The Platelet Thrombin Receptor and Postoperative Bleeding

Ferraris, Victor A.; Ferraris, Suellen P.; Singh, Amandeep; Fuhr, Wendy; Koppel, Darren J.; McKenna, Daniel; Rodriguez, Evelio; Reich, Herbert

doi:10.1016/s0003-4975(97)01348-9

Cited by 69 publications

(28 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We found that the platelet PAR-1 receptor is desensitized for at least 24 hours following CPB (Figure 1) whereas the GP Ib receptor is not ( Figure 2) [70,101]. Furthermore, platelet thrombin responsiveness is maintained following CPB even though the PAR-1 responsiveness is decreased [71]. This evidence supports the concept of a second thrombin receptor on human platelets that is responsible for retained platelet responsiveness after CPB.…”

Section: Other Thrombin Receptors and Hemostasissupporting

confidence: 63%

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Ferraris

2011

Int J Angiol

View full text Add to dashboard Cite

Extracorporeal circulation for the purpose of cardiopulmonary bypass (CPB) is used extensively for repair of cardiac defects. Complex mechanisms, many of which involve the generation of thrombin, are initiated by the institution of CPB. Thrombin is generated during CPB in spite of high doses of heparin. The tissue factor/ factor VII pathway is also activated and is probably responsible for generation of most of the thrombin seen during CPB. Plasma proteins (humoral phase) along with platelets, endothelium and white cells (cellular phase) are also activated by contact of blood with synthetic surfaces. Small amounts of thrombin activate endothelial cells which then generate tissue plasminogen activator (t-PA). Plasmin is generated by the action of t-PA and fibrinolysis ensues. The blood becomes a mix of vasoactive substances that alter vascular smooth muscle tone and endothelial cell contraction. The sum of these reactions is called the Ôwhole body inflammatory responseÕ and is responsible for postoperative morbidity including bleeding and organ system dysfunction.Attempts to control the morbidity of CPB have focused on reversible inhibitors of some of the reactions described above. Potentially helpful new strategies may include: 1) enhanced production of thrombin-activatable fibrinolysis inhibitor (TAFI) to limit fibrinolysis, 2) synthesis of thrombin receptor blockers to limit platelet and endothelial activation, 3) protection of endothelial cell receptors during CPB, 4) control of CPB-induced platelet-PMN and endothelial-PMN adhesion in order to limit postoperative organ system dysfunction, and 5) limitation of tissue factor pathway activation in order to minimize thrombin production during CPB. This review highlights recent developments in the understanding of the molecular mechanisms of the action of thrombin induced by CPB.

show abstract

Section: Other Thrombin Receptors and Hemostasissupporting

confidence: 63%

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Ferraris

2011

Int J Angiol

View full text Add to dashboard Cite

show abstract

“…The functional status of PAR1 perioperatively was probed by examination of the formation of TRAP-6 -inducible platelet:leukocyte conjugates in whole blood. 10 This test re- vealed a significant drop in PAR1 function in the saline treatment group, which was most pronounced at 2 hours after bypass ( Figure 1B). Platelets from the aprotinin group, however, were significantly protected compared with saline (PϽ0.001).…”

Section: Aprotinin Inhibits Platelet Par1 Activation During Cabg Surgmentioning

confidence: 69%

“…PAR1 function was analyzed by tricolor flow cytometry in whole blood that measured the formation of thrombin receptor agonist peptide (TRAP)-6 -dependent platelet:leukocyte conjugates. 10 Whole blood was diluted (3:7) in modified Tyrode's buffer, 10 and 100-L aliquots were incubated at room temperature with TRAP-6 (SFLLRN hexapeptide; Bachem Ltd; 20 mol/L) or buffer. After 10 minutes' incubation, samples were fixed with 1% paraformaldehyde and stained with the following monoclonal antibodies: pan-leukocyte marker CD45-FITC, the monocyte marker CD14-ECD, and the platelet marker CD42b-PE (Beckman Coulter).…”

Section: Platelet Par1 Expression and Function Ex Vivomentioning

confidence: 99%

Clinical Inhibition of the Seven-Transmembrane Thrombin Receptor (PAR1) by Intravenous Aprotinin During Cardiothoracic Surgery

et al. 2004

View full text Add to dashboard Cite

Background-Protease-activated receptor-1 (PAR1) is the principal thrombin receptor in the vasculature, and antagonists against this receptor are in preclinical trials. Aprotinin, already approved for clinical use to reduce transfusion requirements in cardiopulmonary bypass (CPB) surgery, has been shown to inhibit PAR1 activation in vitro. Here, we exploit CPB as a model for thrombin generation in humans to examine whether aprotinin can inhibit platelet PAR1 activation clinically. Methods and Results-PAR1 expression and function on platelets was examined in coronary artery bypass grafting (CABG) patients randomized into 2 groups: (1) those receiving saline infusion during CPB (nϭ17) and (2) those receiving aprotinin (2ϫ10 6 kallikrein inhibitor units [KIU] in pump prime, 2ϫ10 6 KIU loading dose, followed by 0.5ϫ10 6 KIU/h [nϭ13]). Platelets in the saline group showed loss of PAR1-specific function at 2 hours after CPB, but this was preserved in the aprotinin group (PϽ0.001). These effects were most likely targeted at PAR1 receptor cleavage, because (1) the level of thrombin generated during CPB did not vary significantly between groups, (2) expression of SPAN12, which detects only uncleaved PAR1 receptors, was preserved in the aprotinin but not the placebo group (PϽ0.05), and (3) supporting evidence in vitro showed reduced thrombin-induced PAR1 cleavage (PϽ0.001) and platelet aggregation (PϽ0.001) in the presence of aprotinin. Conclusions-This study demonstrates that platelet PAR1 activation by thrombin can be inhibited by aprotinin. Our results extend the clinical mechanism of action of aprotinin and provide the first proof of principle that PAR1 can be inhibited clinically. This has implications beyond cardiac surgery for the development of therapeutic PAR1 blockade.

show abstract

“…These receptors were selected because they are representative of the sites involved in platelet activation that are associated with platelet dysfunction and bleeding after cardiac surgery. 27 The monoclonal antibodies used to study specific platelet surface receptors included PAC-1-FITC (for the platelet fibrinogen receptor), CD 14-FITC (for monocytes), CD 45-PerCP (for human leukocytes of any type), WEDE-15 (for total PAR-1 platelet thrombin receptor), SPAN-12 (for noncleaved PAR-1 thrombin receptor), and CD 42b-PE (for platelet von Willebrand receptor).…”

Section: Platelet Surface Receptor Studies: Flow Cytometrymentioning

confidence: 99%

Aspirin and Postoperative Bleeding After Coronary Artery Bypass Grafting

Ferraris

Ferraris²,

Joseph³

et al. 2002

Annals of Surgery

Self Cite

102

View full text Add to dashboard Cite

ObjectiveTo evaluate the relationship between aspirin ingestion and postoperative bleeding complications, and to test the hypothesis that there is a subset of patients who are aspirin hyperresponders with a proclivity toward platelet dysfunction. Summary Background DataDespite numerous retrospective and prospective analyses, it is still controversial as to whether aspirin ingestion before coronary artery bypass grafting (CABG) is associated with significant postoperative bleeding. MethodsBetween January 1995 and December 1999, the records of 2,606 consecutive patients undergoing CABG were reviewed to identify patients with a history of aspirin ingestion up until the time of surgery. Aspirin ingestion was correlated with postoperative blood transfusion using multivariate analysis. In a subset of preoperative aspirin users (n ϭ 40), bleeding times were measured before and after aspirin use. Flow cytometry was performed in another cohort of patients with known heart disease (n ϭ 30) to determine the effect of aspirin on platelet surface receptors. ResultsDuring the 5-year study period, 63% of the CABG patients were identified as aspirin users. Among these, 23.1% required blood transfusions compared with 19% for the nonusers. Non-red blood cell transfusions were more common in aspirin users, as was reexploration for bleeding. Stratification of these results according to the frequency of aspirin use showed that aspirin is an independent multivariate predictor of postoperative blood transfusion only in high-risk patients. In the prospective studies, aspirin treatment resulted in a significant increase in the template bleeding time, an increase in platelet PAR-1 thrombin receptor activity, and a decrease in the binding of platelets to monocytes. ConclusionsThe findings support the hypothesis that aspirin is associated with a greater likelihood of postoperative bleeding. A platelet function testing algorithm that combines preoperative risk factor assessment, template bleeding times, and flow cytometry may allow the identification of aspirin hyperresponders who are at increased risk for bleeding.

show abstract

The Platelet Thrombin Receptor and Postoperative Bleeding

Cited by 69 publications

References 21 publications

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

Clinical Inhibition of the Seven-Transmembrane Thrombin Receptor (PAR1) by Intravenous Aprotinin During Cardiothoracic Surgery

Aspirin and Postoperative Bleeding After Coronary Artery Bypass Grafting

Contact Info

Product

Resources

About