Platelet Activation and Aggregation in Patients with Advanced Adenocarcinoma Undergoing Chemotherapy: Correlation with a Validated Venous Thromboembolism Risk Score

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3445-3445 ◽  
Author(s):  
Arnab Basu ◽  
Rohit Gosain ◽  
Udaya Tantry ◽  
Kenneth Miller ◽  
Paul A Gurbel
Keyword(s):  
Arachidonic Acid ◽  
Risk Factor ◽  
Venous Thromboembolism ◽  
Platelet Aggregation ◽  
Cancer Patients ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Risk Scores ◽  
Platelet Surface ◽  
Thrombotic Risk

Abstract Background: Cancer is known to increase risk of venous thromboembolism (VTE), which is associated with considerable mortality and morbidity. Chemotherapy is an independent risk factor for thrombosis in cancer patients. We examined platelet activation and reactivity based on the Khorana Score, a validated scoring model for VTE risk in patients receiving chemotherapy. Materials and Methods: Patients (n=25) with advanced stage adenocarcinomas (TNM stage III or greater), were enrolled in this study. Patients on antiplatelet therapy or on anticoagulation were excluded. Approximately 10 ml of Citrated blood samples were collected from central access catheters after discarding initial 5 ml to minimize iatrogenic platelet activation. 1μMol, 2μMol, 5μMol of ADP-induced, 2μMol Arachidonic Acid (AA)-induced and 4μMol Collagen-induced platelet aggregation in Platelet Rich plasma (PRP) was assessed with a light transmission aggregometry assay. Maximal aggregation and aggregation velocity were recorded. Concurrent flowcytometry analysis was done to assess the expressions of CD41 (Glycoprotein GpIIb), CD62p (platelet surface p-Selectin), and PAC-1(Activated GP IIb/IIIa). Thromboembolic risk scores (Khorana Scores, KS) were calculated based on a validated scoring system (Khorana AA, et al. Blood. 2008;111:4902-7) as follows: Table 1.Very high risk cancers (pancreatic or gastric)+2 pointsHigh risk cancers (lung, ovarian, or bladder cancer)+1 pointPlatelet count ≥350 x 109/L+1 pointHemoglobin < 10 gm/dL or use of erythropoietin+1 pointLeukocytosis >11 x 109/L+1 pointBMI > 35+1 point Results: Mean values for maximum platelet aggregation were calculated by groups and compared between patient with KS < 3 and KS > = 3 by two sample t-tests. Differences were statistically significant for all concentrations of ADP and collagen, with a positive trend for Arachidonic acid (Table). A significant linear relationship between maximal platelet aggregation and higher KS was observed. However there were no significant differences observed in the expression of platelet surface p-selectin, CD41 or PAC-1 when comparing patients at Khorana scores 0, 3 or more than 3 (not shown). Table 2.Agonist ConcentrationKhorana Score <3Khorana Score >= 3P valueADP 1μMol20.8%28.14%0.02ADP 2μMol38.6%67%0.002ADP 5μMol66.5%79.85%0.006Arachidonic acid 2μMol61.6%73.85%0.12Collagen 4μMol78.6%90.14%0.01 Discussion: The mechanism of cancer-related thromboembolism is not well understood. Chemotherapy is an added risk factor for the development of VTEs. Several new markers such as soluble p-selectin and mean platelet volume have been investigated as adjunct factors to improve predictive ability. Although our study did not find a correlation of some common platelet surface markers for activation with thrombotic risk scores; we find a strong positive correlation of future thrombotic risk derived via Khorana scores with heightened platelet reactivity. Platelet reactivity may mediate a final common pathway for venous thromboembolism in cancer patients and should be validated further as an adjunctive marker in a large scale study. Disclosures No relevant conflicts of interest to declare.

scholarly journals Decreased platelet reactivity in patients with cancer is associated with high risk of venous thromboembolism and poor prognosis

2017 ◽  
Vol 117 (01) ◽  
pp. 90-98 ◽  
Author(s):  
Julia Riedl ◽  
Alexandra Kaider ◽  
Christine Marosi ◽  
Gerald W. Prager ◽  
Beate Eichelberger ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Ex Vivo ◽  
Platelet Reactivity ◽  
Platelet Response ◽  
Platelet Surface ◽  
Risk Of Death

SummaryPlatelets are suggested to play a crucial role in cancer progression and the prothrombotic state of cancer patients. Here, we aimed to examine the activation status of platelets in cancer patients and investigate their association with risk of death and occurrence of venous thromboembolism (VTE) in a prospective observational cohort study. We measured platelet surface P-selectin, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregate (MPA) formation in vivo and platelet response to ex vivo stimulation with agonists of protease-activated receptor (PAR) −1, −4, and GPVI, by whole blood flow cytometry, before beginning of chemotherapy and repeatedly during the first six months thereafter (total number of samples analysed: 230). Endpoints of the study were occurrence of death or VTE during a two-year follow-up, respectively. Of 62 patients (median age [interquartile range, IQR]: 63 [54–70] years, 48 % female), 32 (51.6 %) died and nine (14.5 %) developed VTE. Association with a higher risk of death was found for lower platelet surface expression of P-selectin and activated GPIIb/IIIa in vivo and in response to PAR-1, −4 and GPVI activation, but not for MPA formation. Furthermore, reduced platelet responsiveness to PAR-1 and GPVI agonists was associated with higher risk of VTE (hazard ratio per decile increase of percentage P-selectin positive platelets: 0.73 [0.56–0.92, p=0.007] and 0.77 [0.59–0.98, p=0.034], respectively). In conclusion, cancer patients with a poor prognosis showed decreased platelet reactivity, presumably as a consequence of continuous activation. Our data suggest that decreased platelet reactivity is associated with increased mortality and VTE in cancer.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Platelet activation in cystic fibrosis

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4635-4641 ◽  
Author(s):  
Brian P. O'Sullivan ◽  
Matthew D. Linden ◽  
Andrew L. Frelinger ◽  
Marc R. Barnard ◽  
Michele Spencer-Manzon ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Gene Encoding ◽  
Platelet Surface ◽  
Beneficial Effects ◽  
Plasma Factor

Abstract Cystic fibrosis (CF) is caused by a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). We examined platelet function in CF patients because lung inflammation is part of this disease and platelets contribute to inflammation. CF patients had increased circulating leukocyte-platelet aggregates and increased platelet responsiveness to agonists compared with healthy controls. CF plasma caused activation of normal and CF platelets; however, activation was greater in CF platelets. Furthermore, washed CF platelets also showed increased reactivity to agonists. CF platelet hyperreactivity was incompletely inhibited by prostaglandin E1 (PGE1). As demonstrated by Western blotting and reverse-transcriptase-polymerase chain reaction (RT-PCR), there was neither CFTR nor CFTR-specific mRNA in normal platelets. There were abnormalities in the fatty acid composition of membrane fractions of CF platelets. In summary, CF patients have an increase in circulating activated platelets and platelet reactivity, as determined by monocyte-platelet aggregation, neutrophil-platelet aggregation, and platelet surface P-selectin. This increased platelet activation in CF is the result of both a plasma factor(s) and an intrinsic platelet mechanism via cyclic adenosine monophosphate (cAMP)/adenylate cyclase, but not via platelet CFTR. Our findings may account, at least in part, for the beneficial effects of ibuprofen in CF. (Blood. 2005;105:4635-4641)

A polyphenol-rich diet is associated with decreased platelet aggregation in breast cancer patients

2019 ◽  
Vol 54 (2) ◽  
pp. 81-84
Author(s):  
Agnieszka Sut ◽  
Marcin Różalski ◽  
Jacek Golański ◽  
Maria Pytel ◽  
Marek Zadrożny
Keyword(s):  
Breast Cancer ◽  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Dietary Intake ◽  
Cancer Patients ◽  
Platelet Reactivity ◽  
Breast Cancer Patients ◽  
Plant Polyphenols ◽  
Multiple Electrode Aggregometry ◽  
Polyphenol Intake

It is well documented that plant polyphenols have both anti-cancer and anti-platelet effects. Hence, the aim of this work was to investigate a relationship between dietary intake of polyphenols and platelet aggregation in newly-diagnosed breast cancer patients. The nutritional value of a diet, including dietary intake of plant polyphenols was estimated. Platelet aggregation was induced with arachidonic acid (0.5 mmol/l), collagen (3.2 μg/ml) or ADP (6.4 μmol/l) and measured using multiple electrode aggregometry (Multiplate<sup>®</sup>) in whole blood. It was found that platelet aggregation was significantly higher in the low polyphenol intake group than the high intake group: the respective values (area under the aggregation curve recorded in units; U) were arachidonic acid: 84.8 vs. 65.3, P=0.003; ADP: 76.5 vs. 67.8, P=0.006; collagen 79.5 vs. 64.3, p=0.024 respectively. The study indicates, for the first time, an association between diet rich in polyphenols and reduced platelet reactivity in breast cancer patients.

Platelet 12-Lipoxygenase Is Required for Dense Granule Secretion and Platelet Aggregation: Role of 12-hLO In Platelet Hemostasis and Thrombosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3203-3203
Author(s):  
Patrick Apopa ◽  
Megha Patel ◽  
Olivier Boutaud ◽  
Michael Holinstat
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Dense Granule ◽  
Clot Formation ◽  
Dense Granule Secretion ◽  
Granule Secretion ◽  
12 Lipoxygenase

Abstract Abstract 3203 Platelet activation plays a central role in regulating hemostasis. Uncontrolled activation of circulating platelets can result in the formation of occlusive thrombi and stroke. Following activation, metabolism of arachidonic acid by 12-lipoxygenase (12-hLO) may play a significant role in regulating the degree and stability of platelet reactivity. Using specific inhibitors for 12-hLO which do not interact with other lipoxygenases or enzymes in the COX-1 pathway, we were able for the first time to asses the involvement of 12-hLO in platelet reactivity. In order to assess the role of 12-hLO in platelet activation and thrombosis, dense granule secretion, platelet aggregation, alpha granule secretion, and platelet adhesion and clot formation under flow were measured. Inhibiting 12-hLO results in a complete inhibition of dense granule secretion with only a partial attenuation of alpha granule secretion indicating a novel regulatory scheme for modulating positive autocrine reinforcement of platelet reactivity and clot formation. Addition of the 12-hLO metabolite, 12-HETE (as low as 250 nM), resulted in a significant (25%) increase in PAR1-mediated dense granule secretion compare to agonist alone indicating that 12-HETE may be the crucial metabolite formed by 12-hLO metabolism of arachidonic acid. Importantly, platelet aggregation and adhesion are also significantly attenuated in the absence of 12-hLO. In fact, collagen-mediated platelet aggregation was shifted over 25 fold to the right in the absence of 12-hLO. These studies support the role of 12-hLO in hemostasis and may be a good target for anti-platelet therapy. Disclosures: No relevant conflicts of interest to declare.

Platelet activation induces metalloproteinase-dependent GP VI cleavage to down-regulate platelet reactivity to collagen

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 186-191 ◽  
Author(s):  
Gillian Stephens ◽  
Yibing Yan ◽  
Martine Jandrot-Perrus ◽  
Jean-Luc Villeval ◽  
Kenneth J. Clemetson ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Immune Modulation ◽  
Soluble Fraction ◽  
Platelet Reactivity ◽  
Cleavage Product ◽  
Platelet Surface ◽  
Variable Expression ◽  
Collagen Receptor ◽  
Stimulation Of

Abstract Glycoprotein (GP) VI, the primary collagen receptor on platelets, has been shown to have variable expression, possibly as a consequence of immune modulation. The present study was designed to determine the mechanism by which GP VI clearance occurs. We found that direct activation of GP VI both by a GP VI–specific antibody and by GP VI ligands (collagen and convulxin) reduced binding of biotinylated convulxin to the stimulated platelets. Analysis of immunoblots of platelets and supernatants showed that the stimulated platelets contained less GP VI, while the soluble fraction contained a 57-kDa cleavage product. Stimulation of platelets with PAR-1 agonists (TRAP peptide and thrombin) also caused GP VI cleavage, although the amount of GP VI loss was less than that observed with direct GP VI ligands. The metalloproteinase (MMP) inhibitors GM6001 and TAPI prevented both the clearance of GP VI from the platelet surface and the appearance of the soluble cleavage product. Induction of GP VI cleavage caused specific down-regulation of collagen-induced platelet aggregation, providing a mechanism for the modulation of platelet responsiveness to this important platelet agonist.

scholarly journals Effects of Antiplatelet Treatment with Aspirin (ASA) on Platelet Reactivity in Patients with Essential Thrombocythemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4253-4253
Author(s):  
Marina Marchetti ◽  
Sara Gamba ◽  
Cinzia Giaccherini ◽  
Cristina Verzeroli ◽  
Laura Russo ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Essential Thrombocythemia ◽  
Platelet Reactivity ◽  
Venous Blood ◽  
Myeloproliferative Neoplasm ◽  
Platelet Surface ◽  
Antithrombotic Prophylaxis ◽  
Mutational Status ◽  
Induced Aggregation

Abstract INTRODUCTION: Essential Thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increased rate of thrombotic complications. Antithrombotic prophylaxis with aspirin (ASA), alone or in combination with cytoreduction with hydroxyurea (HU), is widely utilized in ET patients. However, thrombosis occurrence/recurrence in spite of antithrombotic prophylaxis remains a relevant issue. Growing data support the possible contribution to this failure of the inter-individual variability of pharmacological ASA response. AIM: Aim of this study was to characterize, in a group of ET patients receiving 100 mg/d ASA, the platelet reactivity in terms of platelet aggregation and activation properties. MATERIALS AND METHODS: Venous blood samples were obtained from 77 ET patients (26M/51F), and two control groups, i.e., one including 72 non-ET patients receiving chronic ASA prophylaxis, and the other including 111 healthy control subjects (57M/54F). The mutational status of ET was: 35 patients were JAK2V617F⁺, 22 CALR⁺, 3 MPL⁺, and 17 triple negative. Thirty-three ET patients were on ASA+HU, 23 on ASA alone, 5 on HU alone, and 16 were not receiving any of these drugs. Platelet aggregation was assessed in whole blood by the Multiplate® analyzer (Roche). The platelet response to the thrombin receptor activating peptide (TRAP) trigger was the measure of the overall platelet aggregation capacity, while the response to the arachidonic acid (AA) trigger was the measure of ASA effect on platelet aggregation. A normalized AA-induced aggregation (r-AA-agg), defined as AA/TRAP ratio, was calculated for each sample to reflect the individual variation of platelet inhibition by ASA. The platelet activation status was evaluated before and after aggregation by measuring the surface expression of CD62P (P-selectin) by flow cytometry (Accuri™ C6, BD Bioscience). RESULTS: The analysis of subgroups according to treatments shows that AA-induced platelet aggregation in ASA- and ASA+HU-treated ET patients was significantly lower compared to non-ASA ET subjects (p<0.001), and was significantly greater compared to ASA-treated non-ET patients (145±85 AU; p<0.001). The same results were observed with TRAP-induced platelet aggregation. Accordingly, the r-AA-agg. was greater in ET subjects on ASA (=53%) or ASA+HU (=50%) as compared to non-ET ASA-treated individuals (=19%). Furthermore, among ET patients on ASA±HU, those with platelet >450x109/L showed AA-induced aggregation significantly greater than subjects with platelet <450x109/L. The increment of platelet surface CD62P expression after AA stimulation (as a marker of platelet activation) was not influenced by anti-platelet therapy, but was significantly associated with JAK2V617F mutation. CONCLUSIONS: Our data show that in more than 70% of ET patients, in spite of ASA intake, the platelet reactivity remains higher than in non-ET patients receiving the same drug regimen. This phenomenon, together with the so-called "turnover" resistance, i.e. increased platelet turnover associated to short aspirin half-life, may contribute to aspirin failure in ET. Studies are necessary to evaluate the efficacy and safety of a different dose or timing of ASA administration in these patients. Project funded by "AIRC-IG2013" grant Nr. 14505 from the "Italian Association for Cancer Research" (A.I.R.C.). Disclosures Falanga: Pfizer: Speakers Bureau; Aspen: Speakers Bureau; Janssen: Speakers Bureau.

The Effect of the Phospholipase Inhibitor Mepacrine on Platelet Aggregation, the Platelet Release Reaction and Fibrinogen Binding to the Platelet Surface

1981 ◽  
Vol 45 (03) ◽  
pp. 257-262 ◽  
Author(s):  
P D Winocour ◽  
R L Kinlough-Rathbone ◽  
J F Mustard
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Surface ◽  
Release Reaction ◽  
Fibrinogen Binding ◽  
Platelet Release

SummaryWe have examined whether inhibition by mepacrine of freeing of arachidonic acid from platelet phospholipids inhibits platelet aggregation to collagen, thrombin or ADP, and the release reaction induced by thrombin or collagen. Loss of arachidonic acid was monitored by measuring the amount of 14 C freed from platelets prelabelled with 14 C-arachidonic acid. Mepacrine inhibited 14 C loss by more than 80% but did not inhibit thrombin-induced platelet aggregation and had a small effect on release. ADP-induced platelet aggregation did not cause 14 C loss. Mepacrine inhibited ADP-induced platelet aggregation by inhibiting the association of fibrinogen with platelets during aggregation. The effect of mepacrine on fibrinogen binding could be considerably decreased by washing the platelets but the inhibition of 14 C loss persisted. Platelets pretreated with mepacrine and then washed show restoration of aggregation to collagen. Thus, mepacrine has two effects; 1. it inhibits phospholipases, 2. it inhibits fibrinogen binding. Freeing of arachidonic acid is not necessary for platelet aggregation or the release reaction.

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

1985 ◽  
Vol 54 (04) ◽  
pp. 842-848 ◽  
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.

Diabetic Retinopathy And Thromboxane Like Substance

1981 ◽  
Author(s):  
M A Lazzari ◽  
M Gimeno ◽  
N M Sutton ◽  
J R Lopez
Keyword(s):  
Diabetes Mellitus ◽  
Arachidonic Acid ◽  
Diabetic Retinopathy ◽  
Risk Factor ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Thromboxane A2 ◽  
Initial Step ◽  
Platelet Activity

Diabetes Mellitus (DM) is a risk factor in the development of vasculopathies and its complications. It produces also its own microangiopathy. Evidence was reported of increased platelet activity in DM in different assays. Platelets aggregation and the arachidonic cycle could play a key role in the increased tendency to thrombosis. A disorder of ratio TXA2/PGI2, two opposing prostaglandin derivatives, could be the initial step. We intended to evaluate a thromboxane like substance (TLS) produced from platelet rich plasma (PRP) and to compare between normals and diabetic retinopathy (DR) patients. TLS was measured in 16 controls and 16 patients. Assay was done with the aggregating activity developed in PRP (considered TLS) after addition of arachidonic acid (f.c. 2 mM). The supernatant of the PRP (100 μl) was taken 40 sec. after the aggregation started and were added to a normal PRP treated with aspirin (f.c. 40 μl/ml) adjusted to 250.000 - 300.000 pl/μl and the degree of platelet aggregation measured in a Chrono Log Aggregometer. TLS was inactivated after its incubation during 2 min. at 37°C. This finding suggests this activity is due to TXA2.The results obtained (expressed in % of platelet aggregation) were: controls x 16.37% ± 6.28 and DR x 36.00% ± 9.72.The increase detected in the DR group supports previous experimental reports suggesting the role of the thromboxane A2 in vaso occlusive complication of diabetes mellitus.

Pyridoxal phosphate inhibition of platelet function

1980 ◽  
Vol 238 (1) ◽  
pp. H54-H60 ◽  
Author(s):  
E. Kornecki ◽  
H. Feinberg
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Function ◽  
Pyridoxal Phosphate ◽  
Shape Change ◽  
Serotonin Release ◽  
Platelet Surface ◽  
Partial Inhibition ◽  
Induced Aggregation

The effect of pyridoxal phosphate (PLP) on human platelet function in vitro was studied. PLP inhibited adenosine diphosphate (ADP)-induced shape change, aggregation, and the potentiation by ADP of arachidonic acid-induced aggregation. This inhibition could easily be reversed by increasing concentrations of ADP or by removing PLP. The addition of sodium borohydride to PLP-treated platelets produced an irreversible inhibition of ADP aggregation. Thus it is possible that PLP inhibited ADP-induced platelet function by forming a Schiff base with platelet-surface amino groups. PLP also produced a partial inhibition of platelet aggregation to epinephrine, arachidonic acid, A23187, and a dose-dependent inhibition of [14C]serotonin release to epinephrine and arachidonic acid. PLP did not inhibit [14C]serotonin release to A23187, nor did it suppress arachidonic acid-induced malondialdehyde production. The conclusion is drawn that the partial inhibition by PLP of platelet aggregation observed to epinephrine, arachidonic acid, and A23187 resulted from PLP's inhibition of the effect of released ADP.

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