defibrotide and Catastrophic-Illness

Catastrophic antiphospholipid syndrome (CAPS) is a potentially lethal disease that presents with rapidly progressive multiple organ thromboses. Anticoagulation, corticosteroids, intravenous immunoglobulin, and plasma exchange are the most commonly used treatments for CAPS patients. However, the high mortality despite these medications necessitates new treatment strategies. Following a brief review of current diagnostic and management strategies, we discuss the candidate therapies, i.e., hydroxychloroquine, rituximab, eculizumab, sirolimus, and defibrotide, that can be considered in CAPS patients refractory to traditional treatment.

Topics: Antibodies, Monoclonal, Humanized; Antiphospholipid Syndrome; Antirheumatic Agents; Catastrophic Illness; Humans; Hydroxychloroquine; Immunosuppressive Agents; Patient Care Team; Plasma Exchange; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Rituximab; Sirolimus

The catastrophic variant of the antiphospholipid syndrome (APS) is the most severe form of APS with acute multiple organ involvement and small vessel thrombosis. Refractory catastrophic APS may be defined as patients who did not respond to first-line therapies (anticoagulation, glucocorticoids and plasma exchange and/or intravenous immunoglobulins) and died in the acute phase of the episode or patients with recurrent episodes of catastrophic APS. The purpose of this review is to focus on the current management of these refractory patients and some of the potential new therapeutic approaches.

Topics: Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Anticoagulants; Antiphospholipid Syndrome; Catastrophic Illness; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunotherapy; Multiple Organ Failure; Plasma Exchange; Polydeoxyribonucleotides; Recurrence; Rituximab; Thrombosis; Treatment Outcome

To define at the molecular level the vascular endothelial cell (VEC) injury characteristics of catastrophic antiphospholipid syndrome (CAPS) and to report successful therapeutic use of a VEC modulator, defibrotide.. We describe a 55-year-old man with primary APS with an intractable prothrombotic state (CAPS) resistant to combined therapy with heparin, warfarin, aspirin, and dipyridamole. Treatment with defibrotide was conducted in the context of an investigational phase II protocol where the dose was regulated and individualized by disease/patient-specific molecular and clinical markers.. The patient entered complete remission with defibrotide treatment. During treatment, dose dependent pharmacological actions of defibrotide and key stress markers for VEC injury were identified. Evidence of defibrotide's polypharmacology included downregulation of cytokines, notably tumor necrosis factor-alpha, as the earliest effect, cellular differentiation of VEC, possibly with direct regulatory effect over cellular genes, and the reversal of platelet consumption and prothrombotic state. Von Willebrand antigen levels were used as the sole marker to guide therapy.. This case demonstrates effective remission of CAPS with defibrotide treatment. In contrast to theories that CAPS is triggered by ischemic and thrombotic tissue damage, these data present VEC injury as the primary and representative lesion of CAPS. The pathogenesis may involve concurrent impairment of different VEC functions. Achieving remission may require a polypharmacologic approach, represented here by use of defibrotide.

Topics: Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Catastrophic Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelium, Vascular; Follow-Up Studies; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Risk Assessment; Severity of Illness Index; Treatment Outcome