**3. Factor deficiencies associated with aPL**

#### **3.1 Hypoprothrombinemia**

Acquired deficiency of prothrombin, referred to as lupus anticoagulant hypoprothrombinemia syndrome, is the most known and well defined of all coagulation factor deficiencies associated with aPL. Its precise incidence is unclear, but with the order of magnitude of hundreds of reported cases, it appears to be a rare complication [32, 33]. It typically occurs in the child or adolescent female patients with aPL after viral infections or with systemic immune disorders, most commonly SLE [34]. Adults can be affected as well, albeit less frequently [35]. The preexisting systemic immune disease is not obligatory since cases without were identified; other precipitating conditions include tumors such as lymphomas, particularly with the production of pathological immunoglobulins and drug reactions.

Bleeding severity varies from mild mucocutaneous (epistaxis, ecchymosis), which is the most common, to severe and life-threatening, including localizations such as muscles, genitourinary tract, gastrointestinal tract (GIT), and central nervous system (CNS) [32–38]. A substantial number of patients (up to 50%) have no significant bleeding events and can be even asymptomatic [36]. Concomitant presence of thrombotic events, hemorrhagic-thrombotic syndrome, and CAPS were occasionally described [39–41]. The condition is usually self-limiting when associated with viral infections, whereas it can have a lasting duration or relapses in the presence of autoimmune diseases [36]. Despite the possibility of severe bleeding events, the overall prognosis is good in general, with a reported mortality rate of less than 5%.

Laboratory findings include the prolongation of both prothrombin (PT) and activated partial thromboplastin time (aPTT), variably decreased prothrombin activity (about 10–20% on average, although it may be extremely low or unmeasurable) with a proportional decrease of prothrombin antigen. As mentioned above, a deficiency of other coagulation factors might be present. Therefore, their activity should be checked [32]. Positive testing for LA complements the picture. The finding of PT prolongation in an aPL-positive patient should prompt the testing for prothrombin deficiency even if no bleeding is apparent at the time.

The traditional view based on the initial analyses in the 1980s defined the involved antibodies as non-neutralizing, unable to directly inhibit the prothrombin coagulation activity [42]. Cross-reactivity between the aPL and phospholipid epitopes in the prothrombin molecules is a likely explanation. The aPL form prothrombin antigen–antibody complexes, and their subsequent elimination results in the proportional decrease of both prothrombin activity and antigen. If the clearance is extensive enough to lead to a relevant prothrombin decrease with its activity below 20%, bleeding manifestations may occur. However, some researchers provided conflicting evidence with hints on more complex changes of hemostasis. In the recent analysis of a relatively large cohort of 41 patients, Japanese authors did not observe an exact correlation between prothrombin levels, anti-FII antibody quantity, and

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

bleeding phenotype. They also identify different autoantibodies directed against FVIII besides the anti-prothrombin ones in several patients with the disorder [43]. They confirmed combined coagulation factor deficiencies in a small number of the studied cases as well. Based on this observation and a known heterogeneity of the clinical presentation, it is reasonable to conclude that hypoprothrombinemia is not an isolated change in aPL-positive patients, and a complex evaluation of hemostasis is always required.

The therapeutic approach aims at (1) stopping the active bleeding; (2) eradicating antibodies responsible for prothrombin deficiency; (3) preventing further thromboembolic events [35, 37]. The withdrawal of antithrombotic agents, supplementation of blood components (transfusion of packed red blood cells and fresh frozen plasma), activation of coagulation factor production (vitamin K administration), hemostatic agents (styptics, antifibrinolytics) represent the strategies for bleeding cessation [35]. However, all these approaches can in aPL-positive patients, especially in prolonged use, lead to the increased thrombotic risk. Immunosuppression, with corticosteroids as the first-line choice or other agents (azathioprine, rituximab, cyclophosphamide) and procedures (plasma exchange) as alternatives, leads to antibody eradication. Monotherapy with corticosteroids is efficient in most cases. Measurement of prothrombin levels, whether by clotting, chromogenic or immunologic methods, can be used for the treatment monitoring. Since the risk of thrombosis usually remains significantly increased even in the presence of bleeding and bleeding itself does not protect from thromboembolism, the therapies aimed at bleeding cessation has to be counterweighted by antithrombotic therapy. Both bleeding and thromboembolic risks have to be evaluated carefully in all cases.
