md_a
Member
- Joined
- Aug 31, 2015
- Messages
- 468
An important reason to avoid PUFA is to prevent thrombotic complications related to covid-19.
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COVID-19 concerns aggregate around platelets
In this issue of Blood, articles by Manne et al and Hottz et al highlight platelet hyperactivity in COVID-19–associated pathophysiology.1, 2 Although the hallmarks of COVID-19 include a brisk inflammatory response and respiratory symptoms, the hematologic manifestations of this infection have also garnered attention, with thrombotic complications taking center stage.3, 4 COVID-19–associated coagulopathy has been characterized by an elevated D-dimer, mild thrombocytopenia, and a prolongation of the activated partial thromboplastin time.5 Alongside these laboratory abnormalities, patients present with increased rates of thrombosis.6 The role of platelets in the thrombotic complications of COVID-19 is explored in these 2 articles, establishing that platelet hyperactivity contributes to the coagulopathy seen in COVID-19.
COVID-19 concerns aggregate around platelets
.....
In addition to platelets and extracellular vesicles, activation of the coagulation cascade plays an important role in thrombosis [21]. Broadly divided into two converging pathways, activation of the extrinsic pathway by tissue factor and/or contact activation of the intrinsic pathway, coagulation cascade leads to activation of factor X, a constituent of the prothrombinase complex, resulting in thrombin generation. Thrombin cleaves soluble fibrinogen to insoluble fibrin, which forms interweaving strands, further stabilized by factor XIII. There is interplay between the coagulation cascade and platelets. Not only can thrombin activate platelets through PAR1 and PAR4, but also conversely platelets themselves can catalyze thrombin generation via membrane scramblase activity [22].
Although there is considerable overlap between platelet- and coagulation-mediated effects, the prominent mechanism of initiation varies by setting. Platelet activation is typically most prominent, whereas, [23] whereas in the venous circulation activation of the coagulation cascade predominates [24].
Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis, and Treatment
.........
Valsartan Decreases Platelet Activity and Arterial Thrombotic Events in Elderly Patients with Hypertension
Background:
Angiotensin type 1 receptor (AT1R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT1R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.
Introduction
A large body of evidence has demonstrated that activation of renin-angiotensin system (RAS) plays a key role in the development and progression of hypertension and cardiovascular disease.[1] Angiotensin II (Ang II), the major effector of RAS,[2] exerts its biological effects mainly through specific receptors, namely angiotensin type 1 receptor (AT1R) and type 2 receptor.[3] Since AT1R antagonists have been shown to improve endothelial function and vascular remodeling in addition to their predominant vasodilatation effects,[4,5] these agents are extensively used for blood pressure control in elderly patients with hypertension.[6]
Activation of platelets bears the brunt of complicate cascades of thrombogenesis. Among the physiological activators of platelet, thromboxane A2 (TXA2) is the primary one which is conversed from arachidonic acid in the platelets and catalyzed by cyclooxygenase (COX).[7,8,9] TXA2 is regulated by two isoforms of COX. COX-1 is usually found in the physical condition, whereas COX-2 is induced by lipopolysaccharide and some cytokines.[10,11,12] Clinical studies have demonstrated a close relationship between plasma levels of TXA2 or COX-2 and platelet activities.[13] AT1R antagonists are known to exhibit potent anti-platelet properties which may differ from other anti-platelet agents.[14] However, the impact of these agents on arterial thrombotic events in elderly patients with hypertension remains largely unclear.
Conclusions:
AT1R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.
www.ncbi.nlm.nih.gov
....
Arachidonic acid-induced human platelet aggregation independent of cyclooxygenase and lipoxygenase
Abstract
It is generally agreed that arachidonic acid (20: 4 omega 6) can stimulate platelet aggregation after conversion to prostaglandin G2 and H2 and thence to thromboxane A2. This action is prevented by cyclooxygenase inhibitors. Washed platelets were isolated on metrizamide gradient and resuspended in a Ca2+-free buffer. Their stimulation by C 20: 4 6 was followed by 14C serotonin (5HT) release, thromboxane (TX) synthesis and an increase of light transmission, not dependent on aggregation, accompanied by slight lysis (14%). The addition of extrinsic Ca2+ suppressed lysis and allowed the formation of aggregates. Under these conditions, cyclooxygenase inhibitors such as acetyl salicylic acid, indomethacin or flurbiprofen totally suppressed TX synthesis without preventing platelet aggregation or [14C]-5HT release. Other C 20 polyunsaturated fatty acids could not substitute for C 20: 4 omega 6 in inducing aggregation, and Ca2+ was found to be a prerequisite for protection of the cell against lysis as well as for aggregation in the absence or TX formation. The use of the lipoxygenase inhibitor BW 755 C did not prevent C 20: 4 omega 6-induced aggregation of aspirin-treated platelets, suggesting that the phenomenon was independent of this pathway also. The total suppression of oxidative metabolism with these inhibitors was verified by the analysis of icosanoids using glass capillary column gas chromatography. It is suggested that under these conditions, C 20: 4 omega 6-induced platelet aggregation might be due to an increased membrane permeability to Ca2+ induced by this fatty acid in the absence of oxidation.
pubmed.ncbi.nlm.nih.gov
.........
DHA itself, rather than its decomposition products, facilitates excitatory (glutamate) nerve transmission (Nishikawa, et al., 1994), and that excitatory action causes the release of arachidonic acid (Pellerin and Wolfe, 1991).
The Great Fish Oil Experiment
.........
Arachidonic acid is synthesized from α-linolenic acid derived from linoleic acid, an essential fatty acid, by the enzyme Δ6-desaturase. ... Cyclooxygenase is an enzyme that transforms arachidonic acid into endoperoxides which are used to synthesize prostaglandins, prostacyclin, or thromboxanes.
Arachidonic Acid - an overview | ScienceDirect Topics
...........
Abstract
Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B2 and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA2 and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB2 levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA2 release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety.
pubmed.ncbi.nlm.nih.gov
..........
COVID-19 concerns aggregate around platelets
In this issue of Blood, articles by Manne et al and Hottz et al highlight platelet hyperactivity in COVID-19–associated pathophysiology.1, 2 Although the hallmarks of COVID-19 include a brisk inflammatory response and respiratory symptoms, the hematologic manifestations of this infection have also garnered attention, with thrombotic complications taking center stage.3, 4 COVID-19–associated coagulopathy has been characterized by an elevated D-dimer, mild thrombocytopenia, and a prolongation of the activated partial thromboplastin time.5 Alongside these laboratory abnormalities, patients present with increased rates of thrombosis.6 The role of platelets in the thrombotic complications of COVID-19 is explored in these 2 articles, establishing that platelet hyperactivity contributes to the coagulopathy seen in COVID-19.
COVID-19 concerns aggregate around platelets
.....
Pathophysiology of Thrombosis
The thrombotic response involves activation of platelets and the coagulation cascade [10]. Remembering Virchow’s triad, changes in the blood flow, constituents, or vessel wall can precipitate thrombosis [11]. Platelet activation is initiated by several agonists, including collagen via glycoprotein (GP) VI receptors and thrombin via protease-activated receptors (PAR) 1 and 4. Upon activation, several key processes occur. First, arachidonic acid is converted to thromboxane A2, a potent pro-aggregatory and vasoconstrictive factor [12]. Second, platelets degranulate. Dense granules, containing adenosine diphosphate (ADP), fuse with the cell membrane [13]. ADP then acts on platelet P2Y1 and, most importantly, P2Y12 receptors, further stimulating and amplifying platelet activation [14]. Similarly, alpha granules, containing P-selectin as well as other proinflammatory and procoagulant factors, fuse with the membrane. P-selectin binds to a range on inflammatory cells, including neutrophils and monocytes [15]. Thirdly, through calcium mobilization and dephosphorylation of vasodilator-stimulated phosphoprotein (VASP), platelets undergo shape change from discoid to stellate forms, meaning physical aggregation occurs [16]. Conformational change in the GP IIb/IIIa receptor, which forms cross-links with other GP IIb/IIIa, strengthening platelet-platelet binding, and also stimulating other platelets to activate via outside-in signalling [17]. In addition, platelets and vascular and blood cell also release extracellular vesicles by outward blebbing, which are small particles released by almost all cell types when activated or injured, and composed by multiple bioactive molecules such as RNA, miRNA, cytokines, transcription and growth factors, and even small amounts of DNA, and lipids (they are rich in phospholipids) because they are enveloped in a lipid bilayer cell-derived membrane [18, 19]. Some extracellular vesicles expose phosphatidylserine in their external layer and therefore elicit a 50- to 100-fold higher procoagulant activity than activated platelets [20].In addition to platelets and extracellular vesicles, activation of the coagulation cascade plays an important role in thrombosis [21]. Broadly divided into two converging pathways, activation of the extrinsic pathway by tissue factor and/or contact activation of the intrinsic pathway, coagulation cascade leads to activation of factor X, a constituent of the prothrombinase complex, resulting in thrombin generation. Thrombin cleaves soluble fibrinogen to insoluble fibrin, which forms interweaving strands, further stabilized by factor XIII. There is interplay between the coagulation cascade and platelets. Not only can thrombin activate platelets through PAR1 and PAR4, but also conversely platelets themselves can catalyze thrombin generation via membrane scramblase activity [22].
Although there is considerable overlap between platelet- and coagulation-mediated effects, the prominent mechanism of initiation varies by setting. Platelet activation is typically most prominent, whereas, [23] whereas in the venous circulation activation of the coagulation cascade predominates [24].
Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis, and Treatment
.........
Valsartan Decreases Platelet Activity and Arterial Thrombotic Events in Elderly Patients with Hypertension
Background:
Angiotensin type 1 receptor (AT1R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT1R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.
Introduction
A large body of evidence has demonstrated that activation of renin-angiotensin system (RAS) plays a key role in the development and progression of hypertension and cardiovascular disease.[1] Angiotensin II (Ang II), the major effector of RAS,[2] exerts its biological effects mainly through specific receptors, namely angiotensin type 1 receptor (AT1R) and type 2 receptor.[3] Since AT1R antagonists have been shown to improve endothelial function and vascular remodeling in addition to their predominant vasodilatation effects,[4,5] these agents are extensively used for blood pressure control in elderly patients with hypertension.[6]
Activation of platelets bears the brunt of complicate cascades of thrombogenesis. Among the physiological activators of platelet, thromboxane A2 (TXA2) is the primary one which is conversed from arachidonic acid in the platelets and catalyzed by cyclooxygenase (COX).[7,8,9] TXA2 is regulated by two isoforms of COX. COX-1 is usually found in the physical condition, whereas COX-2 is induced by lipopolysaccharide and some cytokines.[10,11,12] Clinical studies have demonstrated a close relationship between plasma levels of TXA2 or COX-2 and platelet activities.[13] AT1R antagonists are known to exhibit potent anti-platelet properties which may differ from other anti-platelet agents.[14] However, the impact of these agents on arterial thrombotic events in elderly patients with hypertension remains largely unclear.
Conclusions:
AT1R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.
Valsartan Decreases Platelet Activity and Arterial Thrombotic Events in Elderly Patients with Hypertension
Angiotensin type 1 receptor (AT[1] R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT[1] R antagonist valsartan on platelet aggregation and ...
www.ncbi.nlm.nih.gov
....
Arachidonic acid-induced human platelet aggregation independent of cyclooxygenase and lipoxygenase
Abstract
It is generally agreed that arachidonic acid (20: 4 omega 6) can stimulate platelet aggregation after conversion to prostaglandin G2 and H2 and thence to thromboxane A2. This action is prevented by cyclooxygenase inhibitors. Washed platelets were isolated on metrizamide gradient and resuspended in a Ca2+-free buffer. Their stimulation by C 20: 4 6 was followed by 14C serotonin (5HT) release, thromboxane (TX) synthesis and an increase of light transmission, not dependent on aggregation, accompanied by slight lysis (14%). The addition of extrinsic Ca2+ suppressed lysis and allowed the formation of aggregates. Under these conditions, cyclooxygenase inhibitors such as acetyl salicylic acid, indomethacin or flurbiprofen totally suppressed TX synthesis without preventing platelet aggregation or [14C]-5HT release. Other C 20 polyunsaturated fatty acids could not substitute for C 20: 4 omega 6 in inducing aggregation, and Ca2+ was found to be a prerequisite for protection of the cell against lysis as well as for aggregation in the absence or TX formation. The use of the lipoxygenase inhibitor BW 755 C did not prevent C 20: 4 omega 6-induced aggregation of aspirin-treated platelets, suggesting that the phenomenon was independent of this pathway also. The total suppression of oxidative metabolism with these inhibitors was verified by the analysis of icosanoids using glass capillary column gas chromatography. It is suggested that under these conditions, C 20: 4 omega 6-induced platelet aggregation might be due to an increased membrane permeability to Ca2+ induced by this fatty acid in the absence of oxidation.
Arachidonic acid-induced human platelet aggregation independent of cyclooxygenase and lipoxygenase - PubMed
It is generally agreed that arachidonic acid (20: 4 omega 6) can stimulate platelet aggregation after conversion to prostaglandin G2 and H2 and thence to thromboxane A2. This action is prevented by cyclooxygenase inhibitors. Washed platelets were isolated on metrizamide gradient and resuspended...
pubmed.ncbi.nlm.nih.gov
.........
DHA itself, rather than its decomposition products, facilitates excitatory (glutamate) nerve transmission (Nishikawa, et al., 1994), and that excitatory action causes the release of arachidonic acid (Pellerin and Wolfe, 1991).
The Great Fish Oil Experiment
.........
Arachidonic acid is synthesized from α-linolenic acid derived from linoleic acid, an essential fatty acid, by the enzyme Δ6-desaturase. ... Cyclooxygenase is an enzyme that transforms arachidonic acid into endoperoxides which are used to synthesize prostaglandins, prostacyclin, or thromboxanes.
Arachidonic Acid - an overview | ScienceDirect Topics
...........
Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome
Abstract
Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B2 and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA2 and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB2 levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA2 release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety.
Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome - PubMed
Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of...
pubmed.ncbi.nlm.nih.gov
