**2. Thrombocytopenia in patients with aPL**

Though not included in the current diagnostic criteria for APS (Sydney 2012 criteria), thrombocytopenia represents a complication directly linked to aPL [1]. Thrombocytopenia is a frequent finding in aPL-positive patients; it is their most common non-criteria hematologic manifestation. The Euro-Phospholipid project, a large prospective multicenter international study evaluating 1000 European patients with both primary and secondary APS, found thrombocytopenia in 296 (29.6%) of its participants [5]. Other studies focused on the whole population of aPL-positive patients reported comparable incidence, ranging from 20 to 53% [6–10]. Of interest, particular subgroups seem to be more prone to develop thrombocytopenia. Patients with secondary APS associated with systemic lupus erythematosus (SLE) have thrombocytopenia approximately 2-times more often than those with primary APS (reported incidence 40 vs. 21% in the Euro-Phospholipid project) [5]. A low platelet count is more frequent in patients with CAPS [10, 11].

Thrombocytopenia tends to be mild to moderate with the nadir above 50000/μL in most cases. Only a small portion of patients (approximately 10%) develop severe thrombocytopenia, and its occurrence is often associated with other complications, such as TMAs (disseminated intravascular coagulation (DIC), CAPS) [8]. Rapid (within days) progression of thrombocytopenia or its new occurrence in patients with previously normal platelet count can be the first indication of CAPS [11, 12].

Despite being common, thrombocytopenia alone is not usually responsible for clinically relevant bleeding. For example, in the Italian Registry of aPL, only four patients out of 90 with thrombocytopenia experienced major hemorrhagic events [8]. On the other hand, nor it protects, especially if mild to moderate, from thromboembolism. Notwithstanding, if severe and without CAPS, it can account for a minor protective effect. In the Italian Registry with 360 patients included, severe thrombocytopenia was associated with a significantly lower rate of thrombotic events in comparison to the group with normal platelet count; however, the group with mild thrombocytopenia did not show a significant difference (9 vs. 40 vs. 32%) [8]. A recent study analyzing altogether 305 patients with primary

APS, 51 with thrombocytopenia included, observed a higher rate of thrombotic relapses (29% vs. 19%) during a long (median 11 years) follow-up in the group with thrombocytopenia, though the difference did not reach statistical significance [13]. Despite comparable antithrombotic therapy, no difference in major hemorrhage (4% vs. 3%) was observed between the thrombocytopenic and non-thrombocytopenic group, albeit the significantly higher rate of overall bleeding (17% vs. 8%) was in the thrombocytopenic group. The authors conclude that thrombocytopenia may have a prognostic value in primary APS and help identify high-risk patients for APS-related complications [13].

The evidence concerning the association between thrombocytopenia and other clinical features of APS such as hemolytic anemia, livedo reticularis, skin ulcerations, chorea, and cardiac valve dysfunction is conflicting. Some studies, but not all, observed more frequent occurrence of those symptoms in patients with thrombocytopenia.

The pathogenesis of aPL-related thrombocytopenia is likely heterogeneous. aPL can directly or indirectly via B2GPI interact with several platelet membrane glycoproteins (GP) and phospholipids and thus initiate two processes: 1) pathologically enhanced platelet activation and aggregation after their initial activation or damage with subsequent platelet thrombus formation and platelet consumption; 2) immune-mediated pathological platelet clearance. The interaction with platelets involves the binding of anti-B2GPI via B2GPI to the activated platelet surface or direct interaction of aPL with specific platelet membrane glycoproteins (GPIb/IX, GPIIb/IIIa, GPIV) [14]. Particular subtypes of aPL and their quantity likely play a prominent role in the pathogenesis of thrombocytopenia. Anti–B2GPI antibodies of IgG class, LA, a higher titer of aCL of IgG class, and triple aPL positivity were a more common finding in patients with thrombocytopenia [13, 15, 16]. LA and a high titer of aCL were frequent among patients with severe thrombocytopenia. Since LA is associated with the highest prothrombotic risk among aPL, its higher prevalence in these patients could mitigate the bleeding tendencies and contribute to a relatively low rate of major bleedings.

Other pathomechanisms may occasionally contribute to thrombocytopenia in aPL-positive patients. The association, albeit anecdotal, between aPL and the hemophagocytic syndrome (a hyperinflammatory disorder with pathological phagocytosis of blood cells and their precursors in the bone marrow and other tissues) and bone marrow necrosis was described [17, 18]. These disorders decrease platelets via impairing megakaryopoiesis. Splenomegaly after splenic or portal vein thrombosis leads to increased platelet pooling and redistribution from circulation [7].

It should be emphasized that the etiology of thrombocytopenia in aPL-positive patients can be multifactorial and not exclusively linked to these antibodies. Other diseases can contribute to and further deepen the decrease in platelet count. Coincidence with immune thrombocytopenia (ITP), drug-induced thrombocytopenia with heparin-induced thrombocytopenia included, thrombocytopenia related to infections, TMAs, and pregnancy-related thrombocytopenia have been described [18, 19].

The relationship with ITP seems to be particularly interesting and complex. Patients with ITP are frequently positively tested for aPL, with a reported incidence ranging from 25 to 75% [20]. A recent retrospective study of 159 adult patients with primary and secondary severe ITP (platelet count below 50000/μL) identified aPL in 37 (23.2%), with 14 being triple positive. Triple positivity was associated with a lower platelet count [21]. Clinical implications of the relation between ITP and aPL are still discussed and not clear. The available data regarding the risk of thrombosis and treatment are inconclusive. However, a recent study with altogether 196 patients with primary ITP, 49 aPL-positive included, did observe a significantly

#### *Bleeding in Patients with Antiphospholipid Antibodies DOI: http://dx.doi.org/10.5772/intechopen.97856*

higher risk of thrombotic events. Other monitored characteristics (hemorrhage, response to therapy, clinical course, changes in platelet counts) were comparable [19]. Analogically to the observation in APS, it seems that the risk of thrombosis in patients with concomitant ITP and aPL positivity, particularly in those undergoing therapy with corticosteroids and other immunosuppressive agents, is more prominent than the risk of bleeding.

The diagnostic approach has to consider the possibility of aPL as a sole cause of thrombocytopenia as well as the coincidence of other disorders with aPL, especially TMAs. Since patients with aPL/APS are often anticoagulated and treated with immunosuppressives, heparin-induced thrombocytopenia and infectious causes should be addressed in the diagnostic process.

Since thrombocytopenia in aPL-positive patients is predominantly mild and without significant bleeding, outside of CAPS, most patients do not require specific treatment. As a general rule, the goal is to maintain the platelet count above 30000/ μL – a critical threshold for the development of severe spontaneous bleeding. When immune etiology is behind thrombocytopenia, strategies effective in ITP are preferably used [22, 23]. Corticosteroids, initially in high-dose with gradual tapering, alone or combined with intravenous immunoglobulins (IVIg), represent the first-line treatment. In contrast to ITP, the use of IVIg as a first-line treatment is controversial in aPL-positive patients since their administration is potentially associated with an increased risk of thrombotic events [24]. Other immunosuppressive or immunomodulatory agents or procedures (danazol, chloroquine, dapsone, rituximab, plasmapheresis) or splenectomy can be chosen as alternatives for those with inadequate response. Rituximab seems to be a particularly perspective agent. Though only limited clinical data from a small number of patients are available so far, the response and persisting stable platelet count after rituximab have been observed in a reasonably high number (50–83%) of treated patients [25, 26]. It is important to emphasize that most of the included patients had refractory thrombocytopenia without a satisfactory response to previous treatment modalities. Rituximab was tolerated well with no significant increase in thrombotic risk. Its risk profile in the aPL setting appears to be comparable to ITP [25].

The use of thrombopoietin mimetics (TPOMs) remains controversial due to the conflicting clinical data. There is a general agreement on their effectiveness in increasing platelet count, but safety remains an open issue. Several authors did not observe any increase in the thrombotic events during the administration of TPOMs [27, 28]. Others, including those who analyzed larger patient groups, report a prothrombotic risk associated with this therapy in the a-PL positive subgroup [29–31]. Gonzales et al. found in their retrospective study of 46 patients with thrombocytopenia and various systemic autoimmune disorders, all treated with eltrombopag, that 3 (6.5%) participants suffered from thrombotic events while on treatment. Crucially, 6 out of 46 participants had concurrent APS, and 2 of them (33% of all patients with aPL) were among those with thrombosis [30]. Guitton et al. retrospectively studied 18 patients with thrombocytopenia and SLE treated with romiplostim or eltrombopag; 10 had been diagnosed with concurrent aPL/ APS. 5 patients developed thrombosis; 3 of them (30% of all patients with aPL) had APS [31]. These observations suggest a higher thrombotic risk in the aPL-positive group. Though well established in therapy of ITP, the use of TPOMs in aPL-positive patients requires caution and individual evaluation of thrombotic risk. Minimized dosing of TPOMs, aimed to maintain platelet count around 50000/μL, was suggested to decrease thrombotic risk since the thrombotic events are more frequent at platelet count greater than 100000/μL [22].

Except for severe thrombocytopenia, a decrease in platelet count does not fully protect patients with aPL/APS from thromboembolic events, and antithrombotic

prevention or therapy should be continuing as long as possible. However, bleeding risk has to be considered, and an individualized approach is mandatory. In general, full anticoagulation can be given in the setting of platelet count over 50000/μL, and its stopping should be considered seriously in platelet count below 25000/ μL. The patients with platelets between these values should be treated individually with anticoagulants in reduced doses. Half-dose low molecular weight heparins (LMWHs) represent the usual first-choice treatment [22].
