**3. Etiopathogenesis**

Lupus anticoagulants and anticardiolipin antibodies are immunoglobulins that were originally thought to react only with phospholipid. However, it is now well established that these antibodies react directly with epitopes on β2-GPI(McNeil HP 1990, Galli M 1990) or prothrombin(Rao LVM 1996, Bevers EM 1991 ), that subsequently bind to anionic phospholipid. Anticardiolipin antibodies are low-affinity monovalent antibodies to β2-GPI when in solution, and the monovalent complexes bind weakly to anionic phospholipids. However, when the antigen density is high, bivalent complexes are formed that have a high affinity for phospholipid surfaces. The fact that β2-GPI antibodies are polyclonal reacting

event for which no underlying cause may be apparent; (4) patients receiving certain drugs, including procainamide and phenothiazines(a high prevalence of the lupus anticoagulant and a positive antinuclear antibody test are observed in psychotic patients receiving longterm chlorpromazine therapy); other drugs or biologics that can induce the lupus anticoagulant include hydralazine, quinidine, and possibly α-interferon; (5) patients with a recent acute viral infection, in whom the antibody is usually transient; (6) patients with human immunodeficiency virus infection; (7) women with recurrent fetal wastage;(8) occasionally in older patients with malignancies and (9) patients seeking medical attention for a variety of disorders in whom the lupus anticoagulant is discovered as an incidental finding, usually discovered because of a prolonged partial thromboplastin time (PTT)

APA can be detected in the absence of thrombosis or pregnancy morbidity or other systemic autoimmune diseases. During ongoing infectious disease, during treatments with a variety of drugs and even in healthy individuals, APA positivity may occur. The prevalence of APA ranges from 1% to 10% in the general population, 16% in patients with rheumatoid arthritis, and 30% to 40% in patients with SLE(Petri M 2000, Lim W et al 2006). The prevalence of positive tests for lupus anticoagulant and anticardiolipin antibody in a normal population has been reported in several studies. Because of the non-Gaussian distribution of anticardiolipin antibody levels in normal subjects, the cut-off points between normal and abnormal results is difficult to determine. One study reported IgG and IgM anticardiolipin antibodies in approximately 5% of normal individuals, although only 2% had persistently elevated levels on repeat testing. Shi and colleagues detected anticardiolipin antibodies in 6% of normal blood donors, respectively, and detected lupus anticoagulant activity by kaolin clotting time in 4%Shi W 1993). The prevalence of anticardiolipin antibody appears to increase with age. The prevalences of elevated levels of IgG and IgM anticardiolipin antibody in healthy pregnant women were 2% to 3% and 4%, respectively(Harris EN 1991, Aoki K 1994, Lockshin MD 1997). Most of these were low titer; only 0.2% were high titer. In other studies, the incidence of anticardiolipin antibodies in pregnant individuals ranged from 1% to 2%

When the patient does not exhibit any other symptom that would allow the diagnosis of another associated autoimmune disease, the antiphospholipid syndrome is considered primary, or isolated. The term 'secondary' APLS is sometimes used for patients suffering

Lupus anticoagulants and anticardiolipin antibodies are immunoglobulins that were originally thought to react only with phospholipid. However, it is now well established that these antibodies react directly with epitopes on β2-GPI(McNeil HP 1990, Galli M 1990) or prothrombin(Rao LVM 1996, Bevers EM 1991 ), that subsequently bind to anionic phospholipid. Anticardiolipin antibodies are low-affinity monovalent antibodies to β2-GPI when in solution, and the monovalent complexes bind weakly to anionic phospholipids. However, when the antigen density is high, bivalent complexes are formed that have a high affinity for phospholipid surfaces. The fact that β2-GPI antibodies are polyclonal reacting

performed as a routine preoperative evaluation.

and lupus anticoagulant 1% to 4%(Petri M 2000).

from another autoimmune or inflammatory disease.

**3. Etiopathogenesis** 

**2. Epidemiology** 

with different epitopes on the β2-GPI molecule and the increased affinity of the divalent antigen-antibody complexes for phospholipid surfaces explains why some anticardiolipin antibodies have anticoagulant activity and some do not(Arnout J 2003). This anticoagulant activity correlates best with the incidence of thrombosis(Galli M 2003), and a subset of lupus anticoagulants caused by anti–β2-GPI antibodies with specificity for an epitope on domain I. In some patients the anticardiolipin antibody will react with immobilized cardiolipin in vitro but not prolong phospholipid-dependent coagulation tests. Similarly, some of the antiprothrombin antibodies can prolong coagulation tests and some will not.

As with most autoimmune conditions, the etiology of APLS is not understood. It has been demonstrated that normal healthy individuals without APS have memory B cells that produce aPL antibodies; in a study of patients with infectious mononucleosis, 10 to 60 percent of immunoglobulin M aCL-producing cells expressed CD 27, the marker of memory B cells(Lieby P 2003).

Although antibodies against anionic phospholipid moieties arise during the course of infections such as syphilis and lyme disease, those are distinct from antibodies generated by patients with the syndrome because they generally recognize phospholipid epitopes directly and are not associated with the clinical manifestations of the syndrome.

Reports of familial clustering of raised aPL antibody levels indicate that genetic susceptibility can play a role in their development(Donald I. Feinstein 2007). In one study of 84 APLS patients, more than 35% had at least one relative, and more than 20% had two or more relatives, with evidence of at least one clinical feature of APS, such as thrombosis or recurrent fetal loss(Weber M 2000).

Many different mechanisms have been described for thrombosis during APLS, mainly after in-vitro experiments: (1) activation of endothelial cells by complexes of β2 GPI and anti-β2 GPI, these complexes could bind to annexin 2 or even Toll-like receptors on the surface of endothelial cells(Zhang J 2005, Fischetti F 2005); (2) platelet activation after direct binding of the β2 GPI, which targets the autoantibodies on the surface of these cells, the β2 GPI is selectively bound by the activator receptor apo ER 2(Lutters BC 2003); (3) functional dysregulation of hemostasis by the presence of autoantibodies against natural anticoagulant proteins like annexin 5 and activated protein C; (4) abnormal fibrinolysis directly linked to the presence of APL(Cesarman-Maus G 2006).

APL can stimulate platelet aggregation(Lin YL 1992), an effect that might be promoted via signalling through apolipoprotein E receptor 2(apoER2) receptors; the beta2GPI binding site for apo ER2 on platelets was localized to its domain V. Beta2GPI also has a dampening effect on platelet adhesion by interfering with the platelet-von Willebrand factor interaction, and consequently aPL antibodies, by interfering with this dampening, can increase platelet adhesion in flow systems(Hullstein JJ 2007).

Normal endothelial function includes control over thrombosis and thrombolysis, platelets and leukocyte interaction with the vessel wall, and regulation of vascular tone and smooth muscle proliferation. Several in vitro studies and studies on animal models have shown that incubation of endothelial cells with aPL from APLS patients generates different effects on endothelial function via β2 GPI. As a whole this might cooperate in sustaining endothelial perturbation that has been suggested to have a pivotal pathogenetic role in APS associated thrombosis(Stalc M 2006).

Because high-level aPLs may persist for years in asymptomatic persons, it is likely that vascular injury, endothelial cell activation, or both immediately precede the occurrence of thrombosis in those bearing the antibody (second-hit hypothesis). Of note, at least 50% of

Antiphospholipd Syndrome and Venous Thrombosis 59

The first clinical aspect of the APLS is thrombosis, which can affect arterial or venous vessels, as well as small vessels, and must be confirmed by means of imaging studies and/or histopathology. Arterial thrombosis mainly occurs in the central nervous system. But all arteries can be effected and myocardial infarction, peripheral gangrene, aseptic osteonecrosis and adrenal insufficency can develop with respect to effected arterial site. The venous thrombosis commonly localizes to the deep veins of the limbs and can be complicated by pulmonary embolism. As in arterial thrombosis, any segment of the venous

A definitive diagnosis of APLS is based on fulfilling at least one of the Updated Sapporo Clinical criteria(vascular thrombotic event or pregnancy morbidity) and at least one of the laboratory criteria(Table 1). In general, medium titer aCL is considered 40 U or more and high titer, more than 80 U; titers between 20 and 40 U should be evaluated cautiously. Transient APL positivity is common during infections; thus documentation of the persistence(at least 12 weeks apart) of autoimmune APL is crucial for both diagnostic and

The choice of initial APL tests remains a subject of debate. In general, the LA test is more specific for APL-related clinical events. The specificity of aCL for APL-related clinical events increases with higher titers. The IgG isotype is more strongly associated with APL-related clinical events than the IgM isotype. In a patient with suspected APS, testing for LA and IgG/IgM aCL should be ordered initially. If these tests are negative or low-titer and there is still a high level of suspicion for APS, then testing for antiβ2GPI antibodies and IgA aCL/antiβ2GPI can be pursued(George D 2009). Antiphospholipid antibody tests developed based on other phospholipids such as phosphatidylserine, phosphatidylinositol, or phosphatidylethanolamine or phospholipid-binding plasma proteins(such as prothrombin)

Although any vasculature can be affected by thrombosis, stroke and transient ischemic attack are the most common presentations of arterial thrombosis, whereas deep vein thrombosis with or without pulmonary embolism is the most common presentation of venous thrombosis in APLS(George D 2009). Antiphospholipid antibodies can cause both arterial and venous thrombosis in the same patient. Reccurent thromboses tend to occur in the same vascular distribution(venous followed by venous and arterial followed by arterial). in some studies the incidence of venous thrombosis (70%) is greater than the incidence of

Superficial thrombophlebitis, superior vena cava syndrome, renal vein thrombosis, Budd Chiari syndrome, central retinal vein occlusion, pulmonary hypertension due to recurrent pulmonary embolism, and diffuse pulmonary hemorrhage due to microthrombosis are

Of unselected patients with antiphospholipid antibody, 1% to 2.5% per year will develop thromboembolism(Galli M 2003, Finazzi G 1996),and 10% to 25% of patients with deep venous thrombosis will be found to have antiphospholipid antibodies(Ginsburg KS 1992).However, in a prospective population based study of 66140 individuals in Norway(Naess IA 2005), elevated anticardiolipin antibody levels were not a risk factor for

vasculature can be effected, which will induce different manifestations.

therapeutic purposes.

**5. Clinical features** 

are not yet well standardized and accepted.

arterial thrombosis.(Galli M 1997, Triplett DA 1995).

some of the thrombotic manifestations of APLS.

APLS patients with vascular factors possess other acquired thrombosis risk factors at the time of their events(Kaul M 2006, Erkan D 2002).

Both persons congenitally lacking ß2GPI39 and ß2GPI knockout mice appear normal(Sheng Y 2001). ß2GPI polymorphisms influence the generation of aPLs in individuals, but they have only a weak relationship to the occurrence of APLS. A cluster of 50 upregulated genes may have an effect on the occurrence of thrombosis in aPL-positive individuals(Potti A 2006).
