Livedoid vasculopathy and skin ulcers in patients with inherited thrombophilia

ARTICLE

Livedoid vasculopathy (LV) is a rare cutaneous disease usually affecting the lower extremities. It is characterized by persistent livedo reticularis associated with recurrent painful ulcerations resolving with hyperpigmentation and atrophic punctate white scars (atrophie blanche). Histologically, LV shows segmental hyalinization, endothelial proliferation and thrombosis of the upper and mid dermal vessels associated with a mild, mainly perivascular, lymphocytic infiltrate [1].

LV has been considered to be a true vasculitic process but more recent evidence suggests that it is primarily a non-inflammatory occlusive thrombotic vascular disease [2]. Histopathological features and the clinical improvement obtained using fíbrinolytic, anticoagulant and anti-thrombotic therapies support this hypothesis. LV has occasionally been described in association with systemic diseases such as systemic scleroderma, systemic lupus erythematosus and antiphospholipid syndrome [3], but in most cases it is an isolated phenomenon and an underlying associated pathology is not detectable. Recent reports have described cases of LV associated with inherited forms of thrombophilia suggesting a possible pathogenetic role of the hypercoagulable state in the development of cutaneous small vessel thrombosis [4-7].

We report on two male patients with LV and skin ulcers carrying factor V Leiden or homozygous hyperhomocysteinemia.

Case reports

Case 1

A 28-year-old male presented with a two-year history of persistent livedo reticularis and recurrent therapy-resistant large painful ulcerations involving the lower legs and the dorsal aspect of the feet. He denied preceding trauma or intake of any drugs, although he admitted being a smoker. Personal and familial medical histories were unremarkable. Examination revealed deep ulcers covered with a greenish adherent exudate and surrounded by erythematous skin (Fig. 1A, B). Hyperpigmented atrophic skin and punctate white scars were present on the dorsal aspect of the left foot and on the medial malleolar region. Brownish atrophic patches and atrophic stellate white scars were also seen on the dorsal and lateral aspect of the right foot. Both lower limbs showed a mottled red-bluish discoloration in a net-like pattern. Cultures for bacteria showed the growth of Pseudomonas aeruginosa. Routine hematochemical tests were within normal range. Anti-nuclear (ANA), anti-extractable nuclear (ENA), anti-native DNA (nDNA), anti-cardiolipin (aCL), anti-beta2 glycoprotein 1 (beta2-GP1), anti-neutrophil-cytoplasmic (ANCA) and anti-endothelial cell (AECA) antibodies, as well as rheumatoid factor, lupus anti-coagulant (LA) activity, cold agglutinins, cryoglobulins, circulating immune complexes (CIC) and serum complement levels were negative or within normal limits. Serologic tests for HBV, HCV and syphilis were negative. The prothrombin time (PT), activated partial thromboplastin time (aPTT), plasmatic fibrinogen and homocysteinemia were normal, and no deficit in protein C, protein S, antithrombin III, factor VIII and factor IX levels was found. However, a reduced activated protein C (APC) activity of 1.6 (normal > 2) in factor V deficient plasma was revealed. Polymerase chain reaction (PCR) analysis demonstrated a heterozygous G1691A mutation for factor V (factor V Leiden). Prothrombin 20210 (factor II) mutation was absent. Arterial and venous echo-color Doppler of the lower legs showed incontinence of the left popliteal vein. A biopsy of the erythematous skin was performed and histopathological examination showed mild hyperkeratosis and acanthosis of the epidermis, ectatic blood vessels with thickened and edematous walls, occasionally occluded by microthrombi and a lympho-histiocytic infiltrate in the upper and mid dermis. Direct immunofluorescence on cryostat sections did not reveal immunoglobulin or complement deposition. The patient was treated with antibiotics (cefodizime, 2 g bid IV for 10 days followed by ciprofloxacin 500 mg bid PO for 15 days) and locally with antiseptics and enzymes. Moreover, an anticoagulant therapy with low-molecular-weight heparin and oral warfarin was started. Heparin was stopped after 1 week and warfarin was continued for 6 months maintaining a PT International Normalized Ratio (PT-INR) of 2.0 to 3.0. The ulcers improved progressively, with complete healing after 4 months. All first grade relatives, including the father, the two sisters and the brother resulted heterozygous for factor V Leiden.

Case 2

A 34-year-old male presented with a 3-year history of recurrent painful ulcers on the lower legs and feet. His past medical history and family history were not significant. On examination, deep necrotic ulcerations were present on the dorsal aspect of both feet extending to the lateral malleolar region (Fig. 2A, B). Livedoid reddish-purple patches with a reticular pattern were seen on the extremities and the trunk. Routine laboratory tests, autoantibodies (ANA, ENA, nDNA, LA, aCL, ANCA, AECA and anti-beta2-GP1), rheumatoid factor, cryoglobulins, cold-agglutinins, CIC and complement activity were negative or within normal range. The serologic tests for HBV, HIV and syphilis were negative. Anti-HCV antibodies were present, with recombinant immunoblot assay showing high titer anti-C22-3 reactivity, but HCV RNA was undetectable. Hemocoagulative parameters (PT, aPTT, plasmatic fibrinogen, protein C, protein S and APC activity, factor VIII, factor IX and antithrombin III activity) were normal. Increased plasma homocysteine levels were found (27 mumol/l; normal range: 5-15 mumol/l) with normal urinary values, while plasma methionine level was normal. PCR analysis showed a homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Arterial and venous echo-color Doppler of the legs revealed incontinence of the internal saphena bilaterally, while mild hepato-splenomegaly was seen on abdominal echo-scan. Echo-color Doppler study of carotid vessels, echocardiogram and chest X-ray did not show abnormalities. Histological examination revealed mild epidermal hyperkeratosis and upper dermal ectatic blood vessels entirely or partially occluded by thrombi, and a scant, mainly perivascular lympho-histiocytic infiltrate (Fig. 2C). Direct immunofluorescence displayed fibrinogen deposits around the upper and mid dermis vessels. Treatment with vitamin oral B₆, B₁₂ and folate for two months resulted in a remarkable and persistent clinical improvement with normalization of the plasma homocysteine levels.

Discussion

LV is currently regarded as an occlusive thrombotic disease primarily affecting small vessels of the superficial and mid dermis. It has been suggested that platelet activation and/or primary or secondary hypercoagulable states represent important contributors to the development of LV [1, 2]. To date, three reported cases of LV associated with familial thrombophilia have been described. In only one case there was APC resistance due to an heterozygous factor V Leiden mutation [6], while in the remaining two cases a protein C deficiency was found [4, 7]. Moreover, Gibson et al. have proposed a possible association between increased serum homocysteine levels and LV [5]. The two young patients with LV and skin ulcers described in this report had inherited thrombophilia due to the presence of factor V Leiden and hyperhomocysteinemia secondary to homozygous C677T mutation in the MTHFR gene. Moreover, complete healing or marked improvement was achieved respectively by standard anticoagulant therapy [8] or by lowering homocysteine levels, emphasizing the importance of hypercoagulability in the pathogenesis of these cases of LV.

APC is an important physiologic anticoagulant that limits thrombin generation by cleaving factor Va and directly inhibiting factor V. Hereditary APC resistance is currently regarded as the most frequent cause of familial thrombosis and can represent an important risk factor for venous leg ulcerations in some patients [8-10]. The most common defect is a single point mutation in the factor V gene, called factor V Leiden, which results in substitution of glutamine for arginine at position 506 in the APC cleavage site of factor V. This mutation, which has an autosomal mode of inheritance, prevents the inactivation of factor V by APC, leading to a prothrombotic state. People who are heterozygous for factor V Leiden have an increased risk of deep and superficial vein thrombosis of the legs, pulmonary embolism, and thrombosis in the cerebral, visceral and axillary veins. Increased risk of thrombosis by a factor of 50 to 100 among homozygotes for factor V Leiden and by a factor of 5 to 10 among heterozygotes has been reported. Many of these people may not develop thrombotic events unless they also have another associated thrombophilic defect or they are exposed to additional precipitating factors. Among these, venous insufficiency, surgery, immobilization, advanced age, smoking, pregnancy and the use of contraceptives or hormone-replacement therapy have been identified [8, 9]. In addition, factor V Leiden has been suggested to be a pathogenetic risk factor in thrombotic microangiopathy disorders, including thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome [11].

Hyperhomocysteinemia can result from a variety of genetic or environmental mechanisms, such as hereditary deficiencies affecting the trans-sulfuration or remethylation pathways of homocysteine metabolism, renal failure and hypothyroidism. However, deficiencies of folate, vitamin B₁₂ and B₆ account for two thirds of cases of hyperhomocysteinemia [8, 9]. An increase in total plasma homocysteine represents an independent risk factor for coronary, cerebrovascular and peripheral arterial diseases as well as for deep vein thromboses. Moreover, hyperhomocysteinemia may confer an increased risk of cutaneous small vessel thrombosis [5]. Homocysteine acts as an atherogenic and thrombotic agent, increases platelet adhesiveness and interferes with the normal cross-linking of collagen and with normal ground substance metabolism in vascular walls, leading to arterial and venous thrombotic diathesis. High concentrations of homocysteine can also induce the activation of factor V in endothelial cells and inhibit the activation of protein C, compromising a major mechanism by which blood coagulation is controlled [8].

Considering the relatively high prevalence of familial thrombophilia in the population and the very rare incidence of LV, other as yet undefined factors are likely to be involved in the pathogenesis of cutaneous small vessels thrombosis. Nonetheless, a hypercoagulable state, as determined by inherited thrombophilia, represents a relevant risk factor for the development of LV. Therefore, young patients with LV and skin ulcers should be screened for inherited hypercoagulable state.

Article accepted on 11/3/02

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