Treatment of catastrophic antiphospholipid syndrome with defibrotide, a proposed vascular endothelial cell modulator.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Burcoglu-O'Ral
Arsinur
A
Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA.
Erkan
Doruk
D
Asherson
Ronald
R
D017152:Antibodies, Antiphospholipid / Q000032:analysis*; D016736:Antiphospholipid Syndrome / Q000175:diagnosis* / Q000188:drug therapy*; D002388:Catastrophic Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage*; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome
D017152:Antibodies, Antiphospholipid; D010975:Platelet Aggregation Inhibitors; D011089:Polydeoxyribonucleotides; C036901:defibrotide