Antiphospholipid syndrome and Complement; Mechanisms of action
Antiphospholipid syndrome (APS) is an autoimmune disease of unknown cause that predispose to venous, arterial and small vessels thrombosis. There is no cure for APS and, APS-patients have an increased morbidity and mortality despite adequate treatment. Catastrophic antiphospholipid syndrome (CAPS) is a severe form of APS, a potentially life-threatening condition with a mortality estimated to 50%. The majority of antiphospholipid Abs (aPLs) are directed against phospholipid-binding proteins of which β2-glycoprotein I (β2GPI) is the most common. Complement appears to play a central role in the pathogenesis of APS/CAPS. In CAPS, inhibition of complement using the specific C5 inhibitor eculizumab has successfully been used in a few cases and proven to be lifesaving, underscoring the pivotal pathophysiologic role of complement.
With this study we will establish an in vivo model of catastrophic antiphospholipid syndrome, using piglets, and secondly explore the efficacy of complement inhibition by using a C5-inhibitor. We hypothesise that C5-inhibition attenuates thrombogenicity and dampens haemodynamic alteration induced by the CAPS-insult. The study will improve our understanding of the CAPS-pathophysiology and may contribute to an improved treatment of patients with severe APS and importantly, attenuate the fatal progression of CAPS.
We apply for 40 Norwegian farm piglets of either sex with a start weight of 5 kg, randomized into 2 different groups with 8 animals in each group, 2 negative controls, 15 pilots. There are calculated a 20% exclusion of animals due to illness before start of the experiment (7 piglets).
Piglets have resident macrophages in the lungs and are extremely vulnerable to pulmonary vasoconstriction and develop easily pulmonary hypertension. Thus, extended haemodynamic monitoring included a pulmonary artery catheter will be required. The piglets need to be in a low graded inflammatory condition prior to the challenging of antiphospholipid Abs. A balanced titration of live E. coli or LPS is thus required for induction of the inflammatory state and we anticipate the usage of 10-15 piglets before the model is fully established.
The 3R requirements are accomplished by using our long experience with piglets as a research model, and the fact that this project builds on previous experiments.
The study animals will be anesthetized and remain under anaesthetics until they are euthanized.
With this study we will establish an in vivo model of catastrophic antiphospholipid syndrome, using piglets, and secondly explore the efficacy of complement inhibition by using a C5-inhibitor. We hypothesise that C5-inhibition attenuates thrombogenicity and dampens haemodynamic alteration induced by the CAPS-insult. The study will improve our understanding of the CAPS-pathophysiology and may contribute to an improved treatment of patients with severe APS and importantly, attenuate the fatal progression of CAPS.
We apply for 40 Norwegian farm piglets of either sex with a start weight of 5 kg, randomized into 2 different groups with 8 animals in each group, 2 negative controls, 15 pilots. There are calculated a 20% exclusion of animals due to illness before start of the experiment (7 piglets).
Piglets have resident macrophages in the lungs and are extremely vulnerable to pulmonary vasoconstriction and develop easily pulmonary hypertension. Thus, extended haemodynamic monitoring included a pulmonary artery catheter will be required. The piglets need to be in a low graded inflammatory condition prior to the challenging of antiphospholipid Abs. A balanced titration of live E. coli or LPS is thus required for induction of the inflammatory state and we anticipate the usage of 10-15 piglets before the model is fully established.
The 3R requirements are accomplished by using our long experience with piglets as a research model, and the fact that this project builds on previous experiments.
The study animals will be anesthetized and remain under anaesthetics until they are euthanized.