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Non-statin therapy in patients with elevated LDL-C and high platelet reactivity: a narrative review

Nurmukhammad FN, Zhangelova Sh B, Кapsultanova DA, Musagaliyeva AT, Danyarova LB, Rustamova FE, et al.

Med J Malaysia, 2025 Mar;80(2):258-265.
PMID: 40145170

INTRODUCTION: Evidence of an association between elevated LDL-C levels and HRPR - which are highly prevalent separately and both lead to rapid progression of atherosclerosis on ineffective hypolipidaemic therapy - is scarce.
MATERIALS AND METHODS: We searched electronic databases. All available randomized controlled trials (RCTs) were included, and we considered the scientific novelty of the study, the reliability of the reported study results; the high methodological level of the study of non-statin therapy in patients with dyslipidemia and high residual platelet reactivity, with no language or date restrictions. We did separate random-effects meta-analyses for LDL-С, HRRP on their effects on LDL-С levels and outcomes, taking into account the reliability of the reported study results and the high methodological level of the study. The challenge of achieving target LDL-С levels, their impact on high residual platelet reactivity, and the choice of optimal antiplatelet and lipid-lowering therapy remains unresolved.
RESULTS: The integration of newer therapies, such as inclisiran and PCSK9 inhibitors, may play a critical role in achieving optimal outcomes for patients at high cardiovascular risk.
CONCLUSION: The necessity of applying an individual multidisciplinary approach in order to determine the best regimen of antiplatelet and lipid-lowering therapy in patients with coronary heart disease, including after revascularization, is shown. This approach will reduce the risk of recurrent cardiovascular events. Few studies on the relationship between LDL-С and HRPR dictate the need for more detailed research in this area.

Matched MeSH terms: Platelet Activation/drug effects
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*
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 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*
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*
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