Abstract W P114: Assessment of Platelet Thrombus Formation in Patients with Carotid Disease Administered Clopidogrel

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Masako Yamazaki ◽  
Tomoko Ohnishi ◽  
Kazuya Hosokawa ◽  
Yoshikazu Okada ◽  
Akitsugu Kawashima ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Platelet Aggregation ◽  
Carotid Stenosis ◽  
Platelet Function ◽  
Thrombus Formation ◽  
The Other ◽  
Flow Conditions ◽  
Carotid Disease ◽  
Platelet Thrombus ◽  
Flow Pressure

Background: Many studies have demonstrated that high residual platelet function in patients administered clopidogrel is associated with cardiovascular events, although, the majority of those studies examined the patients with coronary artery disease. We studied platelet function in patients with ischemic stroke treated by clopidogrel, and compared residual platelet function according to the severity of carotid disease. Methods: We measured platelet aggregation induced by ADP, VerifyNow P2Y12 assay (PRU), phosphorylation of vasodilator-stimulated phosphoprotein (PRI), platelet-leukocyte complex (PLC), and platelet p-selectin expression (PS) in 30 patients with ischemic stroke administered clopidogrel (21 males and 9 females, mean age was 65 years). We also measured platelet thrombus formation under arterial flow conditions using newly developed microchip-based flow chamber system. In this system, platelet thrombus formation was analyzed by measuring flow pressure changes due to occlusion of microchip and was quantified by calculating area under the flow pressure curve (AUC). Each marker was compared between patients with severe carotid stenosis (15 cases) and those with mild to moderate carotid stenosis (15 cases). Results: Platelet function tests such as percentages of platelet aggregation induced by ADP, PRU, PRI, and PS was not significantly different between different severities of carotid stenosis. On the other hand, AUC values and PLC of patients with severe major carotid stenosis were significantly higher than those with mild to moderate stenosis. Conclusions: These results suggested that clopidogrel inhibits platelet aggregation irrespective of the severity of carotid stenosis. On the other hand, platelet thrombus formation under arterial flow conditions and platelet leukocyte interactions were higher in patients with severe carotid stenosis than those with mild to moderate stenosis.

Analysing responses to aspirin and clopidogrel by measuring platelet thrombus formation under arterial flow conditions

2013 ◽  
Vol 109 (01) ◽  
pp. 102-111 ◽  
Author(s):  
Kazuya Hosokawa ◽  
Tomoko Ohnishi ◽  
Hisayo Sameshima ◽  
Naoki Miura ◽  
Takashi Ito ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Antiplatelet Therapy ◽  
Dual Antiplatelet Therapy ◽  
Thrombus Formation ◽  
Healthy Controls ◽  
Vascular Events ◽  
Shear Rates ◽  
Platelet Thrombus ◽  
Flow Pressure ◽  
Induced Aggregation

SummaryHigh residual platelet aggregability and circulating platelet-monocyte aggregates in patients administered aspirin and clopidogrel are associated with ischaemic vascular events. To determine the relevance of these factors with residual thrombogenicity, we measured platelet thrombus formation using a microchip-based flow-chamber system in cardiac patients receiving aspirin and/or clopidogrel, and evaluated its correlation with agonist-inducible platelet aggregation and platelet-monocyte aggregates. Platelet thrombus formation was analysed by measuring flow pressure changes due to the occlusion of micro-capillaries and was quantified by calculating AUC10 (area under the flow pressure curve). The growth and stability of platelet thrombi that formed inside microchips at shear rates of 1000, 1500, and 2000 s-1 were markedly reduced in patients receiving aspirin and/or thienopyridine compared to healthy controls (n=33). AUC10 values of aspirin therapy patients (n=20) were significantly lower and higher than those of healthy controls and dual antiplatelet therapy patients (n=19), respectively, and showed relatively good correlations with collagen-induced platelet aggregation and platelet-monocyte aggregates at 1000 and 1500 s-1 (r s >0.59, p<0.01). In contrast, AUC10 in dual antiplatelet therapy patients was significantly correlated with ADP-induced platelet aggregation at all examined shear rates (r s >0.59, p<0.01), but did not correlate with collagen-induced aggregation. Aspirin monotherapy patients with high residual platelet thrombogenicity also exhibited significant elevations in both collagen-induced platelet aggregation and platelet-monocyte aggregates. Our results, although preliminary, suggest that residual platelet thrombogenicity in aspirin-treated patients is associated with either collagen-induced platelet aggregation or circulating platelet-monocyte aggregates, but it is predominantly dependent on ADP-induced platelet aggregation in patients receiving dual antiplatelet therapy.

scholarly journals Matrix Metalloproteases and PAR Activation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-43-SCI-43
Author(s):  
Athan Kuliopulos
Keyword(s):  
Platelet Aggregation ◽  
G Protein ◽  
Platelet Activation ◽  
Platelet Function ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Matrix Metalloproteases ◽  
Morbidity And Mortality ◽  
Arterial Blood Flow ◽  
Platelet Thrombus

Abstract Abstract SCI-43 Myocardial infarction due to rupture of atherosclerotic plaques is a leading contributor to morbidity and mortality in the United States, Europe, and other industrialized nations. Although pathoanatomic studies of human atherosclerotic lesions suggest that large plaques can cause ischemic symptoms, a key contributing factor to the morbidity and mortality associated with atherosclerosis is excessive platelet thrombus formation on exposed collagen surfaces following acute plaque rupture. Following their initial tethering to subendothelial collagen and matrix proteins, activation of transiently adhered platelets by autocrine mediators is critical for propagation of the platelet thrombus. Reinforcement of the transient adhesive contacts by activating G protein-dependent shape change, granule release, and integrins permits growth of a stable thrombus that is resistant to the high shear stress of arterial blood flow. Drugs that target the secondary autocrine mediators of platelet thrombus formation such as aspirin and thienopyridines have proven to be beneficial; however, many patients taking these drugs still sustain thrombotic events and might benefit from new therapeutics that interfere with matrix-dependent platelet activation. Matrix metalloproteases (MMPs) have recently emerged as important mediators of platelet function and vascular biology. Initially described as matrix remodeling enzymes involved in tissue repair and cancer invasion, a renewed focus has centered on MMPs and the related metalloprotease disintegrins because of their prominence in vascular wall inflammation and thrombotic thrombocytopenic purpura. Endogenous platelet metalloproteases have been shown to damage platelet function by cleaving cell surface receptors and broad-spectrum metalloprotease inhibitors improve post-transfusion recovery of platelet concentrates. Platelets express several metalloproteases including MMP-1, MMP-2, MMP-3, and MMP-14 on their surface but their roles in platelet aggregation are not well understood. It was recently shown that the G protein-coupled receptor, PAR1, is directly cleaved and activated on the surface of cancer cells by fibroblast-derived MMP-1. PAR1 is the major thrombin receptor of human platelets and is an important mediator of platelet aggregation following tissue factor (TF)-dependent generation of thrombin. However, under pathophysiologic conditions of acute plaque rupture, exposed collagen is the most efficient stimulus of the critical early events of platelet recruitment and propagation under arterial flow, which could trigger metalloprotease activation on the platelet surface. We found that exposure of platelets to collagen caused activation of MMP-1, which in turn directly cleaved PAR1 on the surface of platelets. Unexpectedly, MMP-1 cleaved the N-terminal extracellular domain of PAR1 at a distinct site from the thrombin cleavage site. This cleavage event generated a longer tethered peptide ligand, which was an agonist of platelet activation and PAR1 signaling. Blocking the MMP1-PAR1 pathway inhibited collagen-dependent thrombogenesis, arterial thrombosis and clot retraction, suggesting that therapeutics that target this metalloprotease-receptor system could be a new strategy in the treatment of patients with acute coronary syndromes. Disclosures: No relevant conflicts of interest to declare.

Platelet Suruival and Function in Rats with Enhanced Thrombotic Tendency

1985 ◽  
Vol 54 (04) ◽  
pp. 739-743 ◽  
Author(s):  
Federica Delaini ◽  
Elisabetta Dejana ◽  
Ine Reyers ◽  
Elisa Vicenzi ◽  
Germana De Bellis Vitti ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Nephrotic Syndrome ◽  
Platelet Function ◽  
Laboratory Tests ◽  
Thrombus Formation ◽  
The Other ◽  
Mean Survival Time ◽  
The Mean ◽  
And Function ◽  
Thrombotic Tendency

SummaryWe have investigated the relevance of some laboratory tests of platelet function in predicting conditions of thrombotic tendency. For this purpose, we studied platelet survival, platelet aggregation in response to different stimuli, TxB2 and 6-keto-PGFlα production in serum of rats bearing a nephrotic syndrome induced by adriamycin. These animals show a heavy predisposition to the development of both arterial and venous thrombosis. The mean survival time was normal in nephrotic rats in comparison to controls. As to aggregation tests, a lower aggregating response was found in ADR-treated rats using ADP or collagen as stimulating agents. With arachidonic acid (AA) we observed similar aggregating responses at lower A A concentrations, whereas at higher AA concentrations a significantly lower response was found in nephrotic rats, despite their higher TxB2 production. Also TxB2 and 6-keto-PGFlα levels in serum of nephrotic rats were significantly higher than in controls. No consistent differences were found in PGI2-activity generated by vessels of control or nephrotic rats.These data show that platelet function may appear normal or even impaired in rats with a markedly increased thrombotic tendency. On the other hand, the significance of high TxB2 levels in connection with mechanisms leading to thrombus formation remains a controversial issue.

scholarly journals Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model

Blood ◽  
1986 ◽  
Vol 68 (3) ◽  
pp. 783-786 ◽  
Author(s):  
BS Coller ◽  
JD Folts ◽  
LE Scudder ◽  
SR Smith
Keyword(s):  
Monoclonal Antibody ◽  
Animal Model ◽  
Platelet Aggregation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Antithrombotic Effect ◽  
Antithrombotic Agent ◽  
Antithrombotic Effects ◽  
Platelet Thrombus

A murine monoclonal antibody directed at the platelet glycoprotein IIb/IIIa complex, which blocks platelet aggregation ex vivo, was tested for its antithrombotic effects in an established animal model of acute platelet thrombus formation in partially stenosed arteries. Infusion of 0.7 to 0.8 mg/kg of the F(ab')2 fragment of the antibody completely blocked new thrombus formation despite multiple provocations, making it the most potent antithrombotic agent tested in this model.

Abstract 4023: Aspirin “Resistance”: Role of Pre-existent Platelet Reactivity and Correlation Between Tests

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Andrew L Frelinger ◽  
Youfu Li ◽  
Matthew D Linden ◽  
Inge Tarnow ◽  
Marc R Barnard ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Function ◽  
Normal Subjects ◽  
Aspirin Resistance ◽  
The Other ◽  
List Type ◽  
Platelet Function Test ◽  
Function Test

Background: Aspirin “resistance” (i.e. hyporesponsiveness to aspirin in a platelet function test) has been widely reported, but the underlying mechanism is unclear. We examined the role of pre-existent platelet hyperreactivity in aspirin “resistance”. We also determined the correlation between aspirin resistance defined by serum thromboxane (TX) B 2 (the most specific test of aspirin’s effect) and other assays of platelet function. Methods: Platelet function measured before and after aspirin 81 mg daily for 7 days was analyzed by Spearman’s rank correlation. Normal subjects (n=165) were studied because virtually all clinically relevant patients are already taking aspirin. An additional advantage of the use of normal subjects is that the platelet response to stimuli is not influenced (with resultant increased scatter of the data) by an underlying disease, e.g. coronary artery disease, which causes platelet hyperreactivity. Results: The proportion of the post-aspirin platelet function predicted by the pre-aspirin platelet function was 28.3 ± 7.5% (mean ± asymptotic standard error) for serum TXB 2 , 39.3 ± 6.8% for urinary 11-dehydro TXB 2 , 4.4 ± 7.7% for arachidonic acid-induced platelet aggregation, 40.4 ± 7.1% for ADP-induced platelet aggregation, 26.3 ± 9.2% for the VerifyNow Aspirin Assay®, and 45.0 ± 10.9% for the TEG® PlateletMapping ™ System with arachidonic acid. Spearman rank order correlations were highly significant for comparisons between assays when both pre-aspirin and post-aspirin results were included in the analysis. However, residual serum TXB 2 levels post-aspirin treatment were not significantly associated with post-treatment results of any of the other assays. Platelet count correlated with pre-aspirin serum TXB 2 and VerifyNow Aspirin Assay, but not with any post-aspirin platelet function test. Conclusions: Aspirin “resistance” (i.e. hyporesponsiveness to aspirin in a laboratory test) is in part unrelated to aspirin but is the result of underlying platelet hyperreactivity prior to the institution of aspirin therapy. Individuals identified as aspirin “resistant” defined by serum TXB 2 are not the same individuals identified by the other tests.

scholarly journals Doxorubicin contributes to thrombus formation and vascular injury by interfering with platelet function

2020 ◽  
Vol 319 (1) ◽  
pp. H133-H143 ◽  
Author(s):  
Haichen Lv ◽  
Ruopeng Tan ◽  
Jiawei Liao ◽  
Zhujing Hao ◽  
Xiaolei Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Platelet Aggregation ◽  
Vascular Injury ◽  
Platelet Function ◽  
Thrombus Formation ◽  
Platelet Activity ◽  
Vascular Toxicity ◽  
Platelet Functions

Doxorubicin therapy in mice (antitumor dosage) markedly enhanced platelet functions measured as agonist-induced platelet aggregation, degranulation, and adhesion to endothelial cells, actions leading to thrombus formation and thrombosis-independent vascular injury. Clopidogrel treatment ameliorated thrombus formation and vascular toxicity induced by doxorubicin via inhibiting platelet activity.

Absence of Fibrinogen in Afibrinogenemia Results in Large but Loosely Packed Thrombi under Flow Conditions

2001 ◽  
Vol 85 (04) ◽  
pp. 736-742 ◽  
Author(s):  
Ya-Ping Wu ◽  
Martin IJsseldijk ◽  
Jaap Zwaginga ◽  
Jan Sixma ◽  
Philip de Groot ◽  
...  
Keyword(s):  
Morphological Analysis ◽  
Surface Coverage ◽  
Thrombus Formation ◽  
Flow Conditions ◽  
Thrombotic Complications ◽  
Platelet Thrombus ◽  
The Difference ◽  
Adhesive Proteins ◽  
Lamellipodia Formation

SummaryWe studied the role of fibrinogen in platelet thrombus formation under flow on adhesive proteins using afibrinogenemic blood (LMWH anticoagulated) in a perfusion system. Perfusions with afibrinogenemic blood showed strong increased surface coverage and thrombus volume that normalized upon addition of fibrinogen. Similar studies using citrate anticoagulated blood showed that this was due to fibrinogen and not fibrin. Morphological analysis showed that afibrinogenemic thrombi were loosely packed and consisted mainly of dendritic platelets that contacted one another through filopodia. However, in the presence of fibrinogen, platelets formed lamellipodia and spread out on top of one another. Studies with radiolabeled platelets showed similar numbers of platelets in both conditions demonstrating that the difference is one of packing and the larger size is due to absence of lamellipodia formation and spreading. The found increased thrombus size and loosely packed platelets might help to understand thrombotic complications sometimes seen in afibrinogenemia patients.

scholarly journals Biomechanical thrombosis: the dark side of force and dawn of mechano-medicine

2019 ◽  
Vol 5 (2) ◽  
pp. 185-197 ◽  
Author(s):  
Yunfeng Chen ◽  
Lining Arnold Ju
Keyword(s):  
Platelet Aggregation ◽  
Blood Clotting ◽  
Thrombus Formation ◽  
Dark Side ◽  
Atherosclerotic Plaques ◽  
Excessive Bleeding ◽  
Glycoprotein Vi ◽  
Device Implantation ◽  
Platelet Binding ◽  
Platelet Thrombus

Arterial thrombosis is in part contributed by excessive platelet aggregation, which can lead to blood clotting and subsequent heart attack and stroke. Platelets are sensitive to the haemodynamic environment. Rapid haemodynamcis and disturbed blood flow, which occur in vessels with growing thrombi and atherosclerotic plaques or is caused by medical device implantation and intervention, promotes platelet aggregation and thrombus formation. In such situations, conventional antiplatelet drugs often have suboptimal efficacy and a serious side effect of excessive bleeding. Investigating the mechanisms of platelet biomechanical activation provides insights distinct from the classic views of agonist-stimulated platelet thrombus formation. In this work, we review the recent discoveries underlying haemodynamic force-reinforced platelet binding and mechanosensing primarily mediated by three platelet receptors: glycoprotein Ib (GPIb), glycoprotein IIb/IIIa (GPIIb/IIIa) and glycoprotein VI (GPVI), and their implications for development of antithrombotic ‘mechano-medicine’ .

C57BL/6JOlaHsd Mice with Tandem Deletion of the Multimerin 1 and Alpha-Synuclein Genes Have Impaired Platelet Function in Vivo and in Vitro That Can Be Corrected by Multimerin 1

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3926-3926 ◽  
Author(s):  
Subia Tasneem ◽  
Adili Reheman ◽  
Heyu Ni ◽  
Catherine P.M. Hayward
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Knockout Mice ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Alpha Synuclein ◽  
Type I ◽  
Significant Difference

Abstract Studies of mice with genetic deficiencies have provided important insights on the functions of many proteins in thrombosis and hemostasis. Recently, a strain of mice (C57BL/6JOlaHsd, an inbred strain of C57BL/6J) has been identified to have a spontaneous, tandem deletion of the multimerin 1 and α-synuclein genes, which are also adjacent genes on human chromosome 4q22. Multimerin 1 is an adhesive protein found in platelets and endothelial cells while α-synuclein is a protein found in the brain and in blood that is implicated in neurodegenerative diseases and exocytosis. In vitro, multimerin 1 supports platelet adhesion while α-synuclein inhibits α-granule release. We postulated that the loss of multimerin 1 and α-synuclein would alter platelet function and that recombinant human multimerin 1 might correct some of these abnormalities. We compared platelet adhesion, aggregation and thrombus formation in vitro and in vivo in C57BL/6JOlaHsd and C57BL/6 mice. Thrombus formation was studied by using the ferric-chloride injured mesenteric arteriole thrombosis model under intravital microscopy. We found that platelet adhesion, aggregation and thrombus formation in C57BL/6JOlaHsd were significantly impaired in comparison to control, C57BL/6 mice. The number of single platelets, deposited 3–5 minutes after injury, was significantly decreased in C57BL/6JOlaHsd mice (P <0.05, platelets/min: C57BL/6 = 157 ± 15, n=16; C57BL/6JOlaHsd = 77 ± 13, n=17). Moreover, thrombus formation in these mice was significantly delayed. Thrombi in C57BL/6JOlaHsd were unstable and easily dissolved, which resulted in significant delays (P<0.001) in vessel occlusion (mean occlusion times: C57BL/6 = 15.6 ± 1.2 min, n=16; C57BL/6JOlaHsd = 31.9 ± 2.1 min, n=17). We further tested platelet function in these mice by ADP and thrombin induced platelet aggregation using platelet rich plasma and gel-filtered platelets, respectively. Although no significant differences were seen with ADP aggregation, thrombin-induced platelet aggregation was significantly impaired in C57BL/6JOlaHsd mice. Platelet adhesion to type I collagen (evaluated using microcapillary chambers, perfused at 1500 s−1 with whole blood) was also impaired in C57BL/6JOlaHsd mice. However, platelets from C57BL/6JOlaHsd mice showed a normal pattern of agonist-induced release of α-granule P-selectin. Multimerin 1 corrected the in vitro aggregation and adhesion defects of C57BL/6JOlaHsd platelets. Furthermore, the transfusion of multimerin 1 into C57BL/6JOlaHsd mice corrected the impaired platelet deposition and thrombus formation in vivo. No significant difference was found in tail bleeding time between the two groups of mice. As α-synuclein knockout mice have a shortened time to thrombus formation (Circulation2007;116:II_76), the effects of multimerin 1 on impaired platelet function in C57BL/6JOlaHsd mice provide supportive evidence that multimerin 1 contributes to platelet adhesion and thrombus formation at the site of vessel injury. The findings suggest multimerin 1 knockout mice will be useful to explore platelet function. The first two authors and participating laboratories contributed equally to this study.

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