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Livedoid Vasculopathy


Livedoid Vasculopathy

Article Author:
Vidit Majmundar
Article Editor:
Kalgi Baxi
Updated:
8/10/2020 10:52:13 PM
For CME on this topic:
Livedoid Vasculopathy CME
PubMed Link:
Livedoid Vasculopathy

Introduction

Livedoid vasculopathy is a rare vasculopathy that is typically characterized by bilateral lower limb lesions. Increased thrombotic activity and decreased fibrinolytic activity along with endothelial damage are believed to be the cause of thrombus formation in the capillary vasculature. It is 3 times more common in females than in males, especially in patients aged 15 to 50 years. Management involves identifying the lesion and differentiating it from other lower limb lesions along with skin biopsy to confirm the diagnosis. There is no definite first-line treatment, but general measures like smoking cessation, wound care, and pharmacological measures like anticoagulants and antiplatelets have shown good results. Several newer and experimental therapies have shown promising results in resistant cases.[1][2][3]

Etiology

Vasculopathy occurs when a thrombus forms in the arterial lumen leading to compromised blood flow. It is distinct from vasculitis, which refers to primary inflammation of the vessel wall followed by fibrinoid necrosis. Livedoid vasculopathy is usually associated with phenomena that cause hypercoagulability and thrombus formation, including:

  • Conditions associated with stasis: Chronic venous hypertension of the limbs, varicose veins. This venous stasis associated vasculopathy is generally not surrounded by livedo reticularis.
  • Autoimmune connective tissue diseases: Systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, scleroderma, mixed connective tissue disease
  • Thrombophilias: Inherited causes- factor V Leiden variant, prothrombin gene G20210A mutation, and protein C, protein S, and antithrombin deficiency, etc. Acquired causes- acquired homocysteinemia, cryoglobulinemia, cryofibrinogenemia, acquired antiphospholipid antibody syndrome.
  • Neoplasms: Myeloproliferative disorders, paraproteinemia, etc.
  • Idiopathic[3]

Epidemiology

Livedoid vasculopathy is a rare diagnosis with an approximate incidence of 1 in 1,00,000 per year. It is 3 times more common in females than in males. Most of the patients are 15 to 50 years old.[1]

Pathophysiology

The pathogenesis of livedoid vasculopathy can be explained by increased thrombotic and decreased fibrinolytic activity along with endothelial cell damage.

Biochemical mechanisms involving defects in the proteins and enzymes involved in the coagulation and fibrinolysis pathways can lead to increased platelet and fibrin rich thrombi in the capillaries leading to its typical cutaneous manifestations.[2]

An example of this is when homocysteinemia leads to DNA hypomethylation and prevents the action of histone deacetylase that leads to transcriptional repression along with increased oxidant stress on cells due to increased expression of p66shc in endothelial cells.[4]

Histopathology

The most characteristic histological finding consists of thickening or hyalinization of superficial dermal vessels along with intraluminal fibrin deposits. Red blood cell extravasation and perivascular lymphocytic infiltration may be associated.[1][5]

History and Physical

The patient usually presents with a history of painful recalcitrant ulcers and whitish scars near the ankles, which are associated with a painful burning sensation. The prodrome of this burning pain is a pathognomonic feature in history. Usually, pure livedoid vasculopathy is a skin limited manifestation hence, no systemic symptoms are expected. However, lesions akin to livedoid vasculopathy are seen in autoimmune connective tissue diseases, antiphospholipid antibody syndrome, and inherited thrombophilias hence, a detailed history focusing on these associated diseases must be elucidated.

Livedoid vasculopathy is characterized by punched out ulcers in the peri-malleolar area surrounded by lacy, reticular, reddish to violaceous streaks, also known as livedo reticularis. These ulcers heal forming porcelain white scars surrounded by telangiectasias and represent the vestiges of cutaneous infarction due to disturbed capillary microcirculation. These scars are known as atrophie blanche/capillaritis alba, and they are not specific for livedoid vasculopathy. Ulcers characterize the active stage of disease while livedo reticularis and livedo racemosa (broken net pattern) are precursors to ulceration. The acronym PPURPLE (painful, purpuric, ulcers, with reticular, pattern, of lower extremities) sums up the entire clinical spectrum of this condition. Retiform or stellate purpura is considered a hallmark lesion.

The commonest site is the peri-malleolar area, but they can also be seen on the lower leg and foot. The disease is bilateral in most cases.[3]

Evaluation

The approach for evaluation of a patient presenting with lesions suspicious of livedoid vasculopathy should focus upon confirming the diagnosis, ruling out close differentials, and a workup for associated conditions.

A skin biopsy, preferably a 3-4 mm punch biopsy from the margin of the ulcer or the surrounding livedo, is a must for confirming the diagnosis.

Ankle-brachial pressure index and lower limb venous doppler should be done to rule out chronic venous insufficiency.

Laboratory investigations should focus on ruling out the following:

  • Hypercoagulable states (e.g., factor 5 Leiden mutation, platelet plug disorders, hyperhomocysteinemia, etc.)
  • Fibrinolytic disorders. (e.g., protein C and protein S deficiency)
  • Collagen vascular diseases. (e.g., SLE, scleroderma, APLA)
  • Paraprotenemia[3][6]

Treatment / Management

The treatment approach for livedoid vasculopathy should aim at preventing ulceration, promote rapid healing of existing ulcers and pain relief.

General measures:

  • Pain management: Pain relief is achieved by the use of nonsteroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants like amitriptyline, gabapentin, pregabalin, and anti-epileptics such as carbamazepine as these drugs are known to relieve neuropathic pain.
  • Rapid relief of pain has been reported with the use of IVIG, which causes inhibition of thromboxane A2 and endothelin and thereby improves perfusion.
  • Wound care: General principles of wound healing and management should be followed.
  • Smoking cessation.
  • Compression therapy.

Specific pharmacological measures:

There are no definite therapeutic guidelines for the management of livedoid vasculopathy. However, a combination of anticoagulants, anti-platelet medications, fibrinolytic therapies, and anabolic steroids are reported to be efficacious. Examples of the drugs belonging to these categories are listed below.

  • Anti-platelet agents such as aspirin (325mg/day), dipyridamole, pentoxifylline (400mg/day).
  • Anticoagulants such as low molecular weight heparin, warfarin - with monitoring for the international normalized ratio (INR) 2-3, rivaroxaban (20mg/day), direct thrombin inhibitors such as dabigatran.
  • Fibrinolytic therapies such as recombinant tissue plasminogen activator, danazol, stanozolol.
  • Immunomodulatory and immunosuppressive agents like IVIG, cyclosporine, doxycycline, dapsone (especially in myeloproliferative disorders), sulfasalazine, and PUVA.
  • Vasodilators such as nifedipine, cilostazol.
  • Hyperbaric oxygen therapy.
  • Ketanserin
  • Alprostadil[1][3][7][8][9]

Differential Diagnosis

Differential diagnosis:

  1. Livedo reticularis with ulceration: This active stage is mimicked by cutaneous polyarteritis nodosa (PAN) and often leads to a diagnostic dilemma. Cutaneous PAN is characterized by livedo racemosa, subcutaneous nodules, and starburst livedo. It is a medium vessel cutaneous vasculitis. Presence of subcutaneous nodules, occasional digital gangrene, and histopathology aid in its diagnosis.
  2. 2.  Atrophie blanche: Porcelain white scars are seen in sickle cell disease, hydroxyurea ulcers, malignant atrophic papulosis.
  3. Other close differentials are ANCA associated vasculitis, cutaneous small-vessel vasculitis, cryoglobulinemia, Sneddon syndrome (livedo racemosa with cerebrovascular stroke).[3][5][5][9][10][11]

Prognosis

Livedoid vasculopathy is related to various underlying etiologies that lead to increased thrombosis and decreased fibrinolytic activities along with endothelial damage. Hence, identifying the underlying cause for livedoid vasculopathy and managing the patients with both early general and pharmacological measures can affect the course of the disease. The prognosis also depends on the underlying conditions that lead to livedoid vasculopathy.[1]

Complications

Livedoid vasculopathy mainly presents with ulcerative lesions in both lower limbs. Local complications like secondary skin infections that show typical signs of inflammation are commonly encountered. Other manifestations like pain (due to local hypoxic damage and cytokine reaction), secondary cutaneous hyperpigmentation (due to extravasation of erythrocytes along with hemosiderin deposition in the skin), and mononeuritis multiplex (due to thrombosis of vasa nervorum) and atrophic scarring of skin are seen.[1]

Deterrence and Patient Education

Patient education is an important part of managing the disease. The patient should be educated about the importance of smoking cessation. The importance of complying with the other general measures like compression stockings and wound care is also of utmost importance. Finally, the patient should be instructed about reporting urgently to the clinician in cases of worsening of any symptoms.

Enhancing Healthcare Team Outcomes

Livedoid vasculopathy is a challenging diagnosis. Surprisingly the epidemiological data shows that there is a 5-year delay with adequate diagnosis and management of this condition. Therefore, an interprofessional team that includes nurses, primary clinicians, pharmacists, and dermatologists should be educated about identifying this condition. Many of the patients can be misdiagnosed. Hence, educating health care workers about identifying and performing routine workup before referring to the dermatologist is an important part of enhancing health care. Finally, the dermatologist should also know the importance of getting a skin biopsy of appropriate depth and dimensions to avoid missing the diagnosis.[1]



(Click Image to Enlarge)
Livedoid vasculitis
Livedoid vasculitis
Contributed by Dr. Shyam Verma, MBBS, DVD, FRCP, FAAD, Vadodara, India

References

[1] Freitas TQ,Halpern I,Criado PR, Livedoid vasculopathy: a compelling diagnosis. Autopsy     [PubMed PMID: 30101138]
[2] Goerge T, [Livedoid vasculopathy. Pathogenesis, diagnosis and treatment of cutaneous infarction]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2011 Aug;     [PubMed PMID: 21786003]
[3] Alavi A,Hafner J,Dutz JP,Mayer D,Sibbald RG,Criado PR,Senet P,Callen JP,Phillips TJ,Romanelli M,Kirsner RS, Livedoid vasculopathy: an in-depth analysis using a modified Delphi approach. Journal of the American Academy of Dermatology. 2013 Dec;     [PubMed PMID: 24028907]
[4] Coppola A,Davi G,De Stefano V,Mancini FP,Cerbone AM,Di Minno G, Homocysteine, coagulation, platelet function, and thrombosis. Seminars in thrombosis and hemostasis. 2000;     [PubMed PMID: 11011842]
[5] Hu SC,Chen GS,Lin CL,Cheng YC,Lin YS, Dermoscopic features of livedoid vasculopathy. Medicine. 2017 Mar;     [PubMed PMID: 28296736]
[6] Criado PR,Rivitti EA,Sotto MN,Valente NY,Aoki V,Carvalho JF,Vasconcellos C, Livedoid vasculopathy: an intringuing cutaneous disease. Anais brasileiros de dermatologia. 2011 Sep-Oct;     [PubMed PMID: 22147037]
[7] Juan WH,Chan YS,Lee JC,Yang LC,Hong HS,Yang CH, Livedoid vasculopathy: long-term follow-up results following hyperbaric oxygen therapy. The British journal of dermatology. 2006 Feb;     [PubMed PMID: 16433793]
[8] Rustin MH,Bunker CB,Dowd PM, Chronic leg ulceration with livedoid vasculitis, and response to oral ketanserin. The British journal of dermatology. 1989 Jan;     [PubMed PMID: 2638912]
[9] Vasudevan B,Neema S,Verma R, Livedoid vasculopathy: A review of pathogenesis and principles of management. Indian journal of dermatology, venereology and leprology. 2016 Sep-Oct;     [PubMed PMID: 27297279]
[10] Wu S,Xu Z,Liang H, Sneddon's syndrome: a comprehensive review of the literature. Orphanet journal of rare diseases. 2014 Dec 31;     [PubMed PMID: 25551694]
[11] Mimouni D,Ng PP,Rencic A,Nikolskaia OV,Bernstein BD,Nousari HC, Cutaneous polyarteritis nodosa in patients presenting with atrophie blanche. The British journal of dermatology. 2003 Apr;     [PubMed PMID: 12752140]