**4.3 Catastrophic antiphospholipid syndrome**

CAPS represents the most severe and potentially fatal variant of APS. It is characterized by excessive activation of hemostasis, rapid, multiple, and progressive thrombotic events, typically affecting small vessels, resulting in acute multiple organ dysfunction (usually kidneys, lungs, CNS, heart, skin) and TMAs [63]. Fortunately, CAPS is a relatively infrequent complication, affecting approximately 1% of patients with APS [2]. CAPS is the first manifestation of previously unrecognized or newly formed aPL in up to 50% of patients [10]. However, it can be the complication of preexisting and known aPL or APS as well. Its onset is usually - in about 2/3 of cases - related to precipitating factors such as infections, malignancies, trauma, invasive procedures, activation of underlying autoimmune disease, pregnancy complications, certain medications (oral contraceptives), and withdrawal or inadequate antithrombotic therapy. Pathological complement activation plays a critical role in its development [64].

Thromboembolic events and their complications dominate the clinical picture. Bleeding is typically secondary to the initial thromboembolism, although rarely can be among the initial clinical manifestations [65, 66]. The etiology of hemorrhage in CAPS is complex. It involves thrombocytopenia secondary to excessive platelet activation and consumption, consumption of coagulation factors, endothelial damage and dysfunction, thrombocytopenic thrombotic purpura (TTP)-like hemostatic changes, and development of DIC [67, 68]. Thrombocytopenia is a dominant change in CAPS, affecting up to 40% of patients with the complication. Thrombocytopenia, mainly if it manifests as the acute drop in platelet count in patients with aPL/APS and previously normal platelets, can be the first sign of impeding CAPS and precede the full clinical picture of CAPS for several days [11]. TTP-like changes frequently accompany thrombocytopenia [68]. Clinical presentation of hemorrhage is variable, with every organ system being a possible target. Life-threatening hemorrhage, including bleeding in the CNS and GIT, can occur [65, 66]. As mentioned before, DAH and AH are relatively frequent complications of CAPS.

The therapeutic approach is aggressive with several goals: 1) to suppress the immune system and production of aPL; 2) to prevent and treat thromboembolic events; 3) treat the underlying or provoking disorder. The combined immunosuppressive and immunomodulatory therapy (corticosteroids, IVIg, plasma exchange) together with full anticoagulation (preferably with heparin or LMWHs in the acute phase with the transition to warfarin) represents the initial therapeutic step [63]. Cyclophosphamide is the preferred immunosuppression in patients with underlying SLE. Rituximab and eculizumab are novel therapeutic possibilities that seem to be efficient in patients with predominant hematologic or microthromboangiopathic manifestations or resistant to first-line treatment [63, 69, 70]. Despite aggressive treatment and novel agents, the prognosis remains unfavorable in a significant number of cases, with a mortality rate reaching up to 40% [2]. The individual assessment of thrombotic and bleeding risk is an indispensable part of therapeutic management. The continuation of antithrombotic therapy is preferred over its tapering or withdrawal. Its continuation has to be considered even in the presence of hemorrhage.
