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Platelets are a potential target for circulating aPL that may cause antibody mediated thrombosis. In vitro studies performed in the aggregometer or in flowing conditions and the evaluation of platelet activation markers in vitro and in vivo in patients with the APS demonstrated the ability of aPL to interact with platelets and promote their function. The most reliable explanation for the prothrombotic action of aPL in platelets includes, first, previous platelet activation and the binding of them to platelet membrane phospholipid bound proteins, mainly β-glycoprotein I. Then, in a second step, aPL may act activating platelets, via FcγRIIA or complement C5-9 formation. However, several points of this suggested mechanism of action of aPL on thrombus formation are not clearly established and further studies on the interaction between platelet and aPL are needed.

In conclusion, the following observations can be made. aPL are present in approximately 2% to 4% of the normal population and the prevalence increases with age. There is a high prevalence among patients with autoimmune connective tissue disorders, especially SLE. There is an association with both venous and arterial thrombosis as well as with pregnancy morbidity, but the strength of association varies amongst studies. This probably reflects different populations, study designs, and different assays and definitions used. In several studies the risk of thrombosis appears to be higher with LA and the data suggests a true association rather than epiphenomenon. In a given patient, both aCL and LA should be measured. A significant impact on long-term survival has been noted and aPL also contribute significantly to accumulated damage in diseases such as SLE. The clinical spectrum of APS features is enormous and continues to expand. It behoves us all as clinicians and health care professionals to consider an early diagnosis of Hughes syndrome, with its distinct clinical and serological features, to reduce the risk of morbidity and mortality in our patients.

PAPS has emerged as an important disease entity. Depending on the organ systems involved, it can produce a highly variable clinical picture, with severity ranging from mild asymptomatic disease (often undiagnosed) to major life-threatening events. It may be regarded as the pure form of a condition which is also frequently seen in the context of other autoimmune diseases. In particular it is intricately linked to APS seen in the context of SLE; and these two variants of the condition appear to behave in a similar fashion. Defining PAPS provides us with the opportunity to study the disease in the absence of other co-morbid conditions such as SLE. Advances in our understanding of the pathogenesis of PAPS should facilitate the development of improved treatment and outlook for patients with all forms of the APS.

Genetic factors related to aPL and APS have been widely investigated. Many candidate genes, including HLA class II haplotype, have been presented to predispose aPL or APS. However, it is difficult to determine genetic risk factors related to aPL development and clinical manifestations of APS in these patients as there is a high heterogeneity in antigen specificity and in the pathophysiology of thrombosis.

Whether the aPL are cause of these cardiac complications or simply accompany more basic underlying immunological disturbances cannot be assessed from these studies. However, serial screening of aPL in patients who develop these complications will help to assess the prevalence and usefulness of these antibodies in cardiac diseases. Until these studies become available, clinicians should consider a search for aPL in those patients with the previously reported cardiac complications in whom no other etiology could be found.

Our observations, and those from others, give further support to our hypothesis that “autoimmune aPL” may be generated by immunization with products from bacteria or viruses after incidental exposure or infection. We also were able to generate APS-like syndrome in a strain of mice susceptible to autoimmunity, indicating that other factors are likely to be involved, such as genetic predisposition. Furthermore, not all aPL generated were pathogenic. Based on the clinical experience and on the numerous reports indicating presence of aPL in large number of infectious diseases, it may be expected that not all aPL produced during infection will be pathogenic. A limited number aPL induced by certain viral/bacterial products would be pathogenic in certain genetically predisposed individuals. Further studies to identify the agents responsible for induction the pathogenic aPL are needed. Identification of those bacterial and/or viral agents may help finding strategies for the prevention of production of aPL “pathogenic” antibodies. Alternatively, free peptides may be used to induce tolerance against aPL production or to abrogate their pathogenic effects.

Drugs such as procainamide and phenothiazines can also induce aPL. The prevalence and pathogenicity of drug-induced aPL is generally low and has been discussed in this chapter.

Increased TF expression may contribute to thrombosis in patients with APS. This effect might ultimately depend on antibody engagement of PL binding proteins on the monocyte and the EC surface, leading to signal transduction and altered cell activity. Understanding the intracellular mechanism(s) of aPL mediated TF activation may help to establish new therapeutic approaches to revert the prothrombotic state observed in APS patients.

aPL are strongly related to thrombotic events. It is the most common acquired coagulation defect among the ones accountable for procoagulant states.

Skin involvement might be the first manifestation of APS (41%) and over one third of these patients will develop multisystem thrombotic events during the course of the disease. Therefore, a close monitoring of these patients is warranted.

In conclusion, annexin A5 is a potent anticoagulant protein that forms an antithrombotic shield over anionic phospholipids containing bilayers. Autoantibodies may interfere with this shielding function via high affinity antibodies that recognize phospholipid binding proteins that are capable of interfering with the assembly of the annexin A5 shield on phospholipid surfaces or via direct recognition of annexin A5 functional epitopes by autoantibodies. Antibody mediated interference with the integrity of the two-dimensional annexin A5 crystal shield may be a mechanism for thrombosis and for pregnancy complications, including recurrent spontaneous pregnancy losses, in APS.

Our observations, and those from others, give further support to our hypothesis that “autoimmune aPL” may be generated by immunization with products from bacteria or viruses after incidental exposure or infection. We also were able to generate APS-like syndrome in a strain of mice susceptible to autoimmunity, indicating that other factors are likely to be involved, such as genetic predisposition. Furthermore, not all aPL generated were pathogenic. Based on the clinical experience and on the numerous reports indicating presence of aPL in large number of infectious diseases, it may be expected that not all aPL produced during infection will be pathogenic. A limited number aPL induced by certain viral/bacterial products would be pathogenic in certain genetically predisposed individuals. Further studies to identify the agents responsible for induction the pathogenic aPL are needed. Identification of those bacterial and/or viral agents may help finding strategies for the prevention of production of aPL “pathogenic” antibodies. Alternatively, free peptides may be used to induce tolerance against aPL production or to abrogate their pathogenic effects.

Drugs such as procainamide and phenothiazines can also induce aPL. The prevalence and pathogenicity of drug-induced aPL is generally low and has been discussed in this chapter.