The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

The Role of the P2Y12 Receptor in Tissue Factor Induced Coagulation

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.

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