2. Diagnosis of APS

are generated against different epitopes of the participant of the coagulation system (mainly against phospholipid-binding proteins) that result in thrombosis. These antiphospholipid antibodies are a heterogeneous group of autoantibodies. Lupus anticoagulant (LA), anti-cardiolipin antibodies (ACA) and anti-β2 glycoprotein 1 (aβ2GPI) are the most important among them [2]. APS may be a secondary disease, as it frequently associates to systemic autoimmune diseases such as SLE and also to malignant lymphoproliferative diseases and chronic hepatic disorders [3]. On the contrary, APS can appear without any underlying disease, and in this case, it is

Neurologic involvement in APS is common and can be manifested by headaches, memory impairment, dizziness, epilepsy and blurred vision, but the most common presentations are transient ischaemic attacks and ischaemic strokes. Some of them are not thrombotic manifestations but are generated by connection of aPL antibodies and an antigen in the nervous system [4]. There is a special form of APS: the obstetric antiphospholipid syndrome (OAPS). It is characterised clinically only by obstetrical morbidity: at least two unexplained miscarriages, three non-consecutive miscarriages, preeclampsia, placental abruption, foetal growth restriction, stillbirth, premature birth, or two or more unexplained in vitro fertilisation failures [5, 6]. Catastrophic antiphospholipid syndrome (CAPS) is rare, but very serious form of APS. The mortality rate is very high. CAPS is characterised by thromboses generating in two or more organs in a few days. That leads to infarction and necrosis of the affected tissues causing multiple

Standard care for thrombotic APS is indefinite anticoagulation with a vitamin K antagonist [8]. There is currently insufficient evidence to recommend the routine use of direct oral anticoag-

The 13th Task Force recommendation for primary thromboprophylaxis in APS supports the use of aspirin [10]. A recent meta-analysis conducted on a total of 1208 asymptomatic patients with persistently positive aPL has shown that low-dose aspirin (LDA) is associated with significant risk reduction in arterial but not in venous thrombosis when compared to placebo [11]. Aspirin with low molecular weight or unfractionated heparin may reduce the incidence of pregnancy loss in obstetric APS [12]. Aspirin alone is advised for treating patients with aPL-

Treatment regimens of APS further include hydroxychloroquine, statins, B-cell inhibitors, complement inhibitors, blocking of aPL/B2 GPI receptors on target cells and tissue factor

A combined therapy of anticoagulation, glucocorticoids, plasma exchange and intravenous immunoglobulin (especially in the presence of infection) can be used in complicated cases of multiorgan failure due to thrombosis as in CAPS. Cyclophosphamide can also be used in CAPS in the presence of secondary autoimmune disease such as SLE [15]. Rituximab can also be used in refractory cases after failure or inability to take the above-mentioned combined

However, the majority of aPL-positive patients do not have thrombosis. That is why the stereotypical treatment for APS patients should be avoided and stratification of the thrombotic

therapies or in the presence of micro-angiopathic haemolytic anaemia [16].

called primary antiphospholipid syndrome.

organ failures [7].

54 Thrombocytopenia

inhibitors [14].

ulants (DOAC) in thrombotic APS [9].

associated stroke or acute myocardial infarction [13].

Diagnosis of APS is based on the Sapporo criteria (proposed in 1999 and updated in 2006 after a conference in Sydney, Australia) [19].

These include at least one clinical and at least one laboratory manifestation of APS. Clinical criteria include objectively confirmed venous, arterial, or small vessel thrombosis, and/or obstetric morbidity including recurrent miscarriage, stillbirth, or intrauterine growth retardation.

The laboratory criteria require demonstration of a persistent presence of lupus anticoagulant (LA), anti-cardiolipin (ACA) or anti-2GPI antibody (IgG or IgM). Antiphospholipid antibody positivity can be stated if at least one of these antibodies could be detected twice, 12 weeks apart. LA is measured by the help of coagulation tests, while ACA and anti-β2glycoprotein 1 (aβ2GPI) are determined by means of ELISA. LA results are expressed as qualitative data and only strong positivity carries clinical significance. In case of ACA and aβ2GPI, antibody medium/high titres of IgM and/or IgG subtype have important clinical value (Table 1).

Clinical symptoms of APS include thrombosis in any blood vessel of any organ. Typically, thrombosis may recur and can present both in arteries and in veins. Anti-phospholipid antibodies represent the strongest thrombophiliac factors, mainly LA.

Although thrombosis due to APS does not differ from thrombosis caused by any other factors, some other symptoms and signs may accompany to the elevated blood clotting: for example, if a patient presents with thrombosis and also has livedo reticularis, it is very likely that thrombosis is a manifestation of APS.

Besides, there are only a few situations when arterious and venous thrombosis present on the same patient. This and the recurrence of the thrombotic event is very likely refers to APS.

There are the so-called "non-criteria" clinical features of APS, such as livedo reticularis, cardiac valve disease, haematological manifestations (thrombocytopenia and haemolytic anaemia), nephropathy and neurological manifestations (migraine, chorea and epilepsy).

Non-criteria manifestations mean that the presence of these characteristic features of the disease is not a requisite of the diagnosis, or with other words, they are not the sine qua non of the diagnosis.


According to another study, patients with cerebrovascular events who are less than 50 years old have shown 17.4% prevalence of positive aPL with five times increase in the risk of

Antiphospholipid Syndrome and Thrombocytopenia http://dx.doi.org/10.5772/intechopen.72509

Thrombocytopenia is the most common non-criteria hematologic manifestation of APS. It has

There is a difference between primary and secondary APS patients in respect of the frequency of thrombocytopenia: in Euro-Phospholipid project, the frequency of thrombocytopenia in

Platelets play a key role in APS-related thrombosis due to the presence of multiple receptors that can interact with anti-β2-GPI antibodies (especially apolipoprotein E receptor 2<sup>0</sup> (apoER2<sup>0</sup>

and glycoprotein Ibα (GPIbα)) with consequent release of different pro-coagulant mediators such as thromboxane B2, platelet factor 4 (PF4) and platelet factor 4 variant (CXCL4L1) [28]. In case of APS, thrombosis results from a hypercoagulable state caused by activation of endothelial cells, monocytes and platelets. It has been demonstrated that platelets are required for enhanced activation of the endothelium and fibrin generation by the anti-β2GP1 autoantibody/β2GP1 complex. Thus, the first event is the activation of thrombocytes, endothelial cells

Platelet activation, a major contributing factor of arterial thrombosis in APS, might play a role

First, due to the presence of multiple receptors that can interact with antibodies, platelets can

The role of thrombocytes in the pathogenesis of APS is supported by the fact that circulating platelet- and endothelial-derived microparticle level are elevated in patients with primary

Mouse models of APS have shown that platelets are the first target for circulating anti-β2-GPIβ2-GPI complexes, and the enhancement of endothelium activation is also platelet thrombus-

controversial research data. Decreased thrombocyte number might be present because of

/L is considered as normal in some studies. That may be the cause of some

facilitate the dimerisation of β2-GPI enhancing the coagulation response.

Second, platelets provide a surface for coagulation reactions [30].

The normal value of platelet count is between 150 and 300 � 109

)

57

/L. Platelet number between

patients with PAPS was 21%, while it was 41.9% in patients with secondary APS [27].

been reported with prevalence between 30 and 46% among APS patients [26].

ischaemic stroke [25].

4. Role of platelets in APS

are activated indirectly [29].

APS [31].

dependent [29].

100 and 150 � <sup>10</sup><sup>9</sup>

in APS-related thrombosis in at least two ways:

5. About thrombocytopenia in general

Table 1. Revised classification criteria for antiphospholipid syndrome [19].

Thrombocytopenia is the most relevant non-criteria manifestation of APS.

However, despite the pro-thrombotic nature of APS, thrombocytopenia is one of the most common non-criteria findings of the disease. Recently, thrombocytopenia is proposed to be a diagnostic clinical criterion of APS.

In case of OAPS several disease processes may occur in the placentae of women with antiphospholipid syndrome due to the antiphospholipid autoantibodies, not only thrombosis and infarction, but also inflammatory events, mediated by cytokine release, complement activation, angiogenic imbalance and activation of immune cells [20].

### 3. Epidemiology of APS

Presence of aPL Abs per se does not guarantee a patient will develop APS as only 8.1% of patients with aPL antibodies without a history of clinical thrombosis developed thrombosis during a 5-year follow-up period, suggesting that a patient needs an additional insult to develop the clinical disease [21, 22]. The prevalence of the antibodies increases with age [23].

Forty percent of patients with APS have SLE. The prevalence of ACA in SLE is from 12 to 30%, and LA is found in 5–34%. From the patients with SLE and aPL antibodies 50–70% progress to APS.

The incidence of the APS is around five new cases per 100,000 persons per year, and the prevalence is around 40–50 cases per 100,000 persons [24].

The aPLs are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, 9.5% of patients with deep vein thrombosis and 6% of patients with pregnancy morbidity [16]. These data can underline the significance of APS.

According to another study, patients with cerebrovascular events who are less than 50 years old have shown 17.4% prevalence of positive aPL with five times increase in the risk of ischaemic stroke [25].

Thrombocytopenia is the most common non-criteria hematologic manifestation of APS. It has been reported with prevalence between 30 and 46% among APS patients [26].

There is a difference between primary and secondary APS patients in respect of the frequency of thrombocytopenia: in Euro-Phospholipid project, the frequency of thrombocytopenia in patients with PAPS was 21%, while it was 41.9% in patients with secondary APS [27].
