Direct factor IXa inhibition with the RNA-aptamer pegnivacogin reduces platelet reactivity in vitro and residual platelet aggregation in patients with acute coronary syndromes

Background:Residual platelet reactivity is a predictor of poor prognosis in patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention. Thrombin is a major platelet activator and upon initiation of the coagulation cascade, it is subsequently produced downstream of factor IXa, which itself is known to be increased in ACS. Pegnivacogin is a novel RNA-aptamer based factor IXa inhibitor featuring a reversal agent, anivamersen. We hypothesized that pegnivacogin could reduce platelet reactivity.Methods:Whole blood samples from healthy volunteers were incubated in vitro in the presence and absence of pegnivacogin and platelet reactivity was analysed. In addition, platelet aggregometry was performed in blood samples from ACS patients in the RADAR trial featuring the intravenous administration of pegnivacogin as well as reversal by anivamersen.Results:In vitro, pegnivacogin significantly reduced adenosine diphosphate-induced CD62P-expression (100% vs. 89.79±4.04%, p=0.027, n=9) and PAC-1 binding (100% vs. 83.02±4.08%, p=0.010, n=11). Platelet aggregation was reduced (97.71±5.30% vs. 66.53±9.92%, p=0.013, n=10) as evaluated by light transmission aggregometry. In the presence of the RNA-aptamer reversal agent anivamersen, neither CD62P-expression nor platelet aggregation was attenuated. In patients with ACS treated with aspirin and clopidogrel, residual platelet aggregation was significantly reduced 20 min after intravenous bolus of 1 mg/kg pegnivacogin (100% versus 43.21±8.23%, p=0.020).Conclusion:Inhibition of factor IXa by pegnivacogin decreases platelet activation and aggregation in vitro. This effect was negated by anivamersen. In ACS patients, platelet aggregation was significantly reduced after intravenous pegnivacogin. An aptamer-based anticoagulant inhibiting factor IXa therefore might be a promising antithrombotic strategy in ACS patients.

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High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes

Thrombosis and Haemostasis ◽

10.1160/th06-07-0362 ◽

2007 ◽

Vol 97 (02) ◽

pp. 282-287 ◽

Cited By ~ 40

Author(s):

Corinne Frere ◽

Jacques Quilici ◽

Pierre-Emmanuel Morange ◽

Lyassine Nait-Saidi ◽

Christopher Mielot ◽

...

Keyword(s):

Platelet Aggregation ◽

Antiplatelet Therapy ◽

Acute Coronary Syndromes ◽

Troponin I ◽

Dual Antiplatelet Therapy ◽

Platelet Reactivity ◽

Post Treatment ◽

Increased Risk ◽

Coronary Syndromes ◽

St Elevation

SummaryHigh post-treatment platelet reactivity (HPPR= adenosine diphosphate [ADP] 10 µM-induced platelet aggregation > 70%) identifies low responders to dual antiplatelet therapy with increased risk of recurrent cardiovascular (CV) events after stenting for non-ST elevation acute coronary syndromes (NSTEACS). This study was designed to compare the incidence of periprocedural myocardial infarction (MI) after stenting for NSTEACS patients between non-responders to dual antiplatelet therapy defined by HPPR and normo-responders. One hundred ninety NSTE-ACS consecutive patients undergoing coronary stenting were included in this prospective study. They received 250 mg aspirin and a 600 mg loading dose of clopidogrel at least 12 hours (h) before percutaneous coronary intervention (PCI). A single post-treatment blood sample was obtained before PCI to analyze maximal intensity of ADP-induced platelet aggregation, and troponin levels were analyzed before PCI, and 12 and 24 h after PCI. Troponin I was considered elevated if > 0.4 ng/ ml. HPPR was present in 22% of patients (n=42). Periprocedural MI occurred significantly more frequently in patients with HPPR than in the normo-responders (43% vs. 24%, p=0.014). After being correlated with recurrent ischemic events after stenting for NSTE-ACS, the HPPR seems to be also a marker of increased risk of periprocedural MI for NSTE-ACS patients.

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Comparison of Platelet Aggregation Response and Receptor Occupancy of RPR 109891 Administered Intravenously in Patients With Recent Acute Coronary Syndromes (TIMI15A)

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(97)85242-4 ◽

1998 ◽

Vol 31 (2) ◽

pp. 353A ◽

Cited By ~ 3

Author(s):

L Jennings

Keyword(s):

Platelet Aggregation ◽

Acute Coronary Syndromes ◽

Receptor Occupancy ◽

Aggregation Response ◽

Coronary Syndromes

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A Physiologic Regulator of Collagen-Induced Platelet Aggregation: Inhibition by Clq

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650145 ◽

1981 ◽

Vol 45 (02) ◽

pp. 110-115 ◽

Cited By ~ 5

Author(s):

György Csákó ◽

Eva A Suba

Keyword(s):

Platelet Aggregation ◽

Human Platelet ◽

Platelet Reactivity ◽

High Specificity ◽

Turbidimetric Method ◽

Specific Manner ◽

Aggregation Inhibition ◽

Different Tissues

SummaryPlatelet aggregations were studied by a turbidimetric method in citrated human platelet-rich plasmas (PRP) in vitro. Human Clq inhibited the aggregations caused by collagens derived from different tissues and species. Clq was needed by weight in comparable quantities to collagen for neutralizing the aggregating effect. The dependence of the inhibitory reaction on the preincubation of platelets with Clq and the differences in the occurrence of aggregating substances in supernatants of PRP triggered with collagen in the presence or absence of Clq, confirmed that Clq exerts its effect by preventing fixation of collagen to platelets. In addition, the high specificity of the inhibitory action of Clq for collagen-induced platelet aggregation was demonstrated by results obtained for testing a variety of aggregating agents in combination with Clq and/or collagen.Since normal concentrations of Clq in the blood are in the range of inhibitory doses of Clq for collagen-induced platelet aggregations in vitro and upon activation of complement Clq is known to dissociate from Cl, it is proposed that Clq may participate in a highly specific manner in regulating platelet reactivity to collagen in vivo.

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The Effect of Heparin vs. Citrate on the Interaction of Platelets with Vascular Graft Materials

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660145 ◽

1985 ◽

Vol 54 (04) ◽

pp. 842-848 ◽

Cited By ~ 14

Author(s):

Kandice Kottke-Marchant ◽

James M Anderson ◽

Albert Rabinovitch ◽

Richard A Huskey ◽

Roger Herzig

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Vascular Graft ◽

Time Course ◽

Platelet Reactivity ◽

Polymer Surfaces ◽

In Vitro Perfusion ◽

Citrate Anticoagulation ◽

Platelet Release

SummaryHeparin is known to affect platelet function in vitro, but little is known about the effect of heparin on the interaction of platelets with polymer surfaces in general, and vascular graft materials in particular. For this reason, the effect of heparin vs. citrate anticoagulation on the interaction of platelets with the vascular graft materials expanded polytetrafluoroethylene (ePTFE), Dacron Bionit (DB) and preclotted Dacron Bionit (DB/PC) was studied in a recirculating, in vitro perfusion system. Platelet activation, as shown by a decrease in platelet count, an increase in platelet release and a decrease in platelet aggregation, was observed for all vascular graft materials tested using heparin and was greater for Dacron and preclotted Dacron than for ePTFE. Significant differences between heparin and citrate anticoagulation were seen for platelet release, platelet aggregation and the relative ranking of material platelet-reactivity. However, the trends and time course of platelet activation were similar with both heparin and citrate for the materials tested.

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Effects of Ticlopidine of Platelet Function in Men with Stable Angina Pectoris

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660138 ◽

1985 ◽

Vol 54 (04) ◽

pp. 808-812 ◽

Cited By ~ 7

Author(s):

Ulf Berglund ◽

Henning von Schenck ◽

Lars Wallentin

Keyword(s):

Platelet Aggregation ◽

Angina Pectoris ◽

Platelet Function ◽

Plasma Levels ◽

Platelet Reactivity ◽

Inhibitory Effect ◽

Controlled Study ◽

Double Blind ◽

Platelet Factor

SummaryThe effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP- and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.

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Interactions Between Blood Platelets and Vascular Endothelium in vitro Studies

10.1055/s-0039-1684685 ◽

1979 ◽

Author(s):

M.A. Gimbrone ◽

K.D. Curwen ◽

R. I. Handin

Keyword(s):

Platelet Aggregation ◽

Vascular Endothelium ◽

Potent Inhibitor ◽

Platelet Reactivity ◽

Blood Platelets ◽

Primary Cultures ◽

Adenosine Diphosphate ◽

Human Platelets ◽

Platelet Adherence

Endothelial cells (EC) can actively influence the hemostatic response at sites of vascular injury through multiple mechanisms. For example, EC can degrade adenosine diphosphate, release plasminogen activator, and synthesize prostacyclin (PGI2), a potent inhibitor of platelet aggregation. We have examined whether PGI2 also might account for the normal lack of platelet adherence to the uninjured EC surface. In a monolayer adherence assay, radiolabeled human platelets in citrated plasma showed minimal interaction with primary cultures of human EC (<1 platelet adhering per cell). Platelets from aspirin-treated and untreated donors behaved similarly. However, aspirin pretreatment of EC consistently resulted in ~2-fold increases in platelet adherence which could be completely abolished by exogenous PGI2 (0.5–1.0 μg/ml). SV40-transformed human EC (SVHEC), which are deficient in PGI2 production compared to primary EC, showed 10-30 times more platelet adherence. Exogenous PGI2 produced a dose - related (.001-1.0 μg/ml) decrease in platelet adherence to SVHEC but did not result in the basal levels observed with normal EC monolayers. These data suggest that : 1) In addition to its effects on platelet aggregation, PGI2 can influence platelet endothelial cell interactions; 2) The increased platelet reactivity of transformed EC is associated with, but not completely attributable, to decreased PGI2 production; and 3) Factors other than PGI2 may play a role in the thromboresistance of normal vascular endothelium.

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Open Multicentre Study of the P 2T Receptor Antagonist AR-C69931MX Assessing Safety, Tolerability and Activity in Patients with Acute Coronary Syndromes

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615596 ◽

2001 ◽

Vol 85 (03) ◽

pp. 401-407 ◽

Cited By ~ 143

Author(s):

Keith Oldroyd ◽

Robert Wilcox ◽

Robert Storey ◽

Keyword(s):

Platelet Aggregation ◽

Receptor Antagonist ◽

Acute Coronary Syndromes ◽

Plasma Concentrations ◽

Antithrombotic Agent ◽

Serious Adverse Events ◽

Central Process ◽

Impedance Aggregometry ◽

Safety Parameters ◽

Coronary Syndromes

SummaryPlatelet aggregation is the central process in the pathophysiology of acute coronary syndromes. ADP contributes to thrombosis by activating platelets, and AR-C69931MX is a specific antagonist of this process acting at the P 2T receptor. At 5 hospitals, 39 patients with unstable angina or non-Q wave myocardial infarction, who were receiving aspirin and heparin, were administered intravenous AR-C69931MX with stepped dose increments over 3 h to a plateau of either 2 μg/kg/min for 21 h (Part 1; n = 12) or up to 69 h (Part 2; n = 13) or 4 μg/kg/min for up to 69 h (Part 3: n = 14). Safety parameters, platelet aggregation (PA) induced by ADP 3 μmol/L (impedance aggregometry), bleeding time (BT) and plasma concentrations of AR-C69931XX were assessed. AR-C69931MX was well tolerated. 33 patients completed the study. There were no deaths at 30 days and no serious adverse events attributed to AR-C69931MX. Trivial bleeding (56%) was common. At 24 h, mean inhibition of PA was 96.0 ± 8.6, 94.9 ± 14.4 and 98.7 ± 2.1% and BT was 9.5 ± 8.4, 14.0 ± 9.7 and 16.0 ± 11.1 min for Parts 1, 2 and 3 respectively. At 1 h post-infusion, mean inhibition of PA was 36.2 ± 39.2, 20.7 ± 25.9 and 40.7 ± 36.7% respectively. 90% patients had a plasma half-life for AR-C69931XX of 9 min. In conclusion, AR-C69931MX is a potent, short-acting platelet ADP receptor antagonist suitable for further studies as an antithrombotic agent.

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