**5. Bleeding associated with antithrombotic agents**

Bleeding events, particularly those involving the CNS and GIT, are regarded as potentially serious, but the expected adverse events of antithrombotic therapy. The incidence of major bleeding ranges from 3 to 6 per 100 person-years depending on the anticoagulant. It is high for patients on warfarin in particular [71]. The incidence of bleeding on antiplatelet therapy is generally lower, 3 to 4 per 1000 person-years [72]. The risk increases with the intensity of treatment or concomitant use of several agents. The combination of the anticoagulant with antiplatelet agent increases the risk of bleeding approximately 1.5 to 2-fold in comparison to anticoagulant therapy alone [73].

Since the presence of aPL represents a high-risk thrombophilia, antithrombotics – anticoagulants, antiplatelet agents, or their combination - are administered for a prolonged period, frequently life-long in most aPL-positive patients. The continuous administration of antithrombotic agents is used even in asymptomatic individuals with estimated high prothrombotic risk. Warfarin remains the preferred agent for anticoagulation, with the intent to achieve a higher INR range of 3.0–4.0 in specific clinical situations (recurrent thrombotic events, arterial events) [74].

Based on the current clinical practice and preferred intensity of therapy, aPLpositive patients receiving antithrombotics may seem to have an increased risk of treatment-related bleeding. However, available data show that hemorrhage does not represent the main clinical issue. The mortality rate due to thrombosis and its recurrence remains several times higher than the mortality rate related to bleeding. For example, a review of clinical studies documented 18 deaths related to recurrent thrombosis and only one due to hemorrhage [75]. The analysis of a prospective 10-year follow-up of 1000 patients with APS, performed as a part of the Euro-Phospholipid project, identified 34 deaths attributed to thromboembolism and only 10 to bleeding [76]. Reviews of clinical studies focused on anticoagulant therapy in APS suggest that, if INR on warfarin is within the standard therapeutic range, the major bleeding does not appear to be significantly more frequent in comparison to other patient groups on warfarin and is about 1.5–2.0% per year [77]. If higher INR levels (3.0–4.0) are needed, the risk of bleeding, but predominantly mild, increases significantly, approximately 2 to 2.5 times [77, 78]. As for antiplatelet agents, the rate of bleeding during their prophylactic or therapeutic use appears to be low, and major bleeding is rare [78, 79]. The risk of bleeding increases after invasive procedures, likely due to the use of bridging therapy, the early reintroduction of antithrombotics, and aggressive antithrombotic policies [80, 81]. Then again, thrombotic risk after surgery increases considerably as well despite preventive measures.

Independent predictors of major bleeding include overdose with warfarin (e. g. INR above 4.0), combined antithrombotic therapy, polypharmacy, age over 75 years, history of major bleeding (mostly gastrointestinal), malignancy, uncontrolled arterial hypertension, leukoaraiosis, and patient non-compliance [76–78]. It is critical to evaluate individual bleeding and prothrombotic risk and purposely identify potential risk factors. Caution is especially required when high-intensity anticoagulation or a combination of antithrombotics are indicated.
