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Physiology of Platelets in Humans and Animals

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 42056

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Prof. Dr. Ilya Nikolaevich Medvedev

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Department of Mechanics and Mathematics, Russian State Social University, Moscow 119992, Russia
Interests: platelets; animal physiology; ontogenesis; cardiology; arterial hypertension; metabolic disorders
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Platelet activity is very important for the health and development of diseases. It has been shown that platelets are sensitive to the development of any deviations from the physiological optimum of the organism, increasing the synthesis of important substances with proaggregatory activity.

In the past, the object of investigation in the evaluation of platelet activity was very often humans, given the high clinical significance of violations of platelet hemostasis, leading to the development of thrombophilia. It is recognized that obesity, hypertension, coronary heart disease, and metabolic syndrome are almost always accompanied by the development of the dysfunction of platelets, causing obstruction of blood rheology, the occurrence of hypoxia and metabolic disorders in tissues, and creating the threat of thrombosis.

Currently, the object of study of platelets is increasingly productive animals. This is due to the possibility of the influence of platelet activity on the intensity of capillary blood flow and, consequently, on metabolism in tissues and the realization of the productive potential of farm animals.

The accumulated information on the functioning of platelets suggests that more research is needed to find cost-effective approaches capable of bringing human platelets and productive animals away from hypersensitive status, significantly lowering such activity. In humans, this will minimize the risk of thrombotic complications and prolong life. The weakening of the activity of platelets in productive animals opens the possibility of a substantial stimulation of their productive qualities.

In this context, the aim of this Special Issue is to try to summarize and reflect on the results of recent studies of platelet activity in humans and animals, examining the effectiveness of various options for reducing platelet activity, contributing to the overall improvement and stimulation of exchange processes.

Prof. Dr. Ilya Nikolaevich Medvedev
Guest Editor

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Keywords

platelets
physiology
hemostasis
thrombosis, vitality

Published Papers (13 papers)

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16 pages, 2941 KiB

Open AccessArticle

Genetic Labeling of Cells Allows Identification and Tracking of Transgenic Platelets in Mice

by Irena Krüger, Friedrich Reusswig, Kim Jürgen Krott, Celina Fabienne Lersch, Martina Spelleken and Margitta Elvers

Int. J. Mol. Sci. 2021, 22(7), 3710; https://doi.org/10.3390/ijms22073710 - 2 Apr 2021

Cited by 2 | Viewed by 2717

Abstract

Background: The use of knock-out mouse models is crucial to understand platelet activation and aggregation. Methods: Analysis of the global double fluorescent Cre reporter mouse mT/mG that has been crossbred with the megakaryocyte/platelet specific PF4-Cre mouse. Results: Platelets show bright mT (PF4-Cre negative) and mG (PF4-Cre positive) fluorescence. However, a small proportion of leukocytes was positive for mG fluorescence in PF4-Cre positive mice. In mT/mG;PF4-Cre mice, platelets, and megakaryocytes can be tracked by their specific fluorescence in blood smear, hematopoietic organs and upon thrombus formation. No differences in platelet activation and thrombus formation was observed between mT/mG;PF4-Cre positive and negative mice. Furthermore, hemostasis and in vivo thrombus formation was comparable between genotypes as analyzed by intravital microscopy. Transplantation studies revealed that bone marrow of mT/mG;PF4-Cre mice can be transferred to C57BL/6 mice. Conclusions: The mT/mG Cre reporter mouse is an appropriate model for real-time visualization of platelets, the analysis of cell morphology and the identification of non-recombined platelets. Thus, mT/mG;PF4-Cre mice are important for the analysis of platelet-specific knockout mice. However, a small proportion of leukocytes exhibit mG fluorescence. Therefore, the analysis of platelets beyond hemostasis and thrombosis should be critically evaluated when recombination of immune cells is increased. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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13 pages, 1843 KiB

Open AccessArticle

A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells

by Reza Haschemi, Lukas Maria Gockel, Gerd Bendas and Martin Schlesinger

Int. J. Mol. Sci. 2021, 22(7), 3323; https://doi.org/10.3390/ijms22073323 - 24 Mar 2021

Cited by 12 | Viewed by 2376

Abstract

Pancreatic cancer patients have an elevated risk of suffering from venous thrombosis. Among several risk factors that contribute to hypercoagulability of this malignancy, platelets possess a key role in the initiation of clot formation. Although single mechanisms of platelet activation are well-known in principle, combinations thereof and their potential synergy to mediate platelet activation is, in the case of pancreatic cancer, far from being clear. Applying an inhibitor screening approach using light transmission aggregometry, dense granule release, and thrombin formation assays, we provide evidence that a combination of tissue factor-induced thrombin formation by cancer cells and their platelet P-selectin binding is responsible for AsPC-1 and Capan-2 pancreatic cancer cell-mediated platelet activation. While the blockade of one of these pathways leads to a pronounced inhibition of platelet aggregation and dense granule release, the simultaneous blockade of both pathways is inevitable to prevent platelet aggregation completely and minimize ATP release. In contrast, MIA PaCa-2 pancreatic cancer cells express reduced levels of tissue factor and P-selectin ligands and thus turn out to be poor platelet activators. Consequently, a simultaneous blockade of thrombin and P-selectin binding seems to be a powerful approach, as mediated by heparin to crucially reduce the hypercoagulable state of pancreatic cancer patients. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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23 pages, 5618 KiB

Open AccessArticle

Influence of Antiplatelet Agents on the Lipid Composition of Platelet Plasma Membrane: A Lipidomics Approach with Ticagrelor and Its Active Metabolite

by Jennifer Lagoutte-Renosi, Florentin Allemand, Christophe Ramseyer, Vahideh Rabani and Siamak Davani

Int. J. Mol. Sci. 2021, 22(3), 1432; https://doi.org/10.3390/ijms22031432 - 31 Jan 2021

Cited by 11 | Viewed by 3113

Abstract

Lipids contained in the plasma membrane of platelets play an important role in platelet function. Modifications in the lipid composition can fluidify or rigidify the environment around embedded receptors, in order to facilitate the access of the receptor by the drug. However, data concerning the lipid composition of platelet plasma membrane need to be updated. In addition, data on the impact of drugs on plasma membrane composition, in particular antiplatelet agents, remain sparse. After isolation of platelet plasma membrane, we assessed, using lipidomics, the effect of ticagrelor, a P2Y12 antagonist, and its active metabolite on the lipid composition of these plasma membranes. We describe the exact lipid composition of plasma membrane, including all sub-species. Ticagrelor and its active metabolite significantly increased cholesterol and phosphatidylcholine ether with short saturated acyl chains 16:0/16:0, and decreased phosphatidylcholine, suggesting overall rigidification of the membrane. Furthermore, ticagrelor and its active metabolite decreased some arachidonylated plasmalogens, suggesting a decrease in availability of arachidonic acid from the membrane phospholipids for synthesis of biologically active mediators. To conclude, ticagrelor and its active metabolite seem to influence the lipid environment of receptors embedded in the lipid bilayer and modify the behavior of the plasma membrane. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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16 pages, 10791 KiB

Open AccessArticle

Fluorescent Cytochemical Detection of Polyphosphates Associated with Human Platelets

by Atsushi Sato, Hachidai Aizawa, Tetsuhiro Tsujino, Kazushige Isobe, Taisuke Watanabe, Yutaka Kitamura and Tomoyuki Kawase

Int. J. Mol. Sci. 2021, 22(3), 1040; https://doi.org/10.3390/ijms22031040 - 21 Jan 2021

Cited by 8 | Viewed by 2767

Abstract

Polyphosphate (polyP) is released from activated platelets and activates the intrinsic coagulation pathway. However, polyP may also be involved in various pathophysiological functions related to platelets. To clarify these functions, we established a cytochemical method to reproducibly visualize polyP in platelets. Platelets obtained from healthy non-smoking donors were suspended in phosphate-buffered saline and quickly immobilized on glass slides using a Cytospin. After fixation and membrane permeabilization, platelets were treated with 4′,6- diamidino-2-phenylindole (DAPI) and examined using a fluorescence microscope with a blue-violet excitation filter block (BV-2A). Fixed platelets were also subjected to immunocytochemical examination to visualize serotonin distribution. Under the optimized conditions for polyP visualization, immobilized platelets were fixed with 10% neutral-buffered formalin for 4 h or longer and treated with DAPI at a concentration of 10 µg/mL in 0.02% saponin- or 0.1% Tween-20-containing Hanks balanced salt solution as a permeabilization buffer for 30 min at room temperature (22–25 °C). Based on the results obtained by using activated platelets, treatment with alkaline phosphatases, and serotonin release, the DAPI⁺ targets were identified as polyP. Therefore, this cytochemical method is useful for determining the amount and distribution of polyP in platelets. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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13 pages, 7101 KiB

Open AccessArticle

PLGA-PEG Nanoparticles Show Minimal Risks of Interference with Platelet Function of Human Platelet-Rich Plasma

by Rana Bakhaidar, Sarah O’Neill and Zebunnissa Ramtoola

Int. J. Mol. Sci. 2020, 21(24), 9716; https://doi.org/10.3390/ijms21249716 - 19 Dec 2020

Cited by 10 | Viewed by 2355

Abstract

The expansion of nanotechnology for drug delivery applications has raised questions regarding the safety of nanoparticles (NPs) due to their potential for interacting at molecular and cellular levels. Although polymeric NPs for drug delivery are formulated using FDA-approved polymers such as lactide- and glycolide-based polymers, their interactions with blood constituents, remain to be identified. The aim of this study was to determine the impact of size-selected Poly-lactide-co-glycolide-polyethylene glycol (PLGA-PEG) NPs on platelet activity. The NPs of 113, 321, and 585 nm sizes, were formulated and their effects at concentrations of 0–2.2 mg/mL on the activation and aggregation of platelet-rich plasma (PRP) were investigated. The results showed that NPs of 113 nm did not affect adenosine diphosphate (ADP)-induced platelet aggregation at any NP concentration studied. The NPs of 321 and 585 nm, at concentrations ≥0.25 mg/mL, reduced ADP-activated platelet aggregation. The platelet activation profile remained unchanged in the presence of investigated NPs. Confocal microscopy revealed that NPs were attached to or internalised by platelets in both resting and activated states, with no influence on platelet reactivity. The results indicate minimal risks of interference with platelet function for PLGA-PEG NPs and that these NPs can be explored as nanocarriers for targeted drug delivery to platelets. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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12 pages, 3496 KiB

Open AccessArticle

Relative Centrifugal Force (RCF; G-Force) Affects the Distribution of TGF-β in PRF Membranes Produced Using Horizontal Centrifugation

by Zahra Kargarpour, Jila Nasirzade, Layla Panahipour, Richard J. Miron and Reinhard Gruber

Int. J. Mol. Sci. 2020, 21(20), 7629; https://doi.org/10.3390/ijms21207629 - 15 Oct 2020

Cited by 7 | Viewed by 3192

Abstract

Solid platelet-rich fibrin (PRF) is produced with centrifugation tubes designed to accelerate clotting. Thus, activated platelets may accumulate within the fibrin-rich extracellular matrix even before centrifugation is initiated. It can thus be assumed that platelets and their growth factors such as transforming growth factor-β (TGF-β) are trapped within PRF independent of their relative centrifugal force (RCF), the gravitation or g-force. To test this assumption, we prepared PRF membranes with tubes where clotting is activated by a silicone-coated interior. Tubes underwent 210 g, 650 g and 1500 g for 12 min in a horizontal centrifuge. The respective PRF membranes, either in total or separated into a platelet-poor plasma and buffy coat fraction, were subjected to repeated freeze-thawing to prepare lysates. Gingival fibroblasts were exposed to the PRF lysates to provoke the expression of TGF-β target genes. We show here that the expression of interleukin 11 (IL11) and NADPH oxidase 4 (NOX4), and Smad2/3 signaling were similarly activated by all lysates when normalized to the size of the PRF membranes. Notably, platelet-poor plasma had significantly less TGF-β activity than the buffy coat fraction at both high-speed protocols. In contrast to our original assumption, the TGF-β activity in PRF lysates produced using horizontal centrifugation follows a gradient with increasing concentration from the platelet-poor plasma towards the buffy coat layer. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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13 pages, 2819 KiB

Open AccessArticle

Phospholipase D1 and D2 Synergistically Regulate Thrombus Formation

by Li-Ming Lien, Wan-Jung Lu, Ting-Yu Chen, Tzu-Yin Lee, Hsueh-Hsiao Wang, Hsien-Yu Peng, Ray-Jade Chen and Kuan-Hung Lin

Int. J. Mol. Sci. 2020, 21(18), 6954; https://doi.org/10.3390/ijms21186954 - 22 Sep 2020

Cited by 3 | Viewed by 2427

Abstract

Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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10 pages, 1752 KiB

Open AccessArticle

Characterization of Integrin αIIbβ3-Mediated Outside-in Signaling by Protein Kinase Cδ in Platelets

by Preeti Kumari Chaudhary, Sanggu Kim, Youngheun Jee, Seung-Hun Lee and Soochong Kim

Int. J. Mol. Sci. 2020, 21(18), 6563; https://doi.org/10.3390/ijms21186563 - 8 Sep 2020

Cited by 2 | Viewed by 2281

Abstract

Engagement of integrin αIIbβ3 promotes platelet–platelet interaction and stimulates outside-in signaling that amplifies activation. Protein kinase Cδ (PKCδ) is known to play an important role in platelet activation, but its role in outside-in signaling has not been established. In the present study, we determined the role of PKCδ and its signaling pathways in integrin αIIbβ3-mediated outside-in signaling in platelets using PKCδ-deficient platelets. Platelet spreading to immobilized fibrinogen resulted in PKCδ phosphorylation, suggesting that αIIbβ3 activation caused PKCδ activation. αIIbβ3-mediated phosphorylation of Akt was significantly inhibited in PKCδ -/- platelets, indicating a role of PKCδ in outside-in signaling. αIIbβ3-mediated PKCδ phosphorylation was inhibited by proline-rich tyrosine kinase 2 (Pyk2) selective inhibitor, suggesting that Pyk2 contributes to the regulation of PKCδ phosphorylation in outside-in signaling. Additionally, Src-family kinase inhibitor PP2 inhibited integrin-mediated Pyk2 and PKCδ phosphorylation. Lastly, platelet spreading was inhibited in PKCδ -/- platelets compared to the wild-type (WT) platelets, and clot retraction from PKCδ -/- platelets was markedly delayed, indicating that PKCδ is involved in the regulation of αIIbβ3-dependent interactivities with cytoskeleton elements. Together, these results provide evidence that PKCδ plays an important role in outside-in signaling, which is regulated by Pyk2 in platelets. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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17 pages, 5447 KiB

Open AccessArticle

Immune Modulation of Platelet-Derived Mitochondria on Memory CD4⁺ T Cells in Humans

by Haibo Yu, Wei Hu, Xiang Song and Yong Zhao

Int. J. Mol. Sci. 2020, 21(17), 6295; https://doi.org/10.3390/ijms21176295 - 31 Aug 2020

Cited by 15 | Viewed by 3581

Abstract

CD4⁺ T cells are one of the key immune cells contributing to the immunopathogenesis of type 1 diabetes (T1D). Previous studies have reported that platelet-derived mitochondria suppress the proliferation of peripheral blood mononuclear cells (PBMC). To further characterize the immune modulation of platelet-derived mitochondria, the purified CD4⁺ T cells were treated, respectively, with platelet-derived mitochondria. The data demonstrated that MitoTracker Deep Red-labeled platelet-derived mitochondria could directly target CD4⁺ T cells through C-X-C motif chemokine receptor 4 (CXCR4) and its ligand stromal cell-derived factor-1 (SDF-1), regulating the anti-CD3/CD28 bead-activated CD4⁺ T cells. The result was an up-regulation of Naïve and central memory (T_CM) CD4⁺ T cells, the down-regulation of effector memory (T_EM) CD4⁺ T cells, and modulations of cytokine productions and gene expressions. Thus, platelet-derived mitochondria have a translational potential as novel immune modulators to treat T1D and other autoimmune diseases. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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19 pages, 3618 KiB

Open AccessArticle

Parkin Coordinates Platelet Stress Response in Diabetes Mellitus: A Big Role in a Small Cell

by Seung Hee Lee, Jing Du, John Hwa and Won-Ho Kim

Int. J. Mol. Sci. 2020, 21(16), 5869; https://doi.org/10.3390/ijms21165869 - 15 Aug 2020

Cited by 4 | Viewed by 2935

Abstract

Increased platelet activation and apoptosis are characteristic of diabetic (DM) platelets, where a Parkin-dependent mitophagy serves a major endogenous protective role. We now demonstrate that Parkin is highly expressed in both healthy platelets and diabetic platelets, compared to other mitochondria-enriched tissues such as the heart, muscle, brain, and liver. Abundance of Parkin in a small, short-lived anucleate cell suggest significance in various key processes. Through proteomics we identified 127 Parkin-interacting proteins in DM platelets and compared them to healthy controls. We assessed the 11 highest covered proteins by individual IPs and confirmed seven proteins that interacted with Parkin; VCP/p97, LAMP1, HADHA, FREMT3, PDIA, ILK, and 14-3-3. Upon further STRING analysis using GO and KEGG, interactions were divided into two broad groups: targeting platelet activation through (1) actions on mitochondria and (2) actions on integrin signaling. Parkin plays an important role in mitochondrial protection through mitophagy (VCP/p97), recruiting phagophores, and targeting lysosomes (with LAMP1). Mitochondrial β-oxidation may also be regulated by the Parkin/HADHA interaction. Parkin may regulate platelet aggregation and activation through integrin signaling through interactions with proteins like FREMT3, PDIA, ILK, and 14-3-3. Thus, platelet Parkin may regulate the protection (mitophagy) and stress response (platelet activation) in DM platelets. This study identified new potential therapeutic targets for platelet mitochondrial dysfunction and hyperactivation in diabetes mellitus. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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Review

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21 pages, 30808 KiB

Open AccessReview

Till Death Do Us Part—The Multifaceted Role of Platelets in Liver Diseases

by Marion Mussbacher, Laura Brunnthaler, Anja Panhuber, Patrick Starlinger and Alice Assinger

Int. J. Mol. Sci. 2021, 22(6), 3113; https://doi.org/10.3390/ijms22063113 - 18 Mar 2021

Cited by 20 | Viewed by 6208

Abstract

Platelets are tightly connected with the liver, as both their production and their clearance are mediated by the liver. Platelets, in return, participate in a variety of liver diseases, ranging from non-alcoholic fatty liver diseases, (viral) hepatitis, liver fibrosis and hepatocellular carcinoma to liver regeneration. Due to their versatile functions, which include (1) regulation of hemostasis, (2) fine-tuning of immune responses and (3) release of growth factors and cellular mediators, platelets quickly adapt to environmental changes and modulate disease development, leading to different layers of complexity. Depending on the (patho)physiological context, platelets exert both beneficial and detrimental functions. Understanding the precise mechanisms through which platelet function is regulated at different stages of liver diseases and how platelets interact with various resident and non-resident liver cells helps to draw a clear picture of platelet-related therapeutic interventions. Therefore, this review summarizes the current knowledge on platelets in acute and chronic liver diseases and aims to shed light on how the smallest cells in the circulatory system account for changes in the (patho)physiology of the second largest organ in the human body. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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16 pages, 743 KiB

Open AccessReview

Intravital Assessment of Blood Platelet Function. A Review of the Methodological Approaches with Examples of Studies of Selected Aspects of Blood Platelet Function

by Dawid Polak, Marcin Talar, Cezary Watala and Tomasz Przygodzki

Int. J. Mol. Sci. 2020, 21(21), 8334; https://doi.org/10.3390/ijms21218334 - 6 Nov 2020

Cited by 5 | Viewed by 2475

Abstract

Platelet biology owes to intravital studies not only a better understanding of platelets’ role in primary hemostasis but also findings that platelets are important factors in inflammation and atherosclerosis. Researchers who enter the field of intravital platelet studies may be confused by the heterogeneity of experimental protocols utilized. On the one hand, there are a variety of stimuli used to activate platelet response, and on the other hand there are several approaches to measure the outcome of the activation. A number of possible combinations of activation factors with measurement approaches result in the aforementioned heterogeneity. The aim of this review is to present the most often used protocols in a systematic way depending on the stimulus used to activate platelets. By providing examples of studies performed with each of the protocols, we attempt to explain why a particular combination of stimuli and measurement method was applied to study a given aspect of platelet biology. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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13 pages, 898 KiB

Open AccessReview

The Phenomenon of Clopidogrel High On-Treatment Platelet Reactivity in Ischemic Stroke Subjects: A Comprehensive Review

by Adam Wiśniewski and Karolina Filipska

Int. J. Mol. Sci. 2020, 21(17), 6408; https://doi.org/10.3390/ijms21176408 - 3 Sep 2020

Cited by 28 | Viewed by 4169

Abstract

Clopidogrel is increasingly being used for the secondary prevention of ischemic stroke according to the updated guidelines on acute stroke management. Failure to achieve a drug response is referred to as clopidogrel resistance. Similarly, a higher activation of platelets during clopidogrel therapy—high on-treatment platelet reactivity—is equivalent to a reduced effectiveness of a therapy. Clopidogrel resistance is considered to be a common and multifactorial phenomenon that significantly limits the efficacy of antiplatelet agents. The aim of the current study is to review the latest literature data to identify the prevalance and predictors of clopidogrel high on-treatment platelet reactivity among stroke subjects and to establish the potential impact on clinical outcomes and prognosis. Clinical databases were searched by two independent researchers to select relevant papers on the topic, including all types of articles. Several important predictors contributing to clopidogrel resistance were identified, including genetic polymorphisms, the concomitant use of other drugs, or vascular risk factors, in particular nonsmoking and diabetes. Clopidogrel high on-treatment platelet reactivity has a negative impact on the clinical course of stroke, worsens the early- and long-term prognoses, and increases the risk of recurrent vascular events. Platelet function testing should be considered in selected stroke individuals, especially those predisposed to clopidogrel resistance, for whom an improvement in the efficacy of antiplatelet therapy is essential. This particular group may become the greatest beneficiaries of the modification of existing therapy based on platelet function monitoring. Full article

(This article belongs to the Special Issue Physiology of Platelets in Humans and Animals)

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