Specific platelet mediators and unstable coronary artery lesions. Experimental evidence and potential clinical implications.

Willerson, James T.; Golino, Paolo; Eidt, John F.; Campbell, William B.; Buja, L. Maximilian

doi:10.1161/01.cir.80.1.198

Cited by 418 publications

(154 citation statements)

References 44 publications

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“…Transient total coronary occlusion at the site of plaque rupture that resolved spontaneously before angiography was postulated. 1,42 This view was supported by 3 lines of indirect evidence only, because arteriography and injection of contrast material could cause thrombus dislodgment, leaving an open artery. 43, 44 The first line of indirect evidence was derived from the acute angiographic studies of De Wood et al 45 The prevalence of total occlusion of the infarct artery decreased from 86% (320 of 368) among patients evaluated within 6 hours to 68% (58 of 85) among those studied 6 to 12 hours after symptom onset (PϽ0.05).…”

Section: Acute Myocardial Infarctionmentioning

confidence: 99%

“…55 Time to reflow was considered the essential factor, with total coronary occlusion times of Ͻ20 minutes causing unstable angina pectoris, 20 minutes to 2 hours causing non-Q-wave infarction, and Ͼ2 hours causing Q-wave infarction. 1,2,37,38,42 These occlusion times were not derived from clinical data but were extrapolated from animal models. 56 The mechanism of total coronary artery occlusion is initially a platelet thrombus in all unstable syndromes, including Q-wave infarction, according to the present prevailing view.…”

Section: Q-wave Versus Non-q-wave Myocardial Infarctionmentioning

confidence: 99%

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Thrombi in Acute Coronary Syndromes

2000

Circulation

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O ver the past 35 years, the view has evolved that the acute coronary syndromes, ie, unstable angina pectoris, myocardial infarction, and sudden death, are caused by plaque rupture and formation of a platelet thrombus. There is at least a transient total or subtotal coronary occlusion in all cases of acute myocardial infarction. Q-wave infarcts are thought to differ from non-Q-wave infarcts by more stable platelet thrombi causing more prolonged and/or severe ischemia, leading to more extensive infarction. The greater platelet stability in transmural infarction is attributed to more severe or extensive plaque rupture. 1-3 Unstable angina and non-Qwave infarction, in the present view, are due to less extensive, less stable platelet thrombi that cause less severe, less extensive ischemia and/or infarction.However, autopsy data and more recent clinical findings require significant refinement of this viewpoint on the basis of the following observations. The occlusive thrombi causing Q-wave myocardial infarction contain more fibrin than the thrombi found in the other acute coronary syndromes that are characterized by more platelets and less fibrin. The higher fibrin content of thrombi causing Q-wave infarction explains their greater stability. Furthermore, this higher fibrin content suggests that the coagulation cascade is activated to a greater degree during Q-wave infarction than during non-Q-wave infarction in which platelets play a more dominant role. This review analyzes our evolving concepts focusing on the growing divergence of the different mechanisms underlying the different acute coronary syndromes and their clinical and therapeutic implications. Morphological Basis for the Current Concept of Acute Coronary SyndromesBy the mid-1930s, acute myocardial infarction was shown to be caused by coronary thrombosis resulting from intimal fissuring, which is often associated with dissecting hemorrhage into the underlying plaque. 4 -7 In the late 1930s, however, intimal fissuring was questioned and subendothelial hemorrhages were ascribed to rupture of capillaries within the plaque. 8,9 The causative role of coronary thrombosis became controversial in 1956 when pathologists first reported a low prevalence of thrombi in fatal infarction. 10 -16 The pendulum began to swing back in the mid-1960s because of improved autopsy techniques. Coronary thrombi were found in Ͼ90% of fatal infarcts, most being occlusive.Plaque hemorrhages, which were usually traceable to an intimal tear within the thrombosed segment, were found in most cases. [17][18][19][20][21] These observations reaffirmed that intimal rupture was the essential mechanism causing both subendothelial hemorrhage and intraluminal thrombosis. 22 Having found that three quarters of occlusive coronary thrombi were composed of layers of different ages, Sinapius 17,21 concluded that these thrombi developed in a protracted, recurring course. The oldest portion of thrombus usually sealed the intimal fissure and was rich in platelets. The finding that mural thrombus forma...

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Section: Acute Myocardial Infarctionmentioning

confidence: 99%

Section: Q-wave Versus Non-q-wave Myocardial Infarctionmentioning

confidence: 99%

Thrombi in Acute Coronary Syndromes

2000

Circulation

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“…Loss of these beneficial vascular effects of estrogen in menopause is, therefore, accompanied by increased systemic vascular sensitivity and platelet aggregation 23, 24. More important, activated platelets may liberate both serotonin and thromboxane A 2 , both of which are potent vasoactive compounds 25, 26…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Responsible for Serotonin Vascular Reactivity Sex Differences in the Internal Mammary Artery

Lamin

Jaghoori

Jakobczak

et al. 2018

JAHA

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BackgroundThe increased adverse cardiac events in women undergoing coronary artery bypass grafting are multifactorial and may include clinical, psychosocial, and biological factors. Potential contributing biological factors could include vascular hyperreactivity of the internal mammary artery (IMA) to endogenous vasoconstrictors in women, resulting in a predilection to myocardial ischemia. This study evaluated sex differences in serotonin and thromboxane A2 dependent vasoconstriction in human isolated IMA, with the mechanistic role of (1) the endothelium, (2) nitric oxide (NO), (3) prostaglandins, and (4) receptor activity investigated for any observed sex difference.Methods and ResultsViable isolated human IMA segments were obtained from 116 patients (44 women [mean age, 66.8±12.2 years] and 72 men [mean age, 66.6±10.4 years]) undergoing coronary artery bypass grafting. Cumulative concentration‐response curves for serotonin and thromboxane A2 mimetic, U46619, were determined and revealed an increased sensitivity to serotonin but not U46619 in women. This sex difference to serotonin was further assessed by the following: (1) endothelial denudation, (2) endothelial NO synthase inhibition and NO quantification using electron paramagnetic resonance, (3) cyclooxygenase inhibition and prostaglandin metabolite quantification using mass spectrometry, and (4) quantification of receptor activity status. The female hyperreactivity to serotonin was (1) abolished by endothelial denudation; (2) unaffected by NO synthase inhibition, with no difference in electron paramagnetic resonance–assessed NO levels; (3) abolished by cyclooxygenase inhibition (quantification of prostaglandins in IMA revealed a trend towards reduced 6‐keto prostaglandin F1α in female IMA; P=0.08); and (4) unrelated to receptor activity.ConclusionsThese data indicate that female IMAs are hyperreactive to serotonin but not U46619, with the former attributable to an endothelium‐dependent cyclooxygenase pathway.

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“…Platelet adhesion to exposed subendothelium surfaces of injured vessels with subsequent activation and the resulting aggregation have been shown to be associated with various pathological conditions, including cardiovascular and cerebrovascular thromboembolic disorders, such as unstable angina, myocardial infarction, transient ischemic attack, stroke, and atherosclerosis. [3][4][5][6][7] The platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) has been identified as the final common pathway for all platelet agonists. 8,9 The binding of adhesive proteins, such as fibrinogen, to GPIIb/IIIa causes platelets to aggregate.…”

mentioning

confidence: 99%

“…4 -6,18 Additionally, a higher incidence of coronary artery reocclusion after successful thrombolytic therapy or percutaneous coronary intervention is a persistent clinical problem despite the use of aspirin and/or heparin. 6,7,19 Thus, prevention of reocclusion with an adjunctive pharmacological agent is is being actively pursued with different compounds, including anticoagulant and antiplatelet agents. Previous reports have described the clinical implications of different intravenous platelet GPIIb/IIIa antagonists, such as c7E3, Integrelin, tirofiban (Aggrastat), and RO44-9883.…”

mentioning

confidence: 99%

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Mousa

Kapil

1999

ATVB

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Abstract-Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP754 (roxifiban), a prodrug of XV459, is a recently discovered, potent antiplatelet agent with high affinity and specificity for platelet GPIIb/IIIa receptors that blocks platelet aggregate formation regardless of the agonist (IC 50 ϭ0.030 to 0.05 mol/L) or anticoagulant used for blood collection. DMP754 rapidly converts to its active free-acid form, XV459, which has a comparable high affinity for both resting and activated platelets (K d ϭ1 to 2 nmol/L) and a relatively slow rate of dissociation from resting platelets. The present study was undertaken to determine intravenous and oral antithrombotic efficacies of DMP754 and XV459 and to compare them with those of other antiplatelet and anticoagulant agents in canine models of arterial thrombosis. In these models, thrombosis was induced either electrolytically (200-A anodal current) in the carotid artery or mechanically by external clamping of the femoral artery along with stenosis, which resulted in either total occlusive thrombus formation or cyclic flow reduction, respectively. DMP754 and XV459 were given either intravenously (0.1 mg/kg bolus) or orally (0.1 to 0.4 mg/kg). Additionally, the antithrombotic efficacies of DMP754, aspirin, heparin, and ticlopidine in the canine carotid artery electrolytic injury model were compared. DMP754 demonstrated oral bioavailability of 20.8% in dogs after administration at different doses and prevented cyclic flow reduction (ED 90 -100 ϭϽ0.1 mg/kg IV or PO). Additionally, both DMP754 and XV459 (0.1 mg/kg IV or 0.3 to 0.4 mg/kg PO) demonstrated maximal antithrombotic efficacy in preventing electrically induced carotid and coronary artery thrombosis and significant antithrombotic efficacy (PϽ0.001) at relatively low doses in different settings of arterial thrombosis in the canine model. DMP754 resulted in a significant reduction in thrombus mass and sustained arterial blood flow with 100% prevention of occlusive and nonocclusive thrombosis. In contrast, administration of aspirin (10 mg/kg PO for 2 days), heparin (10 IU/kg IV bolus followed by 90 IU/kg IV infusion over 3 hours), or ticlopidine (300 mg/kg PO for 3 days) before initiation of arterial thrombosis did not reduce the incidence of electrolytic injury-induced occlusive arterial thrombosis. These studies demonstrated a distinct antithrombotic efficacy of DMP754 as compared with existing strategies and suggest potential intravenous and oral antithrombotic uses of DMP754 in the prevention and treatment of thromboembolic disorders. (Arterioscler Thromb Vasc Biol. 1999;19:2535-2541.)

show abstract

Specific platelet mediators and unstable coronary artery lesions. Experimental evidence and potential clinical implications.

Cited by 418 publications

References 44 publications

Thrombi in Acute Coronary Syndromes

Thrombi in Acute Coronary Syndromes

Mechanisms Responsible for Serotonin Vascular Reactivity Sex Differences in the Internal Mammary Artery

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

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