Antagonism of the platelet 5HT2 receptor in the presence of thrombolysis

Belcher, Philip R.; Drake-Holland, Angela J.; Noble, Mark I. M.

doi:10.1016/0167-5273(94)90085-x

Cited by 10 publications

(15 citation statements)

References 32 publications

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“…The possibiity that the 5HT 2A antagonist ICI170809 itself has a lytic effect was disproved by experiments in Aberdeen (unpublished). Indeed clearance of thrombus by thrombolytic drugs such as tPA is followed in dogs by reocclusion, which 5HT 2A antagonism prevents [21]. These results are compatible with the intrinsic anti-thrombolytic effect [24].…”

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Insupporting

confidence: 76%

“…Other 5HT 2A receptor antagonists have been available in the past that also showed ef icacy in acute arterial thrombosis, e.g., ketanserin [26] ritanserin [9], LU 49938 [27], MDL11,939, and LY53,857 [21], MDL 28,133A [28], DV-7028 [29], AT-1015 [30,31], APD791 [32][33][34]. The 5HT 2A antagonists presently available are Th001 (Arteclere TM ), a speci ic platelet receptor antagonist and nefazodone [35], an antidepressant now taken off the market with non-platelet effects and an unknown effect on thrombosis.…”

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Inmentioning

confidence: 99%

“…The serotonin theory [8] supposes that this serotonin mediation is essential for thrombotic occlusion of diseased coronary arteries, owing to the fact that such occlusions are abolished by antagonism of the platelet 5HT 2A receptor [9,19] even when the major stimulus of adrenaline is applied [20] and also in the circumstances where thrombolysis has failed to clear a complete thrombotic occlusion [21].…”

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Inmentioning

confidence: 99%

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Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Mi¹

2017

J Hematol Clin Res

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An enquiry into the lack of attention awarded to serotonin antagonism in the treatment of arterial thrombosis revealed that the mode of action of serotonin and its platelet receptor antagonists was an action upon thrombus growth, and not, as with other anti-platelet drugs upon the initiation of thrombosis. This lack of effect could explain why this approach has been considered not to be effective. However under conditions of arterial stenosis in which there is platelet activation by increased shear stress, and during the growth phase of arterial thrombi, serotonin 5HT 2A antagonism has been demonstrated to have great potentcy in dispersing thrombotic obstruction to blood fl ow. This mode of action, the lack of participation of serotonin in haemostasis, and the absence of serotonin in wounds accounts for the proven lack of effect of effect of pure specifi c 5HT 2A antagonists (i.e., not those with other actions) on operative bleeding and skin bleeding times. This lack of effect on haemostasis solves the dosing problem encountered with other anti-thrombotic drugs, with which drug concentration cannot be controlled with single fi xed doses, leading to the association between increased antithrombotic effi cacy and increased bleeding complications. Thus 5HT 2A antagonism appears to be the preferred approach, from the point of view of safety and lack of bleeding risk; this consideration applies particularly to thrombosis therapy in the context of traumatic accidents, surgical operations and invasive procedures such as angioplasty.

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Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Insupporting

confidence: 76%

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Inmentioning

confidence: 99%

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Inmentioning

confidence: 99%

See 1 more Smart Citation

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Mi¹

2017

J Hematol Clin Res

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“…Another example is the effect of fibrates, which have been used with the idea that lowering lipid levels would prevent the progression of CAD. This does indeed occur, but since fibrates also lower levels of fibrinogen the effects (pro-atheromatous of lipids, protective of fibrates) may be mediated through thrombosis, again in line with our hypothesis [45][46][47].…”

Section: Identification Of 'Normals' Suitable For Antithrombotic Propsupporting

confidence: 66%

Modification of Coronary Artery Disease Using Antithrombotic Therapy

Drake-Holland

1995

European Journal of Cardiovascular Prevention & Rehabilitat

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“…The serotonin theory [25] supposes that this serotonin mediation is essential for thrombotic occlusion of diseased coronary arteries, owing to the fact that such occlusions are abolished by antagonism of the platelet 5HT 2A receptor [26,27], even when the major stimulus of adrenaline is applied [28] and also in the circumstances where thrombolysis has failed to clear a complete thrombotic occlusion [29].…”

Section: The Importance Of Platelet Serotonin Positive Feedbackmentioning

confidence: 99%

Commentary: On the Pathophysiology of Coronary Heart Disease

Noble¹

2017

J Med Surg Pathol

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This article highlights some important aspects of the pathophysiology of coronary artery disease, namely:• The distribution of lesions within the arterial tree at sites of low wall shear stress.• The potential role of low flow-mediated arterial dilatation at sites of low wall stress.• Low flow-mediated dilatation leads to low nitric oxide production by the arterial endothelium and consequent reduced protection against lesion formation.• Flow-mediated dilatation is reduced by high lumenal glucose concentration.• The role of the glycocalyx dysfunction in mediating flow-mediated dilatation and consequent reduced NO production by the arterial endothelium and cell adhesion.• Stenoses cause convective acceleration of blood velocity and a consequent increase in platelet shear stress.• Increased platelet shear stress activates platelets with release of serotonin.• Serotonin activates more platelet activation via the 5HT 2A platelet receptor causing a positive feedback and thrombus growth.• Arterial thrombus growth is abolished by 5HT 2A receptor antagonists, the key to improved treatment of the disease.• One 5HT 2A receptor antagonist has been shown in humans to be safe and to cause no excess bleeding from wounds.

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Antagonism of the platelet 5HT2 receptor in the presence of thrombolysis

Cited by 10 publications

References 32 publications

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Modification of Coronary Artery Disease Using Antithrombotic Therapy

Commentary: On the Pathophysiology of Coronary Heart Disease

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