**1. Introduction**

Antiphospholipid syndrome (APS) is a systemic autoimmune thromboinflammatory disorder characterized by vascular thrombosis and pregnancy-related morbidity accompanied by persistent positive antiphospholipid antibodies (aPL) [1, 2]. APS is considered the most common acquired form of thrombophilia worldwide [3]. Obstetric APS is a complex entity that can affect both the mother and the fetus throughout pregnancy with high morbidity. The clinical complications of obstetric APS are diverse and include recurrent fetal loss, stillbirth, intrauterine growth failure, and preeclampsia [4]. In addition to thrombosis and pregnancy loss, other pathological manifestations regularly occur with APS including thrombocytopenia, destruction of heart valves, accelerated atherosclerosis, nephropathy, movement disorders, and cognitive decline [5]. Catastrophic APS (CAPS) is characterized by the rapid development of thrombosis in multiple organs and micro-thrombosis within a short period of time. Pediatric APS is a rare condition that is distinctly different from adult APS [6].

The classification of APS for clinical trials and studies is currently based on the international consensus statement established in Sapporo in 1999 and updated in Sydney in 2006, and includes a clinical criterion (vascular thrombosis or pregnancy morbidity) and a laboratory criterion (positive test result for aPL) [1] as shown in **Figure 1**. aPL are a heterogeneous family of IgG and/or IgM or, more rarely, IgA autoantibodies with an affinity for negatively charged phospholipids or proteinphospholipid complexes. Their persistent presence in sera has been associated with increased prothrombotic risk in various autoimmune diseases. The aPL that constitute the laboratory criteria for APS include lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2-glycoprotein I antibodies (anti-β2GPI) of immunoglobulin IgG and IgM classes. Extensive evidence has accumulated over the past decade that several other than those included in the APS classification criteria may be relevant to APS pathogenesis. Among them, antiprothrombin antibodies, especially antibodies against phosphatidylserine-prothrombin complex (aPS/PT), are supported by the most studies in the literature showing their strong correlation to LA activity and to clinical manifestations of APS [7–9]. An international multidisciplinary initiative "APS action", jointly supported by the American College of

#### **Figure 1.**

*Classification criteria for APS and definition of high and low risk profile. Created with BioRender.com.*

Rheumatology (ACR) and the European League Against Rheumatism (EULAR) is currently underway to establish a new diagnostic criterion for APS.

APS can either be a disease in the absence of evidence of other autoimmune disease, or it can be secondary to another autoimmune disease such as systemic lupus erythematous (SLE) [10]. The profile of aPL, including type and titer, is an important factor determining the risk for thrombotic and obstetric events [11, 12]. The presence of LA, triple positivity or double positivity with positive LA, and the persistent presence of high titers of aCL and anti-β2GPI antibodies pose a high risk for the development of APS. In contrast, isolated positivity at low or medium titers of aCL or anti- β2GPI antibodies, particularly when transiently positive, poses a low risk.

A very rare, but life-threatening form of multiorgan thrombosis is known as catastrophic anti-phospholipid syndrome (CAPS) [13–15]. It is characterized by simultaneous thrombosis in multiple organs within a short period of time, that is, within a few days. Thrombosis often occurs at unusual sites, and small and medium-sized arteries are most frequently involved [16]. Less than 1% of patients with APS develop CAPS. CAPS is the first manifestation of APS in about half of diagnosed CAPS patients. The remaining patients have a history of APS. The mortality rate has decreased over time, mainly due to triple therapy (anticoagulation, corticotherapy and therapeutic plasma exchange—TPE—or intravenous immunoglobulin—IVIG), but it still exceeds 30% [17]. An international registry established in 2000 by the European Forum on Anti-Phospholipid Anti-bodies, and the last reported data (2016) includes 500 patients [17].

The other major clinical manifestations of APS are obstetric. These include unexplained death of one or more morphologically normal fetuses at or after 10-week gestation, premature delivery of one or more morphologically normal newborns before 34-week gestation due to either eclampsia, severe preeclampsia, or recognized features of placental insufficiency, and three or more unexplained, consecutive spontaneous abortions before 10-week gestation.

### **2. Clinical manifestations of APS are heterogeneous and nonspecific**

The heterogeneity and non-specificity of potential clinical signs illustrates that APS is as a true systemic autoimmune disease and underscores the need for a better *Introductory Chapter: Antiphospholipid Antibodies - A Laboratory Criterion… DOI: http://dx.doi.org/10.5772/intechopen.103846*

understanding of disease mechanisms that will enable a personalized approach to treatment. Despite some improvements in the diagnosis and prognosis of APS and the prevention of thrombosis reoccurrence, robust laboratory biomarkers are still lacking.

Because APS affects young patients in the most productive years of their lives, the consequences of organ or tissue damage lead to impaired health-related quality of life (HRQoL). There are several reasons why APS could adversely affect HRQoL. The clinical manifestations are diverse, and many of them damage vital tissues. In addition, APS may overlap with rheumatoid arthritis (RA) and SLE, both of which already significantly affect HRQoL. Another aspect that affects HRQoL in APS is treatment with high-dose anticoagulation indefinitely in patients with thrombosis and/or at high risk of thrombosis.

In the general population, the incidence of clinical manifestations present in APS is high and could often be triggered by other underlying factors. Consequently, the diagnosis of APS relies predominantly on laboratory measurements. However, current laboratory tests are hampered by technical limitations in the pre-analytical and analytical phases and by the fact that there is no standardization of these tests. Despite the many attempts to increase the specificity of laboratory criteria and the establishment of consensus criteria for serology, a high number of patients are still misdiagnosed. One of the most important reasons for this is the high heterogeneity of aPL in patients with APS. Thus, it remains to be clarified whether different manifestations are caused by subpopulations of autoantibodies against different epitope specificities that are currently detected by the same test(s). Unfortunately, most APS patients exhibit more than one type of aPL, making it difficult to assign pathogenic effects to one epitope specificity or another. In addition, the diagnosis of pediatric APS is even more challenging since it is such a rare condition. Diagnosis may be delayed or missed when adult APS criteria are used, because in pediatric APS, non-thrombotic clinical manifestations, such as thrombocytopenia, hemolytic anemia, and neurologic disorders such as migraine, epilepsy, and chorea, may precede thrombotic manifestations.
