**Antiphospholipd Syndrome and Venous Thrombosis**

Ertugrul Okuyan

*Bagcilar Education and Research Hospital Istanbul Turkey* 

### **1. Introducton**

54 Venous Thrombosis – Principles and Practice

Willems, HP.; den Heijer, M.; Gerrits, WB.; Schurgers, LJ.; Havekes, M.; Blom, HJ. & Bos,

Vol.17, pp. 120-124.

GM. (2006). Oral anticoagulant treatment with coumarin derivatives does not influence plasma homocysteine concentration. *European Journal of Internal Medicine,*

> Antiphospholipid syndrome(APLS) is a prothrombotic state characterized by recurrent venous thrombotic events including deep venous thrombosis, as well as pulmonary embolism, arterial thrombosis, recurrent fatal loss due to placental thrombosis and the presence of circulating antiphospholipid antibodies(APA) (Roubey RAS, 2001). As both thrombosis and pregnancy morbidity have a large number of other origins, the diagnosis of APLS relies on the quality and reliability of the laboratory investigations, on the persistent positivity of the APA assays, and sometimes on the lack of any other cause. Although a broad spectrum of APA exists, the universally accepted diagnostic APA tests are lupus anticoagulant(LA) functional coagulation assay; anticardiolipin antibody(ACA) enzymelinked immunosorbent assay(ELISA); and anti-β2-glycoprotein I antibody(aβ2GPI) ELISA.

> Antiphospholipid antibodies were first described in 1906 in patients with syphilis. These complement-fixing antibodies reacting with extracts from bovine hearts(mitochondrial phospholipid cardiolipin) formed the basis for the serologic syphilis test(Venereal Disease Research Laboratory-VDRL assay). Mass population screening for syphilis demonstrated that patients with systemic lupus erythematosus(SLE) without clinical syphilis had persistently false-positive VDRL tests(Haserick J,et al 1952, Baker WF, et al 2008). As falsepositive VDRL tests in patients with SLE were also found to be associated with prolonged in vitro coagulation, the term 'lupus anticoagulant' was introduced.

> The lupus anticoagulant is an antibody that prolongs phospholipid dependent coagulation tests in vitro. It was given this name in 1972 because clear proof of its site of action was lacking, and because the anticoagulant had been recognized in patients with systemic lupus erythematosus(Donald I Feinstein 2009 ). It is a misnomer because the lupus anticoagulant is more frequently encountered in patients without lupus and is associated with thrombosis rather than with bleeding. Immunoglobulins reacting with other hemostatic factors, such as von Willebrand factor (VWF), factor VIII, factor IX, and factor XI, inhibitors of thrombin and fibrin polymerization, and factor XIII have also been described in patients with SLE(Donald I Feinstein 2009), but they are rare compared with the lupus anticoagulant.

> Patients with the lupus anticoagulant who do not have established SLE fall into several different categories: (1) patients with "lupus-like"chronic autoimmune disorders but without findings that fit the criteria for the diagnosis of SLE; (2) patients with other chronic systemic autoimmune disorders; (3) patients presenting with a venous or arterial thrombotic

Antiphospholipd Syndrome and Venous Thrombosis 57

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

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

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

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

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

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

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

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

antiprothrombin antibodies can prolong coagulation tests and some will not.

and are not associated with the clinical manifestations of the syndrome.

B cells(Lieby P 2003).

recurrent fetal loss(Weber M 2000).

the presence of APL(Cesarman-Maus G 2006).

adhesion in flow systems(Hullstein JJ 2007).

thrombosis(Stalc M 2006).

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) performed as a routine preoperative evaluation.
