patients with livedoid vasculopathy.

Livedoid vasculopathy (also known as atrophie blanche, livedo vasculitis, segmental hyalinizing vasculitis, and livedo reticularis with summer/winter ulceration) is an idiopathic disorder that was first described by Bard and Winkelmann1 in 1967. Although this uncommon chronic condition has previously been classified as a localized vasculitic process, it appears instead to be a cutaneous vasculopathy.2 The disorder most commonly affects young to middle-age women, with a male-female ratio of 1:3.3 The earliest lesions consist of painful, purpuric macules that are primarily located on the lower extremities. The lesions then superficially ulcerate and slowly heal over 3 to 4 months, leaving atrophic, stellate scars with surrounding telangiectasias.4 Histologically, deposition of homogeneous, fibrinoid material within superficial dermal blood vessels is observed along with occasional extravasation of erythrocytes. There is no evidence of leukocytoclastic vasculitis.5 Although the etiology is unknown, microcirculatory or thrombotic mechanisms have been implicated in the pathogenesis owing to the relative success of fibrinolytic and antiplatelet therapies. However, livedoid vasculopathy remains a difficult condition to manage, with no clearly defined treatment of choice. Herein, we provide a retrospective analysis of a case of livedoid vasculopathy that responded dramatically to warfarin therapy despite being refractory to treatment with multiple other systemic medications.

REPORT OF A CASE

A 50-year-old man presented with a 2-year history of recurrent, painful ulcerations that were affecting the medial aspect of his malleoli and calves. His medical history was significant for hypertension, which was adequately controlled with diet and exercise. He had been evaluated by a dermatologist 2 years earlier. A biopsy specimen obtained at the time reportedly showed leukocytoclastic vasculitis. Also, the patient’s initial workup revealed a weak positivity for anticardiolipin antibody. Based on these results, anticardiolipin syndrome with thrombotic vasculopathy was initially diagnosed. Treatment with nonsteroidal anti-inflammatory medications and oral prednisone resulted in no significant improvement.

A rheumatologist also assessed the patient because of his preliminary diagnosis of possible primary antiphospholipid antibody syndrome. The results of the following laboratory investigations were negative or normal: complete blood cell count, comprehensive metabolic panel, and tests for lupus anticoagulant, anticardiolipin antibody, antinuclear antibody, and complement levels. The findings of noninvasive vascular studies (venous and arterial Doppler studies) were also within normal limits. The patient was subsequently referred (to J.P.C.) for additional evaluation and recommendations regarding treatment.

Physical examination revealed erythematous ulcerations with hemorrhagic crust on the medial aspect of both malleoli (Figure 1). His lower extremities also exhibited vascular engorgement in a livedoid pattern that extended from his shins to the plantar aspect of both feet (Figure 2). Blood chemistry tests were positive for cryofibrinogen. Also, serologic tests were positive for β2-glycoprotein IgA antibody but did not demonstrate similar IgM or IgG antibodies. Results of the following laboratory investigations were negative or normal: complete blood cell count, comprehensive metabolic panel, erythrocyte sedimentation rate, protein electrophoresis, and tests for anticardiolipin antibody, antineutrophil cytoplasmic antibody, anti-Ro/SS-A and anti-La/SS-B antibodies, antinuclear antibody, anti–double-stranded DNA antibody, rapid plasma reagin, hepatitis C antibody, and factor V Leiden mutation. The tissue specimen from the patient’s original biopsy was also reviewed and revealed a vaso-occlusive disorder with secondary epidermal necrosis. The histopathologic findings supported a vasculopathic reaction rather than a vasculitic process due to a larger proportion of fibrinous vascular occlusion than associated inflammation. A chest x-ray film and an echocardiogram showed no significant abnormalities other than mild left ventricular hypertrophy. Given the patient’s clinical presentation, the review of previous histopathologic findings, and the results of laboratory evaluation, livedoid vasculopathy related to the fibrinogen positivity was diagnosed.

Figure 1.
Superficial erosions and early ulceration over the medial aspect of the malleolus.

Superficial erosions and early ulceration over the medial aspect of the malleolus.

Figure 2.
Livedo reticularis on the plantar surface of the foot.

Livedo reticularis on the plantar surface of the foot.

Oral hydroxychloroquine sulfate (200 mg twice a day) and oral aspirin (325 mg/d) therapy was initiated. However, new ulcerations continued to develop, without significant improvement. Two months after the hydroxychloroquine therapy was begun, oral dipyridamole (75 mg 3 times per day) was added to the treatment regimen, also without clinical improvement. After 9 months of treatment with hydroxychloroquine without a significant change in the patient’s lesions, this therapy was discontinued and oral stanozolol therapy (2 mg twice a day) was initiated. The addition of stanozolol to the treatment regimen resulted in mild improvement of the lesions. An elevated homocysteine level was discovered on subsequent laboratory evaluation, and folic acid and nicotinamide were also added to the treatment regimen. Diagnostic studies performed throughout the patient’s care consistently revealed cryofibrinogen positivity, with no noted seasonal variation.

The patient was then referred to the dermatology department at Wake Forest University, Winston-Salem, NC, for additional evaluation. The physicians at the university concurred with the diagnosis of livedoid vasculopathy and added pentoxifylline (400 mg 3 times per day) to his treatment regimen. However, because of his complaints of sexual dysfunction related to the stanozolol therapy, the dosage of the therapy was tapered, after which his skin lesions worsened.

Approximately 18 months after his initial presentation to our clinic, he was hospitalized owing to the acute development of atrial fibrillation. His cardiologist elected to discontinue his stanozolol therapy, along with his other medications, and, as therapy for his cardiac condition, to prescribe warfarin sodium (3 mg/d) along with rate-controlling medications (propafenone hydrochloride and metoprolol succinate). An echocardiogram again revealed left ventricular hypertrophy, which was unchanged from his previous study. He spontaneously reverted to a normal sinus rhythm before electric cardioversion. Within 1 month of the initiation of the warfarin therapy, there was dramatic improvement of his skin lesions, with complete resolution of the lower extremity ulcerations and no additional lesional development. The dosage of warfarin sodium therapy was increased (5 mg/d), with maintenance of the international normalized ratio between 1.5 and 2.0. The patient continued to experience quiescence of his disease, with only hyperpigmented, atrophic scars consistent with atrophie blanche during long-term warfarin therapy (Figure 3). After a disease-free interval of approximately 30 months, the dosage of his anticoagulant therapy was decreased. He promptly experienced a relapse of his skin lesions. Laboratory investigations revealed a subtherapeutic protime and an international normalized ratio of 1.1. The warfarin dosage was then increased, and the patient again experienced improvement of his condition.

Figure 3.
Dyspigmentation and atrophic scars located over the medial aspect of the malleolus after warfarin sodium therapy.

Dyspigmentation and atrophic scars located over the medial aspect of the malleolus after warfarin sodium therapy.

COMMENT

Livedoid vasculopathy is a chronic occlusive vasculopathy characterized by recurrent, purpuric lesions of the lower extremities that progress to painful, irregularly shaped ulcerations. These ulcerations heal slowly and produce the distinctive porcelain, stellate scars with ectatic vessels of atrophie blanche. Although atrophie blanche is a consequence of the lesions of livedoid vasculopathy, it is not pathognomonic of this disorder and can occur in association with other conditions such as stasis dermatitis and collagen vascular diseases.2,4,6,7

Although it is quite distinctive from a vasculitis or immune-mediated process, livedoid vasculopathy has been confused with small vessel vasculitis in the past and can be misdiagnosed, as demonstrated by our patient’s diagnostic history. The term segmental hyalinizing vasculitis was commonly used to describe livedoid vasculopathy in the 1970s.1,8 The concept of a vasculitic pathogenesis was supported by the presence of fibrin, immunoglobulin, and complement in the vessel walls of the lesions. However, livedoid vasculopathy is an interesting disorder—the clinical presentation and the histopathologic features of the lesions temporally evolve. Histologic examination of early lesions clearly shows sole deposition of fibrin in the lumen of dermal vessels without associated immunoglobulin or complement.4 Also, the scarcity of polymorphonuclear leukocytes and the absence of leukocytoclasia argue against a primary vasculitic process.5 However, very different results are produced by evaluation of late lesions, which demonstrate IgM, IgG, and C3 deposition along with fibrinous occlusion of the vessels.4 This immunologic reaction is now believed to be a secondary event rather than primarily involved in the pathogenesis of livedoid vasculopathy. The changing histologic appearance of the lesions underscores the importance of acquiring a biopsy specimen from an early lesion to obtain the correct diagnosis of the patient’s disorder and to appropriately guide treatment.

Although the exact pathogenesis of livedoid vasculopathy remains unknown, the disorder is believed to be a vasculopathy mediated by disordered coagulation or fibrinolysis. Livedoid vasculopathy has been associated with both abnormal fibrinolytic activity and abnormal platelet function.9,10 Recent investigations have supported the theory of disordered coagulation as an etiologic factor by demonstrating elevated fibrinopeptide A,11 defective release of tissue plasminogen activator, and increased amounts of plasminogen activator inhibitor.9 Other reports indicate that abnormal platelet function may also play a pivotal role by showing that patients with livedoid vasculopathy exhibit increased levels of P-selectin.3 The favorable clinical response of patients to fibrinolytic, anticoagulant, and antiplatelet therapies is additional evidence for disordered coagulation or a thrombotic mechanism as the pathogenetic basis of livedoid vasculopathy.

Our patient also demonstrated cryofibrinogenemia along with elevated homocysteine levels, with no seasonal or temporal variation. Elevated homocysteine levels have been implicated as a risk factor for thrombotic events. The current treatment regimen for hyperhomocysteinemia is supplementation with vitamin B6, vitamin B12, and folate.12 Similarly, cryoglobulins have also been implicated in intravascular thrombotic processes that can result in skin infarction and necrosis.13 Cryoglobulinemia exhibits a myriad of cutaneous manifestations, including purpura, cold urticaria, Raynaud phenomenon, hemorrhagic crusts, and skin infarction and ulceration.14 The primary treatment for this disorder is immunosuppressive therapy, such as steroids, plasmapheresis, or cyclophosphamide.15 The use of warfarin in the management of skin lesions associated with cryofibrinogenemia has generated both successful and unsuccessful outcomes.13,16 Although our patient did exhibit both cryofibrinogenemia and hyperhomocysteinemia, we believed that these conditions were secondary to his livedoid vasculopathy.

As illustrated by our case, livedoid vasculopathy remains extremely difficult to treat. The most widely used initial treatments include aspirin, dipyridamole, subcutaneous heparin, and pentoxifylline.1719 Also, clinical improvement has been achieved with the use of danazol,20 tissue plasminogen activator,21 nifedipine,22 sulfasalazine,23 ketanserin,24 intravenous immunoglobulin,25 and psoralen–UV-A.26 Our patient’s lesions were unresponsive to a variety of treatments, including aspirin, dipyridamole, pentoxifylline, hydroxychloroquine, and prednisone. His lesions were partially responsive to stanozolol therapy. However, he experienced dramatic clinical improvement after he began treatment with warfarin, which was incidentally prescribed as anticoagulant therapy after atrial fibrillation developed. Active disease progression was halted within just 1 month of sustained warfarin therapy, during which he experienced complete resolution of his ulcerations.

Although long-term warfarin therapy after the administration of tissue plasminogen activator has been reported in the literature as a successful treatment for livedoid vasculopathy, Francès and Barete27 recently discussed the efficacy of the use of vitamin K antagonists alone, specifically fluindione, in the treatment of refractory livedoid vasculopathy.21 The use of vitamin K antagonists in the treatment of this disorder is a logical choice because of the reported success of other anticoagulant medications, such as heparin. Warfarin is a commonly used vitamin K antagonist that produces its anticoagulant effect by inhibiting the vitamin K conversion cycle that is necessary for the biologic activation of coagulation factors (factors II, VII, IX, and X) and proteins C and S via posttranslational carboxylation.28 The use of warfarin rather than heparin for long-term anticoagulation therapy has numerous advantages, including oral administration, once-daily administration, lower incidence of thrombocytopenia, and decreased cost.

Livedoid vasculopathy remains an uncommon disorder that can be difficult to manage effectively. Anticoagulant, antiplatelet, and fibrinolytic therapies have been used in the treatment of this disease, with varying degrees of success. Our patient exhibited livedoid vasculopathy that was unresponsive to treatment with a variety of agents but quickly improved with the administration of warfarin. Consequently, warfarin therapy may be considered a treatment option for patients with refractory livedoid vasculopathy.

Back to top
Article Information

Correspondence: Jeffrey P. Callen, MD, 310 East Broadway, Suite 2A, Louisville, KY 40202 (jefca@aol.com).

Financial Disclosure: None.

Disclaimer: Dr Callen is the associate editor of the ARCHIVES, but he was not involved in the editorial evaluation or decision to accept this article for publication.

Accepted for Publication: May 2, 2005.

References
1.
Bard  JWWinkelmann  RK Livedo vasculitis: segmental hyalinizing vasculitis of the dermis. Arch Dermatol 1967;96489- 499
PubMedArticle
2.
Jorizzo  JL Livedoid vasculopathy: what is it? Arch Dermatol 1998;134491- 493
PubMedArticle
3.
Papi  MDidona  BDe Pitá  O  et al.  Livedo vasculopathy vs small vessel cutaneous vasculitis: cytokine and platelet P-selectin studies. Arch Dermatol 1998;134447- 451
PubMedArticle
4.
Shornick  JKNicholes  BKBergstresser  PRGilliam  JN Idiopathic atrophie blanche. J Am Acad Dermatol 1983;8792- 798
PubMedArticle
5.
Maessen-Visch  MBKoedam  MIHamulyák  KNeumann  HA Atrophie blanche. Int J Dermatol 1999;38161- 172
PubMedArticle
6.
Margolis  DJKruithof  EKOBarnard  MHowe  KLazarus  GS Fibrinolytic abnormalities in two different cutaneous manifestations of venous disease. J Am Acad Dermatol 1996;34204- 208
PubMedArticle
7.
Acland  KMDarvay  AWakelin  SHRussell-Jones  R Livedoid vasculitis: a manifestation of the antiphospholipid syndrome? Br J Dermatol 1999;140131- 135
PubMedArticle
8.
Winkelmann  RKSchroeter  ALKierland  RRRyan  TM Clinical studies of livedoid vasculitis (segmental hyalinizing vasculitis). Mayo Clin Proc 1974;49746- 750
PubMed
9.
Calamia  KTBalabanova  MPerniciaro  CWalsh  JS Livedo (livedoid) vasculitis and the factor V Leiden mutation: additional evidence for abnormal coagulation. J Am Acad Dermatol 2002;46133- 137
PubMedArticle
10.
Drucker  CRDuncan  WC Antiplatelet therapy in atrophie blanche and livedo vasculitis. J Am Acad Dermatol 1982;7359- 363Article
11.
McCalmont  CSMcCalmont  THJorizzo  JLWhite  WLLeshin  BRothberger  H Livedo vasculitis: vasculitis or thrombotic vasculopathy? Clin Exp Dermatol 1992;174- 8
PubMedArticle
12.
Edirisinghe  SP Homocysteine-induced thrombosis. Br J Biomed Sci 2004;6140- 47
PubMed
13.
Ball  GVGoldman  LN Chronic ulcerative colitis, skin necrosis, and cryofibrinogenemia. Ann Intern Med 1976;85464- 466
PubMedArticle
14.
Cohen  SJPittelkow  MRSu  WP Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients. J Am Acad Dermatol 1991;2521- 27
PubMedArticle
15.
Ferri  CZignego  ALPileri  SA Cryoglobulins. J Clin Pathol 2002;554- 13
PubMedArticle
16.
Blain  HCacoub  PMusset  L  et al.  Cryofibrinogenaemia: a study of 49 patients. Clin Exp Immunol 2000;120253- 260
PubMedArticle
17.
Heine  KGDavis  GW Idiopathic atrophie blanche: treatment with low-dose heparin. Arch Dermatol 1986;122855- 856
PubMedArticle
18.
Sauer  GC Pentoxifylline (Trental) therapy for the vasculitis of atrophie blanche. Arch Dermatol 1986;122380- 381
PubMedArticle
19.
Lee  SSAng  PTan  SH Clinical profile and treatment outcome of livedoid vasculitis: a case series. Ann Acad Med Singapore 2003;32835- 839
PubMed
20.
Hsiao  GHChiu  HC Livedoid vasculitis: response to low-dose danazol. Arch Dermatol 1996;132749- 751
PubMedArticle
21.
Klein  KLPittelkow  MR Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992;67923- 933Article
22.
Purcell  SMHayes  TJ Nifedipine treatment of idiopathic atrophie blanche. J Am Acad Dermatol 1986;14851- 854
PubMedArticle
23.
Bisalbutra  PKullavanijaya  P Sulfasalazine in atrophie blanche. J Am Acad Dermatol 1993;28275- 276
PubMedArticle
24.
Rustin  MHABunker  CBDowd  PM Chronic leg ulceration with livedoid vasculitis, and response to oral ketanserin. Br J Dermatol 1989;120101- 105
PubMedArticle
25.
Ravat  FEEvans  AVRussell-Jones  R Response of livedoid vasculitis to intravenous immunoglobulin. Br J Dermatol 2002;147166- 169
PubMedArticle
26.
Lee  JHChoi  HJKim  SMHann  SKPark  YK Livedoid vasculitis responding to PUVA therapy. Int J Dermatol 2001;40153- 157
PubMedArticle
27.
Francès  CBarete  S Difficult management of livedoid vasculopathy. Arch Dermatol 2004;1401011
PubMedArticle
28.
Hirsh  JDalen  JEAnderson  DR  et al.  Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119 ((suppl)) 8S- 21S
PubMedArticle
×