Differential effects of dialysis and ultrafiltrate from individuals with CKD, with or without diabetes, on platelet phosphatidylserine externalization

2008 ◽  
Vol 294 (1) ◽  
pp. F220-F228 ◽  
Author(s):  
Yingjie Wang ◽  
Werner Beck ◽  
Reinhold Deppisch ◽  
Sally M. Marshall ◽  
Nicholas A. Hoenich ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Annexin V ◽  
Uremic Toxins ◽  
Additional Increase ◽  
Phosphatidylserine Externalization ◽  
Increased Risk ◽  
Small Subpopulation ◽  
Protein Kinase Cδ

Individuals with chronic kidney disease (CKD) and/or diabetes mellitus (DM) are at increased risk of cardiovascular events and have elevated externalization of phosphatidylserine (PS; which propagates thrombus formation) in a small subpopulation of platelets. The purpose of this study was to examine the effect of 1) removing uremic toxins by hemodialysis on PS externalization in patients with either CKD or CKD and DM and 2) ultrafiltrate (UF) from these individuals on PS externalization in healthy platelets. PS externalization was quantified by a fluorescence-activated cell sorter using annexin V in platelet-rich plasma. PS externalization was elevated threefold in CKD patients and returned to basal values during 3-h hemodialysis. In contrast, it was elevated fivefold in individuals with CKD and DM and was still threefold above control after 3-h treatment. UF significantly increased PS externalization in a small subpopulation of platelets from healthy controls. The effect of UF from individuals with CKD and DM was significantly greater than that from patients with CKD alone, and the responses were partially inhibited by the protein kinase Cδ (PKCδ) inhibitor rottlerin and the 5-hydroxytryptamine (5-HT)2A/2Creceptor antagonist ritanserin. The data suggest that uremic toxins present in UF mediate PS externalization in a small subpopulation of platelets, at least in part, via the 5-HT2A/2Creceptor and PKCδ and demonstrate that DM further enhances platelet PS externalization in CKD patients undergoing hemodialysis. This may explain, at least in part, the additional increase in vascular damage observed in CKD patients when DM is present.

Is Increased Platelet Aggregation Is a Risk Factor for Cardiovascular Disease in Women With Idiopathic Central Precocious Puberty

2021 ◽  
Author(s):  
Ahmet Bolat ◽  
CENGİZ Zeybek ◽  
ORHAN GÜRSEL ◽  
MEHMET EMRE TAŞÇILAR
Keyword(s):  
Platelet Aggregation ◽  
Precocious Puberty ◽  
Cardiovascular Events ◽  
Platelet Rich Plasma ◽  
Central Precocious Puberty ◽  
Adenosine Diphosphate ◽  
Control Group ◽  
Time Value ◽  
Idiopathic Central Precocious Puberty ◽  
Increased Risk

Abstract BackgroundEarly menarche in girls is associated with an increased risk of cardiovascular events later in life, but the role of platelets in this risk has not been investigated during puberty. Here, we evaluated the effects of idiopathic central precocious puberty (ICPP) on platelet aggregation in platelet-rich plasma samples from female patients. MethodsThe study included 40 girls diagnosed with ICPP between February 2012 and June 2016, and a control group consisting of 30 healthy females. Adenosine diphosphate (ADP) and collagen-induced platelet aggregation were studied with photometric aggregometry. ResultsThere was no difference in the platelet count or volume between girls with ICPP and the control group. In addition, the ADP-induced maximum aggregation time, value, and slope did not significantly differ between the study and control groups (p > 0.05). However, the collagen-induced maximum aggregation time, value, and slope were significantly higher in the study group (p < 0.001). ConclusionsIncreased collagen-induced platelet aggregation was detected in girls with ICPP. Thus, early treatment of ICPP may be important because of the increased risk of cardiovascular events later in life. Extensive studies with more patients are needed to determine the mechanisms of platelet dysfunction in girls with ICPP.

Abstract 19437: Elevated Platelet Turnover in Patients Receiving Dual Antiplatlet Therapy Could Permit the Formation of Uninhibited Platelet Clusters That Act as Seeds for Thrombus Formation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Thomas Hoefer ◽  
Timothy D Warner
Keyword(s):  
Light Transmission ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Imaging Techniques ◽  
Once Daily ◽  
Increased Risk ◽  
Light Transmission Aggregometry ◽  
Platelet Aggregates ◽  
Dynamic Relationships ◽  
Drug Free

Introduction: ACS patients who also have conditions associated with increased platelet turnover, such as diabetes or chronic kidney disease, are at increased risk of atherothrombotic events despite receiving dual-antiplatelet therapy (DAPT). It may well be that aspirin and thienopyridines, such as clopidogrel or prasugrel, prescribed once daily as pharmacologically short-lived but irreversibly acting agents, are less effective in these patients because of the daily emergence of a significant subpopulation of uninhibited platelets. Hypothesis: Here we investigated the potentially crucial roles of subpopulations of uninhibited platelets in overcoming DAPT and driving aggregation. Methods: Aliquots of platelet rich plasma were incubated with aspirin, prasugrel active metabolite (PAM) plus aspirin, or vehicle and platelets were differently labelled with membrane dyes. Aliquots were then combined in various proportions and platelet responses measured in standard light transmission aggregometry. Aggregates formed in response to platelet agonists were then fixed and detailed structural analyses made by advanced imaging techniques, including confocal microscopy and ImageStream flow cytometry, to determine the interactions of different platelet populations. Results: Platelet aggregation responses and images of platelet aggregates demonstrated complex, dynamic relationships between platelet subpopulations. Summary analysis indicated that aggregates containing aspirin-treated (90-60%) and drug-free (10-40%) platelets had random distributions of drug-free platelets in response to ADP or AA. In contrast, aggregates containing DAPT-inhibited (90-60%) platelets and drug-free (10-40%) platelets showed marked clustering of drug-free platelets at aggregate cores surrounded by recruited DAPT-inhibited platelets. Conclusions: We show that a subpopulation of drug-free platelets can provide seeds for the formation of aggregates that then recruit DAPT-inhibited platelets. Such interaction between platelet subpopulations are of direct relevance to ACS patients with underlying conditions associated with elevated platelet turnover and may well provide an explanation for the failure of DAPT with aspirin and thienopyridines.

Advanced glycation end products elicit externalization of phosphatidylserine in a subpopulation of platelets via 5-HT2A/2Creceptors

2007 ◽  
Vol 293 (1) ◽  
pp. C328-C336 ◽  
Author(s):  
Yingjie Wang ◽  
Werner Beck ◽  
Reinhold Deppisch ◽  
Sally M. Marshall ◽  
Nicholas A. Hoenich ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Inflammatory Responses ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Increased Risk ◽  
Glycation End Products ◽  
End Products

Advanced glycation end products (AGE) are substantially elevated in individuals with diabetes and/or chronic kidney disease (CKD). These patients are at greatly increased risk of cardiovascular events. The purpose of this study was to investigate the novel hypothesis that AGE elicit externalization of the platelet membrane phospholipid phosphatidylserine (PS). This contributes to hemostasis through propagation of the coagulation cascade leading to thrombus formation. Platelet-rich plasma (PRP) was prepared by differential centrifugation, and PS externalization was quantified by a fluorescence-activated cell sorter using annexin V-FITC. Human serum albumin (HSA)-AGE was generated by incubating HSA with glucose for 2, 4, or 6 wk, and total HSA-AGE was assessed by fluorescence intensity. The 2-wk HSA-AGE preparation (0–2 mg/ml) stimulated a concentration-dependent increase in PS externalization in a subpopulation of platelets that was threefold at 2 mg/ml. In contrast, the 4- and 6-wk preparations were maximal at 0.5 mg/ml and fivefold in magnitude. These effects mirrored the change in total HSA-AGE content of the preparations. The PS response was maximal at 10 min and inhibited by the PKC-δ inhibitor rottlerin and the serotonin [5-hydroxytryptamine (5-HT)]2A/2Creceptor antagonist ritanserin in a dose-dependent manner. Moreover, the 5-HT2A/2Creceptor agonist 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane mimicked the effect of HSA-AGE on PS externalization. These data demonstrate, for the first time, that HSA-AGE stimulates PS externalization in a subpopulation of platelets via the 5-HT2A/2Creceptor. This may have important consequences for platelet involvement in inflammatory responses and the increased cardiovascular risk observed in individuals with diabetes and/or CKD.

scholarly journals Does Exercise Influence the Susceptibility to Arterial Thrombosis? An Integrative Perspective

2021 ◽  
Vol 12 ◽  
Author(s):  
Line Nørregaard Olsen ◽  
Mads Fischer ◽  
Phillip Adrian Evans ◽  
Lasse Gliemann ◽  
Ylva Hellsten
Keyword(s):  
Arterial Thrombosis ◽  
Cardiovascular Events ◽  
Acute Exercise ◽  
Thrombus Formation ◽  
Physical Exertion ◽  
Epidemiological Studies ◽  
Moderate Intensity ◽  
Moderate Intensity Exercise ◽  
Increased Risk

Arterial thrombosis is the primary cause of death worldwide, with the most important risk factors being smoking, unhealthy diet, and physical inactivity. However, although there are clear indications in the literature of beneficial effects of physical activity in lowering the risk of cardiovascular events, exercise can be considered a double-edged sword in that physical exertion can induce an immediate pro-thrombotic environment. Epidemiological studies show an increased risk of cardiovascular events after acute exercise, a risk, which appear to be particularly apparent in individuals with lifestyle-related disease. Factors that cause the increased susceptibility to arterial thrombosis with exercise are both chemical and mechanical in nature and include circulating catecholamines and vascular shear stress. Exercise intensity plays a marked role on such parameters, and evidence in the literature accordingly points at a greater susceptibility to thrombus formation at high compared to light and moderate intensity exercise. Of importance is, however, that the susceptibility to arterial thrombosis appears to be lower in exercise-conditioned individuals compared to sedentary individuals. There is currently limited data on the role of acute and chronic exercise on the susceptibility to arterial thrombosis, and many studies include incomplete assessments of thrombogenic clotting profile. Thus, further studies on the role of exercise, involving valid biomarkers, are clearly warranted.

scholarly journals Correlation between Inflammation and Fibrinolysis Impairment on Central Obesity: A Study for hsCRP, PAI-1, PAP and TAFI

2011 ◽  
Vol 3 (2) ◽  
pp. 127
Author(s):  
Winni Agustiani ◽  
Mansyur Arif ◽  
Ilhamjaya Patellongi
Keyword(s):  
Cardiovascular Events ◽  
Central Obesity ◽  
Thrombus Formation ◽  
Close Association ◽  
Inflammatory Marker ◽  
Strong Inhibitor ◽  
Cross Sectional ◽  
Increased Risk ◽  
Study Results ◽  
Pai 1

BACKGROUND: Inflammation in the vascular wall plays an important role in the pathogenesis of atherosclerosis. Current studies have shown that increase of systemic inflammatory marker like the acute phase component C-reactive protein (CRP) are associated with an unfavorable progression of disease and an increased risk for acute cardiovascular events. Recently, a close association of Metabolic Syndrome (MetS) with hemostatic abnormalities has been reported. Among hemostatic abnormalities, an increase in plasminogen activator inhibitor (PAI)-1, a strong inhibitor of fibrinolysis, is considered a core feature of MetS. High PAI-1 concentrations may be associated with thrombus formation, also causing cardiovascular events. Therefore, we investigated the association between markers for chronic inflammation (CRP) and the markers of fibrinolytic impairment (PAI-1, PAP, TAFI) in subjects with central obesity.METHODS: This was a cross-sectional study in 80 male Indonesian subjects, aged 30-60 years old with central obesity, conducted from January to March 2008 in Bandung.RESULTS: The study results showed that there was a difference of PAI-1 levels between MetS and Non-MetS group. There were significant correlations between hsCRP and PAI-1 (r=0.252, p=0.024 ), hsCRP and PAP (r=0.253, p=0.024), and also between PAI-1 and PAP (r=-0.239, p=0.033 ) respectively. But, no correlation found between hsCRP and TAFI.CONCLUSIONS: There was correlation between inflammation and fibrinolysis impairment on central obesity. Concentrations oh hsCRP, PAI-1 and TAFI were significantly higher in MetS.KEYWORDS: inflammation, fibrinolysis impairment, hsCRP, PAI-1, PAP, TAFI

Lack of Stability of Aggregates after Thrombin-Induced Reaggregation of Thrombin-Degranulated Platelets

1992 ◽  
Vol 67 (04) ◽  
pp. 453-457 ◽  
Author(s):  
Raelene L Kinlough-Rathbone ◽  
Marian A Packham ◽  
Dennis W Perry ◽  
J Fraser Mustard ◽  
Marco Cattaneo
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Aggregate Stability ◽  
Relative Importance ◽  
Platelet Aggregates ◽  
The Stability ◽  
Von Willebrand ◽  
Induced Aggregation ◽  
Willebrand Factor

SummaryThe stability of platelet aggregates is influenced by the extent of the release of granule contents; if release is extensive and aggregation is prolonged, deaggregation is difficult to achieve. The relative importance of the contributions of released substances to aggregate stability are not known, although stable thrombin-induced aggregates form in platelet-rich plasma from patients with barely detectable plasma or platelet fibrinogen, and ADP stabilizes thrombin-induced aggregates of platelets from patients with delta storage pool deficiency which otherwise deaggregate more readily than normal platelets. We degranulated platelets with thrombin (0.9 U/ml caused greater than 90% loss of delta and alpha granule contents) and recovered them as individual platelets in fresh medium. The degranulated platelets were reaggregated by thrombin (2 U/ml). To prevent continuing effects of thrombin, FPRCH2C1 was added when thrombin-induced aggregation of thrombin-degranulated platelets reached its maximum. EDTA (5 mM) or EGTA (5 mM) added at maximum aggregation did not deaggregate these platelets, indicating that the stability of these aggregates does not depend on Ca2+ in the medium. Whereas with control platelets a combination of PGE1 (10 μM) and chymotrypsin(10 U/ml) was required for deaggregation, with thrombin-degranulated platelets either PGE1 or chymo-trypsin alone caused extensive deaggregation. The rate and extent of deaggregation of thrombin-degranulated platelets by a combination of PGE1 and chymotrypsin was greater than with control platelets.Electron microscope gold immunocytochemistry using antihuman fibrinogen IgG, anti-von Willebrand factor and anti-fibronectin showed a) that fibrinogen in the vacuoles of degranulated platelets was visible at focal points of platelet contact in the aggregates, but that large areas of platelet contact had no fibrinogen detectable between them; and b) in comparison to fibrinogen, little fibronectin or von Willebrand factor (vWf) was detectable in the platelets.Since the linkages between thrombin-degranulated platelets reaggregated by thrombin can be disrupted either by raising cAMP (thus making glycoprotein IIb/IIIa unavailable) or by proteolysis, these linkages are less stable than those formed between normal platelets. It might therefore be expected that platelets that take part in thrombus formation and then recirculate are likely to form less stable thrombi than platelets that have not released their granule contents.

Prolonged Expression of Procoagulant Activity of Human Platelets Degranulated by Thrombin

1995 ◽  
Vol 74 (03) ◽  
pp. 958-961 ◽  
Author(s):  
Raelene L Kinlough-Rathbone ◽  
Dennis W Perry
Keyword(s):  
Catalytic Activity ◽  
Thrombus Formation ◽  
Annexin V ◽  
Human Platelets ◽  
Procoagulant Activity ◽  
Prothrombinase Complex ◽  
Arterial Thrombus ◽  
Flowing Blood

SummaryPlatelets are exposed to thrombin when they take part in arterial thrombus formation, and they may return to the circulation when they are freed by fibrinolysis and dislodged by flowing blood. Thrombin causes the expression of procoagulant activity on platelets, and if this activity persists, the recirculating platelets may contribute to subsequent thrombosis. We have developed techniques to degranulate human platelets by treatment with thrombin, and recover them as single, discrete platelets that aggregate in response to both weak and strong agonists. In the present study we examined the duration of procoagulant activity on the surface of thrombin-degranulated platelets by two methods: a prothrombinase assay, and the binding of 125I-labeled annexin. Control platelets generated 0.9 ± 0.4 U thrombin per 107 platelets in 15 min. Suspensions of thrombin-degranulated platelets formed 5.4 ± 0.1 U thrombin per 107 platelets in this time. Binding of 125I-annexin V was also greater with thrombin-treated platelets than with control platelets (controls: 1.7 ±0.1 ng annexin/107 platelets; thrombin-degranulated platelets: 6.8 ± 0.2 ng annexin/107 platelets). With thrombin-degranulated platelets, increased procoagulant activity and annexin binding persisted for at least 4 h after degranulation and resuspension, indicating that the catalytic activity for the prothrombinase complex is not reversed during this time. These platelets maintained their ability to aggregate for 4 h, even in response to the weak agonist, ADP. Thus, platelets that have taken part in thrombus formation and returned to the circulation may contribute to the promotion of further thrombotic events because of the persistence of procoagulant activity on their surface.

A Comparison of the in Vitro and in Vivo Thrombogenic Activity of Factor IX Concentrates Using Stasis (Wessler) and Non-Stasis Rabbit Models

1980 ◽  
Vol 44 (02) ◽  
pp. 081-086 ◽  
Author(s):  
C V Prowse ◽  
A E Williams
Keyword(s):  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Factor Ix ◽  
Coagulation System ◽  
In Vitro Tests ◽  
Clinical Use ◽  
Low Activity

SummaryThe thrombogenic effects of selected factor IX concentrates were evaluated in two rabbit models; the Wessler stasis model and a novel non-stasis model. Concentrates active in either the NAPTT or TGt50 in vitro tests of potential thrombogenicity, or both, caused thrombus formation in the Wessler technique and activation of the coagulation system in the non-stasis model. A concentrate with low activity in both in vitro tests did not have thrombogenic effects in vivo, at the chosen dose. Results in the non-stasis model suggested that the thrombogenic effects of factor IX concentrates may occur by at least two mechanisms. A concentrate prepared from platelet-rich plasma and a pyrogenic concentrate were also tested and found to have no thrombogenic effect in vivo.These studies justify the use of the NAPTT and TGt50 in vitro tests for the screening of factor IX concentrates prior to clinical use.

Circulating Stem/Progenitor Cells as Prognostic Biomarkers in Macro- and Microvascular Disease: A Narrative Review of Prospective Observational Studies

2018 ◽  
Vol 25 (35) ◽  
pp. 4507-4517 ◽  
Author(s):  
Mauro Rigato ◽  
Gian Paolo Fadini
Keyword(s):  
Cardiovascular Disease ◽  
Progenitor Cells ◽  
Cardiovascular Events ◽  
Observational Studies ◽  
English Language ◽  
Microvascular Disease ◽  
Patient Characteristics ◽  
Diabetic Patients ◽  
Increased Risk ◽  
Cell Phenotypes

Background: Circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) are immature cells involved in vascular repair and related to many aspects of macro and microvascular disease. <p> Objective: We aimed to review studies reporting the prognostic role of CPCs/EPCs measurement on development of cardiovascular disease and microangiopathy. <p> Methods and Results: We reviewed the English language literature for prospective observational studies reporting the future development of cardiovascular disease or microangiopathy in patients having a baseline determination of CPCs/EPCs. We retrieved 34 studied reporting on cardiovascular outcomes and 2 studies reporting on microvascular outcomes. Overall, a reduced baseline level of CPCs/EPCs was associated with a significant increased risk of cardiovascular events, all-cause death, and onset/progression of microangiopathy. The most predictive phenotypes were CD34+ and CD34+CD133+. The main limitation was related to the high heterogeneity among studies in terms of patient characteristics and cell phenotypes. <p> Conclusion: The present review shows that a reduced level of circulating progenitor cells is a risk factor for the development of future cardiovascular events and death. In addition, low CPCs/EPCs levels predict the onset or worsening of microalbuminuria and retinopathy in diabetic patients.

Antithrombotic Therapy in Lower Extremity Artery Disease

2020 ◽  
Vol 18 (3) ◽  
pp. 215-222 ◽  
Author(s):  
Mislav Vrsalovic ◽  
Victor Aboyans
Keyword(s):  
Lower Extremity ◽  
Antiplatelet Therapy ◽  
Antithrombotic Therapy ◽  
Cardiovascular Events ◽  
Cardiovascular Outcomes ◽  
Lower Limbs ◽  
Stent Type ◽  
Increased Risk ◽  
Artery Disease ◽  
Lower Extremity Artery Disease

Lower extremity artery disease (LEAD) is a marker of a more advanced atherosclerotic process often affecting multiple vascular beds beyond the lower limbs, with a consequent increased risk for all-cause and cardiovascular mortality. Antithrombotic therapy is the cornerstone of management of these patients to prevent ischaemic cardiovascular and limb events and death. In patients with symptomatic LEAD, the efficacy of aspirin has been established long ago for the prevention of cardiovascular events. In the current guidelines, clopidogrel may be preferred over aspirin following its incremental ability to prevent cardiovascular events, while ticagrelor is not superior to clopidogrel in reducing cardiovascular outcomes. Dual antiplatelet therapy (DAPT, aspirin with clopidogrel) is currently recommended for at least 1 month after endovascular interventions irrespective of the stent type. Antiplatelet monotherapy is recommended after infra-inguinal bypass surgery, and DAPT may be considered in below-the-knee bypass with a prosthetic graft. In symptomatic LEAD, the addition of anticoagulant (vitamin K antagonists) to antiplatelet therapy increased the risk of major and life-threatening bleeding without benefit regarding cardiovascular outcomes. In a recent trial, low dose of direct oral anticoagulant rivaroxaban plus aspirin showed promising results, not only to reduce death and major cardiovascular events, but also major limb events including amputation. Yet, this option should be considered especially in very high risk patients, after considering also the bleeding risk. Despite all the evidence accumulated since >40 years, many patients with LEAD remain undertreated and deserve close attention and implementation of guidelines advocating the use of antithrombotic therapies, tailored according to their level of risk.

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