antiphospholipid syndrome · 2012-05-19 · eular on-line course on rheumatic diseases – module...

Eular On-line Course on Rheumatic Diseases – module n°19 Munther A. Khamashta, Maria Laura Bertolacchini, Monika Ostensen

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ANTIPHOSPHOLIPID SYNDROME

1. Global learning outcome

This module will enable the participant to recognise, diagnose and treat patients with

antiphospholipid syndrome.

2. Specific learning outcomes

1. Recognise that the antiphospholipid syndrome is not a rare disease and that patients with

symptoms suggestive of antiphospholipid syndrome are frequently seen in daily clinical practice.

2. Recognise that the antiphospholipid syndrome involves a wide spectrum of clinical

manifestations.

3. Although major thrombotic events are the hallmark of the disease other subtle manifestations

such as cognitive impairment or mood disorders are also frequent.

4. Design a diagnostic screening algorithm for the individual patient

5. Develop treatment strategies for patients with antiphospholipid syndrome, tailored to the clinical

picture.

6. Critically evaluate the limited scientific evidence for the diagnosis and treatment of patients with

antiphospholipid antibodies with and without the antiphospholipid syndrome.

3. Background

The first description of antiphospholipid antibodies (aPL), a complement-fixing antibody that reacted

with extracts from bovine hearts, was by Wasserman in 1906 whilst he was carrying out his research

into the development of the serological test for syphilis (1). In 1941, the relevant antigen was

identified as cardiolipin, a mitochondrial phospholipid (2) and basis for the Venereal Disease

Research Laboratory (VDRL) test for syphilis. Blood screening for this disease led to the

observation that many patients with SLE had a positive VDRL test, without any other clinical or

serological evidence of syphilis (3).


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The knowledge of the “lupus anticoagulant phenomenon” goes back to 1950’s when Conley and

Hartmann reported prolongation of the coagulation times, occasionally the prothrombin time, in

patients with SLE (4). This was followed by the first report of “circulating anticoagulant” and

recurrent abortions (5), the association of the “circulating anticoagulant” and the biological false

positive serological test for syphilis (BFP-STS) (6) and its association with thrombotic manifestations

in SLE patients (7). Only in 1972 Feinstein and Rapaport introduced the term “lupus anticoagulant”

to describe it as an inhibitor directed against coagulation cascade phospholipids, particularly at the

prothrombin conversion to thrombin step (8).

In 1983, a solid phase immunoassay for anticardiolipin antibodies (aCL) was developed (9). This

assay was much more sensitive than the VDRL test for detecting aCL in patients with SLE and early

observations of the association of aPL with thrombotic events were confirmed (9). At the time this

complex clinical syndrome was named ‘anticardiolipin syndrome’ (10-12). This was most certainly a

distinct syndrome, occurring in ANA-negative lupus patients, atypical lupus patients and even in

individuals with no lupus at all (13). In 1987 the name “anticardiolipin syndrome” was changed to

“antiphospholipid syndrome” (APS) from the observation that patient’s sera were also cross-reactive

with other phospholipids apart from cardiolipin (14). The term “primary antiphospholipid syndrome”

was also introduced (15) and soon after, two large series of patients were published (16, 17).

In 1992, Asherson et al (18) reported a series of patients with APS who developed acute multiorgan

failure, defining this clinical situation as “catastrophic APS”.

The APS is now defined more precisely as a disorder in which the presence of aPL is associated

with the clinical features of arterial and/or venous thrombosis, and pregnancy morbidity (11, 19).

4. Definition and epidemiology

The APS is a thrombophilic disorder characterised by arterial and/or venous thrombosis and/or

pregnancy morbidity, always associated with the presence of a specific group of autoantibodies

called aPL. When APS is present by itself, it is referred to as primary APS; and when it is part of a

systemic disorder/autoimmune disease, classically SLE, it is known as secondary APS. A number

of conditions have been reported in association with aPL as listed in table 1.

There appear to be very few, if any differences between the clinical complications associated with

the primary and the secondary form of the syndrome (20) and the rates of arterial or venous

thrombosis or fetal loss do not appear to be different (20-22).


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Table 1: Conditions reported in association with aPL

Connective tissue disorders Infection

SLE Leprosy

Rheumatoid arthritis Syphilis

Sjögren’s syndrome Human immunodeficiency virus

Scleroderma Hepatitis C

Myositis Cytomegalovirus

Drugs Parvovirus

Hydralazine Mycoplasma

Procainamide Malignancy

Phenytoin Other

Quinine/quinidine Sarcoidosis

Interferon α Accelerated atheroma

Crohn’s disease Diabetes

Systemic vasculitis

However, the distinction between the primary APS and APS due to SLE can sometimes be difficult

since some features such as thrombocytopenia, anemia, renal and central nervous system

involvement may be seen in both conditions (23).

Due to the association with SLE and pregnancy loss, the APS is largely recognised as a disease of

young women. This reflects a reporting bias since young patients with thrombosis and pregnancy

loss are more likely to be investigated albeit the syndrome has also been reported in children,

elderly and in male subjects (23).

Using standardised techniques, aPL are detected in less than 1% of apparently normal individuals

and in up to 3% of the elderly population without clinical manifestations of the APS. The estimated

prevalence of aPL in patients with SLE varies ranging from around 20% (24, 25) to 60% (26-28). A

European study of 1000 patients revealed that APS was associated with SLE in 36% of the cases

(29). Prevalence of aPL in other connective tissue diseases or infections varies; the predominant

isotype is of IgM class in low titres and usually is not associated with aPL-related clinical features.

APS has a significant impact in survival and increasing evidence shows that thrombosis contributes

to the damage accrued in patients with SLE. A retrospective study shows that 50% of the SLE

patients with aCL developed APS in a 10-year follow-up (30). APS independently contributes to

irreversible organ damage as well as mortality in these patients (31, 32). The risk of recurrent

thrombotic events is substantially increased in patients with established APS with thrombosis,

especially if tight anticoagulation is not maintained (33).


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5. Antiphospholipid antibodies

aPL are a family of immunoglobulins of IgG, IgM, IgA or a combination of these isotypes, which were

initially thought to recognise anionic phospholipids. Over the years, this concept has changed and

different specificities have been described for aPL (Table 2) (34).

Table 2: Different specificities of antiphospholipid antibodies

• Antibodies to phospholipids

Cardiolipin

Phosphatidylserine

Phosphatidic acid

Phosphatidylinositol

Phosphatidylcholine

Phosphatidylethanolamine

• Antibodies to phospholipid binding proteins

β2GPI Factor XII

Prothrombin C4b binding protein

Annexin V Complement C4 and C5

Protein C Heparan sulphate

Protein S Thrombin

Low and High molecular weight kininogens Other

aPL are not uncommon since they have been found in about 25% of patients with unexplained

venous thrombosis, 20% of young patients with stroke (35), around 18% of patients with premature

coronary artery thrombosis (36, 37) and in about 30% of patients with recurrent pregnancy loss (38).

The risk of thrombosis (39), recurrent pregnancy loss (39-41) and thrombocytopenia (39) has been

associated with high levels of antibodies to cardiolipin (aCL). IgG isotypes are more related with

clinical complications when compared with IgM (42). The role of IgA aCL is still controversial (43-

46).

Autoantibodies to phospholipids other than cardiolipin have been less well studied and

characterised. An explanation for this is that reactivity to other phospholipids has often been found

to correlate with aCL reactivity and cardiolipin was the anionic phospholipid most focused upon (47).


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Lupus anticoagulant (LA) is a functional measurement of the capacity of heterogeneous aPL that

interfere with phospholipid-dependent stages of blood coagulation in vitro and inhibit both the

intrinsic and common pathways of coagulation (48). Paradoxically, LA are associated with a

thrombotic tendency rather than bleeding, generally associated with coagulation inhibitors. LA has

been reported in a wide variety of patient populations, ranging from autoimmune diseases (e.g. SLE,

rheumatoid arthritis), drug exposure (e.g. chlorpromazine, procainamide, hydralazine), infections

and lymphoproliferative disorders to individuals with no apparent underlying disease (48). The

estimated prevalence in patients with SLE varies ranging from 6-65% (28, 42, 49). Not all patients

with LA have aCL and vice versa. The proportion of SLE patients with both LA and aCL varies from

61 to 91% (49-51). This wide variation in prevalence reflects differences in assay methods and

case-mix of patients.

The LA assays have been thought to detect antibodies against anionic phospholipids. However,

recent data indicates that certain LA are specific for either phospholipid-bound β2-Glycoprotein I

(β2GPI) (52) or prothrombin (53, 54).

5.1. Antibodies to phospholipid binding proteins

5.1.1. β2-Glycoprotein

In 1990, two independent groups (55, 56) identified β2GPI as the plasma cofactor required for aCL

binding to cardiolipin. β2GPI is a normal plasma glycoprotein, a single chain 50 kD polypeptide. Its

function is unclear, although it may function as a natural anticoagulant (57, 58). β2GPI antibodies

are more specific than aCL in predicting thrombosis, differentiating pathogenic (autoimmune) from

non-pathogenic (infection or drug induced) antibodies, since β2GPI is an absolute requirement for

binding of autoimmune aCL to cardiolipin in ELISA (56, 59).

Most antibodies associated with APS and detected in standard aCL and/or LA assays are directed

against β2GPI or prothrombin. aPL can also be detected in immunoassays utilising purified protein

antigens in the absence of phospholipids (60, 61). Initial clinical studies of anti-β2GPI ELISAs

suggest that positivity in these assays is more closely associated with clinical manifestations of the

APS than positivity in conventional aCL ELISAs (59).

This is predominantly due to enhanced diagnostic specificity; although anti-β2GPI assays have also

identified a small number of patients who have clinical manifestations of the APS but are negative in

conventional aPL assays (62).


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5.1.2. Prothrombin

Prothrombin appears to be a common antigenic target of aPL (63). However, its clinical significance

is far from clear. Most of the studies available in the literature investigated the clinical significance of

antiprothrombin antibodies detected by ELISA using prothrombin coated on irradiated plates and

positive correlations with the clinical manifestations of the APS have been reported (64-66).

Petri et al (64) were the first to show antiprothrombin antibodies positive predictive value for

thrombosis in patients with SLE. However, Pengo et al (67) could not confirm these data when

studying patients with thrombosis, undoubtedly reflecting the heterogeneity and lack of appropriate

standardisation for the detection of these antibodies. Galli et al (68) found antiprothrombin

antibodies in 58% of their APS patients but failed to demonstrate any association with thrombotic

events in this group. On the other hand, Puurunen et al (65), Horbach et al (69) and Muñoz-

Rodriguez et al (70) reported a positive correlation between antiprothrombin antibodies and

thrombosis in SLE. We also found a correlation between the presence of antiprothrombin antibodies

and the occurrence of vascular events when we studied 207 patients with SLE (66).

In 1997, Galli et al (68) suggested that the prevalence of antiprothrombin antibodies increased up

from 58% when using prothrombin coated on irradiated plates (aPT) to 90% when prothrombin was

presented complexed to phosphatidylserine (aPS-PT). Our group reported that aPS-PT conferred

an odds ratio of 2.8 for venous thrombosis and of 4.1 for arterial thrombosis in patients with SLE

(71). Atsumi et al (72) supported these data by showing that the presence of aPS-PT conferred an

odds ratio of 3.6 for APS in 265 Japanese patients with systemic autoimmune diseases.

Antibodies directed to prothrombin have also been shown to be responsible for the LA activity (53).

This was later confirmed by Horbach et al (73) and Atsumi et al (72). In all cases, the authors

suggested that the LA activity might not be caused by antiprothrombin antibodies alone but by a

combination of different types of antibodies (e.g. anti-β2GPI). Moreover, multivariate logistic

regression analysis showed that the coexistence of IgG antiprothrombin and LA activity was a

significant risk factor for venous thromboembolism (74).

5.1.3. Annexin V

Annexin V, one member of the annexin family, has high affinity for anionic phospholipids enabling it

to displace coagulation factors from phospholipid surfaces (75). This protein is present in placenta

and vascular endothelium and behaves as a potent natural anticoagulant. Antibodies against this

protein have been investigated as a possible explanation of recurrent abortions or fetal death in APS

(76, 77).


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Rand et al (77) suggested that aPL can displace annexin V from cellular surfaces, resulting in

prothrombotic surfaces exposure which may then initiate the thrombotic complications seen in these

patients. Based on this hypothesis, van Heerde et al (78) studied plasma levels of annexin V in an

attempt to confirm that the levels of this protein were increased in patients with aPL. The authors

showed that levels of annexin V were increased in SLE patients, independently of the presence of

aPL. Moreover, no correlation with thromboembolic history was found. Based on these

observations, the authors refuted Rand’s hypothesis, suggesting that displacement of annexin V is

not a common mechanism for thrombosis in patients with aPL. Recently, Rand et al (79), using

atomic force microscopy, showed that a monoclonal aPL disrupted the annexin V crystallisation

pattern over the phospholipid bilayer, reducing the anticoagulant effect of the protein and promoting

thrombin generation. This is the first morphological evidence that aPL disrupt the formation of the

annexin V anticoagulant shield although confirmation of these data is essential.

5.1.4. Components of the protein C pathway

Protein C and protein S are natural inhibitors of coagulation. Congenital deficiency of these proteins

is associated with an increased risk of venous thrombosis (80). Once activated, protein C

inactivates, together with protein S, factors Va and VIIIa (81).

Some data suggest that autoantibodies could be directed against components of protein C pathway

(82), which includes protein C (83), protein S (84, 85) and thrombomodulin (86).

Protein C and protein S are vitamin K-dependent plasma proteins, activated by the thrombin-

thrombomodulin complex. They also bear Gla-domain as a phospholipid-binding site. Oosting et al

(82) reported that IgG fractions from some patients with aPL and/or a history of thrombosis interfere

with the anticoagulant activity of protein C and protein S. Interestingly, some patients have

antibodies to β2GPI, prothrombin, protein C and protein S and all combinations of them. Data from

our unit showed that monoclonal aCL bound to protein C in the presence of both cardiolipin and

β2GPI. These data suggest that protein C could be a target of aCL by forming a complex with

cardiolipin and β2GPI, leading to protein C dysfunction (83).

Early reports described transient and reversible deficiency in protein S function at the time of

thromboembolism in patients with APS (87, 88). Some studies have suggested that aPL may cause

a functional deficiency by binding to the free form of protein S (89, 90), exerting neutralising

properties. Parke et al (91) reported that patients with aPL had low levels of free protein S.


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These findings were reinforced by Song et al (92) when they reported that 44% of the SLE patients

in their study had free protein S antigen levels below the lower limit established for the normal

population. They also found anti-protein S in 26% of their SLE patients. Data from our unit showed

that anti-protein S are frequent in SLE patients with thrombosis and pregnancy morbidity and that

these antibodies do not interfere with free protein S in plasma since its level and/or functional activity

is not impaired (85).

Merrill et al (84) investigated the clinical significance of anti-protein S antibodies in 139 patients with

SLE and/or aPL. They found a prevalence of 53%. Notably, the combination of β2GPI and protein

S reactivity was associated with an increased historical incidence of thrombosis when compared to

the risk of either anti-β2GPI or anti-protein S alone, suggesting that these antibodies may be

predictive of thrombosis. Preliminary data from our unit (93) showed that the presence of anti-

protein S antibodies might increase the risk of having such an event since 35% of patients with anti-

protein S had a history of a thrombotic event, giving a new insight in the possible involvement of

antibodies directed to protein S in the APS.

5.1.5. Other phospholipid binding proteins

A number of other autoantibodies have been detected in patients with APS, including antibodies to

vascular heparan sulfate proteoglycan (94) heparin (95), phosphatidylethanolamine (96), high and

low molecular weight kininogen, prekallikrein and Factor XI (97) and thrombin (98).

Antibodies to factor XII have also been described (99-101). In our experience, their presence is

associated with thrombosis and adverse obstetric history making these antibodies a novel marker

for the APS (102).

Arvieux et al (103) suggested that some aCL might recognise not only β2GPI but also thrombin-

modified antithrombin, C4b binding protein and lipopolysaccharide binding protein. Recently,

Rampazzo et al (104) isolated and identified 3 other cardiolipin-binding proteins, complement

component C4, complement factor H and a kallikrein-sensitive glycoprotein in patients with APS.

Munakata et al (105) described complement-fixing aCL suggesting that these antibodies are more

specific than the standard aCL assay in relation to thrombotic episodes. For the time being, the

association of such antibodies with APS and their clinical significance is not yet known.


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6. Origin and pathogenic mechanisms of antiphospholipid antibodies

The origin of aPL and mechanisms involved in their production are not understood. The origin of

aPL was extensively investigated and several research groups have induced high levels of aPL in

experimental animals by immunisation with β2GPI (106-108). However, although immunisation with

foreign β2GPI can induce pathogenic aPL, it is unlikely that aPL production is induced with foreign

β2GPI in APS patients. The observation that aPL of the autoimmune type may be associated with

thrombosis in patients with Epstein-Barr virus, cytomegalovirus (109, 110), hepatitis C (111-113),

adenovirus (114) or parvovirus (115) suggests that certain infections may induce autoimmune aPL

that are not transient.

Recent data shows that aPL may be induced in experimental animals by immunisation with products

from bacteria or viruses, supporting the hypothesis that these antibodies may be generated after

incidental exposure or infection, a mechanism involving “molecular mimicry” (116). Immunisation of

mice with viral and bacterial peptides with function and sequence similarity to the phospholipid-

binding site of β2GPI (Table 3) induced high levels of aPL and aβ2GPI (116). These peptide-

induced aPL are also able to enhance thrombosis and activate endothelial cells in vivo and in vitro

(117).

Table 3: Viral and bacterial peptides with function and sequence similar to the phospholipid

binding site of β2-glycoprotein I

Peptides Sequence Origin

GDKV GDKVSFFCKNKEKKC β2-Glycoprotein I

TADL TADLAIASKKKKKRPSPKPE Adenovirus

TIFI TIFILFCCSKEKRKKKQAAT Cytomegalovirus

VITT VITTLYYRRKKKSPSDT Cytomegalovirus

SGDF SGDFEYTYKGKKKKMAFATS Bacillus subtilis

A number of studies have also discussed the mechanisms involved in aPL-mediated thrombosis and

pregnancy loss. Nevertheless, the link between aPL, APS and thrombosis has not been elucidated.

Several hypotheses have been proposed to explain the pathogenic effects of these autoantibodies.

As a consequence of initial damage, anionic phospholipids are exposed on the cell surface (e.g.

endothelium, trophoblasts, platelets), the surfaces of which become reactive, inducing the

production of procoagulant substances. The phospholipids are covered by phospholipid binding

proteins, such as β2GPI or prothrombin.


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If aPLs are present against such surface-bound proteins, aPLs may bind them and subsequently

induce the production of procoagulant substances such as tissue factor, plasminogen activator

inhibitor (PAI-1), or adhesion molecules (118) (Figure 1). This activation might explain clotting

events in APS patients.

Figure 1 - Hypothetical mechanism at the endothelial cell level

Activation signal(1)

anionic phospholipids(2)

Endothelialcell

TF

Adhesionmolecules

PAI-1

PBP (3)

aPL (4)

(5) THROMBOSIS

PBP: phospholipid binding proteins; aPL: antiphospholipid antibodies; TF: tissue factor; PAI-1:

plasminogen activator inhibitor 1. After an activation signal or damage (1), anionic phospholipids

are exposed on the cell membrane (2). The PBP binds to them on the surface (3). Circulating aPL

recognise these complexes, binding to them (4). The endothelial cell is thus activated, via specific

pathways or via Fcγ receptors, inducing release of procoagulant substances (5), with the

consequent activation of the coagulation pathway, platelet aggregation and thrombosis.

Some of the evidence for a cause-and-effect role for aCL comes from animal models of APS

induced by immunisation of mice. Pregnant mice passively and actively immunised with human or

mouse aCL develop fetal loss and thrombocytopenia (119). Interestingly, injection of the aCL co-

factor (β2GPI) into animals results in the development of circulating aPL, while cardiolipin injected

alone is relatively non-immunogenic (106).


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Furthermore, an in vivo experiment demonstrated that human aCL from thrombotic patients infused

into mice induced larger and more persistent thrombi than normal immunoglobulins (120). This data

supports a direct role for the antibodies in the pathogenesis of thrombosis.

Several additional abnormalities have been reported to be related with aPL such as acquired

deficiencies of protein S (91), abnormalities in prostacyclin production (121), autoantibodies against

endothelial cell proteins including thrombomodulin (122) and heparin sulfate (95), and antibodies

against platelet-activating factors (123). Recent studies from our unit have shown that increased

tissue factor expression (124-126) and induction of endothelin I (127), the most potent endothelium-

derived contracting factor, may be involved in the pathogenesis of thrombosis in the APS.

In vitro studies have also shown that aPL recognition of both anionic phospholipids and adhered

β2GPI on trophoblast cell structures might represent a potential pathogenetic mechanism for

defective placentation in women with the APS (128).

Recent data also suggests that in vivo complement activation is also required for aPL-mediated

tissue injury. Holers et al (129) reported that complement blockade at the point of C3 activation

prevented fetal loss and growth restriction in a murine model of APS induced by passive transfer of

human aPL-IgG antibodies. Furthermore, Girardi et al (130) shows that C5-deficient mice are

protected from aPL-induced pregnancy complications since the fetal resorption rate was lower and

the embryo weight higher than the control mice, respectively. Recently, it has been shown that

neutrophils, in response to aPL antibody-generated C5a, are able to express tissue factor

potentiating inflammation in the deciduas and leading to miscarriages (131).

7. Genetics of the antiphospholipid syndrome

A number of studies have examined HLA antigens in patients with the primary and secondary APS.

Most studies have involved small number of patients. In primary APS, an association has been

noted with DR53, DR4, DQ7 and DR5 (132-135). In APS associated with SLE, an increased

frequency of DR7 has been reported (134, 136, 137).

HLA DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701

haplotypes have been suggested as responsible for anti-β2GPI antibody production(138, 139),

giving a new insight into the molecular epitope(s) that might induce or react with autoimmune aPL.

HLA DQB1*0301, DQB1*0302, DQB1*0303 and DQB1*06 alleles may be genetic determinants of

LA (140).


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Some reports have addressed the issue of a familial predisposition to the development of APS.

Several reports have shown a higher incidence of aCL in first-degree relatives of patients with SLE

or primary APS (141-148). Recently, Goel et al (149) in their family studies on APS have performed

aPL and pedigree analysis suggesting a Mendelian autosomal dominant mode of inheritance for this

disorder. Modelling studies strongly rejected environmental and autosomal recessive inheritance for

the disease.

A number of other genetic variants have been investigated as risk factors for the development of

APS. In particular, polymorphisms in genes involved in thrombus formation have been explored.

Factor V Leiden is the most common thrombophilia in Caucasoid populations. However, the

presence of Factor V Leiden did not alter the clinical features of APS (150-153). Prothrombin

promotor G20210A, another common genetic risk for venous thrombosis, was found to be rare in

patients with APS, which means that this genetic variant did not affect venous thrombosis in patients

with aPL (154-156). Other genetic polymorphisms noted in patients with APS are

methylenetetrahydrofolate reductase C677-->T (MTHFR), an enzyme involved in the re-methylation

of homocysteine to produce methionine (150), angiotensin-converting enzyme (157) and

plasminogen activator and plasminogen activator inhibitor-1 (158).

8. Clinical manifestations 8.1. Thrombosis

The APS is a noninflammatory autoimmune disease where the most critical pathological process is

thrombosis, which results in most of the clinical features suffered by these patients.

Arterial or venous thrombosis together with or without an adverse pregnancy history can be present.

Deep vein thrombosis has been the most commonly reported venous manifestation, often recurrent

and accompanied by pulmonary embolism. Occlusion of the intracranial arteries are the most

common arterial manifestation, with the majority of patients presenting with stroke.

As any organ and any size of vessel can be affected; thus, the range of clinical features is extremely

wide.


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8.1.1. Central nervous system

There is a very broad spectrum of CNS involvement in APS. Cerebral ischemia associated with aPL

is the most common arterial thrombotic manifestation (22, 30). Many studies have found that aPL

are associated with an increased risk for cerebral ischemia (35, 159-163) but some have not (164-

166). The age of onset in APS is several decades earlier that in the typical stroke population and the

ischemic events may occur in any territory.

A less common form of cerebral thrombotic disease associated with aPL is sagittal venous sinus

thrombosis (167, 168). As with stroke, this manifestation in patients with aPL occurs at a younger

age than in individuals without aPL.

Migraine is one of the most prominent complains in patients with APS (169) but its association with

aPL is still controversial. Several studies failed to demonstrate an association between the

presence of aPL and migraine (170, 171). A recent study has shown that although the prevalence

of headache in SLE is similar to that reported for the general population, aPL are more significantly

prevalent in the group of patients with headache compared to those without (172).

Cognitive deficits associated with APS may vary from mild neurocognitive disorders to severe

vascular dementia. Patients affected by mild cognitive dysfunction often complain of poor

concentration or forgetfulness. Verbal memory deficits, decreased psychomotor speed and

decreased overall productivity have been correlated with aPL (173-175). Whether these cognitive

deficits result from recurrent cerebral ischemia or whether there is other underlying mechanisms

remains unknown. Psychiatric problems, such as mood disorders and psychosis, have also been

associated with aPL (176).

Some patients with APS may exhibit features often seen in multiple sclerosis (177). Myelitis, balance

and sensory problems not surprisingly often lead to an erroneous diagnosis of multiple sclerosis.

Differential diagnosis is difficult, and compounded by a number of features, notably: single-point-in-

time MRIs may fail to differentiate and borderline positive aPL levels may be dismissed as being of

no significance. Serial MRIs may help to distinguish (the picture in multiple sclerosis is changing), as

may an EEG (178). The clinical findings of livedo and a dry Schirmer’s test point towards APS. So

also may be a previous history of thrombosis or pregnancy loss, an abnormal localisation of the

lesions on MRI, and the response to anticoagulant therapy might be helpful in the differential

diagnosis (179). Anecdotally, some patients who apparently have multiple sclerosis but who are

positive for aPL have benefited from anticoagulation though this is often a difficult clinical decision

(180).


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Seizures have been consistently associated with the presence of aPL (181-183). APS patients with

epilepsy seem to have a higher prevalence of focal ischemic events and amaurosis fugax and a

higher frequency of valvular pathology (184). The etiology is still unknown but some authors have

suggested direct interaction between aPL and neuronal tissue (185-187).

Less frequently described manifestations of APS include chorea (13, 188, 189), transverse

myelopathy (190-193), Guillain-Barre syndrome (172, 194), sensorineural hearing loss (195, 196)

and ocular syndromes with retinal and choroidal ischemia (16, 197-199). Although the pathological

lesion is likely to be thrombotic (small vessel ischemia), there is some evidence for direct

neurotoxicity (200).

8.1.2. Heart

Several cardiac lesions apart from coronary artery disease have been reported in association with

aPL (201). Heart valve lesions are the most common cardiac manifestations described in patients

with aPL. The prevalence of valvulopathy has been reported in 35% to 75% of patients with APS,

according to different series (202, 203). Most of the cases are asymptomatic with around 5% of the

cases progressing to cardiac failure requiring valve replacement. Valve masses (vegetations) and

diffuse valvular thickening are the two morphologic ecocardiographic patterns most frequently see in

APS. The predominant functional abnormality is regurgitation, whereas stenosis is rarely seen.

Although mitral valve is the most commonly affected site, followed by the aortic valve (204), isolated

tricuspid valve involvement has also been described (205). It is likely that thrombosis on a damaged

valve and healing with fibrosis are key players in the valve deformity. Wether aPL are instrumental in

the initial damage of the valves remains to be elucidated, but deposits of immunoglobulins (including

aCL) and complement in diseased valves have been documented, suggesting a role in the

development of valvular pathology (206).

Infective endocarditis is uncommon, but a condition of pseudoendocarditis has been described in

both SLE and primary APS and is characterised by fever, murmurs, valve vegetations, splinter

hemorrhages, increased aPL and negative blood cultures (207).

Coronary artery disease is also well documented in patients with APS and the association between

aPL and myocardial infarction or cardiac death has been confirmed by prospective studies (208,

209). Isolated unstable angina has also been reported occasionally in patients with the APS (16). It

is our recommendation that all patients developing myocardial infarction under the age of 40 should

be tested for aPL.


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Uncommon cardiac manifestations of APS include intracardiac thrombus, which can be

misdiagnosed as a cardiac tumour (210, 211), myocardial dysfunction (212) and syndrome X,

characterised by angina-like chest pain, a positive exercise test and angiographically normal

coronary arteries (213).

The increased prevalence of an abnormal ankle-brachial index (a bedside test which reliably

identifies lower extremity peripheral artery disease) suggests that patients with APS are at increased

risk of atherosclerosis (214-216).

8.1.3. Lungs

Patients with APS may develop a broad spectrum of pulmonary involvement. The most common

pulmonary manifestation of the APS is pulmonary embolism and infarction, usually seen as the first

manifestation of the disease (217, 218). Recurrent pulmonary embolism may lead to

thromboembolic pulmonary hypertension (219).

Pulmonary hypertension is found in around 1.8% to 3.5% of the patients with APS (20). Several

cases of pulmonary hypertension complicating primary APS have been described (16, 220).

Adult respiratory distress syndrome is a very rare but devastating clinical syndrome with a mortality

of 52%, usually seen in patients with catastrophic APS (218, 221).

Although quite uncommon, some patients may present with diffuse alveolar hemorrhage as the first

manifestation of APS. This potentially life-threatening condition is usually diagnosed by open lung

biopsy which shows microvascular thrombosis and secondary alveolar hemorrhage with or without

pulmonary capillaritis (222).

8.1.4. Kidney

The description of the APS has brought about a radical review of the pathophysiology of renal lupus.

A significant contribution to pathology as well as to treatment and prognosis has been made by the

re-assessment of the degree of microvascular thrombosis in lupus kidney biopsies, especially in

aPL-positive individuals.


16 ©2007-2008 EULAR

The kidney is a major target organ in the APS where both arterial and venous vessels, as well as the

intraparenchymatous arteries and microvasculature may all be affected (223). As renal damage in

SLE is primarily due to immune complex-mediated glomerulonephritis, patients with SLE and

secondary APS can develop kidney involvement due to a combination of both processes (224).

Moreover, the impairment of renal function in SLE patients with aPL can also occur in the absence

of APS-related manifestations. In this case, distinguishing between SLE-nephritis (immune complex

disease) from APS-nephritis (thrombotic disease) can only be accomplished by kidney biopsy (225).

Renal artery occlusion and renal artery stenosis have been described in APS patients with

hypertension (226-229). The localised and stenotic (thrombotic) arterial lesions are totally different

in appearance from the picture of renal artery disease seen in atheroma in older patients. The

hypertension in APS patients treated with careful anticoagulation is, significantly, much better

controlled (230). Renal infarction may result from partial or total, transient or permanent occlusion of

the renal arteries. Thrombosis of the renal veins (231, 232) and thrombotic microangiopathy (223)

has also been described in APS. Tektonidou et al found a strog association between APS

nephropathy, arterial thrombosis and livedo reticularis (233).

8.1.5. Skin

The most frequent skin manifestations are livedo reticularis and skin ulcers (234-237).

Livedo reticularis is characterised by a mottled purple reticular pattern with different localisation,

extension, infiltration, and regularity of the fishnet pattern. In APS it is usually disseminated and

have an irregular branching or broken pattern (219). Its association with aPL has been described in

several studies (13, 234, 235, 238). In APS, livedo reticularis is usually persistent and

anticoagulation has no effect on its extent or severity. It is clear that livedo reticularis is a marker of

poor prognosis and more severe disease in APS and as such is a powerful physical sign when

suspecting this disorder (237, 239).

Skin ulcers are frequently present in the extremities. However, extensive cutaneous necrosis

associated with aPL has been reported in the literature (240).

Subungual splinter hemorrhages appear as tiny linear longitudinally oriented, reddish-brown to

black, distal subungual lesions that fail to blanch under pressure. Subungual splinter hemorrhages

are seen in around 5% of the patients with APS and their presence in a patient with aPL may alert

the physician to the occurrence of other thrombotic events (241, 242).


17 ©2007-2008 EULAR

Digital gangrene has been described in patients with aPL (235, 243). A variety of other cutaneous

lesions, including purpura, tender nodules, papules and palmar-plantar erythema, anetoderma have

been described in APS (235, 244, 245).

8.1.6. Liver and gastrointestinal tract

Intestinal ischemia and perforation due to thrombosis are rare but well described, especially in the

context of the catastrophic APS. We have recently reported a sizeable series of patients with APS

and celiac artery stenosis. Many of the patients had “classical” features of mesenteric ischemia with

abnormal pain after large meals, upper abdominal bruits and so on. Others were relatively

asymptomatic, presumably because of good collateral circulation (246).

Liver thrombosis, including Budd-Chiari syndrome, was a feature of the original clinical description of

the syndrome (10). Liver function abnormalities are, in fact, common in APS patients, possibly as a

result of either vascular “sludging” or small vessel thrombosis (247).

8.1.7. Hemocytopenias

Thrombocytopenia is a frequent haematological manifestation of APS, seen in around 25% of the

patients (248, 249). Thrombocytopenia is rarely severe; platelet counts are usually between 50-

100x109, and bleeding is not a common problem (250). The exact role of aPL in the development of

thrombocytopenia is still not known. Some data showed that specific anti-platelet glycoprotein

antibodies found in patients with aPL may also be involved. Galli et al (251) found antibodies to the

platelet membrane glycoproteins IIb/IIIa and Ib/IX in 40% of aPL positive patients and a positive

correlation between these antibodies and thrombocytopenia. Godeau et al (252) also showed

antibodies to a panel of platelet membrane glycoproteins in the sera of patients with

thrombocytopenia and APS. Although why aPL are so frequently associated with anti-platelet

glycoprotein antibodies still remains to be elucidated, these data suggest that antibodies to the

platelet membrane glycoproteins may act along with aPL in the development of thrombocytopenia.

Hemolytic anemia may be present in patients with APS and sometimes associated with

thrombocytopenia, the so-called Evans syndrome. Although a positive Coombs test is not rare in

APS, hemolytic anemia is uncommon (250, 253, 254). A significant correlation between aPL and

hemolytic anemia has been found by different groups (234, 255-257).

A small number of cases of marrow infarction have been described (258).


18 ©2007-2008 EULAR

8.1.8. Musculoskeletal

Avascular necrosis of bone is most commonly of the femoral head, but also of other bones such as

the navicular is a complication of APS, presumably as a result of ischemia in vulnerable sites (259-

261). Tektonidou et al (259) found MRI scanning to be a sensitive test with 20% of primary APS

patients showing evidence of avascular necrosis. Metatarsal fracture and other spontaneous

fractures have been reported in the spine, ribs and elsewhere (261, 262). The patients presented

with fractures that occurred spontaneously or after trivial trauma and many had normal bone mineral

density and were not taking corticosteroids.

More recently, reflex sympathetic dystrophy was reported in a patient with APS (263).

8.1.9. Endocrine system

The spectrum of clinical manifestations in APS is constantly growing to involve almost every organ

system in the body. Although unusual, endocrinologic complications of APS have also been reported

(264). Adrenal insufficiency is the most common endocrinologic manifestation and can be the

presenting symptom of APS. A few cases of hypopituitarism and ovarian and testicular involvement

have been reported. aPL has been detected in the sera of diabetic patients, probably associated

with some macroangiopathic complications and in patients with autoimmune thyroid disease.

8.2. Pregnancy

APS is frequently diagnosed following investigation for recurrent miscarriage, pregnancy morbidity

being one of the major manifestations of the syndrome. In pregnancies that do not end in

miscarriage or fetal loss, there is high incidente of early onset pre-eclampsia, intrauterine growth

restriction, placental abruption and premature delivery (265).


19 ©2007-2008 EULAR

8.2.1. Pregnancy morbidity

Pre-eclampsia has been reported to be highly prevalent in patients with APS (265-269), being the

major contributor to preterm delivery in these patients. The association between aPL and pre-

eclampsia has been confirmed in 2 prospective studies of unselected patients (270, 271) but not by

others (272, 273).

The risk of HELLP, a syndrome characterised by haemolysis, elevated liver enzymes and low

platelets, is increased in APS with a wide reported rate observed (0.66 to 10.6%) (274-276). Around

two third of the cases have been reported to be associated with preeclampsia/eclampsia (276).p

Placental insufficiency may also be manifested by fetal growth restriction, found in approximately

30% of the patients with APS (265, 266, 268, 269). Two early prospective studies failed to

demonstrate a relationship between aPL and fetal growth impairment (270, 272). However, a more

recent study (271) showed that 12% of aPL positive women had small-for-gestational age babies

compared to 2% of the aPL negative women.

Fetal distress has been reported in up to a 50% of the offspring (265), although its association with

aPL has not been confirmed.

Pre-eclampsia and fetal growth restriction are responsible of preterm delivery occurring in around

30% of pregnant women with APS (265, 268).

Placental pathology may show extensive infarction, necrosis, and thrombosis (266, 277-280).

However, these histological abnormalities are non-specific and are not always present in the

placenta of women with APS (281).

Many investigators have found a statistically higher rate of aPL in women with infertility, though not

all agree (282). Proof that aPL are associated with a specific type of infertility or influence pregnancy

outcome with assisted reproductive technology is lacking.

8.2.2. Pregnancy loss

Women with aPL have an unusually high proportion of pregnancy losses within the fetal period (≥10

weeks of gestation) (267, 283), in contrast with unselected women with sporadic or recurrent

miscarriage where the pregnancy losses occur more commonly in the pre-embryonic period (less

than 6 weeks of gestation) or the embryonic period (6-9 weeks of gestation). The prevalence of aPL

in the general obstetric population is low (<2%), so universal screening is not warranted (284).


20 ©2007-2008 EULAR

However, any woman with a history of three or more firts trimester miscarriages should be tested for

these antibodies. Rai et al (285) have reported that 15% of women with a history of three or more

consecutive miscarriages have persistently positive aPL results.

The prospective fetal loss rate in primary APS is reported to be 50% to 70% (286, 287), with some

studies suggesting a rate as high as 90% in patients with SLE/APS (266, 288). Previous poor

obstetric history (270, 289, 290) along with antibody level (291), particularly of the IgG isotype (292)

remain the most important predictors of future risk.

9. Catastrophic antiphospholipid syndrome

The term catastrophic APS (CAPS) is used to define an accelerated form of APS resulting in

multiorgan failure concurrently over a short period of time, typically days to weeks. Catastrophic

APS is an infrequent but life threatening situation, seen in approximately 1% of the patients with

APS (29). It still remains a serious complication with a poor prognosis. Preliminary classification

criteria for CAPS have been elaborated (293) and recently validated after analysing data from an

International Registry of patients with this condition (CAPS registry) (294).

It is recognised that precipitating factors, such as infections, postpartum and surgery may

contribute to the development of catastrophic APS (294). Additional precipitating clinical features

include malignancy, medication, anticoagulation withdrawal, and SLE exacerbation (295).

Cerebral involvement (mainly consisting of stroke), cardiac involvement, and infections are the main

causes of death in patients with CAPS. The presence of SLE was related to a higher mortality rate

(296), leading to death in around 47% of the cases (294). Surviving an episode of CAPS is

typically associated with a good prognosis as only 26% develop further APS-related episodes

(297). Recurrence of CAPS in the same patient is unusual.

10. Diagnosis of the antiphospholipid syndrome

The diagnosis of the APS depends greatly upon laboratory diagnostics. In clinical practice,

laboratory diagnosis of APS relies on the demonstration of a positive aCL antibody test by an in-

house or commercially available enzyme-linked immunosorbent assay (ELISA) or on the presence

of LA by a coagulation-based test (298, 299). The aCL test is positive in about 80% of patients with

APS, the LA test is positive in about 20%, and both are positive in about 60% of cases (29).

Persistence of the positive tests must be demonstrated and other causes and underlying factors

considered. It is important that both tests be performed in patients suspected of having APS.


21 ©2007-2008 EULAR

These assays not only detect aCL and/or LA but also a heterogeneous group of antibodies that bind

serum proteins (the so called phospholipid binding proteins), such as β2 glycoprotein I (β2GPI)

and/or prothrombin.

The diagnostic value of all available assays to detect aPL is a matter of ongoing debate. Although

the presence of LA correlates best with thrombosis (300), accurate determination is not always

possible due to anticoagulant treatment. Data on the predictive value of alternatives such as the

anti-β2GPI assay are insufficient and prospective cohort studies are needed (301). However, some

laboratories include testing for these antibodies as part of their routine screening for APS.

11. Classification criteria for APS

An international consensus statement on classification criteria for definite APS was published in

1999 (302). A patient with APS must meet at least one of two clinical criteria (vascular thrombosis

or pregnancy complications) and at least one of two laboratory criteria (aCL and/or LA). Other

features such as thrombocytopenia, hemolytic anemia, transient ischemic attacks, livedo reticularis,

chorea, migraine, cardiac valve disease and transverse myelopathy or myelitis that have been

reported to be associated with aPL were not included as essential features due to the lack of strong

clinical and experimental evidence (23, 302).

These criteria were designed to provide uniform groups for clinical studies, rather than diagnostic

aids. Although they have been shown to be specific and sensitive for the classification of the primary

and secondary APS (303) the absence of “major” or “essential” features in the presence of “minor”

features should not discourage the clinician from making the diagnosis if other causes of such

features have been ruled out (23).

A recent consensus update has included anti-β2GPI as a laboratory criterion for APS (304) and

laboratories around the world are being encouraged to standardize their methodology for the

detection of these antibodies (table 4).


22 ©2007-2008 EULAR

Table 4: Simplified 2006 updated criteria for the classification of definite APS

Clinical criteria

1) Vascular thrombosis: ≥1 arterial, venous or small vessel thrombosis in any tissue or organ,

confirmed by imaging or histopathology in the absence of significant evidence of inflammation in the

vessel wall

2) Pregnancy morbidity:

a) ≥1 unexplained death of a morphologically normal foetus at or beyond the 10th week of gestation,

or

b) ≥1 premature births of a morphologically normal neonate at or beyond the 34th week of gestation,

due to severe pre-eclampsia, eclampsia or placental insufficiency, or

c) ≥3 unexplained consecutive spontaneous abortions before the 10th week of gestation (maternal

anatomic or hormonal abnormalities and chromosomal causes excluded)

Laboratory criteria

1) IgG and/or IgM aCL, in medium or high titre, on 2 or more occasions, at least 12 weeks apart,

measured by a standardised ELISA for β2-glycoprotein I-dependent aCL

2) IgG and/or IgM anti-β2GPI in titer >99th percentile, on 2 or more occasions, at least 12 weeks

apart, measured by a standardised ELISA

3) LA on 2 or more occasions at least 12 weeks apart, detected according to the guidelines of the

International Society on Thrombosis and Haemostasis

12. Seronegative APS

Current criteria for the classification of APS recommend the use of standardised enzyme–linked

immunoassay that measure β2GPI-dependent IgG and IgM aCL and/or the LA according to the

recommended criteria from the International Society on Thrombosis and Hemostasis Subcommittee

on Lupus Anticoagulant-Phospholipid-dependent antibodies (305).

There are, however, a small number of patients with the classical features of APS, including

pregnancy losses, thrombotic events and livedo reticularis, where the aPL testing is persistently

negative, leading to the concept of ‘seronegative APS’. Although it is universally recognised that the

routine screening tests (aCL and/or LA) might miss some cases, careful differential diagnosis and

repeat testing are mandatory before the diagnosis of ‘seronegative APS’ can be made (306). A very

tiny minority of these patients may have anti-β2GPI and/or antiprothrombin antibodies, but it may be

that these patients have other explanation for their clinical features (307, 308).


23 ©2007-2008 EULAR

13. Management of the antiphospholipid syndrome

Data regarding management and prognosis is limited and current therapeutic approaches are based

mainly on the clinician’s best judgement. The thrombotic complications are unpredictable and the

mechanisms triggering these events in individual patients are ill defined. Despite advances in

studies of mechanisms of thrombosis in APS, and the development of newer tests for the diagnosis,

the serological “fingerprint” of the patient most at risk for arterial or venous thrombosis, remains

elusive.

13.1. Management of thrombosis-free aPL-positive subjects

The controversy concerning whether or not prophylactic treatment is indicated for patients with aPL

who have no history of thrombosis remains unresolved as there are no available data to identify

which patients with aPL will thrombose. To date, it is recommended that individuals with a

persistently positive aCL (moderate/high titres) and/or unequivocally positive LA tests take low-dose

aspirin (75-100mg daily) along with the removal or reduction of other risk factors for thrombosis (i.e.

smoking, obesity, high blood pressure, hypercholesterolemia and estrogen-containing oral

contraceptive pills) (309). Hydroxychloroquine could be safely prescribed as it has been shown to

be protective against the development of thrombosis in aPL-positive patients with SLE (310).

13.2. Management after the first thrombotic episode

Patients with APS should be treated with long-term anticoagulation, although the optimal intensity of

anticoagulation therapy is uncertain (311). Retrospective studies in the 1990s suggested that

thrombosis in APS patients should be managed with high-intensity (target INR 3.0-4.0) oral

anticoagulation (33, 312).

However, the more recent prospective studies suggest only an INR of 2.0-3.0 is required (313-315).

As most of these studies were done in patients with venous thrombosis, some prefer to advocate an

INR of 2.0-3.0 for those with venous thrombosis reserving intensive anticoagulation (INR 3.0-4.0) for

those with recurrent venous thrombosis or arterial thrombosis.

Around 30% to 60% of APS patients with thrombosis will be subjected to recurrences (22, 30, 33,

312, 316, 317). Although there is wide recognition that patients with arterial events should have

long-term anticoagulation, the length of anticoagulation in those with APS and venous

thromboembolism has been hotly debated (318).


24 ©2007-2008 EULAR

Data emerging suggests that following a documented aPL-associated thrombotic episode warfarin

therapy should be continued for longer periods in these patients (possibly for life) than otherwise

healthy individuals without aPL (319). It is not clear, however whether prolonged anticoagulation is

necessary in APS patients whose first thrombotic episode developed in association with surgery,

oral contraceptive pill, pregnancy or other circumstantial thrombotic risk factors.

Additional therapy with aspirin may be used in cases of recurrent venous thrombosis or arterial

thrombosis, however, the effectiveness in this situation is not known. What is well known is that the

risk of hemorrhage is increased when aspirin is used alongside oral anticoagulant therapy (320) and

the physician must be aware of this.

Treatment of children with APS or aPL-related events has been similar to adults with this condition.

Up to date there are no standard recommendations for therapy based on long-term observation of

the outcome of APS in children. Antithrombotic therapy is recommended for children who present

with thrombosis and have aPL but the duration and intensity of this therapy remains unclear.

Intermediate intensity anticoagulation therapy have been suggested (321), however, the

effectiveness of such therapy and the length of treatment required are unknown (322).

The role of steroids and immunosuppressive drugs in the treatment of patients with aPL and

thrombosis is uncertain. Such drugs have severe side effects when given for prolonged periods and

aPL are not always suppressed by these agents. Furthermore, some series of patients with APS

have shown that corticosteroids and immunosuppressive therapy, prescribed to control lupus

activity, did not prevent further thrombotic events (221). The use of these drugs is probably justified

only in patients with life-threatening conditions with repeated episodes of thrombosis despite

adequate anticoagulation therapy, namely catastrophic APS. In this rare but life-threatening

condition, the combination of anticoagulation, steroids, and plasmapheresis or intravenous

gammaglobulins (IVIG) has also been used with successful recovery in 58% of the patients (323).

13.3. Management in adverse pregnancy history

Pregnancy complicated by APS requires expert care and a team approach by obstetricians,

physicians, and hematologists. Patients with APS should undergo preconceptional assessment and

counselling. A detailed medical and obstetric history should be obtained, and the presence of

significant levels of aPL should be confirmed. The patient should be informed of the potential

maternal and obstetric problems, including fetal loss, thrombosis or stroke, pre-eclampsia, fetal

growth impairment, and preterm delivery.


25 ©2007-2008 EULAR

The pharmacological management of pregnancy in women with APS is the subject of much debate.

It has included prednisone and aspirin, aspirin alone, low-dose aspirin and heparin, IVIg and even

supportive care alone. There are several non-randomised studies in women with fetal loss

suggesting that low-dose aspirin is effective (324). Randomised controlled trials are few, small and

contradictory in their results (325). While aspirin alone may have a role in women with early

pregnancy losses, most experts support the use of heparin therapy in addition to low-dose aspirin. A

systematic review of randomised controlled therapeutic trials published recently showed that

combination therapy with aspirin and heparin might reduce pregnancy loss in women with aPL by

54% (326).

Women with APS and previous thromboembolism are at extremely high risk in pregnancy and the

puerperium and should be given antenatal thromboprophylaxis with subcutaneous heparin. Our

recent experience demonstrated that a 90% live birth rate can be achieved in women with APS with

significant past pregnancy morbidity and/or thrombosis (327).


26 ©2007-2008 EULAR

SUMMARY

• APS is the most common acquired thrombophilia

• Venous and arterial thrombosis in young individuals and pregnancy morbidity are the hallmark of

the disease

• Deep vein thrombosis has been the most commonly reported venous manifestation, often

recurrent and accompanied by pulmonary embolism.

• Occlusion of the intracranial arteries is the most common arterial manifestation, with the majority

of patients presenting with stroke.

• Given the clinical setting, testing for both aCL and LA is essential for the diagnosis of APS

• There appear to be very few, if any differences between the clinical complications associated

with the primary and the secondary form of the syndrome and the rates of arterial or venous

thrombosis or fetal loss do not appear to be different

• Differential diagnosis must be considered before labelling a patient as having “seronegative

APS”

• Catastrophic APS is an infrequent but life threatening situation, resulting in multiorgan failure

concurrently over a short period of time, typically days to weeks.

• Correct identification of patients with APS is important, because prophylactic anticoagulant

therapy can prevent thrombosis from recurring


27 ©2007-2008 EULAR

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158. S Yasuda, A Tsutsumi, T Atsumi, ML Bertolaccini, K Ichikawa, MA Khamashta, GR Hughes and T Koike. 2002. Gene polymorphisms of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with antiphospholipid antibodies. J Rheumatol; 29: 1192-1197

159. SR Levine, MJ Deegan, N Futrell and KM Welch. 1990. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology; 40: 1181-1189

160. RL Brey, RG Hart, DG Sherman and CT Tegeler. 1990. Antiphospholipid antibodies and cerebral ischemia in young people. Neurology; 40: 1190-1196

161. APASS. 1993. Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. The Antiphospholipid Antibodies in Stroke Study (APASS) Group. Neurology; 43: 2069-2073

162. M Camerlingo, L Casto, B Censori, G Drago, A Frigeni, B Ferraro, MC Servalli, E Radice and A Mamoli. 1995. Anticardiolipin antibodies in acute non-hemorrhagic stroke seen within six hours after onset. Acta Neurol Scand; 92: 69-71

163. SR Levine, RL Brey, KL Sawaya, L Salowich-Palm, J Kokkinos, B Kostrzema, M Perry, S Havstad and J Carey. 1995. Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Ann Neurol; 38: 119-124

164. J Montalban, J Rio, M Khamashta, A Davalos, M Codina, GT Swana, ME Calcagnotto, J Sumalla, S Mederer, A Gil and e al. 1994. Value of immunologic testing in stroke patients. A prospective multicenter study. Stroke; 25: 2412-2415

165. KS Ginsburg, MH Liang, L Newcomer, SZ Goldhaber, PH Schur, CH Hennekens and MJ Stampfer. 1992. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med; 117: 997-1002

166. APASS. 1997. Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. The Antiphospholipid Antibodies and Stroke Study Group (APASS). Neurology; 48: 91-94

167. JR Carhuapoma, P Mitsias and SR Levine. 1997. Cerebral venous thrombosis and anticardiolipin antibodies. Stroke; 28: 2363-2369

168. MA Deschiens, J Conard, MH Horellou, A Ameri, M Preter, F Chedru, MM Samama and MG Bousser. 1996. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke; 27: 1724-1730

169. MJ Cuadrado, MA Khamashta, D D'Cruz and GRV Hughes. 2001. Migraine in Hughes syndrome - heparin as a therapeutic trial? Q J Med; 94: 114-115

170. GE Tietjen, M Day, L Norris, S Aurora, A Halvorsen, LR Schultz and SR Levine. 1998. Role of anticardiolipin antibodies in young persons with migraine and transient focal neurologic events: a prospective study. Neurology; 50: 1433-1440


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171. J Montalban, R Cervera, J Font, J Ordi, J Vianna, HJ Haga, M Tintore, MA Khamashta and GRV Hughes. 1992. Lack of association between anticardiolipin antibodies and migraine in systemic lupus erythematosus. Neurology; 42: 681-682

172. G Sanna, ML Bertolaccini, MJ Cuadrado, H Laing, MA Khamashta, A Mathieu and GRV Hughes. 2003. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol; 30: 985-92

173. SD Denburg, RM Carbotte, JS Ginsberg and JA Denburg. 1997. The relationship of antiphospholipid antibodies to cognitive function in patients with systemic lupus erythematosus. J Int Neuropsychol Soc; 3: 377-386

174. JG Hanly, C Hong, S Smith and JD Fisk. 1999. A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus. Arthritis Rheum; 42: 728-734

175. S Menon, E Jameson-Shortall, SP Newman, MR Hall-Craggs, R Chinn and DA Isenberg. 1999. A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus. Arthritis Rheum; 42: 735-741

176. M Schwartz, M Rochas, B Weller, A Sheinkman, I Tal, D Golan, N Toubi, I Eldar, B Sharf and D Attias. 1998. High association of anticardiolipin antibodies with psychosis. J Clin Psychiatry; 59: 20-23

177. JW Ijdo, AM Conti-Kelly, P Greco, M Abedi, M Amos, JM Provenzale and TP Greco. 1999. Anti-phospholipid antibodies in patients with multiple sclerosis and MS-like illnesses: MS or APS? Lupus; 8: 109-115

178. CE Lampropoulos, M Koutroumanidis, PP Reynolds, I Manidakis, GR Hughes and DP D'Cruz. 2005. Electroencephalography in the assessment of neuropsychiatric manifestations in antiphospholipid syndrome and systemic lupus erythematosus. Arthritis Rheum; 52: 841-6

179. MJ Cuadrado, MA Khamashta, A Ballesteros, T Godfrey, MJ Simon and GRV Hughes. 2000. Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature. Medicine (Baltimore); 79: 57-68

180. S Ferreira, DP D'Cruz and GR Hughes. 2005. Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: where do we stand? Rheumatology (Oxford); 44: 434-42

181. MT Herranz, G Rivier, MA Khamashta, KU Blaser and GRV Hughes. 1994. Association between antiphospholipid antibodies and epilepsy in patients with systemic lupus erythematosus. Arthritis Rheum; 37: 568-571

182. E Toubi, MA Khamashta, A Panarra and GRV Hughes. 1995. Association of antiphospholipid antibodies with central nervous system disease in systemic lupus erythematosus. Am J Med; 99: 397-401

183. D Verrot, M San-Marco, C Dravet, P Genton, P Disdier, G Bolla, JR Harle, L Reynaud and PJ Weiller. 1997. Prevalence and signification of antinuclear and anticardiolipin antibodies in patients with epilepsy. Am J Med; 103: 33-37

184. Y Shoenfeld, S Lev, I Blatt, M Blank, J Font, P von Landenberg, N Lev, J Zaech, R Cervera, JC Piette, ML Bertolaccini, GR Hughes, P Youinou, PL Meroni, V Pengo, JD Alves, A Tincani, G Szegedi, G Lakos, G Sturfelt, A Jonsen, T Koike, M Sanmarco, A Ruffatti, Z Ulcova-Gallova, S Praprotnik, B Rozman, M Lorber, J Chapman, PJ van-Breda-Vriezman and J Damoiseaux. 2004. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol; 31: 1344-8

185. HH Liou, CR Wang, HC Chou, VL Arvanov, RC Chen, YC Chang, CY Chuang, CY Chen and MC Tsai. 1994. Anticardiolipin antisera from lupus patients with seizures reduce a GABA receptor-mediated chloride current in snail neurons. Life Sci; 54: 1119-1125


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186. J Chapman, M Cohen-Armon, Y Shoenfeld and AD Korczyn. 1999. Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes. Lupus; 8: 127-133

187. R Cimaz, PL Meroni and Y Shoenfeld. 2006. Epilepsy as part of systemic lupus erythematosus and systemic antiphospholipid syndrome (Hughes syndrome). Lupus; 15: 191-7

188. RA Asherson and GRV Hughes. 1988. Antiphospholipid antibodies and chorea. J Rheumatol; 15: 377-379

189. R Cervera, RA Asherson, J Font, M Tikly, L Pallares, A Chamorro and M Ingelmo. 1997. Chorea in the antiphospholipid syndrome: clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and recent literature. Medicine (Baltimore); 76: 203-212

190. EN Harris, AE Gharavi, CG Mackworth-Young, BM Patel, G Derue and GR Hughes. 1985. Lupoid sclerosis: a possible pathogenetic role for antiphospholipid antibodies. Ann Rheum Dis; 44: 281-283

191. C Lavalle, S Pizarro, C Drenkard, J Sanchez-Guerrero and D Alarcon-Segovia. 1990. Transverse myelitis: a manifestation of systemic lupus erythematosus strongly associated with antiphospholipid antibodies. J Rheumatol; 17: 34-37

192. GJ Ruiz-Arguelles, J Guzman-Ramos, J Flores-Flores and J Garay-Martinez. 1998. Refractory hiccough heralding transverse myelitis in the primary antiphospholipid syndrome. Lupus; 7: 49-50

193. DP D'Cruz, S Mellor-Pita, B Joven, G Sanna, J Allanson, J Taylor, MA Khamashta and GR Hughes. 2004. Transverse myelitis as the first manifestation of systemic lupus erythematosus or lupus-like disease: good functional outcome and relevance of antiphospholipid antibodies. J Rheumatol; 31: 280-5

194. EN Harris, H Englert, G Derve, GR Hughes and A Gharavi. 1983. Antiphospholipid antibodies in acute Guillain-Barre syndrome. Lancet; 2: 1361-1362

195. E Toubi, J Ben-David, A Kessel, L Podoshin and TD Golan. 1997. Autoimmune aberration in sudden sensorineural hearing loss: association with anti-cardiolipin antibodies. Lupus; 6: 540-542

196. M Naarendorp and H Spiera. 1998. Sudden sensorineural hearing loss in patients with systemic lupus erythematosus or lupus-like syndromes and antiphospholipid antibodies. J Rheumatol; 25: 589-592

197. C Castanon, MC Amigo, JL Banales, A Nava and PA Reyes. 1995. Ocular vaso-occlusive disease in primary antiphospholipid syndrome. Ophthalmology; 102: 256-262

198. JP Dunn, SW Noorily, M Petri, D Finkelstein, JT Rosenbaum and DA Jabs. 1996. Antiphospholipid antibodies and retinal vascular disease. Lupus; 5: 313-322

199. B Wiechens, JO Schroder, B Potzsch and R Rochels. 1997. Primary antiphospholipid antibody syndrome and retinal occlusive vasculopathy. Am J Ophthalmol; 123: 848-850

200. R Furie, T Ishikawa, V Dhawan and D Eidelberg. 1994. Alternating hemichorea in primary antiphospholipid syndrome: evidence for contralateral striatal hypermetabolism. Neurology; 44: 2197-9

201. F Tenedios, D Erkan and MD Lockshin. 2006. Cardiac manifestations in the antiphospholipid syndrome. Rheum Dis Clin North Am; 32: 491-507

202. G Nesher, J Ilany, D Rosenmann and AS Abraham. 1997. Valvular dysfunction in antiphospholipid syndrome: prevalence, clinical features, and treatment. Semin Arthritis Rheum; 27: 27-35

203. N Espinola-Zavaleta, J Vargas-Barron, T Colmenares-Galvis, F Cruz-Cruz, A Romero-Cardenas, C Keirns and MC Amigo. 1999. Echocardiographic evaluation of patients with primary antiphospholipid syndrome. Am Heart J; 137: 973-978


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204. M Hojnik, J George, L Ziporen and Y Shoenfeld. 1996. Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome. Circulation; 93: 1579-1587

205. AA Turjanski, JD Finkielman and M Vazquez-Blanco. 1999. Isolated tricuspid valve disease in antiphospholipid syndrome. Lupus; 8: 474-476

206. A Afek, Y Shoenfeld, R Manor, I Goldberg, L Ziporen, J George, S Polak-Charcon, MC Amigo, R Garcia-Torres, R Segal and J Kopolovic. 1999. Increased endothelial cell expression of alpha3beta1 integrin in cardiac valvulopathy in the primary (Hughes) and secondary antiphospholipid syndrome. Lupus; 8: 502-507

207. RA Asherson, M Tikly, H Staub, PT Wilmshurst, DJ Coltart, M Khamashta and GRV Hughes. 1990. Infective endocarditis, rheumatoid factor, and anticardiolipin antibodies. Ann Rheum Dis; 49: 107-108

208. O Vaarala, M Manttari, V Manninen, L Tenkanen, M Puurunen, K Aho and T Palosuo. 1995. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation; 91: 23-27

209. O Vaarala, M Puurunen, M Manttari, V Manninen, K Aho and T Palosuo. 1996. Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men. Thromb Haemost; 75: 456-459

210. LJ Leventhal, MA Borofsky, PD Bergey and HRJ Schumacher. 1989. Antiphospholipid antibody syndrome with right atrial thrombosis mimicking an atrial myxoma. Am J Med; 87: 111-113

211. JA Aguilar and C Summerson. 2000. Intracardiac thrombus in antiphospholipid antibody syndrome. J Am Soc Echocardiogr; 13: 873-875

212. WH Leung, KL Wong, CP Lau, CK Wong and HW Liu. 1990. Association between antiphospholipid antibodies and cardiac abnormalities in patients with systemic lupus erythematosus. Am J Med; 89: 411-419

213. S Nair, MA Khamashta and GR Hughes. 2002. Syndrome X and Hughes syndrome. Lupus; 11: 332

214. A Theodoridou, L Bento, DP D'Cruz, MA Khamashta and GR Hughes. 2003. Prevalence and associations of an abnormal ankle-brachial index in systemic lupus erythematosus: a pilot study. Ann Rheum Dis; 62: 1199-203

215. MA Baron, MA Khamashta, GR Hughes and DP D'Cruz. 2005. Prevalence of an abnormal ankle-brachial index in patients with primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis; 64: 144-6

216. C Christodoulou, M Zain, ML Bertolaccini, S Sangle, MA Khamashta, GR Hughes and DP D'Cruz. 2006. Prevalence of an abnormal ankle-brachial index in patients with antiphospholipid syndrome with pregnancy loss but without thrombosis: a controlled study. Ann Rheum Dis; 65: 683-4

217. RA Asherson and R Cervera. 1995. Review: antiphospholipid antibodies and the lung. J Rheumatol; 22: 62-66

218. G Espinosa, R Cervera, J Font and RA Asherson. 2002. The lung in the antiphospholipid syndrome. Ann Rheum Dis; 61: 195-198

219. JC Piette and BJ Hunt. Pulmonary hypertension and antiphospholipid antibodies. In: MA Khamashta, ed. Hughes syndrome. Antiphospholipid syndrome. London: Springer-Verlag, 2000: 96-104

220. H Nagai, K Yasuma, T Katsuki, A Shimakura, K Usuda, Y Nakamura, S Takata and K Kobayashi. 1997. Primary antiphospholipid syndrome and pulmonary hypertension with prolonged survival. A case report. Angiology; 48: 183-187


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221. RA Asherson, R Cervera, JC Piette, J Font, JT Lie, A Burcoglu, K Lim, FJ Munoz-Rodriguez, RA Levy, F Boue, J Rossert and M Ingelmo. 1998. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore); 77: 195-207

222. E Gertner. 1999. Diffuse alveolar hemorrhage in the antiphospholipid syndrome: spectrum of disease and treatment. J Rheumatol; 26: 805-807

223. MC Amigo and R Garcia-Torres. Kidney disease in antiphospholipid syndrome. In: MA Khamashta, ed. Hughes syndrome. Antiphospholipid syndrome. London: Springer-Verlag, 2006: 99-111

224. KE Moss and DA Isenberg. 2001. Comparison of renal disease severity and outcome in patients with primary antiphospholipid syndrome, antiphospholipid syndrome secondary to systemic lupus erythematosus (SLE) and SLE alone. Rheumatology (Oxford); 40: 863-7

225. CM Nzerue, K Hewan-Lowe, S Pierangeli and EN Harris. 2002. "Black swan in the kidney": renal involvement in the antiphospholipid antibody syndrome. Kidney Int; 62: 733-44

226. RA Asherson, GE Noble and GR Hughes. 1991. Hypertension, renal artery stenosis and the "primary" antiphospholipid syndrome. J Rheumatol; 18: 1413-1415

227. E Rossi, C Sani, M Zini, MC Casoli and G Restori. 1992. Anticardiolipin antibodies and renovascular hypertension. Ann Rheum Dis; 51: 1180-1181

228. T Godfrey, MA Khamashta and GRV Hughes. 2000. Antiphospholipid syndrome and renal artery stenosis. Q J Med; 93: 127-129

229. SR Sangle, DP D'Cruz, W Jan, MY Karim, MA Khamashta, IC Abbs and GR Hughes. 2003. Renal artery stenosis in the antiphospholipid (Hughes) syndrome and hypertension. Ann Rheum Dis; 62: 999-1002

230. S Sangle, D D'Cruz, M Khamashta, MF Tungekar, I Abbs and G Hughes. 2002. Goldblatt's kidney, Hughes syndrome and hypertension. Lupus; 11: 699-703

231. RA Asherson, N Buchanan, E Baguley and GR Hughes. 1993. Postpartum bilateral renal vein thrombosis in the primary antiphospholipid syndrome. J Rheumatol; 20: 874-876

232. MC Amigo and R Garcia-Torres. 2000. Morphology of vascular, renal, and heart lesions in the antiphospholipid syndrome: relationship to pathogenesis. Curr Rheumatol Rep; 2: 262-270

233. MG Tektonidou, F Sotsiou, L Nakopoulou, PG Vlachoyiannopoulos and HM Moutsopoulos. 2004. Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome. Arthritis Rheum; 50: 2569-79

234. D Alarcon-Segovia, M Delezé, CV Oria, J Sanchez-Guerrero, L Gomez-Pacheco, J Cabiedes, L Fernandez and S Ponce de Leon. 1989. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus: a prospective analysis of 500 consecutive patients. Medicine (Baltimore); 68: 353-365

235. GE Gibson, WP Su and MR Pittelkow. 1997. Antiphospholipid syndrome and the skin. J Am Acad Dermatol; 36: 970-982

236. CA Battagliotti. Skin manifestations of the antiphospholipid antibody syndrome. In: MA Khamashta, ed. Hughes syndrome. Antiphospholipid syndrome. London: Springer-Verlag, 2000: 59-69

237. C Frances, S Niang, E Laffitte, F Pelletier, N Costedoat and JC Piette. 2005. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum; 52: 1785-93


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238. L Naldi, F Locati, L Marchesi, S Cortelazzo, G Finazzi, M Galli, A Brevi, T Cainelli and T Barbui. 1993. Cutaneous manifestations associated with antiphospholipid antibodies in patients with suspected primary antiphospholipid syndrome: a case-control study. Ann Rheum Dis; 52: 219-222

239. E Toubi, I Krause, A Fraser, S Lev, L Stojanovich, J Rovensky, M Blank and Y Shoenfeld. 2005. Livedo reticularis is a marker for predicting multi-system thrombosis in antiphospholipid syndrome. Clin Exp Rheumatol; 23: 499-504

240. S Paira, S Roverano, A Zunino, ME Oliva and ML Bertolaccini. 1999. Extensive cutaneous necrosis associated with anticardiolipin antibodies. J Rheumatol; 26: 1197-1200

241. C Frances, JC Piette, V Saada, T Papo, B Wechsler, O Chosidow and P Godeau. 1994. Multiple subungual splinter hemorrhages in the antiphospholipid syndrome: a report of five cases and review of the literature. Lupus; 3: 123-128

242. F Mujic, M Lloyd, MJ Cuadrado, MA Khamashta and GRV Hughes. 1995. Prevalence and clinical significance of subungual splinter haemorrhages in patients with the antiphospholipid syndrome. Clin Exp Rheumatol; 13: 327-331

243. VA Alegre, DA Gastineau and RK Winkelmann. 1989. Skin lesions associated with circulating lupus anticoagulant. Br J Dermatol; 120: 419-429

244. RA Asherson, S Jacobelli, H Rosenberg, P Mckee and GR Hughes. 1992. Skin nodules and macules resembling vasculitis in the antiphospholipid syndrome--a report of two cases. Clin Exp Dermatol; 17: 266-269

245. J Romani, F Perez, M Llobet, M Planaguma and RM Pujol. 2000. Anetoderma associated with antiphospholipid antibodies: case report and review of the literature. J Eur Acad Dermatol Venereol; 15: 175-178

246. SR Sangle, W Jan, IS Lau, AN Bennett, GR Hughes and DP D'Cruz. 2006. Coeliac artery stenosis and antiphospholipid (Hughes) syndrome/antiphospholipid anti-bodies. Clin Exp Rheumatol; 24: 349

247. RA Asherson, MA Khamashta and GRV Hughes. 1991. The hepatic complications of the antiphospholipid antibodies. Clin Exp Rheumatol; 9: 341-344

248. MJ Cuadrado, F Mujic, E Munoz, MA Khamashta and GRV Hughes. 1997. Thrombocytopenia in the antiphospholipid syndrome. Ann Rheum Dis; 56: 194-196

249. G Finazzi. 1997. The Italian Registry of Antiphospholipid Antibodies. Haematologica; 82: 101-105

250. MJ Cuadrado and GR Hughes. 2001. Hughes (antiphospholipid) syndrome. Clinical features. Rheum Dis Clin North Am; 27: 507-524

251. M Galli, M Daldossi and T Barbui. 1994. Anti-glycoprotein Ib/IX and IIb/IIIa antibodies in patients with antiphospholipid antibodies. Thromb Haemost; 71: 571-575

252. B Godeau, JC Piette, P Fromont, L Intrator, A Schaeffer and P Bierling. 1997. Specific antiplatelet glycoprotein autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome. Br J Haematol; 98: 873-879

253. M Hazeltine, J Rauch, D Danoff, JM Esdaile and H Tannenbaum. 1988. Antiphospholipid antibodies in systemic lupus erythematosus: evidence of an association with positive Coombs' and hypocomplementemia. J Rheumatol; 15: 80-86

254. C Montecucco and R Caporali. Hemocytopenias in antiphospholipid syndrome. In: MA Khamashta, ed. Hughes syndrome. Antiphospholipid syndrome. London: Springer-Verlag, 2000: 20-31


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255. PA Merkel, Y Chang, SS Pierangeli, K Convery, EN Harris and RP Polisson. 1996. The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases. Am J Med; 101: 576-583

256. R Cervera, J Font, A Lopez-Soto, F Casals, L Pallares, A Bove, M Ingelmo and A Urbano-Marquez. 1990. Isotype distribution of anticardiolipin antibodies in systemic lupus erythematosus: prospective analysis of a series of 100 patients. Ann Rheum Dis; 49: 109-113

257. KY Fong, S Loizou, ML Boey and MJ Walport. 1992. Anticardiolipin antibodies, haemolytic anaemia and thrombocytopenia in systemic lupus erythematosus. Br J Rheumatol; 31: 453-455

258. J Moore, DD Ma and A Concannon. 1998. Non-malignant bone marrow necrosis: a report of two cases. Pathology; 30: 318-20

259. MG Tektonidou, K Malagari, PG Vlachoyiannopoulos, DA Kelekis and HM Moutsopoulos. 2003. Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis Rheum; 48: 732-6

260. RA Asherson, F Liote, B Page, O Meyer, N Buchanan, MA Khamashta, P Jungers and GRV Hughes. 1993. Avascular necrosis of bone and antiphospholipid antibodies in systemic lupus erythematosus. J Rheumatol; 20: 284-288

261. S Vasoo, S Sangle, M Zain, D D'Cruz and G Hughes. 2005. Orthopaedic manifestations of the antiphospholipid (Hughes) syndrome. Lupus; 14: 339-45

262. S Sangle, DP D'Cruz, MA Khamashta and GR Hughes. 2004. Antiphospholipid antibodies, systemic lupus erythematosus, and non-traumatic metatarsal fractures. Ann Rheum Dis; 63: 1241-3

263. A Tsutsumi, T Horita, J Ohmuro, T Atsumi, K Ichikawa, K Tashiro and T Koike. 1999. Reflex sympathetic dystrophy in a patient with the antiphospholipid syndrome. Lupus; 8: 471-3

264. I Uthman, I Salti and M Khamashta. 2006. Endocrinologic manifestations of the antiphospholipid syndrome. Lupus; 15: 485-9

265. F Lima, MA Khamashta, NM Buchanan, S Kerslake, BJ Hunt and GRV Hughes. 1996. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol; 14: 131-136

266. DW Branch, JR Scott, NK Kochenour and E Hershgold. 1985. Obstetric complications associated with the lupus anticoagulant. N Engl J Med; 313: 1322-1326

267. MD Lockshin, ML Druzin, S Goei, T Qamar, MS Magid, L Jovanovic and M Ferenc. 1985. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med; 313: 152-156

268. DW Branch, RM Silver, JL Blackwell, JC Reading and JR Scott. 1992. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol; 80: 614-620

269. A Caruso, S De Carolis, S Ferrazzani, G Valesini, L Caforio and S Mancuso. 1993. Pregnancy outcome in relation to uterine artery flow velocity waveforms and clinical characteristics in women with antiphospholipid syndrome. Obstet Gynecol; 82: 970-977

270. NS Pattison, LW Chamley, EJ McKay, GC Liggins and WS Butler. 1993. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynaecol; 100: 909-913

271. M Yasuda, K Takakuwa, A Tokunaga and K Tanaka. 1995. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol; 86: 555-559


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273. DW Branch, TF Porter, L Rittenhouse, S Caritis, B Sibai, B Hogg, MD Lindheimer, M Klebanoff, C MacPherson, JP VanDorsten, M Landon, R Paul, M Miodovnik, P Meis and G Thurnau. 2001. Antiphospholipid antibodies in women at risk for preeclampsia. Am J Obstet Gynecol; 184: 825-832

274. M Backos, R Rai, N Baxter, IT Chilcott, H Cohen and L Regan. 1999. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynaecol; 106: 102-7

275. D Huong, B Wechsler, O Bletry, D Vauthier-Brouzes, G Lefebvre and JC Piette. 2001. A study of 75 pregnancies in patients with antiphospholipid syndrome. J Rheumatol; 28: 2025-30

276. D Le Thi Thuong, N Tieulie, N Costedoat, MR Andreu, B Wechsler, D Vauthier-Brouzes, O Aumaitre and JC Piette. 2005. The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women. Ann Rheum Dis; 64: 273-8

277. F De Wolf, LO Carreras, P Moerman, J Vermylen, A Van Assche and M Renaer. 1982. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant. Am J Obstet Gynecol; 142: 829-34

278. R Nayar and JM Lage. 1996. Placental changes in a first trimester missed abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome; a case report and review of the literature. Hum Pathol; 27: 201-6

279. HJ Out, CD Kooijman, HW Bruinse and RH Derksen. 1991. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Reprod Biol; 41: 179-186

280. S Stone, R Pijnenborg, L Vercruysse, R Poston, MA Khamashta, BJ Hunt and L Poston. 2006. The Placental Bed in Pregnancies Complicated by Primary Antiphospholipid Syndrome. Placenta; 27: 457-67

281. CM Salafia and AL Parke. 1997. Placental pathology in systemic lupus erythematosus and phospholipid antibody syndrome. Rheum Dis Clin North Am; 23: 85-97

282. HH Hatasaka, DW Branch, WH Kutteh and JR Scott. 1997. Autoantibody screening for infertility: explaining the unexplained? J Reprod Immunol; 34: 137-53

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