Disturbed Plasmatic Modulation Of Arachidonic Acid (AA) Metabolism In Platelets From Rats With Nephrotic Syndrome: An Early Parameter Of Thrombotic Risk?

The nephrotic syndrome in humans is associated with an increased risk for arterial and venous thrombosis, the pathogenesis of which appears to be very complex. We have developed an experimental model of nephrotic syndrome in rats which follows a single i.v. injection of adriamycin (AIM, 5-10 mg/kg b.w.). Starting from 2 weeks after ADM-injection, rats showed a remarkably increased susceptibility to thrombotic stimuli; indeed, the occlusion time of a polyethylene cannula inserted in the abdominal aorta was 22±15 hours in treated animals versus 62±5 in control animals (n=16, p< 0.001). Concomitantly the rats showed: increased plasma fibrinogen and factor VIII: C activity, shortened APTT, low antithrombin and markedly depressed fibrinolytic activity. Moreover, platelet-rich plasma (PRP) of treated rats produced significantly higher amounts of both malondialdehyde (MDA) (spectrophotometric assay) and thromboxane B2 (RIA) in response to AA. When MDA generation was studied with a kinetic approach, the PRP of nephrotic animals had significantly lower apparent Km for AA in respect to the controls (0.15 ± 0.07 mM AA versus 0.90 ± 0.25 mM AA, p<0.01). Washed platelets from both groups, in contrast, showed similar Km values for AA (0.10 mM ± 0.04 versus 0.12 ± 0.03).MDA generation by washed normal platelets resuspended in plasma was normal if plasma had been collected 1 or 3 days after ADM administration but was already significantly higher with plasma collected 5, 7 or 14 days after treatment. The concomitant mild hypoalbuminemia does not completely account for this plasma abnormality. Thus, in the model, an abnormal plasmatic modulation of platelet AA metabolism could be detected much earlier than the coagulation/fibrinolysis changes and the hypersensitivity to thrombotic stimuli.

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Enhanced Platelet Aggregation And Arachidonic Acid Metabolism Associated To Reduced Sensitivity To Exogenous Prostacyclin In Hypercholesterolemic Subjects

10.1055/s-0038-1653320 ◽

1981 ◽

Author(s):

E Tremoli ◽

P Maderna ◽

S Colli ◽

M Sirtori ◽

C R Sirtori

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Platelet Rich Plasma ◽

Inhibitory Effect ◽

Arachidonic Acid Metabolism ◽

Type Ii ◽

Thrombotic Risk ◽

Cholesterol Levels ◽

Clinical Series ◽

Age And Sex

The platelet sensitivity to aggregating agents and the production of arachidonic acid (AA) metabolites were studied in 97 hypercholesterolemic patients (WHO types IIA and IIB;serum cholesterol levels >250 mg/dl, LDL>170 mg/dl,triglycerides >180 mg/dl). The findings were compared with those of 55 age and sex matched normocholesterolemic subjects.Platelet aggregation was studied in platelet rich plasma (PRP) with ADP, collagen, epinephrine and thrombofax* as aggregating agents. Malondialdehyde (MDA) production was determined according to Smith et al.. Thromboxane B2 (TXB2) was measured in washed platelets stimulated with AA by a specific RIA. The platelet sensitivity to the inhibitory effect of synthetic prostacyclin (PGI2) was also assessed in 40 of the patients and in 20 age and sex matched control subjects, using fixed concentrations of aggregating agents.Platelets from patients required to aggregate significantly lower concentrations of collagen, epinephrine and thrombofax* (p< 0.001) and of ADP ( p<O.05); MDA production by thrombin and collagen and TXB formation were significantly raised (p<0.001) in the patient group. Higher concentrations of PGI2 were required to inhibit the aggregation of platelets in the type II patients.The reported findings confirm in a large clinical series the potential role of platelet hyperreactivity in the thrombotic risk of type II hypercholesterolemia.

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Enhanced Affinity for Arachidonic Acid in Platelet-Rich Plasma from Rats with Adriamycin-Induced Nephrotic Syndrome

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657275 ◽

1982 ◽

Vol 48 (03) ◽

pp. 260-262 ◽

Cited By ~ 8

Author(s):

F Delaini ◽

A Poggi ◽

M B Donati

Keyword(s):

Arachidonic Acid ◽

Nephrotic Syndrome ◽

Platelet Rich Plasma ◽

Platelet Response ◽

Heavy Proteinuria ◽

Washed Platelet ◽

Cyclooxygenase Activity ◽

Stable Product ◽

Kinetics Of ◽

Thrombotic Tendency

SummaryWe have measured the response to arachidonic acid (AA) in platelet-rich plasma (PRP) of rats with Adriamycin-induced nephrotic syndrome. For this purpose we measured the kinetics of generation of malondialdehyde (MDA), a stable product of cyclooxygenase activity, in response to platelet stimulation with different concentrations of the substrate. The apparent Km of platelet cyclo-oxygenase for AA was similar in PRP from control rats and rats treated 1–5 days previously, whereas it was significantly reduced, as compared to controls, in PRP of rats treated 2–5 weeks previously. Such a difference was not observed when washed platelet suspensions were tested instead of PRP. Experiments with crossed platelet/plasma systems indicated that in rats treated from 2–5 weeks, a plasmatic abnormality was indeed responsible for the increased affinity of platelets for AA.It is conceivable that in this nephrotic syndrome model characterized by heavy proteinuria, some plasmatic component would be lost with the urine which is normally modulating the platelet response to AA. The observed increase in platelet affinity for AA could at least partially contribute to the enhanced thrombotic tendency reported in the same experimental model.

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Primary Nephrotic Syndrome in Adults as a Risk Factor for Pulmonary Embolism: An Up-to-Date Review of the Literature

International Journal of Nephrology ◽

10.1155/2014/916760 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Aibek E. Mirrakhimov ◽

Alaa M. Ali ◽

Aram Barbaryan ◽

Suartcha Prueksaritanond ◽

Nasir Hussain

Keyword(s):

Pulmonary Embolism ◽

Nephrotic Syndrome ◽

Membranous Nephropathy ◽

Cell Aggregation ◽

Renal Vein Thrombosis ◽

Patient Counseling ◽

Thrombotic Risk ◽

Vein Thrombosis ◽

Increased Risk ◽

Prophylactic Anticoagulation

Patients with nephrotic syndrome are at an increased risk for thrombotic events; deep venous thrombosis, renal vein thrombosis, and pulmonary embolism are quite common in patients with nephrotic syndrome. It is important to note that nephrotic syndrome secondary to membranous nephropathy may impose a greater thrombotic risk for unclear reasons. Increased platelet activation, enhanced red blood cell aggregation, and an imbalance between procoagulant and anticoagulant factors are thought to underlie the excessive thrombotic risk in patients with nephrotic syndrome. The current scientific literature suggests that patients with low serum albumin levels and membranous nephropathy may benefit from primary prophylactic anticoagulation. A thorough approach which includes accounting for all additional thrombotic risk factors is, therefore, essential. Patient counseling regarding the pros and cons of anticoagulation is of paramount importance. Future prospective randomized studies should address the question regarding the utility of primary thromboprophylaxis in patients with nephrotic syndrome.

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Plasma non-esterified fatty acids contribute to increased coagulability in type-2 diabetes through altered plasma zinc speciation

10.1101/744482 ◽

2019 ◽

Cited By ~ 1

Author(s):

Amélie I. S. Sobczak ◽

Kondwani G. H. Katundu ◽

Fladia A. Phoenix ◽

Siavash Khazaipoul ◽

Ruitao Yu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fatty Acids ◽

Platelet Rich Plasma ◽

Fibrin Clot ◽

Plasma Zinc ◽

Thrombotic Risk ◽

Esterified Fatty Acids ◽

Increased Risk ◽

Zinc Speciation

AbstractZn2+ is an essential regulator of coagulation and its availability in plasma is fine-tuned through buffering by human serum albumin (HSA). Non-esterified fatty acids (NEFAs) transported by HSA reduce its ability to bind/buffer Zn2+. This is important as plasma NEFA levels are elevated in type-2 diabetes mellitus (T2DM) and other diseases with an increased risk of developing thrombotic complications. The presence of 5 mol. eq. of myristate, palmitate, stearate, palmitoleate and palmitelaidate reduced Zn2+ binding to HSA. Addition of myristate and Zn2+ increased thrombin-induced platelet aggregation in platelet-rich plasma and increased fibrin clot density and clot time in a purified protein system. The concentrations of key saturated (myristate, palmitate, stearate) and monounsaturated (oleate, vaccinate) NEFAs positively correlated with clot density in subjects with T2DM (and controls). Collectively, these data strongly support the concept that elevated NEFA levels contribute to an increased thrombotic risk in T2DM through dysregulation of plasma zinc speciation.

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Stimulated Platelet Aggregation, Thromboxane B2 Formation and Platelet Sensitivity to Prostacyclin - A Critical Evaluation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650170 ◽

1981 ◽

Vol 45 (03) ◽

pp. 204-207 ◽

Cited By ~ 42

Author(s):

Wolfgang Siess ◽

Peter Roth ◽

Peter C Weber

Keyword(s):

Arachidonic Acid ◽

Platelet Count ◽

Platelet Aggregation ◽

Reliable Method ◽

Platelet Rich Plasma ◽

Critical Evaluation ◽

Vascular Diseases ◽

Thromboxane B2 ◽

Test Time ◽

Stimulation Of

SummaryPlatelets have been implicated in the development of atherosclerotic and thrombotic vascular diseases. Evaluation of platelet aggregation in relation to endogenously formed compounds which affect platelet function may provide information of clinical and pharmacological relevance. We describe a method in which thromboxane B2 (TXB2) formation was analyzed following stimulation of platelet-rich plasma (PRP) with ADP, 1-epinephrine, collagen, and arachidonic acid. In addition, we determined platelet sensitivity to prostacyclin following ADP- and collagen-induced platelet aggregation. The parameters under study were found to depend on the platelet count in PRP, on the type and dose of the aggregating agent used, and on the test time after blood sampling. By standardization of these variables, a reliable method was established which can be used in clinical and pharmacological trials.

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Testosterone Potentiation of Ionophore and ADP Induced Platelet Aggregation : Relationship to Arachidonic Acid Metabolism

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653405 ◽

1981 ◽

Vol 46 (02) ◽

pp. 538-542 ◽

Cited By ~ 42

Author(s):

R Pilo ◽

D Aharony ◽

A Raz

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Unsaturated Fatty Acids ◽

Human Platelet ◽

Platelet Rich Plasma ◽

Arachidonic Acid Metabolism ◽

Ionophore A23187 ◽

Low Concentrations ◽

Induced Aggregation

SummaryThe role of arachidonic acid oxygenated products in human platelet aggregation induced by the ionophore A23187 was investigated. The ionophore produced an increased release of both saturated and unsaturated fatty acids and a concomitant increased formation of TxA2 and other arachidonate products. TxA2 (and possibly other cyclo oxygenase products) appears to have a significant role in ionophore-induced aggregation only when low concentrations (<1 μM) of the ionophore are employed.Testosterone added to rat or human platelet-rich plasma (PRP) was shown previously to potentiate platelet aggregation induced by ADP, adrenaline, collagen and arachidonic acid (1, 2). We show that testosterone also potentiates ionophore induced aggregation in washed platelets and in PRP. This potentiation was dose and time dependent and resulted from increased lipolysis and concomitant generation of TxA2 and other prostaglandin products. The testosterone potentiating effect was abolished by preincubation of the platelets with indomethacin.

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Platelet Suruival and Function in Rats with Enhanced Thrombotic Tendency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660122 ◽

1985 ◽

Vol 54 (04) ◽

pp. 739-743 ◽

Cited By ~ 2

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.

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Thrombosis in IBD in the Era of JAK Inhibition

Current Drug Targets ◽

10.2174/1389450121666200902164240 ◽

2020 ◽

Vol 22 (1) ◽

pp. 126-136

Author(s):

Virginia Solitano ◽

Gionata Fiorino ◽

Ferdinando D’Amico ◽

Laurent Peyrin-Biroulet ◽

Silvio Danese

Keyword(s):

Small Molecules ◽

Arterial Thrombosis ◽

Protective Role ◽

Jak Inhibitors ◽

Thrombotic Risk ◽

Increased Risk ◽

Bowel Diseases ◽

Thrombotic Complications ◽

Inflammatory Bowel ◽

Inflammatory Effect

: Patients with inflammatory bowel diseases (IBD) have an increased risk of thrombosis. The interaction between inflammation and coagulation has been extensively studied. It is well-known that some drugs can influence the haemostatic system, but several concerns on the association between therapies and increased risk of thrombosis remain open. While biologics seem to have a protective role against thrombosis via their anti-inflammatory effect, some concerns about an increased risk of thrombosis with JAK inhibitors have been raised. We conducted a literature review to assess the association between biologics/small molecules and venous/arterial thrombotic complications. An increased risk of venous and arterial thrombosis was found in patients treated with corticosteroids, whereas anti-TNF were considered protective agents. No thromboembolic adverse event was reported with vedolizumab and ustekinumab. In addition, thromboembolic events rarely occurred in patients with ulcerative colitis (UC) after therapy with tofacitinib. The overall risk of both venous and arterial thrombosis was not increased based on the available evidence. Finally, in the era of JAK inhibitors, treatment should be individualized by evaluating the pre-existing potential thrombotic risk balanced with the intrinsic risk of the medication used.

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Molecular Evaluation of MicroRNA-146 Gene Variability (rs2910164 C> G) and its Association with Increased Susceptibility to Coronary Artery Disease

MicroRNA ◽

10.2174/2211536609666201209151130 ◽

2020 ◽

Vol 09 ◽

Author(s):

Rashid Mir ◽

Imadeldin Elfaki ◽

Chandan k Jha ◽

Jamsheed Javid ◽

Suriya Rehman ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Genetic Factors ◽

Mirna Gene ◽

Amplification Refractory Mutation System ◽

Coronary Artery Diseases ◽

Increased Risk ◽

Inheritance Model ◽

Artery Disease ◽

Increased Susceptibility

Aim: Apart from the modifiable risk factors, genetic factors are believed to also influence the outcome of the coronary artery diseases (CAD). Under the genetic factors, miRNA polymorphisms, namely Hsa-miR-146a-5p (rs2910164) have become an important tool to study the mechanism that underlies the pathogenesis of this disease. Therefore, we investigated the association of miR-146a gene variations with susceptibility of coronary artery diseases. Methodology: This study was conducted on 100 CAD patients and 117 matched healthy individuals. Genotyping of the Hsa-miR-146a-5p C>G gene variation was performed by using amplification refractory mutation system PCR method (ARMS-PCR). Results: The distribution of Hsa-miR-146a-5p rs2910164 C>G genotypes observed between patients and controls was significantly different (P=0.048). Moreover, the frequency of G allele (fG) was found to be significantly higher among patients than in controls (0.36 vs. 0.25). Our findings showed that the Hsa-miR-146a-5p C>G variant was associated with an increased risk of CAD in codominant inheritance model CC vs. CG genotype (OR = 1.84, 95 % CI, 1.02-3.31; p=0.040) and (OR = 3.18, 95 % CI, 1.02-9.9; p=0.045) for CC vs. GG genotype in dominant inheritance model. Whereas the G allele significantly increased the risk of coronary artery disease (OR =1,81, 95 % CI, 1.18-2.78; p=0.006) compared to C allele. Taken together, these results demonstrated that miR-146a/rs2910164 is associated with susceptibility to coronary artery disease, providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusion: Our findings indicated that Hsa-miR-146a-5p rs2910164 GG genotype and G allele are associated with an increased susceptibility to Coronary Artery Disease. A larger sample size can be the key to progress in establishing the genetic co-relation of miRNA gene polymorphisms and cardiovascular diseases.

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MiR-126-3p and MiR-223-3p as Biomarkers for Prediction of Thrombotic Risk in Patients with Acute Myocardial Infarction and Primary Angioplasty

Journal of Personalized Medicine ◽

10.3390/jpm11060508 ◽

2021 ◽

Vol 11 (6) ◽

pp. 508

Author(s):

Milan Hromadka ◽

Zuzana Motovska ◽

Ota Hlinomaz ◽

Petr Kala ◽

Frantisek Tousek ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Predictive Accuracy ◽

Cardiovascular Death ◽

Primary Angioplasty ◽

Bleeding Complications ◽

Clinical Predictors ◽

Thrombotic Risk ◽

Increased Risk ◽

One Year

Aim. This study was designed to evaluate the relationship between microRNAs (miRNAs), miR-126-3p and miR-223-3p, as new biomarkers of platelet activation, and predicting recurrent thrombotic events after acute myocardial infarction (AMI). Methods and Results. The analysis included 598 patients randomized in the PRAGUE-18 study (ticagrelor vs. prasugrel in AMI). The measurements of miRNAs were performed by using a novel miRNA immunoassay method. The association of miRNAs with the occurrence of the ischemic endpoint (EP) (cardiovascular death, nonfatal MI, or stroke) and bleeding were analyzed. The miR-223-3p level was significantly related to an increased risk of occurrence of the ischemic EP within 30 days (odds ratio (OR) = 15.74, 95% confidence interval (CI): 2.07–119.93, p = 0.008) and one year (OR = 3.18, 95% CI: 1.40–7.19, p = 0.006), respectively. The miR-126-3p to miR-223-3p ratio was related to a decreased risk of occurrence of EP within 30 days (OR = 0.14, 95% CI: 0.03–0.61, p = 0.009) and one year (OR = 0.37, 95% CI: 0.17–0.82, p = 0.014), respectively. MiRNAs were identified as independent predictors of EP even after adjustment for confounding clinical predictors. Adding miR-223-3p and miR-126-3p to miR-223-3p ratios as predictors into the model calculating the ischemic risk significantly increased the predictive accuracy for combined ischemic EP within one year more than using only clinical ischemic risk parameters. No associations between miRNAs and bleeding complications were identified. Conclusion. The miR-223-3p and the miR-126-3p are promising independent predictors of thrombotic events and can be used for ischemic risk stratification after AMI.

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