the plasma large-volume exchange rct

Conditions: Purpura, Thrombotic Thrombocytopenic; Hemolytic Uremic Syndrome

Summary: thrombotic thrombocytopenia purpura / hemolytic uremic syndrome (ttp/hus) is a rare, life-threatening disorder. ttp/hus causes multiple blood clots to form, which prevents blood from reaching the brain and kidneys. ttp/hus affects 3-5 people per million per year. anyone can develop ttp/hus, but it is most common among 30-40 year olds, and women are twice as likely as men to acquire the condition. ttp/hus sometimes develops as a result of medication use, pregnancy or cancer; however, for the majority of patients (80%) the cause of ttp/hus is unknown. in 1991, researchers discovered that plasma exchange was superior to plasma infusion in treating idiopathic ttp/hus. during plasma exchange the patient's blood plasma is removed and replaced with healthy blood plasma. without plasma exchange, the survival rate for ttp/hus is extremely low, with fewer than 5% of patients surviving. treating ttp/hus with plasma exchange improved the survival rate to 80%. although this represents a dramatic improvement, researchers are still searching for methods to improve survival. no major advances in treating ttp/hus have occurred in the past 20 years. recent research suggests that high-dose plasma exchange may improve the survival of ttp/hus patients. the investigators will conduct a randomized controlled trial to test whether treating ttp/hus patients with high-dose versus standard-dose plasma exchange improves the treatment response. the investigators will recruit 150 patients with ttp/hus from 9 centres across canada over three years. the investigators will evaluate whether high-dose plasma exchange improves the treatment response, survival, and whether it reduces the number and volume of plasma exchange procedures and duration of hospital stay.

background: thrombotic thrombocytopenia purpura / haemolytic uremic syndrome (ttp/hus) is a rare blood disorder with a high mortality rate of \>95% when left untreated. in 1991, researchers discovered that treating ttp/hus with plasma exchange vs. plasma infusion dramatically improved the survival rate, from 60% to 80%.the optimal plasma dose for treating ttp/hus is unknown; however, recent research suggests that high-dose plasma exchange may improve survival in patients with ttp/hus. hypothesis: treatment of ttp/hus with high-dose vs. standard-dose plasma exchange will significantly decrease the composite outcome of 1) treatment failure at day 5 and/or 2) non-response or death at 2 weeks. methods: the investigators will conduct a multi-centre, parallel group randomized controlled trial. the investigators anticipate recruiting 150 eligible patients with idiopathic ttp/hus from 9 centres across canada over 2.25 years. patients will be randomized to receive high-dose plasma exchange (125 ml/kg/day up to 10 l/day plasma volume) or standard-dose plasma exchange (50-75 ml/kg/day; approximately 1-1.5 plasma volume). the primary composite outcome includes treatment failure at day 5 or non-response or death from any cause at 2 weeks. secondary outcomes include the individual components of the primary outcome, non-response or death from any cause at month 1 and month 6, days to remission, duration of hospital stay, number and volume of plasma exchange treatments, and cost minimization. research team: our multi-centre team is part of the canadian apheresis group, which was established in 1980 and currently operates in 30 centres across canada. collectively, the canadian apheresis group treats 150 ttp/hus patients each year. our team includes experienced haematologists, nephrologists, epidemiologists and a biostatistician. the investigators have successfully collaborated on several projects and have an excellent publication record (\>50 publications across more than 15 journals including the new england journal of medicine). timeline and budget: because ttp/hus is a relatively rare disorder (an orphan disease), the investigators will recruit patients over 2.25 years from across canada to achieve a sufficiently large sample size. a cost minimization study will be carried out in conjunction with the rct to provide insight into potential costing. future directions: if the investigators can demonstrate that high-dose plasma exchange significantly improves the primary outcome, the investigators will pursue a multi-national collaboration with american, chinese and european centres to investigate other important outcomes including optimal dosing, cost-effectiveness and survival. implications: this study has the potential to be the first major advancement in treating ttp/hus in twenty years.

Eligibility criteria:
inclusion criteria: 1. age \> 18 year-old 2. first presentation of ttp/hus 3. meet all of the following diagnostic criteria: * platelet count \< 150 x 109 /l * microangiopathic haemolytic anaemia (blood film with presence of red blood cell fragmentation) * ldh \> 1.25 x the upper limits of normal * no alternative diagnosis exclusion criteria: 1. secondary ttp/hus 2. relapsing ttp/hus 3. hypersensitivity to blood product 4. patient has received 2 or more plasma exchange treatment since symptom started over the last 1 week 5. received medication, including cyclosporine, cyclophosphamide, rituximab for treatment of ttp/hus 6. other causes of thrombocytopenia than ttp/hus

Keywords: thrombotic thrombocytopenia purpura hemolytic uremic syndrome plasma exchange improve treatment response ttp/hus