8 Skin Manifestations of Antiphospholipid
Syndrome
Carlos A. Battagliotti
Several skin manifestations have been described in patients with antiphospholipid
syndrome (APS) (Table 8.1) [1–3]. The most frequent skin lesions are livedo reticularis and skin ulcers.
Vascular occlusion is generally the first and most frequent manifestation
observed in patients with antiphospholipid antibodies (aPL), accounting for 41% of
the cases. Forty percent of these patients present with other multisystem thrombotic phenomena during the course of the disease, underscoring the significance of
skin lesions as a diagnostic marker and predictor of systemic involvement.
In spite of the association of skin lesions with different isotypes of immunoglobulins, the presence of IgA anticardiolipin antibodies (aCL) has been reported as an
independent predictive factor for skin lesions (skin ulcers, chilblain lupus, and vasculitis) [4].
Livedo Reticularis
Livedo reticularis is the most common skin manifestation in patients with APS,
characterized by a dark purple reticular pattern usually involving the upper and
lower limbs [3, 5].
The skin normally receives its blood supply through a vascular system arranged
in the form of cones with their base towards the skin surface. Each cone is supplied
by an arteriole. The pattern of livedo reticularis corresponds to areas of anastomoTable 8.1. The skin and antiphospholipid syndrome. ●
●
●
●
●
●
●
●
●
●
Livedo reticularis
Sneddon’s syndrome
Skin ulcers
Necrotizing vasculitis
Livedoid vasculitis
Cutaneous gangrene
Superficial thrombophlebitis
Pseudovasculitic lesions: Nodules, papules, pustules, palmar–plantar erythema
Subungual bleeding
Anetoderma
86
Skin Manifestations of Antiphospholipid Syndrome
87
Table 8.2. Livedo reticularis and associated diseases. ●
●
●
●
●
●
●
Antiphospholipid syndrome
Systemic lupus erythematosus (with or without aPL)
Systemic vasculitis (polyarteritis nodosa, cryoglobulinemia)
Pseudovasculitic syndromes (cholesterol embolization)
Overlapping syndromes
Scleroderma
Infectious diseases (syphilis, tuberculosis)
sis between the two cones where diminished blood flow is associated with the dilatation of venules and capillaries. Therefore, the alteration in arterial blood flow
caused by the livedo may result from:
●
●
●
Blood inflow obstruction
Blood hyperviscosity
Blood outflow obstruction
Livedo may be observed in normal subjects, especially women, after exposure to
cold, displaying a symmetrical and regular mottled pattern. However, the relationship with a large number of pathological conditions (Table 8.2) is very important. A
detailed examination of the features of the reticular pattern, including location,
extension, symmetry, and regularity, and the presence of associated skin lesions will
contribute to the differential diagnosis [3, 6–8].
The pattern of involvement associated with APS is generally disseminated, with
incomplete circular segments, non-infiltrated, persistent, or irregular with wide
ramifications (livedo racemosa). Some patients present a fine, regular, and complete network (Fig. 8.1).
Figure 8.1. Livedo reticularis of the gluteal region and
both thighs of a patient with SLE and APS. 88
Hughes Syndrome
In a recent study, the presence of livedo reticularis was associated with arterial
but no venous events, suggesting that livedo reticularis could be consider as a
marker of the arterial APS subset [9].
Sneddon’s Syndrome
In 1965, Sneddon described the association between livedo reticularis and stroke
[10]. Later on, the presence of aPL in some of the patients that carry the syndrome
suggests that a subset of patients might have APS [11–13].
Although there are differences in the terminology used for the Sneddon syndrome livedo, its features are very clear. The skin lesions are extensive, patchy,
persistent, and do not disappear with skin heating. Usually, this is the pattern
observed in patients with a prior condition that accounts for the vascular
lesion (secondary Sneddon’s syndrome), such as autoimmune or thrombophilic
diseases.
Beyond the initial description, there are numerous reports of cardiac and renal
involvement and development of hypertension, as well as gynecological and
obstetrical complications [14, 15]. There are no laboratory tests that contribute
to a definite diagnosis; however, 35% of patients with Sneddon’s syndrome have
anti-endothelial cell antibody as opposed to patients with stroke and no livedo
reticularis. Prognosis is variable, mainly depending on the extension and
progression of brain lesions that might lead to a severe and definite mental
deterioration.
The pathological study of livedo reticularis shows endothelitis and obliterating
endarteritis without necrotizing vasculitis [13]. In some cases the characteristics of
APS overlap so that in all patients affected with livedo reticularis with noninflammatory small vessel thrombosis in their biopsy, the measurement of aPL is
mandatory.
Skin Ulcers
Lower limb ulcers are one of the most frequent skin manifestations in patients with
APS [2]. They have been observed in 20% to 30% of patients. The prevalence of skin
ulcers is very high when associated with aCL in systemic lupus erythematosus (SLE)
[3, 5].
Although characteristics are variable, ulcers are painful, small (0.5–3.0 cm in
diameter), with stellate, oval, or irregular borders surrounded by a purple-brownish
and recurrent purple halo. They are generally located in the ankles, legs, and feet.
Healing is difficult; when accomplished it results in a white scar with a pigmented
halo [16, 17] (Fig. 8.2).
Giant ulcers and cases resembling gangrenous pyoderma have been reported
[18–20], although in the latter case, the characteristic undercut of the borders of
pyoderma are absent. Post-phlebitic ulcers are seldom seen though an increased
prevalence of aPL has been described in elderly patients with venous ulcers (Figs.
8.2 and 8.3).
Skin Manifestations of Antiphospholipid Syndrome
89
Figure 8.2. Patient with primary APS that presents necrotic ulcers on the leg and necrosis of the toes. Figure 8.3. Primary APS with giant skin ulcer on the left leg refractory to anticoagulant and fibrinolytic treatment. 90
Hughes Syndrome
Necrotizing Vasculitis and Livedoid Vasculitis
Generally, no inflammatory changes are observed in the biopsies taken from skin
lesions of patients suffering from APS. The association with vasculitis might reflect
the coexistence of two diseases, most commonly SLE.
In 1967, Bard and Winkelmann described a group of patients with chronic and
recurrent livedoid-like lesions circumscribed to the lower limbs and with histological images of hyalinizating segmentary vasculitis of the dermis vessels related to
thrombotic occlusion and lymphocytic infiltration [21]. This disorder was termed
livedoid vasculitis or segmentary hyalinizing vasculitis. These cases presented with
livedo lesions, purpura with a trend towards ulceration that became covered with
dark crusts, and inflammatory borders. After weeks or months they healed, forming
porcelain-white star-like scars, atrophic with telangiectasis and hyperpigmented
borders. These latter lesions have been termed white atrophy and some authors
consider it as a disorder per se. The term was coined by Milian in 1929, who attributed its formation to a previous ulceration with a probable syphilitic or tuberculous
etiology. There is consensus in that there are different stages in the evolution of the
same process that leads to livedoid vasculitis. Other authors believe that “white
atrophy” is the end stage of different disorders that result in a stellate porcelain-like
star [22–24].
Livedoid vasculitis predominates in young women with characteristic lesions on
the lower limbs; it recurs with seasonal exacerbations. Its presentation might be
primary or idiopathic. However, it is sometimes related to SLE, Sjögren’s syndrome,
APS, polyarteritis nodosa, rheumatoid arthritis, scleroderma, Raynaud’s phenomenon, cryoglobulinemia, macroglobulinemia, venous vascular pathology, and diabetes [23, 25].
Controversy exists as to the pathogenesis but possible suggested mechanisms
include imbalance of the coagulation and fibrinolysis system and alteration of
platelet function.
Skin lesions typically found are erythematosus plaques, petechial purpura, livedo,
painful ulcers of different sizes, white atrophy, telangiectases, and hyperpigmentation. In some patients, direct immunofluorescence of skin vessels reveals IgG, IgM,
IgA, fibrin, and, to a lesser degree, deposits of complement [26].
Histological characteristics of livedoid vasculitis overlap with the vascular
changes seen in the APS. Segmental hyalinization and non-inflammatory occlusion
of the dermal arterioles leading to skin ulceration is observed.
Cutaneous Gangrene and Necrosis
Digital gangrene is a well-recognized manifestation in patients with APS [2, 3, 27].
The process starts with erythematosus macules, cyanosis, or pseudocellulitis ending
in necrosis. In patients with SLE or other autoimmune diseases, aPL quite often
coexists with other pathogenic factors such as cryoglobulins, antiendothelial cell
antibodies, or hepatitis viruses. Patients who are smokers, hypertensive, or are on
oral contraceptives have an increased risk of necrosis (Figs 8.4, 8.5, and 8.6).
Angiographic images show occlusion or severe stenosis of middle- and large-size
vessels.
Skin Manifestations of Antiphospholipid Syndrome
91
Figure 8.4. Evolution to gangrene with distal necrosis of the left foot toes in the patient carrier of primary APS
shown in Figure 8.3. Figure 8.5. Cure by spontaneous amputation of the left foot toes affected with gangrene in a patient with
primary APS. 92
Hughes Syndrome
Figure 8.6. Digital necrosis with gangrene of the fingers of a patient with SLE and APS. Some patients (3%) develop extensive superficial skin necrosis generally involving the limbs, head, and buttocks [28]. The onset is sudden, with an extensive and
painful purpuric lesion followed by a necrotic plaque with purpuric and active
edges and bullous lesions. The thrombozing microangiitis seen in examined tissues
is characteristic [2, 29].
Superficial Thrombophlebitis
Thrombotic episodes in the deep veins of the lower limbs are common. Similar
mechanisms might lead to the involvement of the superficial venous territory [3].
Pseudo-vasculitic Lesions: Nodules, Papules, Pustules,
Palmo–Plantar Erythema
A wide variety of skin lesions might be included under the term pseudo-vasculitic,
erythematosus macules, painful nodules, and purpura, among others. APS accounts
for the microthrombosis observed in skin vessels [3, 30] (Figs. 8.7 and 8.8).
Subungual Hemorrhages
Chipe-like subungual hemorrhages are longitudinally distributed, small reddish-toblack linear lesions, which persist after ungual compression. They are not exclusively associated with the APS because ungual trauma can be seen in healthy
subjects as well as patients with infectious endocarditis. They are caused by thrombotic or embolic phenomena. It is worth pointing out that the presence of these
Skin Manifestations of Antiphospholipid Syndrome
93
Figure 8.7. SLE along with APS presenting with
papuloerythematosus skin lesion (irregular borders)
on the lower limb. lesions in several fingers is related to an underlying pathological process [3, 5].
Their sudden onset on multiple fingers is usually concomitant to other thrombotic
event [31, 32].
Anetoderma
Anetoderma is a rare elastolytic disorder characterized by a limited area of slack
skin associated with loss of substance on examination and a loss of elastic tissue in
the histopathology [33]. Although its cause is unknown, an immunological mechanism has been suggested as playing an important role in this elatolytic disease.
Some reports suggest that anetoderma may be the presenting sign of autoimmune
disorders [34, 35], particularly in those with aPL [25, 35].
What Do Skin Lesion Biopsies of Patients with APS Show?
The main histopathological picture is non-inflammatory thrombosis in small- and
medium-sized arteries and/or veins of the dermis and hypodermis [3, 36]. A pattern
that might be associated or be the only one observed is that of obliterating endarterial occlusion, characterized by narrowing of the vessel lumen with endothelial cell
proliferation and fibrohyalinization of the vessel wall. The absence of vasculitis is
characteristic. Lymphocytic or lymphoplasmocytic infiltrating isolates might be
94
Hughes Syndrome
Figure 8.8. Biopsy of skin with non-inflammatory vascular thrombosis (venular) of a patient with SLE and APS. observed. Based on skin involvement, the following histopathologic pattern is
observed [36]:
●
●
Gangrenous lesion
Vascular thrombosis
Dermal hemorrhage
Obliterating endarteritis
Epidermal necrosis
Ulcerous lesion
Vascular thrombosis
Capillary proliferation
Obliterating endarteritis
Dermal hemorrhage
Deposit of hemosiderin
Skin Manifestations of Antiphospholipid Syndrome
●
95
Livedo reticularis
Center of the reticular pattern (apparently normal skin):
Normal biopsy
Obliterating endarteritis in deep arterioles of the dermis or hypodermis
Tissue of the reticulate (involved segment of the skin):
Hyperplasia of dermal vessels
Wherever the site of biopsy in livedo reticularis, thrombosis is rare except in the
case of catastrophic APS or in the presence of ulcers and necrosis.
Association of Skin Lesions with Different Organ
Involvement
It should be remembered that 41% of patients with APS begin their disease with
skin manifestations and that 40% of patients will develop multisystem thrombotic
phenomena during the course of the disease. The association of livedo reticularis
with cerebrovascular involvement has already been pointed out (Sneddon’s syndrome). The presence of multiple subungual hemorrhages might coincide with
thrombotic events of other organs such as the brain, skin, adrenal glands, kidney,
etc.
Entities Associated with APS
Different pathologic entities have been described to occur in association with APS.
It should be underscored that patients affected with inflammatory bowel disease
(ulcerative colitis, Crohn’s disease) are susceptible to thrombosis during the active
stage of the disease in relation to aPL. Up to 10% of patients will develop ischemic
lesions of the central nervous system and embolic events, including peripheral
necrosis [37, 38]. Skin lesions observed in this life-threatening syndrome are livedo
reticularis, acrocyanosis, extensive skin necrosis, palmar erythema, and gangrene
[39].
Treatment
It is hard to predict if the patient who only has a skin lesion will later develop an
extra cutaneous thrombotic event. However, it is worth remembering that 40% of
patients that begin with skin lesions will eventually undergo systemic involvement.
Hence, it is important to consider extensive skin necrosis and digital ischemia as
major thrombotic events; in these cases, patients should receive long-term anticoagulant treatment [40–42]. The approach to minor skin manifestations is less clear. It
is yet to be defined whether platelet antiaggregation is enough or whether it will be
necessary to attempt the use of more aggressive treatments.
Alternative treatments should be developed for patients resistant to standard
approaches [43]. Thrombolytic agents in low dose have been proposed in patients
with skin lesions where the thrombotic events account for the clinical picture (i.e.,
96
Hughes Syndrome
livedoid vasculitis). Thrombolytic agents not only accomplish the patency of
involved arteries but also play a significant role by increasing microcirculation.
Some patients have been treated with streptokinase or urokinase with or without
heparin with varying degree of responses. The intravenous infusion of recombinant
tissue plasminogen activator at a dose of 20 mg/day diluted in saline solution
during 8 hours for 10 days resulted in the healing of ulcer lesions [44]. Unwanted
effects such as bleeding that might threaten the patient’s life should be considered.
This therapeutic modality should be selected when all the other alternatives have
failed. It is critical to test coagulation status prior to and during infusion; treatment
should be withdrawn as soon as minimum bleeding is noticed [44, 45].
Although anecdotal, the efficacy of sildenafil, a phosphodiesterase inhibitor, in
the treatment of non-healing ulcers has also been reported [46].
Conclusion
aPL are strongly related to thrombotic events. It is the most common acquired
coagulation defect among the ones accountable for procoagulant states.
Skin involvement might be the first manifestation of APS (41%) and over one
third of these patients will develop multisystem thrombotic events during the
course of the disease. Therefore, a close monitoring of these patients is warranted.
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