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Thrombocytopenia in dengue infection: mechanisms and a potential application

Khazali AS, Hadrawi WH, Ibrahim F, Othman S, Nor Rashid N

Expert Rev Mol Med, 2024 Oct 14;26:e26.
PMID: 39397710 DOI: 10.1017/erm.2024.18

Thrombocytopenia is a common symptom and one of the warning signs of dengue virus (DENV) infection. Platelet depletion is critical as it may lead to other severe dengue symptoms. Understanding the molecular events of this condition during dengue infection is challenging because of the multifaceted factors involved in DENV infection and the dynamics of the disease progression. Platelet levels depend on the balance between platelet production and platelet consumption or clearance. Megakaryopoiesis and thrombopoiesis, two interdependent processes in platelet production, are hampered during dengue infection. Conversely, platelet elimination via platelet activation, apoptosis and clearance processes are elevated. Together, these anomalies contribute to thrombocytopenia in dengue patients. Targeting the molecular events of dengue-mediated thrombocytopenia shows great potential but still requires further investigation. Nonetheless, the application of new knowledge in this field, such as immature platelet fraction analysis, may facilitate physicians in monitoring the progression of the disease.

Matched MeSH terms: Platelet Activation
Fulltext Effect of ultrapure lipopolysaccharides derived from diverse bacterial species on the modulation of platelet activation

Vallance TM, Ravishankar D, Albadawi DAI, Layfield H, Sheard J, Vaiyapuri R, et al.

Sci Rep, 2019 12 03;9(1):18258.
PMID: 31796818 DOI: 10.1038/s41598-019-54617-w

Platelets are small circulating blood cells that play essential roles in the maintenance of haemostasis via blood clotting. However, they also play critical roles in the regulation of innate immune responses. Inflammatory receptors, specifically Toll-like receptor (TLR)-4, have been reported to modify platelet reactivity. A plethora of studies have reported controversial functions of TLR4 in the modulation of platelet function using various chemotypes and preparations of its ligand, lipopolysaccharide (LPS). The method of preparation of LPS may explain these discrepancies however this is not fully understood. Hence, to determine the impact of LPS on platelet activation, we used ultrapure preparations of LPS from Escherichia coli (LPSEC), Salmonella minnesota (LPSSM), and Rhodobacter sphaeroides (LPSRS) and examined their actions under diverse experimental conditions in human platelets. LPSEC did not affect platelet activation markers such as inside-out signalling to integrin αIIbβ3 or P-selectin exposure upon agonist-induced activation in platelet-rich plasma or whole blood whereas LPSSM and LPSRS inhibited platelet activation under specific conditions at supraphysiological concentrations. Overall, our data demonstrate that platelet activation is not largely influenced by any of the ultrapure LPS chemotypes used in this study on their own except under certain conditions.

Matched MeSH terms: Platelet Activation/drug effects*; Platelet Activation/immunology
Physicochemical evaluation and in vitro hemocompatibility study on nanoporous hydroxyapatite

Ooi CH, Ling YP, Abdullah WZ, Mustafa AZ, Pung SY, Yeoh FY

J Mater Sci Mater Med, 2019 Mar 30;30(4):44.
PMID: 30929088 DOI: 10.1007/s10856-019-6247-5

Hydroxyapatite is an ideal biomaterial for bone tissue engineering due to its biocompatibility and hemocompatibility which have been widely studied by many researchers. The incorporation of nanoporosity into hydroxyapatite could transform the biomaterial into an effective adsorbent for uremic toxins removal especially in artificial kidney system. However, the effect of nanoporosity incorporation on the hemocompatibility of hydroxyapatite has yet to be answered. In this study, nanoporous hydroxyapatite was synthesized using hydrothermal technique and its hemocompatibility was determined. Non-ionic surfactants were used as soft templates to create porosity in the hydroxyapatite. The presence of pure hydroxyapatite phase in the synthesized samples is validated by X-ray diffraction analysis and Fourier transform infrared spectroscopy. The TEM images show that the hydroxyapatite formed rod-like particles with the length of 21-90 nm and diameter of 11-70 nm. The hydroxyapatite samples exhibit BET surface area of 33-45 m2 g-1 and pore volume of 0.35-0.44 cm3 g-1. The hemocompatibility of the hydroxyapatite was determined via hemolysis test, platelet adhesion, platelet activation and blood clotting time measurement. The nanoporous hydroxyapatite shows less than 5% hemolysis, suggesting that the sample is highly hemocompatible. There is no activation and morphological change observed on the platelets adhered onto the hydroxyapatite. The blood clotting time demonstrates that the blood incubated with the hydroxyapatite did not coagulate. This study summarizes that the synthesized nanoporous hydroxyapatite is a highly hemocompatible biomaterial and could potentially be utilized in biomedical applications.

Matched MeSH terms: Platelet Activation/drug effects
Fulltext The formyl peptide fMLF primes platelet activation and augments thrombus formation

Salamah MF, Ravishankar D, Vaiyapuri R, Moraes LA, Patel K, Perretti M, et al.

J Thromb Haemost, 2019 Jul;17(7):1120-1133.
PMID: 31033193 DOI: 10.1111/jth.14466

Essentials The role of formyl peptide receptor 1 (FPR1) and its ligand, fMLF, in the regulation of platelet function, hemostasis, and thrombosis is largely unknown. Fpr1-deficient mice and selective inhibitors for FPR1 were used to investigate the function of fMLF and FPR1 in platelets. N-formyl-methionyl-leucyl-phenylalanine primes platelet activation and augments thrombus formation, mainly through FPR1 in platelets. Formyl peptide receptor 1 plays a pivotal role in the regulation of platelet function.
BACKGROUND: Formyl peptide receptors (FPRs) play pivotal roles in the regulation of innate immunity and host defense. The FPRs include three family members: FPR1, FPR2/ALX, and FPR3. The activation of FPR1 by its high-affinity ligand, N-formyl-methionyl-leucyl-phenylalanine (fMLF) (a bacterial chemoattractant peptide), triggers intracellular signaling in immune cells such as neutrophils and exacerbates inflammatory responses to accelerate the clearance of microbial infection. Notably, fMLF has been demonstrated to induce intracellular calcium mobilization and chemotaxis in platelets that are known to play significant roles in the regulation of innate immunity and inflammatory responses. Despite a plethora of research focused on the roles of FPR1 and its ligands such as fMLF on the modulation of immune responses, their impact on the regulation of hemostasis and thrombosis remains unexplored.
OBJECTIVE: To determine the effects of fMLF on the modulation of platelet reactivity, hemostasis, and thrombus formation.
METHODS: Selective inhibitors for FPR1 and Fpr1-deficient mice were used to determine the effects of fMLF and FPR1 on platelets using various platelet functional assays.
RESULTS: N-formyl-methionyl-leucyl-phenylalanine primes platelet activation through inducing distinctive functions and enhances thrombus formation under arterial flow conditions. Moreover, FPR1 regulates normal platelet function as its deficiency in mouse or blockade in human platelets using a pharmacological inhibitor resulted in diminished agonist-induced platelet activation.
CONCLUSION: Since FPR1 plays critical roles in numerous disease conditions, its influence on the modulation of platelet activation and thrombus formation may provide insights into the mechanisms that control platelet-mediated complications under diverse pathological settings.

Matched MeSH terms: Platelet Activation*
Fulltext Impact of specific functional groups in flavonoids on the modulation of platelet activation

Ravishankar D, Salamah M, Akimbaev A, Williams HF, Albadawi DAI, Vaiyapuri R, et al.

Sci Rep, 2018 Jun 22;8(1):9528.
PMID: 29934595 DOI: 10.1038/s41598-018-27809-z

Flavonoids exert innumerable beneficial effects on cardiovascular health including the reduction of platelet activation, and thereby, thrombosis. Hence, flavonoids are deemed to be a molecular template for the design of novel therapeutic agents for various diseases including thrombotic conditions. However, the structure-activity relationships of flavonoids with platelets is not fully understood. Therefore, this study aims to advance the current knowledge on structure-activity relationships of flavonoids through a systematic analysis of structurally-related flavones. Here, we investigated a panel of 16 synthetic flavones containing hydroxy or methoxy groups at C-7,8 positions on the A-ring, with a phenyl group or its bioisosteres as the B-ring, along with their thio analogues possessing a sulfur molecule at the 4th carbon position of the C-ring. The antiplatelet efficacies of these compounds were analysed using human isolated platelets upon activation with cross-linked collagen-related peptide by optical aggregometry. The results demonstrate that the hydroxyl groups in flavonoids are important for optimum platelet inhibitory activities. In addition, the 4-C=O and B ring phenyl groups are less critical for the antiplatelet activity of these flavonoids. This structure-activity relationship of flavonoids with the modulation of platelet function may guide the design, optimisation and development of flavonoid scaffolds as antiplatelet agents.

Matched MeSH terms: Platelet Activation/drug effects*
Effect of the Novel Biodegradable N, O-Carboxymethylchitosan and Oligo-Chitosan on the Platelet Thrombogenicity Cascade in von Willebrand Disease

Periayah MH, Halim AS, Mat Saad AZ, Yaacob NS, Hussein AR, Abdul Karim F, et al.

Thromb Res, 2015 Sep;136(3):625-33.
PMID: 26254703 DOI: 10.1016/j.thromres.2015.07.027

Von Willebrand disease (vWD) is the second least common hemostatic disorder in Malaysia, and it has a low prevalence. This study examined the underlying platelet thrombogenicity cascades in the presence of different formulations of chitosan-derivatives in vWD patients. This paper aimed to determine the significant influence of chitosan biomaterial in stimulating the platelet thrombogenicity cascades that involve the von Willebrand factor, Factor 8, Thromboxane A2, P2Y12 and Glycoprotein IIb/IIIa in vWD.

Matched MeSH terms: Platelet Activation/drug effects
Fulltext Ruthenium-conjugated chrysin analogues modulate platelet activity, thrombus formation and haemostasis with enhanced efficacy

Ravishankar D, Salamah M, Attina A, Pothi R, Vallance TM, Javed M, et al.

Sci Rep, 2017 07 18;7(1):5738.
PMID: 28720875 DOI: 10.1038/s41598-017-05936-3

The constant increase in cardiovascular disease rate coupled with significant drawbacks of existing therapies emphasise the necessity to improve therapeutic strategies. Natural flavonoids exert innumerable pharmacological effects in humans. Here, we demonstrate the effects of chrysin, a natural flavonoid found largely in honey and passionflower on the modulation of platelet function, haemostasis and thrombosis. Chrysin displayed significant inhibitory effects on isolated platelets, however, its activity was substantially reduced under physiological conditions. In order to increase the efficacy of chrysin, a sulfur derivative (thio-chrysin), and ruthenium-complexes (Ru-chrysin and Ru-thio-chrysin) were synthesised and their effects on the modulation of platelet function were evaluated. Indeed, Ru-thio-chrysin displayed a 4-fold greater inhibition of platelet function and thrombus formation in vitro than chrysin under physiologically relevant conditions such as in platelet-rich plasma and whole blood. Notably, Ru-thio-chrysin exhibited similar efficacy to chrysin in the modulation of haemostasis in mice. Increased bioavailability and cell permeability of Ru-thio-chrysin compared to chrysin were found to be the basis for its enhanced activity. Together, these results demonstrate that Ru-thio-coupled natural compounds such as chrysin may serve as promising templates for the development of novel anti-thrombotic agents.

Matched MeSH terms: Platelet Activation/drug effects*
Effect of menopause on platelet activation markers determined by flow cytometry

Roshan TM, Normah J, Rehman A, Naing L

Am J Hematol, 2005 Dec;80(4):257-61.
PMID: 16315264

Pre-menopausal women have a lower risk of cardiovascular disease compared to post-menopausal women. Cardiovascular disease is more age dependent in women than in men. The association of platelet activation and cardiovascular thrombotic events is well established. Standardized techniques were used to evaluate platelet activation markers by flow cytometry, using 3-color analysis (CD 61PerCP, CD 62P, and PAC-1) in 49 post-menopausal (mean +/- SD age, 56.16 +/- 33.51 years) and 42 pre-menopausal (age, 39.38 +/- 7.07 years) women. Results of our study showed a significant increase in CD 62P in post-menopausal women as compared to the pre-menopausal group (2.66 +/- 4.26% vs. 0.52 +/- 2.71%, P < 0.001). Similarly, PAC-1 was significantly increased in post-menopausal women (21.54 +/- 2.48% vs. 3.70 +/- 2.31%, P < 0.001). Furthermore, there was a significant association of CD 62P with serum estradiol in both groups. PAC-1 was significantly associated with age in both groups. The results suggest the role of platelets in the increased incidence of thrombotic events and disease in post-menopausal women.

Matched MeSH terms: Platelet Activation*
Numerical investigation on the effect of bileaflet mechanical heart valve's implantation tilting angle and aortic root geometry on intermittent regurgitation and platelet activation

Abbas SS, Nasif MS, Al-Waked R, Meor Said MA

Artif Organs, 2020 Feb;44(2):E20-E39.
PMID: 31378963 DOI: 10.1111/aor.13536

Platelet activation induced by shear stresses and non-physiological flow field generated by bileaflet mechanical heart valves (BMHVs) leads to thromboembolism, which can cause fatal consequences. One of the causes of platelet activation could be intermittent regurgitation, which arises due to asynchronous movement and rebound of BMHV leaflets during the valve closing phase. In this numerical study, the effect of intermittent regurgitation on the platelet activation potential of BMHVs was quantified by modeling a BMHV in the straight and anatomic aorta at implantation tilt angles 0°, 5°, 10°, and 20°. A fully implicit Arbitrary Lagrangian-Eulerian-based Fluid-Structure Interaction formulation was adopted with blood modeled as a multiphase, non-Newtonian fluid. Results showed that the intermittent regurgitation and consequently the platelet activation level increases with the increasing implantation tilt of BMHV. For the straight aorta, the leaflet of the 20° tilted BMHV underwent a rebound of approximately 20° after initially closing, whereas the leaflet of the 10°, 5°, and 0° tilted BMHVs underwent a rebound of 8.5°, 3°, and 0°, respectively. For the anatomic aorta, the leaflet of the 20° tilted BMHV underwent a rebound of approximately 24° after initially closing, whereas the leaflet of the 10°, 5°, and 0° tilted BMHVs underwent a rebound of 14°, 10°, and 7°, respectively. For all the implantation orientations of BMHVs, intermittent regurgitation and platelet activation were always higher in the anatomic aorta than in the straight aorta. The study concludes that the pivot axis of BMHV must be implanted parallel to the aortic root's curvature to minimize intermittent regurgitation and platelet activation.

Matched MeSH terms: Platelet Activation*
Fulltext Platelets kill circulating parasites of all major Plasmodium species in human malaria

Kho S, Barber BE, Johar E, Andries B, Poespoprodjo JR, Kenangalem E, et al.

Blood, 2018 Sep 20;132(12):1332-1344.
PMID: 30026183 DOI: 10.1182/blood-2018-05-849307

Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet-erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the Plasmodium species studied, particularly mature stages, and was greatest in P vivax patients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4+TUNEL+ parasites). These PF4+TUNEL+ parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet-associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and Plasmodium species, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet-erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.

Matched MeSH terms: Platelet Activation*
Fulltext The endogenous antimicrobial cathelicidin LL37 induces platelet activation and augments thrombus formation

Salamah MF, Ravishankar D, Kodji X, Moraes LA, Williams HF, Vallance TM, et al.

Blood Adv, 2018 Nov 13;2(21):2973-2985.
PMID: 30413433 DOI: 10.1182/bloodadvances.2018021758

Platelet-associated complications including thrombosis, thrombocytopenia, and hemorrhage are commonly observed during various inflammatory diseases such as sepsis, inflammatory bowel disease, and psoriasis. Despite the reported evidence on numerous mechanisms/molecules that may contribute to the dysfunction of platelets, the primary mechanisms that underpin platelet-associated complications during inflammatory diseases are not fully established. Here, we report the discovery of formyl peptide receptor 2, FPR2/ALX, in platelets and its primary role in the development of platelet-associated complications via ligation with its ligand, LL37. LL37 acts as a powerful endogenous antimicrobial peptide, but it also regulates innate immune responses. We demonstrate the impact of LL37 in the modulation of platelet reactivity, hemostasis, and thrombosis. LL37 activates a range of platelet functions, enhances thrombus formation, and shortens the tail bleeding time in mice. By utilizing a pharmacological inhibitor and Fpr2/3 (an ortholog of human FPR2/ALX)-deficient mice, the functional dependence of LL37 on FPR2/ALX was determined. Because the level of LL37 is increased in numerous inflammatory diseases, these results point toward a critical role for LL37 and FPR2/ALX in the development of platelet-related complications in such diseases. Hence, a better understanding of the clinical relevance of LL37 and FPR2/ALX in diverse pathophysiological settings will pave the way for the development of improved therapeutic strategies for a range of thromboinflammatory diseases.

Matched MeSH terms: Platelet Activation/drug effects*
Fulltext RNA sequencing (RNA-Seq) of lymph node, spleen, and thymus transcriptome from wild Peninsular Malaysian cynomolgus macaque (Macaca fascicularis)

Ee Uli J, Yong CSY, Yeap SK, Rovie-Ryan JJ, Mat Isa N, Tan SG, et al.

PeerJ, 2017;5:e3566.
PMID: 28828235 DOI: 10.7717/peerj.3566

The cynomolgus macaque (Macaca fascicularis) is an extensively utilised nonhuman primate model for biomedical research due to its biological, behavioural, and genetic similarities to humans. Genomic information of cynomolgus macaque is vital for research in various fields; however, there is presently a shortage of genomic information on the Malaysian cynomolgus macaque. This study aimed to sequence, assemble, annotate, and profile the Peninsular Malaysian cynomolgus macaque transcriptome derived from three tissues (lymph node, spleen, and thymus) using RNA sequencing (RNA-Seq) technology. A total of 174,208,078 paired end 70 base pair sequencing reads were obtained from the Illumina Hi-Seq 2500 sequencer. The overall mapping percentage of the sequencing reads to the M. fascicularis reference genome ranged from 53-63%. Categorisation of expressed genes to Gene Ontology (GO) and KEGG pathway categories revealed that GO terms with the highest number of associated expressed genes include Cellular process, Catalytic activity, and Cell part, while for pathway categorisation, the majority of expressed genes in lymph node, spleen, and thymus fall under the Global overview and maps pathway category, while 266, 221, and 138 genes from lymph node, spleen, and thymus were respectively enriched in the Immune system category. Enriched Immune system pathways include Platelet activation pathway, Antigen processing and presentation, B cell receptor signalling pathway, and Intestinal immune network for IgA production. Differential gene expression analysis among the three tissues revealed 574 differentially expressed genes (DEG) between lymph and spleen, 5402 DEGs between lymph and thymus, and 7008 DEGs between spleen and thymus. Venn diagram analysis of expressed genes revealed a total of 2,630, 253, and 279 tissue-specific genes respectively for lymph node, spleen, and thymus tissues. This is the first time the lymph node, spleen, and thymus transcriptome of the Peninsular Malaysian cynomolgus macaque have been sequenced via RNA-Seq. Novel transcriptomic data will further enrich the present M. fascicularis genomic database and provide future research potentials, including novel transcript discovery, comparative studies, and molecular markers development.

Matched MeSH terms: Platelet Activation
Attenuation of Thrombosis by Crude Rice (Oryza sativa) Bran Policosanol Extract: Ex Vivo Platelet Aggregation and Serum Levels of Arachidonic Acid Metabolites

Wong WT, Ismail M, Tohit ER, Abdullah R, Zhang YD

Evid Based Complement Alternat Med, 2016;2016:7343942.
PMID: 27800004

Background. Vascular occlusion or thrombosis was often attributed to uncontrolled platelet activation. Influence of sugarcane policosanol extract on platelet was reported but little was known of rice bran policosanol, particularly its mechanisms of actions on platelet activities. Objective. Antiplatelet mechanisms of rice bran policosanol extract (RBE) were studied using hyperlipidemic Sprague Dawley rats. Ex vivo platelet aggregation, platelet count (PC), bleeding time (BT), and coagulation time were assayed. Serum eicosanoids and other aggregation-related metabolites levels were quantified. Design. Rats were divided into 6 groups for comparisons (vehicle control Tween 20/H2O, high dose policosanol 500 mg/kg, middle dose policosanol 250 mg/kg, low dose policosanol 100 mg/kg, and positive control aspirin 30 mg/kg). Results. Low dose 100 mg/kg of RBE inhibited aggregation by 42.32 ± 4.31% and this was comparable with the effect of 30 mg/kg aspirin, 43.91 ± 5.27%. Results showed that there were no significant differences in PC, BT, and coagulation time among various groups after RBE treatment. Serum thromboxane A2 was attenuated while prostacyclin level increased upon RBE treatment. Conclusions. RBE reduced ex vivo ADP-induced platelet aggregation without giving adverse effects. No changes in full blood count suggested that rice bran policosanol did not disturb biological blood cell production and destruction yet it reduced aggregation through different mechanisms.

Matched MeSH terms: Platelet Activation
Increased PAC-1 expression among patients with multiple myeloma on concurrent thalidomide and warfarin

Abdullah WZ, Roshan TM, Hussin A, Zain WS, Abdullah D

Blood Coagul Fibrinolysis, 2013 Dec;24(8):893-5.
PMID: 24030118 DOI: 10.1097/MBC.0b013e3283642ee2

Treatment with thalidomide is associated with vascular thrombosis. The effect of thalidomide on platelet activation is unclear, although the use of aspirin is justified for thromboprophylaxis. A study on platelet activation markers was done among multiple myeloma patients receiving thalidomide therapy with warfarin as thromboprophylaxis. Strict criteria and procedure were set to avoid misinterpretation of platelet activation other than due to the thalidomide's effect. Blood specimen pre and post thalidomide therapy were used for flow cytometric analysis. Platelet surface P-selectin, CD62P expression and PAC-1 (antibody that recognizes conformational change of the GPIIb/IIIa complex) were examined by using three-colour flowcytometer. Increased expression marker for PAC-1 was observed after 4 weeks of thalidomide treatment (P platelet activation activity seen in these patients. The mechanism of thrombosis by thalidomide is probably multifactorial and one of them is likely through platelet activation. Further study on the affected pathway/s in the platelet activation process would confirm the exact mechanism of thalidomide-induced thrombosis and potential extended usage of this drug in future.

Matched MeSH terms: Platelet Activation/drug effects
Short-term estrogen replacement therapy reduces platelet marker levels in Malaysian postmenopausal women

Sheikh SA, Roshan TM, Khattak MN, Baig AA, Noor SJ, Hassan R, et al.

Menopause Int, 2011 Mar;17(1):6-10.
PMID: 21427417 DOI: 10.1258/mi.2011.011001

In healthy postmenopausal women (PMW) increased platelet activation has been associated with adverse cardiovascular events. There is much debate about the relationship between platelet function and serum estradiol level in PMW. This study assessed the effect of short-term oral estrogen replacement therapy (ERT) on platelet activation markers (CD62P and PAC-1) and its correlation with age and body mass index (BMI) among healthy PMW.

Matched MeSH terms: Platelet Activation

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