**1. Introduction**

Antiphospholipid syndrome (APS) was first described in 1983 with steadily improving clinical and scientific refinements since that time. It was initially recognized with the discovery of lupus anticoagulant immunoglobulin that binds to phospholipids and proteins associated with the cell membrane and its association with other autoimmune conditions. Over the years, the clinical manifestations of APS were further delineated, followed by the discovery of other antiphospholipid antibodies. Currently, APS is defined as an autoimmune condition characterized by the presence of venous or arterial thrombosis and/or pregnancy-related complications in patients with antiphospholipid antibodies [1]. Notably, APS can occur as a *primary* disease process or *secondary* to another condition, primarily autoimmune conditions, including systemic lupus erythematous (SLE), rheumatoid arthritis, sjogren's disease, or systemic sclerosis. It can more rarely be secondary to malignancy [2] and infections, including syphilis and HIV [3].

Clinically, APS can manifest in a variety of ways and affect multiple organ systems. Presenting symptoms can range from relatively benign to severe. One subtype (to be discussed in Section 2) termed catastrophic APS (CAPS) is defined as APS that affects >3 organs in a short period of time (<7 days) with pathologic evidence of small-vessel occlusion. The most common venous manifestation of APS is deep vein thrombosis, while stroke is the most common arterial manifestation of this disease [4]. Obstetric complications include placental insufficiency and recurrent pregnancy loss, typically after 10 weeks of gestation. There are, however, a multitude of other manifestations including cardiac valvular disease, coronary artery disease, livedo reticularis, renal small artery vasculopathy, and thrombocytopenia, which are *not* included in the formal classification criteria [1]. Neurologically, antiphospholipid antibodies have also been found to be more rarely related to migraine, seizures, movement disorders, and cognitive impairment [5]. Given this broad range of clinical manifestations, it is important that clinicians have a clear understanding of when to suspect this condition and its appropriate management.

Antiphospholipid antibodies (aPL) are a serological marker for APS and their presence is key to the definition and classification for APS. Phospholipids are molecules found in the blood that aid in clot formation. They form complexes with other plasma proteins and are the target of aPL antibodies; thus, one may expect to clinically see a bleeding disorder when phospholipids are disrupted. However, these autoantibodies primarily cause endothelial dysfunction and disruption of coagulation factors as they compete with coagulation factors for available phospholipids, thereby leading to a procoagulant state and clot formation [6]. The pathophysiology of aPL antibodies is not fully elucidated, but the current thought is that of a "two-hit" hypothesis. The first hit being a patient-specific susceptibility, and the second hit being a trigger or inciting event. This theory is based on the idea that about 1–5% of the population may have positive aPL antibodies without any clinical manifestations, indicating the need for a trigger that leads to the pathologic state [2, 4]. In a patient carrying aPL antibodies, endothelial cell activation occurs in the setting of oxidative stress in conditions such as infection, surgery, and pregnancy. This is thought to subsequently lead to a series of events including complement activation, cytokine release, increased expression of tissue factor on endothelial cells, increased platelet adhesiveness, and impairment of thrombolysis [2, 4]. Overall, this creates a procoagulant state leading to the range of clinical manifestations as described.

aPL antibodies are a heterogeneous group of autoantibodies that primarily include *lupus anticoagulant (LA), anti-cardiolipin IgG/IgM (aCL), and anti-beta-2 glycoprotein-I (aB2GPI) IgG/IgM,* with these three specific antibodies included in the formal classification criteria for APS [1]. As shown in **Figure 1** there is some overlap between these antibodies, but overall, they are distinct leading to a variety of clinical manifestations [5]. In addition to the three antibodies in the classification criteria, there are a number of other proposed antibodies of yet unclear clinical significance and diagnostic value. These include anti-prothrombin and antiphosphatidylserine-prothrombin complex, aCL IgA and anti-B2GPI IgA. These antibodies are sometimes used to aid in diagnosis if there is a very high clinical suspicion for APS without the presence of the typical autoantibodies in the classification criteria [7]. It is important to note that while B2GPI is considered a primary APS antigen, subgroups of protein domains can be targeted by specific antibodies. For example, antibodies targeting B2GPI Domain I, in particular, have been correlated with a high risk of thrombosis [8].

The presence of LA alone is thought to hold the highest risk for thrombosis among all antiphospholipid antibodies. Thrombotic risk is much lower in patients who have only a positive aCL or anti-B2GPI antibody [1, 3]. The risk is thought to be much higher however in patients with multiple positive antibodies, especially those found to be "triple positive" [3]. Thrombotic risk is also much higher in patients who have secondary APS is associated with SLE and in patients with primary APS with concurrent vascular comorbidities including hypertension, hypercholesterolemia, tobacco, and oral contraceptive use [7].

*Antiphospholipid Syndrome and Stroke DOI: http://dx.doi.org/10.5772/intechopen.101777*

#### **Figure 1.**

*There are a variety of antiphospholipid antibodies associated with APS, as detected with different methods, some are overlapping, but each has distinct properties. Image adapted from Misita et al. [6]*.

The initial classification criteria for APS, called the Sapporo criteria, was first developed in 1999 and most recently updated in 2006 [1]. As shown in **Table 1**, the criteria currently require one clinical manifestation of thrombosis or pregnancy complication, and one laboratory criteria present on two occasions at least 12 weeks apart.

As mentioned, there are other autoantibodies implicated in APS that are not yet included in the classification criteria. The remainder of this chapter will discuss the clinical manifestations, epidemiology, pathophysiology, diagnosis, and treatment in more detail.
