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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Healthy Volunteers
• Intervention / Treatment: Drug: Prasugrel; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Medical University of Vienna, Department of Clinical Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Prasugrel	Drug: Prasugrel; 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.; Other Names: Generic name: Prasugrel; Brand name: Efient; Manufacturer: Eli Lilly; Dose: 60mg loading dose (6 tablets a 10mg) on trial day 1
PLACEBO_COMPARATOR: pills consisting of lactose-starch	Drug: Placebo; 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.; Other Names: Content: Pills consisting of lactose-starch; Manufacturer: AKH Anstaltsapotheke; 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?

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

Collaborators and Investigators

• Sponsor: Medical University of Vienna

Publications and helpful links

General Publications

• Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi: 10.1056/NEJMoa0706482. Epub 2007 Nov 4.
• Jilma B, Blann A, Pernerstorfer T, Stohlawetz P, Eichler HG, Vondrovec B, Amiral J, Richter V, Wagner OF. Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin. Am J Respir Crit Care Med. 1999 Mar;159(3):857-63. doi: 10.1164/ajrccm.159.3.9805087.
• Pernerstorfer T, Hollenstein U, Hansen JB, Stohlawetz P, Eichler HG, Handler S, Speiser W, Jilma B. Lepirudin blunts endotoxin-induced coagulation activation. Blood. 2000 Mar 1;95(5):1729-34.
• Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med. 2000 Feb;28(2):451-7. doi: 10.1097/00003246-200002000-00027.
• Kirschenbaum LA, Aziz M, Astiz ME, Saha DC, Rackow EC. Influence of rheologic changes and platelet-neutrophil interactions on cell filtration in sepsis. Am J Respir Crit Care Med. 2000 May;161(5):1602-7. doi: 10.1164/ajrccm.161.5.9902105.
• Spiel AO, Derhaschnig U, Schwameis M, Bartko J, Siller-Matula JM, Jilma B. Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a randomized controlled trial. Clin Sci (Lond). 2012 Nov;123(10):591-600. doi: 10.1042/CS20120194.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (ACTUAL): October 1, 2010
• Study Completion (ACTUAL): November 1, 2010

Study Registration Dates

• First Submitted: April 6, 2010
• First Submitted That Met QC Criteria: April 6, 2010
• First Posted (ESTIMATE): April 7, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): July 11, 2011
• Last Update Submitted That Met QC Criteria: July 8, 2011
• Last Verified: July 1, 2011

More Information

Terms related to this study

• Keywords: platelet activation; human endotoxemia; tissue factor induced coagulation; thienopyridines
• Additional Relevant MeSH Terms: Platelet Aggregation Inhibitors; Prasugrel Hydrochloride
• Other Study ID Numbers: LPSP2Y12; 2008-001320-32 (EUDRACT_NUMBER)