Browsing by Subject "Platelets"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Genome sequencing unveils a regulatory landscape of platelet reactivity
    (Springer Nature, 2021-06-15) Keramati, Ali R.; Chen, Ming-Huei; Rodriguez, Benjamin A. T.; Yanek, Lisa R.; Bhan, Arunoday; Gaynor, Brady J.; Ryan, Kathleen; Brody, Jennifer A.; Zhong, Xue; Wei, Qiang; NHLBI Trans-Omics for Precision (TOPMed) Consortium; Kammers, Kai; Kanchan, Kanika; Iyer, Kruthika; Kowalski, Madeline H.; Pitsillides, Achilleas N.; Cupples, L. Adrienne; Li, Bingshan; Schlaeger, Thorsten M.; Shuldiner, Alan R.; O’Connell, Jeffrey R.; Ruczinski, Ingo; Mitchell, Braxton D.; Faraday, Nauder; Taub, Margaret A.; Becker, Lewis C.; Lewis, Joshua P.; Mathias, Rasika A.; Johnson, Andrew D.; Medicine, School of Medicine
    Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
  • Thumbnail Image
    Item
    Platelet Delta (δ)-Storage Pool Deficiency: A Case Series and Review of the Literature
    (MDPI, 2023-06-29) Beirat, Amir F.; Menakuru, Sasmith R.; Kalra, Maitri; Medicine, School of Medicine
    Hereditary platelet delta (δ)-storage pool deficiency is a rare condition in which there are fewer dense granules in platelets disrupting primary hemostasis. It can cause a mild-moderate bleeding tendency with normal coagulation studies; hence, it is an underdiagnosed diagnostic challenge. The authors present three patients with hereditary platelet delta (δ)-storage pool deficiency who had heavy menstrual bleeding, excessive bleeding following surgery, mucocutaneous bleeding, and a bleeding score greater than or equal to 6. These cases reveal the susceptibility of underdiagnosing platelet disorders and the significance of utilizing a bleeding assessment tool to help guide further workup with transmission electron microscopy to visualize the fewer dense granules in platelets. Although bleeding is typically moderate, it can be severe in certain scenarios, like after mucosal surgeries, and can lead to death, highlighting the importance of the condition's recognition and prophylactic treatment.
  • Thumbnail Image
    Item
    The Platelet-activating Factor Receptor Protects Epidermal Cells from Tumor Necrosis Factor (TNF) α and TNF-related Apoptosis-inducing Ligand-induced Apoptosis through an NF-κB-dependent Process
    (American Society for Biochemistry and Molecular Biology, 2001-12-07) Southall, Michael D.; Isenberg, Jason S.; Nakshatri, Harikrishna; Yi, Qiaofang; Pei, Yong; Spandau, Dan F.; Travers, Jeffrey B.
    A number of chemical mediators can induce human keratinocytes and epidermal-derived carcinomas to undergo apoptosis, or programmed cell death. Recent evidence suggests pro-inflammatory cytokines, such as interleukin-1β or transforming growth factor α, protects carcinomas from numerous pro-apoptotic stimuli. Platelet-activating factor (1-alkyl-2-acetyl-3-glycerophosphocholine; PAF) is a lipid mediator with pro-inflammatory effects on numerous cell types. Although PAF can be metabolized to other bioactive lipids, the majority of PAF effects occur through activation of a G protein-coupled receptor. Using a model system created by retroviral transduction of the PAF receptor (PAF-R) into the PAF-R-negative human epidermal cell line KB and the PAF-R-expressing keratinocyte cell line HaCaT, we now demonstrate that activation of the epidermal PAF-R results in protection from apoptosis induced by tumor necrosis factor (TNF) α or TNF-related apoptosis-inducing ligand. The PAF-mediated protection was inhibited by PAF-R antagonists, and protection did not occur in PAF-R-negative KB cells. Additionally, we show protection from TNFα- or TRAIL-induced apoptosis by PAF-R activation is dependent on the transcription factor nuclear factor (NF)-κB, because PAF-R activation-induced NF-κB and epidermal cells transduced with a super-repressor form of inhibitor κB were not protected by the PAF-R. These studies provide a mechanism whereby the epidermal PAF-R, and possibly other G protein-coupled receptors, can exert anti-apoptotic effects through an NF-κB-dependent process.
  • Thumbnail Image
    Item
    Platelets in Alcohol-Associated Liver Disease: Interaction With Neutrophils
    (Elsevier, 2024) Wang, Juan; Wang, Xianda; Peng, Haodong; Dong, Zijian; Liangpunsakul, Suthat; Zuo, Li; Wang, Hua; Medicine, School of Medicine
    Alcohol-associated liver disease (ALD) is a major contributor to liver-related mortality globally. An increasing body of evidence underscores the pivotal role of platelets throughout the spectrum of liver injury and recovery, offering unique insights into liver homeostasis and pathobiology. Alcoholic-associated steatohepatitis is characterized by the infiltration of hepatic neutrophils. Recent studies have highlighted the extensive distance neutrophils travel through sinusoids to reach the liver injury site, relying on a platelet-paved endothelium for efficient crawling. The adherence of platelets to neutrophils is crucial for accurate migration from circulation to the inflammatory site. A gradual decline in platelet levels leads to diminished neutrophil recruitment. Platelets exhibit the ability to activate neutrophils. Platelet activation is heightened upon the release of platelet granule contents, which synergistically activate neutrophils through their respective receptors. The sequence culminates in the formation of platelet–neutrophil complexes and the release of neutrophil extracellular traps intensifies liver damage, fosters inflammatory immune responses, and triggers hepatotoxic processes. Neutrophil infiltration is a hallmark of alcohol-associated steatohepatitis, and the roles of neutrophils in ALD pathogenesis have been studied extensively, however, the involvement of platelets in ALD has received little attention. The current review consolidates recent findings on the intricate and diverse roles of platelets and neutrophils in liver pathophysiology and in ALD. Potential therapeutic strategies are highlighted, focusing on targeting platelet–neutrophil interactions and activation in ALD. The anticipation is that innovative methods for manipulating platelet and neutrophil functions will open promising avenues for future ALD therapy.
  • Thumbnail Image
    Item
    Systems biology of platelet-vessel wall interactions
    (Springer, 2014) Chen, Yolande; Corey, Seth Joel; Kim, Oleg V.; Alber, Mark S.; Department of Medicine, IU School of Medicine
    Platelets are small, anucleated cells that participate in primary hemostasis by forming a hemostatic plug at the site of a blood vessel's breach, preventing blood loss. However, hemostatic events can lead to excessive thrombosis, resulting in life-threatening strokes, emboli, or infarction. Development of multi-scale models coupling processes at several scales and running predictive model simulations on powerful computer clusters can help interdisciplinary groups of researchers to suggest and test new patient-specific treatment strategies.