**2. Clinical presentation**

APS can present as a wide range of clinical manifestations with the major clinical features consisting of arterial and venous thromboses, and obstetrical complications. The most common obstetrical manifestations of APS are recurrent early miscarriage, placental insufficiency, early pre-eclampsia, and fetal death, all of which should prompt evaluation for the presence of aPL [12].

Thrombotic events in APS may occur in virtually any vascular bed, with the cerebral circulation being the arterial territory most commonly affected, usually in the form of stroke or transient ischemic attack [13]. APS has also been associated with many other clinical features including livedo reticularis, epilepsy, thrombocytopenia, and cognitive dysfunction, however, the strength of association is not sufficiently high to include them in the syndrome definition. The clinical characteristics of a cohort of 1000 patients with APS (Euro-Phospholipid Project) are displayed in **Table 2** [14].

#### **2.1 Classification criteria: additional considerations**

As described in Section 1, the first set of criteria for APS was established in Sapporo, Japan in 1999 after an expert workshop [9]. This was modified, including Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria that follow arc met\* clinical criteria

1. Vascular thrombosis†

One or more clinical episodes‡ of arterial, venous, or small vessel thrombosis§ , in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e. unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

2. Pregnancy morbidity


In studies of populations of patients who have more than one type of pregnancy morbidity, investigators arc strongly encouraged to stratify groups of subjects according to a, b, or c above.

Laboratory criteria\*\*


*\* Classification of APS should be avoided if less than 12 weeks or more than 5 years separate the positive aPL test and the clinical manifestation.*

*† Coexisting inherited or acquired factors for thrombosis arc, not reasons for excluding patients from APS trials. However, two subgroups of APS patients should be recognized, according to (a) the presence, and (b) the absence of additional risk factors for thrombosis. Indicative (but not exhaustive) such eases include: age (>55 in men, and >65 in women), and the presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index* ≥*30 kg m–<sup>2</sup> , microalbuminuria, estimated GFR < 60 ml min<sup>1</sup> ), inherited thrombophilias, oral contraceptives, nephrotic syndrome, malignancy, immobilization, and surgery. Thus, patients who fulfill criteria should be stratified according to contributing causes of thrombosis.*

*‡ A thrombotic episode in the past could be considered as a clinical criterion, provided that thrombosis is proved by appropriate diagnostic means and that no alternative diagnosis or cause of thrombosis is found. § Superficial venous thrombosis is not included in the clinical criteria.*

*¶ Generally accepted features of placental insufficiency include: (i) abnormal or non-reassuring fetal surveillance test (s), e.g. a non-reactive non-stress test, suggestive of fetal hypoxemia, (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, e.g. absent end-diastolic flow in the umbilical artery, (iii) oligohydramnios, e.g. an amniotic fluid index of 5 cm or less, or (iv) a postnatal birth weight less than the 10th percentile for the gestational age.*

*\*\*Investigators arc strongly advised classifying APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination): IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-β<sup>2</sup> glycoprotein-I antibody present alone.*

#### **Table 1.**

*The classification criteria for APS [1].*

the addition of anti-β2GPI antibodies in Sydney, Australia in 2006. The revised APS classification criteria strongly recommend investigating coexisting inherited and acquired thrombosis risk factors in patients with APS [1]. A recent assessment of the 2006 revised APS classification criteria has shown that only 59% of the patients meeting the 1999 APS Sapporo classification criteria met the revised criteria [15]. In addition, many of the older studies evaluated for only a few of the specific aPL

