The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

Study Overview
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Brief Summary
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Severe sepsis still carries a high mortality rate despite advantages in intensive care medicine and antimicrobial therapy. The inflammatory and procoagulant host response to infection are intricately linked and interactions between platelets, leukocytes and the endothelium play a central role in the pathogenesis of septic shock and disseminated intravascular coagulation (DIC). Interestingly, one key player cell in coagulation, i.e. the platelet, has been somewhat neglected as to its position in the pathogenesis of coagulation abnormalities in sepsis. However, thienopyridines, irreversible platelet P2Y12 ADP-receptor antagonists, e.g. prasugrel, could potentially provide beneficial anticoagulatory and antiinflammatory effects: P2Y12 ADP-receptor antagonists reduce TF-induced coagulation activation in various ex vivo and in vitro models. Moreover, various lines of evidence indicate that thienopyridines may block platelet leukocyte interactions and thereby reduce the propagation of the coagulation and inflammation process. LPS-infusion in healthy volunteers provides a standardized model to safely study non overt DIC and to document possible effects of therapeutic and prophylactic interventions. The investigators hypothesize that thienopyridines, irreversible platelet P2Y12 ADP-receptor antagonists, may blunt TF-triggered coagulation activation in humans, which will be studied in a TF-dependent coagulation model in humans.

Official Title
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The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

Conditions
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Healthy Volunteers, Sepsis

Intervention / Treatment
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* Drug: Prasugrel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent obtained before any trial-related activities. Men aged >18 and <41 years Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant Normal laboratory values unless the investigator considers an abnormality to be clinically irrelevant Exclusion Criteria: Known or suspected allergy to trial product or related products (Prasugrel, Clopidogrel, Ticlopidine) Known or suspected hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption Treatment with an investigational drug within three weeks prior to this trial Treatment with a drug (e.g. ketoconazole, omeprazole) that interferes with cytochrome P450, the enzyme responsible for the conversion of prasugrel to its active form, three weeks prior to this trial Participation in an LPS trial within the last 6 weeks Smoking of more than 5 cigarettes per day Hereditary deficiency of protein C or S, or a mutation of FV (Leiden), or any other known abnormality affecting coagulation, fibrinolysis or platelet function History of gastro-duodenal ulcera, cardiovascular disease, vasculitis, diabetes mellitus, or hypertension History of brain tumor or history of neurosurgery Hemorrhagic diathesis, trauma or surgery within last 3 months History of hemorrhagic retinopathy Hematuria or detection of occult blood in stool sample Liver or kidney dysfunction Regular use of medication or abuse of alcohol Use of any medication within one week prior to the first trial day Symptoms of a clinically relevant illness in the 3 weeks before the first trial day Excessive sporting activities Weight >95kg and <60kg

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prasugrel<br> | Drug: Prasugrel<br>* Prasugrel will be given as loading dose (60mg) on the first trial day two hours prior to endotoxin infusion. Prasugrel is an orally administered prodrug that is converted in the liver by CYP to its active metabolite.<br>* Other names: Dose: 60mg loading dose (6 tablets a 10mg) on trial day 1;|
| Placebo Comparator: pills consisting of lactose-starch<br> | Drug: Placebo<br>* A pharmacist not otherwise involved in the trial will encapsulate pills consisting of lactose-starch. Six pills will be administered as placebo 2 hours before LPS administration on trial day 1.<br>* Other names: Dose: Same number of pills as in the prasugrel period (6 tablets on trial day 1); identically encapsulated by a pharmacist not otherwise involved in the trial;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| prothrombin fragments (F1+2) | To explore whether P2Y12 ADP-receptor antagonism can block activation of the coagulation cascade induced by endotoxemia, in particular decrease LPS mediated thrombin formation as measured by prothrombin fragment (F1+2). | -2 to 24 hours after LPS infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| platelet-leukocyte co-aggregation | to explore whether P2Y12 ADP-receptor antagonism decreases platelet -leukocyte co-aggregation | -2 to 24 hours after LPS infusion | 
| tissue factor expression | to investigate the influence of P2Y12 ADP-receptor antagonism on tissue factor expression | -2 to 24 hours after LPS infusion | 
| anti-platelet effects of prasugrel | to explore if low dose endotoxemia interferes with the anti-platelet effects of prasugrel | -2 to 24 hours after LPS infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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human endotoxemia, tissue factor induced coagulation, platelet activation, thienopyridines