Report

Oxford, UK
International
IJD
Blackwell
0011-9059
45 Publishing
Journal Ltd,
Ltd.
of Dermatology
2003

Cutaneous manifestations associated with antiphospholipid

Diógenes et al.
XXXX
REPORT

antibodies
Maria José Nogueira Diógenes, MD, PhD, Pedro Coelho N. Diógenes,
Raquel Maia de Morais Carneiro, MD, Carlos C. Ribeiro Neto, MD,
Fernando B. Duarte, MD, and Rosangela R. A. Holanda, MD

From the Department of Clinical Medicine, Abstract

Federal University of Ceará, the Laboratory of
Central de Análises Clínicas (CAC), and the
Ceará State Hemotherapy Center, HEMOCE,
Fortaleza, Brazil
Correspondence
Maria José Nogueira Diógenes
Rua Monsenhor Bruno, 630/502
CEP 60115 –190 – Fortaleza
Ceará
Brazil
E-mail: marind@secrel.com.br
This study took place at the Department of
Dermatology and Hematology, Walter
Cantídio University Hospital, Federal
University of Ceará, Fortaleza, Brazil.
Background Primary Antiphospholipid Antibody Syndrome (PAAS) is characterized by
detection of antiphospholipid antibodies associated with venous or arterial thrombosis and /or
miscarriages by patients with no other associated disease such as systemic lupus
erythematosus (SLE). Primary Antiphospholipid Antibody Syndrome has many clinical
manifestations of which dermatological ones are probably the most common. The purpose of
this study was to determine the frequency of each cutaneous lesion, describing clinical features
essential for diagnosis, in patients with Antiphospholipid Antibody Syndrome (AAS) attending
Walter Cantídio University Hospital.
Methods Sixty patients with clinical findings suggestive of AAS were screened, and submitted
for clinical and laboratory evaluations including lupus anticoagulant (KCT), anticardiolipin
antibodies (IgG and IgM: ELISA), routine laboratory tests and screening tests for possible
associated conditions.
Results Twenty-five cases of primary and 14 cases of secondary AAS were diagnosed by
clinical and laboratory evidences. Persistent elevated antiphospholipid antibodies without
history of thromboembolic events or miscarriages were demonstrated in 21 patients. Forty
percent of the patients with AAS had a cutaneous feature as the major complaint. These were
dermographism (15), acrocyanosis (13), urticaria (9), diffuse alopecia (9), livedo reticularis
(seven), Raynaud’s phenomenon (three), purpura (two), ulcers and necrosis (four), nodules
(four), pterygium ungueum (one) and subungual hemorrhage (one).
Conclusions Dermatological complaints are very frequent in patients with AAS and may be
the first clue to the syndrome. Therefore a careful history and detailed physical examination are
essential to diagnose AAS. All dermatologists should investigate the possibility of AAS when
facing cutaneous findings related to venous or arterial thrombosis or microthrombosis.

reticularis, purpura, cyanotic macules, hemorrhages (ecchy-

Introduction
Primary Antiphospholipid Antibody Syndrome (PAAS) is
characterized by detection of antiphospholipid antibodies
(lupus anticoagulant, LA, and /or anticardiolipin antibody,
aCL), associated with arterial or venous thrombosis and/or
miscarriage by patients with no associated condition such as
autoimmune, malignant or infectious diseases.1–6 Thrombo-
cytopenia may also be present.1–3,5,6
Antiphospholipid Antibody Syndrome (AAS) has clinical
manifestations, affecting almost every organ or system (see
Table 1). The most common manifestations are probably
cutaneous ones12 such as leg ulcers,22–25 lower limb thrombo-
phlebitis, cutaneous necrosis, peripheral ischemia and
632 gangrene, acrocyanosis, Raynaud’s phenomenon, livedo
mosis), cutaneous nodules and others.7,8,13,21,23,26
Laboratory diagnosis is made by detection of anticardioli-
pin antibodies (IgG and IgM) by ELISA3,27 and/or LA tests.
Lupus anticoagulant is measured by diluted Russell’s viper
venom time (dRVVT) or Kaolin clotting time (KCT). Low
levels of reactive C protein, protein C and protein S indicate
additional risk of thrombosis.28–32
Considering the high frequency of cutaneous manifesta-
tions in a previous series and the overall systemic activity in
this syndrome, the purpose of this study is to determine the
frequency of each cutaneous lesion, describing clinical fea-
tures essential for diagnosis in patients with AAS attending
Walter Cantídio University Hospital, Federal University of
Ceará.

International Journal of Dermatology 2004, 43, 632– 637 © 2004 The International Society of Dermatology
Diógenes et al. Cutaneous manifestations of antiphospholipid antibodies Report 633

Table 1 Systemic manifestations associated with the antiphospholipid Antibodies Syndrome

Organ or system affected Systemic manifestation Reference

CNS Transient ischemic attacks, Sneddon’s syndrome, chorea, 7–12

multiple infarct dementia, transverse myelopathy, cerebral
venous thrombosis, pseudotumor cerebri, migraines, epilepsy
Heart Angina, myocardial infarction, cardiac valvular vegetations, 12–14
intracardiac thrombus, heart failure, arrhythmias
Lungs Emboli and pulmonary hypertension 12
Hematologic Thrombocytopenia, hemolytic anemia 15
Gastrointestinal Hepatic infarction, gastric ulceration, esophageal 15 –18
necrosis and perforation, Budd–Chiari syndrome,
Hepatomegaly, elevated liver enzymes
Kidneys Renal failure, glomerular thrombus, hypertension, 12
renal arterial end vein thrombosis
Female teproductive system Miscarriage, HELLP (hemolysis, elevated liver 12,19,20
enzymes low platelets) syndrome
Eyes Vascular retinal occlusions 15
Endocrine Adrenal failure 21
Musculoskeletal system Avascular necrosis of bones 12

an attempt to diagnose the condition. Patients with more systemic

Patients and Methods
A total of 60 patients attended the Department of Dermatology of
Walter Cantídio Hospital (Federal University of Ceará) and were
included in the study.
The screening criteria included at least one of the following:
1 A history of thromboembolic events and/or miscarriage;
1–6
2 Previous positive tests for antiphospholipid antibodies;
3 An actual dermatologic manifestation related to the syndrome
(leg ulcers, lower limb thrombophlebitis, cutaneous necrosis,
peripheral ischemia and gangrene, acrocyanosis, Raynaud’s phe-
nomenon, livedo reticularis, pterygium ungueum, purpura, cyan-
otic macules, hemorrhages, atrophie-blanche, capillaritis, lichen
aureus, subungual hemorrhages, anetoderma,
cutaneous nodules, palmar erythema and
7,8,12,13,21–26,33
melanoderma), and
4 An important family history of relatives with AAS and a
nonspecific-associated symptom such as migraine.34
All patients were submitted for a medical interview and a physical
examination. The medical interview included: Patient’s major
complaint, former pathological and familiar history, past history of
AAS, and presence of any associated condition known to elevate
titers of antiphospholipid antibodies.7,8,13,35– 42 Dermatological
examination was documented photographically. Laboratory
examinations performed included: complete blood count, platelet
count, erythrocyte sedimentation rate, PPD, VDRL, antinuclear
antibodies test, AST, ALT, glucose, creatinine, urinalysis, stool
examinations for ova and parasites, direct Coombs’ test,
protein electrophoresis, triglycerides, HDL, VLDL and LDL
cholesterol,43– 45 LA (KCT or dRVVT), aCL (IgG and IgM) ELISA
(INOVA), antinative DNA, anti-RNP, anti-RO, anti-LA and
anti-SM.3,27 If patients referred any symptoms of possible
associated conditions, further laboratory tests were performed in
complications7 and greater risk of recurrence were also tested for
deficiency of protein S, protein C and resistance to activated
protein C, and had their antithrombin III and fibrinogen levels
measured.28 – 32 Histologic samples from skin lesions (nodules,
cutaneous necrosis and ulcers) was collected, fixed in formalin,
processed in paraffin and stained with hematoxylin-eosin.46 If a
thrombotic state was suspected, imaging studies were performed
(arteriogram and Doppler studies).
Only patients with positive LA and /or aCL (IgG and /or IgM), on
titers superior to 20 gpl or 20 mpl were included in the study. The
antiphospholipid antibodies were measured every 3 months or
during follow up for those patients with clinical complaints.45
Patients with ongoing infectious disease and /or drug use
(hormones) had their infection treated or drug removed first and,
after 3 months, antiphospholipid antibodies tests were repeated.
Only those who persisted with positive titers were included.
Patients were divided in three groups. Patients who had a
history of thromboembolic events and /or miscarriages or
pregnancy complications, with positive antiphospholipid
antibodies, were diagnosed, by definition, as AAS. In this first group,
patients were grouped as having secondary or primary syndrome
if associated autoimmune, malignant or hematological diseases
and were diagnosed or not, respectively.3 Patients with no history
of thromboembolic events and /or miscarriages but with cutaneous
manifestations related to the syndrome (livedo reticularis,
acrocyanosis, Raynaud’s phenomenon and purpura) were tested
for LA and aCL, and if they had at least three positive tests for
antiphospholipid antibodies repeated every 3 months they were
also selected. This last group was characterized as having
persistent positive antiphospholipid antibodies (PPAA).
All patients were followed for at least 1 year. Follow up included
regular laboratory investigations, and a clinical and therapeutic

© 2004 The International Society of Dermatology International Journal of Dermatology 2004, 43, 632– 637
634 Report Cutaneous manifestations of antiphospholipid antibodies Diógenes et al.

evaluation. The therapeutic strategies included Aspirin or Warfarin,
depending on the clinical symptoms.5,12
Results
A total of 60 patients with AAS or persistent antiphospholi-
pid antibodies were included. Forty-seven patients were
female and 13 male. The mean age of all patients was 39.9
years old (12–80). The mean age for patients with AAS was
45.7 (12–80) and for patients with PPAA was 29.19 (15–46).
The presenting symptom was related to AAS in 16 (40%)
out of 39 cases of AAS.
Primary AAS was diagnosed in 25 patients, and secondary
AAS in 14 patients. The associated conditions were: systemic
lupus erythematosus (SLE; seven), Behçet’s disease (two),
rheumatoid arthritis (one), polycythemia vera (one), Sjögren
syndrome (one) and malignancies (two).
Twenty-one patients had persistent antiphospholipid
antibodies and no systemic manifestation related to the
syndrome. In some of these cases, a history of hormone use (11
cases) or inflammatory, proliferative or infectious conditions
was diagnosed (two dermatitis herpetiformis, one leproma-
tous leprosy, two urinary tract infection, one sinusitis, two
multiple myeloma, two plaque scleroderma). Hormones were
suspended and infections treated, but the patients still had at
least three positive antiphospholipid assays in a period of
1 year.
Histological findings of biopsies of all four ulcers and
necrotic areas were not specific. Biopsies of nodules revealed
thrombus on dermal microvessels in three out four cases.
Biopsies from other sites revealed associated conditions
contributing to the diagnosis of secondary syndrome.
Laboratory findings were: All patients had positive aCL
(IgG and IgM). All patients had a negative partial thrombo-
plastin time. Fourteen patients had positive LA (KCT). Twenty
patients had positive LA (dRVVT). Erythrocyte sedimentation
rate was greater than 40 mm/h in 21 cases. Low levels of protein
S were evidenced in two out of seven cases measured.
Systemic manifestations accessed are described in Table 2
and dermatological manifestations in Table 3.
Discussion
Of a total of 60 patients, 47 were female and 13 were male,
with a ratio of 3.6 : 1. Previous reports described a ratio of
2 : 1 in patients with PAAS,47 and 4 : 1–5 : 1 in patients
with a positive lupus anticoagulant test.48,49 In this study,
patients with primary and secondary AAS, as well as patients
with PPAA, were included; all contributing to the female
preponderance.
The mean age for all patients with antiphospholipid anti-
bodies (n = 60) was 39.9 years old. For patients with AAS
(n = 39) the mean age was 45.7 years, and for those with
PPAA was 29.19 years (range, 15–46 years). A classical study
of primary AAS reported a mean age of 38.5 years (varying
from 21 to 59 years).34 Cases in children have been
described.49,50 In our study, the patients with PPAA were
slightly younger than those with an established syndrome.
This may suggest that this group of patients may develop
thrombotic events at older ages and should be closely followed.

Table 2 Systemic manifestations accessed

Primary AAS Secondary AAS PPAA
in patients with antiphospholipid
Systemic manifestations (n = 25) (n = 14) (n = 21)
antibodies (60 cases, Walter Cantídio
Renal necrosis (1) 0 1 0 University Hospital, Federal University of
Necrosis of bones (1) 0 1 0 Ceará, March 1998 to March 2001)
Superficial and deep venous thrombosis (9) 4 5 0
Stroke (7) 4 3 0
Myocardial infarction (1) 0 1 0
Pseudotumor cerebri (1) 1 0 0
Hepatic infarction (1) 1 0 0
Miscarriages (16) 14 2 0a
Pregnancy complications (11) 6 3 2
Raynaud’s phenomenon (3) 0 3 0
Amaurosis (4) 2 2 0
Seizures (2) 2 0 0
Headache (24) 11 6 7
Chorea (1) 1 0 0
Pulmonary thromboembolism (1) 0 1 0

a
In two cases there was a pregnancy loss, but to date there has not been any recurrence
of the miscarriage.
AAS = Antiphospholipid Antibody Syndrome; PPAA = persistent positive
antiphospholipid antibodies, with no history of thrombosis and/or miscarriages.

International Journal of Dermatology 2004, 43, 632– 637 © 2004 The International Society of Dermatology
Diógenes et al. Cutaneous manifestations of antiphospholipid antibodies Report 635

Table 3 Dermatological manifestations

Primary AAS Secondary AAS PPAA
accessed in patients with
Dermatological manifestations (n = 25) (n = 14) (n = 21)
antiphospholipid antibodies (60 cases,
Walter Cantídio University Hospital, Dermographism (24) 10 5 9
Federal University of Ceará, March 1998 Chronic urticaria (16) 6 3 7
to March 2001) Acrocyanosis (19) 8 5 6
Raynaud’s phenomenon (3) 1 2 0
Livedo reticularis (10) 4 3 3
Diffuse alopecia (11) 5 4 2
Pterygium ungueum (1) 0 1 0
Purpura (4) 1 1 2
Ulcers and necrosis (4) 2 2 0
Subungual hemorrhage (1) 0 1 0
Nodules (4) 2 2 0a

a
In one case the patient presented with a nonthrombotic nodule, but later developed the
primary syndrome.
AAS = Antiphospholipid Antibody Syndrome; PPAA = persistent positive
antiphospholipid antibodies, with no history of thrombosis and /or miscarriages.

All patients had positive aCL (IgG and IgM). All patients
had a negative partial thromboplastin time. Fourteen patients
had positive LA (KCT). Twenty patients had positive LA
(dRVVT). Low levels of protein S were evidenced in two out
of seven cases measured. The APTT has low sensitivity for
low LA activity, missing as much as 50% of patients in one
study with SLE patients and LA activity with other tests.26
Previous data on laboratory findings in this syndrome have
addressed the problem that not all patients have both LA and
aCL antibodies detected,7,47,51 with agreement of tests in only
50–75% of cases of AAS.7,47,51 Some authors have stated that
aCL antibody tests are more sensitive and have less observer
error.3,13 Almost all patients with LA have detectable aCL
antibodies (90%) and almost all patients with AAS have
detectable aCL antibodies.3 Low protein C and protein S
levels are described in patients with AAS and are associated
with an additional risk of thrombotic events.28–32
Sixteen (40%) patients out of 39 had a dermatological
manifestation related to the syndrome as the main complaint.
A previous study also developed in a dermatology depart-
ment described cutaneous lesions as a primary sign of AAS in
41% of cases. More serious systemic thrombosis developed in
40% of those patients.7,46 Another study26 showed cutaneous
manifestations in 70% of catastrophic PAAS cases.
All systemic manifestations found in our group of patients
have been previously described.7–21 The most frequent derma-
tological findings were dermographism, chronic urticaria,
acrocyanosis, livedo reticularis and alopecia. Dermogra-
phism was diagnosed in patients of all three groups (40%).
This manifestation has not been described previously in
association with the syndrome; nevertheless, as a result of its
highly frequent presence among patients with antiphospholi-
pid antibodies it will be the subject of future studies. Chronic
urticaria (26% of all patients), also not described previously
in association with the syndrome, was also a common mani-
festation. All patients with chronic urticaria were investigated
for possible common causes. No cause for chronic urticaria
was found in the primary AAS patients and PPAA patients,
although no assay for FcεRIα autoantibodies was performed.
Chronic urticaria is now ascribed to autoimmunity in
approximately 50% of cases, with anti FcεRIα antibodies
playing a major role.52 Autoimmune conditions were associ-
ated more frequently with patients with chronic urticaria
having functional autoantibodies than in those without.52 As
chronic urticaria is frequently autoimmune in etiology, as
well as being associated with autoimmune conditions, its
finding in PAAS and its occurrence in the PPAA patients with-
out the syndrome will be a target of future studies to prove the
possible association of chronic urticaria with antiphospholipid
antibodies. The three cases of urticaria described in
secondary antiphospholipid syndrome could be related to
the underlying disorder in these patients. Other cutaneous
manifestations found in this study, such as acrocyanosis
(31% of all), diffuse alopecia (18%), livedo reticularis (17%),
ulcers and necrosis, purpura, nodules, Raynaud’s phenome-
non, pterygium ungueum and subungual hemorrhage, have
already been described in patients with AAS.7,8,12,13,21–26,33
A previous report53 described livedo reticularis as the most
common dermatological manifestation (55%) in PAAS
patients. In another study,7 thrombophlebitis, presenting
as an edema and erythema of the ankle and lower leg, was
the most common (34%) finding among 70 patients with LA
activity.
In seven (50%) of 14 secondary cases, the syndrome was
associated with SLE. Similar results were described by
Derksen et al. who found SLE in 49% of secondary cases.36
Previous reports12,13,47,51,54 have described secondary cases to
be associated with the other clinical conditions diagnosed in

© 2004 The International Society of Dermatology International Journal of Dermatology 2004, 43, 632– 637
636 Report Cutaneous manifestations of antiphospholipid antibodies
this study such as Sjögren syndrome and rheumatoid arthritis,
though thrombotic events are rare in these cases.
Histological findings of skin ulcers and necrotic areas were
not specific. Three out of four skin nodules studied revealed
thrombus on dermal microvessels. Biopsies from other sites
revealed features of associated conditions. According to the
literature, almost all findings of vascular occlusion in AAS are
of thrombotic and not inflammatory nature.2,3,13,15,54 Capil-
laries may coexist, as perivascular inflammatory reaction is
usually a consequence and not a cause of the vessel’s throm-
botic event.15
Patients with persistent positive antiphospholipid anti-
bodies, but no systemic manifestation related to the syndrome,
were included in this study because it has been shown that
they are at higher risk of future thrombosis.54 Thirty to 50%
of patients with positive LA later develop thrombosis.54 Only
a small percentage of patients with antiphospholipid anti-
bodies, especially aCL, develop thrombosis, miscarriages or
thrombocytopenia,3 although high titers of aCL IgG have
been linked with an increased risk of future thrombosis.28 As
only a minority of patients develop thrombosis, they should
not be treated initially, but should be carefully followed up.3
In one case of this study, the patient presented with a non-
thrombotic skin nodule and later developed the primary syn-
drome, justifying the careful follow up of patients with
persistent antiphospholipid antibodies and no documented
evidence of thrombosis.
Dermatological complaints are frequent in patients with
AAS and may be the first clue to the syndrome. So, every
dermatologist should investigate the possibility of AAS,
not only when facing dermatological findings related to
the development of thrombus and microthrombus, but also
when observing acrocyanosis and livedo reticularis.
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