Clinical Features Related to Antiphospholipid Syndrome in Patients with Chronic Viral Infections (Hepatitis C Virus/HIV Infection): Description of 82 Cases
Clinical Features Related to Antiphospholipid Syndrome in Patients with Chronic Viral Infections (Hepatitis C Virus/HIV Infection): Description of 82 Cases
Manuel Ramos-Casals 1
Ricard Cervera 1
Mariana Lagrutta 1
Francisco Medina 0
Mario Garc´ıa-Carrasco 1
Gloria de la Red 1
Albert Bov e´ 1
Miguel Ingelmo 1
Josep Font 1
0 Department of Rheumatology, Hospital de Especialidades, Centro Me ́dico Nacional Siglo XXI , Mexico DF , Mexico
1 Department of Autoimmune Diseases, Institut d'Investigacions Biome`diques
We analyzed the spectrum of clinical features related to antiphospholipid syndrome (APS) in patients with chronic viral infections, such as hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection. We selected patients from the HISPAMEC registry who repeatedly tested positive for antiphospholipid antibodies (aPL) and who had features of APS, and we searched the MEDLINE database for additional cases. A total of 82 patients were included (45 had chronic HCV infection, 32 had HIV infection, and 5 had HCVHIV coinfection). The main features of APS were avascular bone necrosis (20 patients), peripheral thrombosis (17), thrombocytopenia (15), neurologic features (13), cardiac manifestations (12), pulmonary embolism (9), gastrointestinal manifestations (8), and cutaneous manifestations (8). The main APS-related features in HCVinfected patients were intraabdominal thrombosis and myocardial infarction, whereas, in HIV-infected patients, the main features were avascular bone and cutaneous necrosis. These viruses might act in some patients as chronic triggering agents that induce a heterogeneous, atypical presentation of APS.
Antiphospholipid syndrome (APS) is an autoimmune
disease characterized by arterial or venous thrombosis
and often by multiple fetal losses and (usually
moderate) thrombocytopenia, in association with presence
of antiphopholipid antibodies (aPLs) (mainly
anticardiolipin antibodies [aCLs] and lupus anticoagulant
]. aPLs have also been detected in patients with
acute and chronic infections and malignant diseases,
and their presence has been associated with use of some
]. Infectious agents have recently been
implicated in the pathogenesis of APS, particularly in
its catastrophic form, and intercurrent bacterial
infections might constitute one of the main precipitating
factors of the catastrophic response in some patients
However, the etiopathogenic role of chronic viral
diseases, such as hepatitis C virus (HCV) infection and
HIV infection, has been little studied in association with
APS. HCV infection has been associated with some
systemic autoimmune diseases, such as Sjo¨gren
], rheumatoid arthritis [
], and systemic lupus
]. Nevertheless, its association with
APS is controversial [
], and although the presence of
aPLs in patients with chronic HCV infection is
common, it is rarely associated with thrombotic events [
Buskila et al. [
Puri et al. [
Baid et al. [
Orbea-Rios et al. [
Cailleux et al. [
Gonzalez et al. [
Fickert et al. [
Hernandez et al. [
Leder et al. [
Turhal et al. [
Brown et al. [
Panuk et al. [
Calza et al. [
Similarly, a high prevalence of aPLs with a low frequency of
associated thrombosis has also been noted among patients with
HIV infection [
We report 21 new cases of chronic viral infection with
APSrelated clinical or hematological manifestations. In addition, we
review the literature for additional cases, with the aim of
characterizing the spectrum of clinical manifestations related to APS
in patients with HCV and/or HIV infection.
PATIENTS AND METHODS
In 2001, several reference centers from Spain and Latin
American countries with substantial experience in the management
of autoimmune diseases associated with chronic viral infection
constituted the Hispanoamerican Study Group of Autoimmune
Manifestations of Chronic Viral Disease (HISPAMEC), with the
aim of creating a registry of patients with coexisting systemic
autoimmune diseases and HCV and/or HIV infection. From
the HISPAMEC registry, we selected patients who presented
with repeated test results positive for aPLs together with clinical
features of APS. The diagnosis of APS was based on the
preliminary classification criteria proposed in 1999 by Wilson et
], although some patients who received diagnoses before
1999 met the criteria proposed by Harris et al. [
included thrombocytopenia. A diagnosis of catastrophic APS
was considered when a patient presented with acute devastating
APS with multiple organ involvement (13 organs), as recently
]. We defined the different clinical and analytical
manifestations on the basis of the largest published clinical
description of APS [
HIV/AIDS • CID 2004:38 (1 April) • 1011
In addition, we searched the MEDLINE database for articles
published during the period of January 1980 through August
2003 using the search terms “antiphospholipid syndrome,”
“antiphospholipid antibodies,” “anticardiolipin antibodies,” “lupus
anticoagulant,” “thrombosis,” “infarction,”
“thrombocytopenia,” “fetal loss,” “HCV,” “HTLV-III,” “retroviruses,” and
“HIV.” We identified additional articles through an exhaustive
hand search of the bibliographies of the retrieved articles. Only
well-documented cases were finally included in our study.
Characteristics of HISPAMEC patients. We identified 21
patients (12 of whom had chronic HCV infection, 6 of whom
had HIV infection, and 3 of whom had HCV-HIV coinfection)
who presented with repeated test results positive for aPLs and
APS-related clinical features. Thirteen patients (62%) were
men, and 8 (38%) were women, with a mean age at the time
of APS diagnosis of 40.8 years (range, 29–73 years). Three
patients presented with HCV-associated SLE. APS was
diagnosed in 20 patients with a previously known HCV-HIV
infection, with the main clinical features leading to APS diagnosis
being thrombotic phenomena (n p 9), thrombocytopenia
(n p 3), detection of aPLs in a patient with a past history of
miscarriages (n p 1), and other causes (n p 7). In the
remaining patient, APS was diagnosed before HCV infection,
which was detected on the basis of elevated transaminase levels.
The clinical manifestations of APS were peripheral venous
thrombosis in 5 patients, avascular bone necrosis in 5,
pulmonary embolism in 4, fetal loss in 4, severe cytopenia in 4,
stroke in 2, myocardial infarction in 2, optic neuropathy in 2,
digital ischemia in 1, and portal/splenic venous thrombosis in
1. One patient presented with catastrophic APS with multiorgan
thrombotic manifestations (cardiac, pancreatic, splenic,
hematological, and renal). Other clinical features were malar rash
(n p 2), oral ulcers (n p 2), cutaneous vasculitis (n p 2), CNS
involvement (n p 2), articular involvement (n p 1),
glomerulonephritis (n p 1), and serositis (n p 1). Hematological
features included anemia (hemoglobin level, !10 g/dL; 6
patients [29%]), leukopenia (leukocyte count, !4 109
leukocytes/L; 3 patients [14%]), and thrombocytopenia (platelet
count, !150 109 platelets/L; 9 patients [43%]), which was
severe (!30 109 platelets/L) in 4 patients. Nineteen patients
tested positive for aCLs at medium/high titers, and 10 tested
positive for LA.
Characteristics of all identified patients. Table 1 shows
the main characteristics of 82 patients with chronic viral
infections presenting APS-related manifestations (the
aforementioned cases plus 61 well-defined cases identified in the
literature search) [
]. Forty-five patients (55%) presented
with chronic HCV infection, 32 (39%) presented with HIV
1012 • CID 2004:38 (1 April) • HIV/AIDS
infection, and 5 (6%) presented with HCV-HIV coinfection.
Seven patients presented with associated autoimmune diseases,
such as systemic lupus erythematosus (4 patients), vasculitis (2
patients; polyarteritis nodosa and leukocytoclastic vasculitis),
and Crohn disease (1 patient). Epidemiological data were
available for 65 patients: 41 patients (63%) were male, and 24 (27%)
were female, with a mean age of 37.4 years (range, 4–77 years).
APS-related features are summarized in table 2 and included
avascular bone necrosis (20 patients [24%]), fetal losses (5
[21%] of 24 female patients), peripheral thrombosis (17
patients [21%]; deep vein thrombosis in 15 patients, superficial
thrombophlebitis in 2, and arterial thrombosis in 2),
thrombocytopenia (15 patients [20%]), neurologic features (13
patients [16%], including stroke in 10 patients, migraine in 4,
transient ischemic attack in 2, and epilepsy in 2), cardiac
manifestations (12 patients [15%]; myocardial infarction in 11
patients and valvular vegetations in 1), pulmonary embolism (9
patients [11%]), gastrointestinal manifestations (8 patients
[10%]; splachnic venous thrombosis in 5 patients, mesenteric
ischemia in 1, splenic infarction in 1, and splenic vein
thrombosis in 1), cutaneous manifestations (8 patients [10%];
cutaneous necrosis in 5 patients, livedo reticularis in 2, and digital
gangrene in 1), renal manifestations (5 patients [6%]; renal
thrombotic microangiopathy in 5 patients, renal vein
thrombosis in 2, and renal artery thrombosis in 1), ophthalmic
manifestations (4 patients [5%]; optic neuropathy in 3 patients and
retinal vein thrombosis in 1), and hepatic manifestations (3
patients [4%]; portal thrombosis in 2 patients and Budd-Chiari
syndrome in 1). Other features included testicular thrombosis
in one patient and catastrophic APS in another. aCLs were
present in 80 patients (97%), and LA was present in 17 (57%)
of 30 patients.
Compared with HIV-infected patients (table 3),
HCV-infected patients had a higher mean age (44 vs. 31 years; P p
.001) and were more often female (50% vs. 27%; P p .063).
HCV-infected patients also had a higher prevalence of cardiac
manifestations (27% vs. 0%; P ! .001) and abdominal
manifestations (29% vs. 3%; P p .004), as well as a trend toward a
higher prevalence of thrombocytopenia (22% vs. 6%; P p
.057). In contrast, HCV-infected patients had no bone
involvement (0% vs. 59%; P ! .001) and showed a trend toward a
lower prevalence of skin involvement (4% vs. 16%; P p .092).
HCV and HIV are considered the causes of the 2 major
epidemic viral infections in the past 2 decades, with a recent
phenomenon being the increasing description of autoimmune
features in HCV- and HIV-infected patients. On the one hand,
chronic HCV infection has been associated with detection of
autoantibodies and systemic autoimmune diseases [
the other hand, the use of HAART therapy is giving rise to a
substantial change in the clinical spectrum of HIV infection,
in which, as in chronic HCV infection, an increasing frequency
of associated autoimmune and lymphomatous processes is
being described [
]. The persistent stimulation of the immune
system triggered by these chronic viral infections may favor the
development of autoimmune manifestations.
Historically, aPLs have always being closely associated with
infectious agents: they were first detected in serum samples
obtained from patients with syphilis [
]. Later, in a review of
APS cases in patients with viral infections, Uthman and Gharavi
] identified isolated cases associated with such viruses as
cytomegalovirus, varicella zoster virus, and Epstein-Barr virus.
Recently, the possible association of APS with chronic viral
infections (e.g., HCV and/or HIV infection) has generated
growing interest, but this is still controversial.
In spite of the infrequent association of APS with HCV
], we describe a total of 45 HCV-infected patients
with APS, a number that has allowed the clinical
characterization of this small subset of patients with APS. In comparison
with patients in general studies of APS [
], the HCV-infected
patients with APS in our study had a higher mean age and a
differentiated clinical spectrum of thrombotic involvement;
furthermore, they had a lower frequency of the more typical
features of APS, such as peripheral thrombosis and neurological
features, and, in contrast, a higher prevalence of atypical or
infrequent features of APS, such as myocardial infarction and
intraabdominal thrombotic events. In addition, in patients with
APS and HCV infection, we observed a higher frequency of
positive immunological markers that are often detected in
chronic HCV infection, such as antinuclear antibodies (77%
of our patients and 46% of the total patients), cryoglobulins,
hypocomplementemia, and rheumatoid factor (75%, 58%, and
50% of our patients, respectively). Cryoglobulinemia is closely
associated with HCV infection, but its possible role in the
development of APS-related features has been little studied [
]. The higher presence of LA in patients with APS and HCV
infection (80%) may well explain the occurrence of thrombotic
events in this subset of HCV-infected patients, because its
prevalence in unselected series of HCV-infected patients is extremely
We also present data on 31 HIV-infected patients with APS,
5 (16%) of whom had HIV-HCV coinfection. Analysis of
APSrelated features in HIV infection shows a similar pattern to
those in HCV infection, with a higher frequency of test results
positive for aPLs combined with a very infrequent rate of
thrombotic events and APS [
]. The first evidence of
APSHIV/AIDS • CID 2004:38 (1 April) • 1013
related features in HIV infection came from the studies of
thennamed HTLV-III infection in the United States in the 1980s
]. However, the few reports of thrombotic events in
HIVinfected patients are mostly related to extrinsic causes, such as
opportunistic infections and metabolic disturbances after
HAART therapy [
]. Other factors, such as decreased levels
of functional protein C or acquired protein S deficiency, have
also been implicated [
], showing a multifactorial origin of
HIV-related thrombosis, with aPLs playing a limited role, as
evidenced by the 31 HIV-infected patients with APS features
presented in this study. Clinical characterization of HIV-related
APS includes a predominance of male patients, with a mean
age of 30 years and, like HCV-related APS, with a more
heterogeneous clinical presentation than that observed in large
studies of unselected APS patients. However, the pattern of
clinical expression of APS in HIV-infected patients is different
from that in HCV-infected patients, with a higher frequency
of bone and cutaneous involvement and a lower frequency of
cardiac and intraabdominal features. Noteworthy is the
description of 14 HIV-infected patients with aPL-associated
avascular bone necrosis (ABN), given that Tektonidou et al. [
using resonance imaging, have recently demonstrated a higher
prevalence of asymptomatic ABN in patients with primary APS,
suggesting that clinicians should be alert to the possibility of
this unusual manifestation of APS in patients with both primary
and HIV-related APS.
Only 1 (1.3%) of the 76 patients with APS associated with
chronic viral infection developed the catastrophic form of APS,
whose pathogenesis involves several triggering factors, with
infections being increasingly described as a major precipitator.
The first evidence came from Rojas-Rodrı´guez et al. [
found that bacterial infections were triggering factors for the
development of catastrophic APS in 6 of 8 patients, whereas
Asherson et al. [
] found infections (mainly acute) in 28 (35%)
of 80 patients with catastrophic APS. This important role of
bacterial agents as triggering factors for catastrophic APS may
be associated with the acute nature of the infection, which
might induce a disproportionate immune response involving
superantigen-related mechanisms [
]. Asherson and Shoenfeld
] recently raised the possibility of a molecular mimicry
between the infectious agent and some autoantigen, such as
This study has demonstrated a broad spectrum of
APSrelated features in patients with chronic viral infections such
as HCV and HIV, most of which are considered atypical or are
infrequently detected in general series of APS. Compared with
the largest published series of unselected patients with APS [
HCV-HIV–coinfected patients have a higher frequency of
specific APS-related features, such as myocardial infarction,
cutaneous necrosis, renal microangiopathy, avascular bone
necrosis, and optic neuropathy, and, in contrast, a lower frequency
1014 • CID 2004:38 (1 April) • HIV/AIDS
of more typical features of APS, such as peripheral thrombosis,
neurological features, livedo reticularis, or thrombocytopenia
It may be hypothesized that 2 opposite etiopathogenic
situations occur in patients with APS and chronic viral infections.
On one hand, several autoimmune phenomena related to HCV/
HIV infections, such as the presence of aPLs,
thrombocytopenia, digital ischemia, or cutaneous necrosis, might mimic APS
in some patients, or, because of the frequent detection of aPLs
in HCV-HIV–coinfected patients, a casual association with
thrombotic events might lead to the fulfillment of the APS
classification criteria. On the other hand, HCV and HIV might
act as etiopathogenic agents for the development of a true APS
in a small subset of patients. To differentiate both
etiopathogenic associations, determination of b2-GPI antibodies in these
patients might play a key role in distinguishing the pathogenic
or b2-GPI–dependent aCLs (etiopathogenic association) from
the nonpathogenic b2-GPI–independent aCLs (mimicry or
casual association). The data presented in this study suggested
that APS is infrequently observed in patients with chronic viral
diseases in comparison with other systemic autoimmune
diseases, such as Sjo¨gren syndrome or systemic lupus
]. Nevertheless, the progressive use of antiviral
therapies will lead to increased chronicity of both these viral
infections, with a probable increase in the number of patients
presenting with autoimmune features. In the near future,
diagnosis and treatment of these processes will present an
important clinical challenge in the treatment of patients with
chronic HCV and HIV infections.
In conclusion, we describe a subset of patients with chronic
viral infections (HCV and HIV infections) who presented a
specific clinical picture of APS. The main APS-related features
in HCV-infected patients were intraabdominal thrombosis and
myocardial infarction, whereas, in HIV-infected patients, they
were avascular bone and cutaneous necrosis. Infectious agents
may play an etiopathogenic role in the clinical expression of
some patients with APS, with bacterial infections probably
acting as acute triggering agents of a devastating, multiorgan form
of APS (catastrophic APS), whereas viruses, such as HCV and
HIV, might act in some patients as chronic triggering agents
that induce a heterogeneous, atypical presentation of APS.
MEMBERS OF THE HISPANOAMERICAN STUDY
GROUP OF AUTOIMMUNE MANIFESTATIONS
OF CHRONIC VIRAL DISEASE (HISPAMEC)
Manuel Ramos-Casals (Coordinator), Mario Garcı´a-Carrasco,
Ricard Cervera, Miguel Ingelmo and Josep Font (Department of
Autoimmune Diseases, Hospital Clinic, IDIBAPS, School of
Medicine, University of Barcelona, Barcelona, Spain); Xavier
Forns and Jose Ma Sanchez-Tapias (Department of Hepatology,
Hospital Clinic, Barcelona); Armando Lo´ pez-Guillermo
(Department of Hematology, Hospital Clinic, Barcelona); Jose Rosas
and Gregorio Santos (Rheumatology Unit, Hospital de la
VilaJoiosa, Vila-Joiosa, Alacant, Spain); Francisco Medina
(Department of Rheumatology, Hospital de Especialidades, Centro
Me´dico Nacional Siglo XXI, Mexico DF, Mexico); Luis Javier Jara
(Department of Rheumatology, Hospital de Especialidades,
Centro Me´dico Nacional La Raza, Mexico DF, Mexico); Juan Manuel
Anaya, Rheumatology Unit (Corporacio´ n para Investigaciones
Biolo´ gicas and Clı´nica Universitaria Bolivariana, School of
Medicine, Universidad Pontificia Bolivariana, Medellı´n, Colombia);
and Juan Carlos Restrepo (Hospital Pablo Tobo´ n Uribe and
University of Antioquia, Medellı´n, Colombia).
We wish to thank David Buss for his editorial assistance.
HIV/AIDS • CID 2004:38 (1 April) • 1015
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1016 • CID 2004 : 38 ( 1 April) • HIV/AIDS