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Semin Thromb Hemost 2024; 50(08): 1187-1190
DOI: 10.1055/s-0044-1787663
Historical Commentary

Platelet Pathophysiology: Unexpected New Research Directions

Alan D. Michelson
1   Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
,
Andrew L. Frelinger III
1   Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
,
Robin L. Haynes
2   Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts
,
Hannah C. Kinney
2   Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts
,
Thomas Gremmel
3   Department of Internal Medicine I, Cardiology and Intensive Care Medicine, Landesklinikum Mistelbach-Gänserndorf, Mistelbach, Austria
4   Institute of Cardiovascular Pharmacotherapy and Interventional Cardiology, Karl Landsteiner Society, St. Pölten, Austria
5   Karl Landsteiner University of Health Sciences, Krems, Austria
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Funding This article received funding from Eunice Kennedy Shriver National Institute of Child Health and Development Grant P01-HD036379 (to H.C.K.).
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We are very honored that our 2016 review of platelet physiology[1] is one of the top three most downloaded papers in Seminars and Thrombosis and Haemostasis from 2014 to 2023. But why study platelet physiology? Because these remarkable little cells play key roles in many important pathophysiological processes, including thrombosis, hemorrhage, inflammation, antimicrobial host defense, wound healing, angiogenesis, and tumor growth and metastasis.[2] In addition to primary disorders of platelet number and function, platelets have a critical role in many other very common diseases, including coronary artery disease, stroke, peripheral vascular disease, and diabetes mellitus.[2] There remain many incompletely understood aspects of platelet physiology and its relationship to diseases, a few examples of which are the role of platelets in innate and adaptive immunity,[3] [4] the genetic basis of thrombocytopenia,[5] the role of platelet activation in coronavirus disease 2019,[6] the role of platelet activation in liver disease,[7] and novel targets for antiplatelet therapy.[8] [9] [10] But science in general, and the study of platelet physiology in particular, can sometimes lead researchers in an unexpected new direction, as will be discussed in this commentary focused on the relationship between platelet function and sudden infant death syndrome (SIDS).

SIDS is defined as the sudden unexpected death of an apparently healthy infant less than 1 year of age that remains unexplained despite a complete autopsy with ancillary testing, examination of the death scene, and review of the clinical history.[11] [12] SIDS is the leading cause of postneonatal mortality in the United States.[13] [14] [15] There are no currently available biomarkers of SIDS in living infants. However, a subset of infants who die of SIDS have abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14-3-3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal ([Fig. 1]).[16] [17] [18] [19] [20] [21]

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Fig. 1 Platelet physiology and neuron physiology involve many of the same molecules and pathways. Previously identified abnormalities in neurons of SIDS subjects are shown in purple. (Adapted from Kinney et al[40].) GP, glycoprotein; SIDS, sudden infant death syndrome; VMAT, vesicular monoamine transporter; 5-HT, 5-hydroxytryptamine.

Serotonin is synthesized in the gut, where it is released primarily after stimulation of enterochromaffin cells.[22] [23] [24] Once 5-HT enters the intestinal vasculature, it is sequestered inside platelets by the 5-HT transporter ([Fig. 1]), and then into dense granules by the vesicular monoamine transporter ([Fig. 1]). Approximately 95% of the 5-HT in blood is carried in platelet-dense granules,[25] and serum contains the secretion products of activated platelets, including their dense granules. Platelet activation leads to secretion of dense granule contents, and the secreted 5-HT binds to the platelet surface 5-HT receptor 5-HT2A ([Fig. 1]), activating signaling pathways that amplify initial platelet activation.[26] [27] [28] Downstream events following 5-HT binding to 5-HT2A include increases in cytosolic calcium and F-actin ([Fig. 1]).

Because (a) approximately 20 to 80% of SIDS deaths are associated with 5-HT receptor (5-HT1A or 5-HT2A/C) binding abnormalities in regions of the brainstem critical in homeostatic regulation,[29] [30] (b) approximately 95% of the 5-HT in blood is carried in platelet-dense granules[25] and serum contains the secretion products of activated platelets (including their dense granules), and (c) blood platelets have similar 5-HT signaling pathways to brain neurons ([Fig. 1]), we hypothesized that SIDS is associated with an alteration in serum 5-HT levels. Indeed, we demonstrated that serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15; SIDS, 177.2 ± 15.1 [mean ± SE] ng/mL vs. controls, 91.1 ± 30.6 ng/mL; p = 0.014), as determined by ELISA.[31] This increase was validated using high-performance liquid chromatography. Thirty-one percent (19/61) of SIDS cases had 5-HT levels greater than 2 SD above the mean of the controls, thus defining a subset of SIDS cases with elevated 5-HT.[31] There was no association between genotypes of the serotonin transporter promoter region polymorphism and serum 5-HT level. This study demonstrated that SIDS is associated with peripheral abnormalities in the 5-HT pathway, and that high serum 5-HT may serve as a potential forensic biomarker in autopsied SIDS infants with serotonergic defects.[31]

Because (a) brain neurons have 5-HT and 14-3-3 signaling pathways which are abnormal in SIDS ([Fig. 1]) and (b) blood platelets have similar 5-HT and 14-3-3 signaling pathways to neurons ([Fig. 1]), we then hypothesized that SIDS is, at least in part, a multiorgan dysregulation of 5-HT and that platelets may be a peripherally accessible marker for SIDS brain abnormalities. However, before we could address this hypothesis, we needed to overcome some major hurdles. As we recently discussed,[32] direct study of SIDS is inherently difficult due to the infrequent and unexpected nature of the disease, regulatory issues, and logistical and methodological issues surrounding specimen collection and storage. Regulatory issues were addressed by means of a Californian law which identified research on SIDS to be in the public interest and allows samples collected at autopsy to be made available for research.[31] [32] Platelet analysis requires free-flowing, unclotted blood which, somewhat surprisingly, is found at autopsy either because coagulation has not occurred or because fibrinolysis has taken place following postmortem coagulation. Previous studies have reported that platelets in postmortem blood are largely unactivated.[33] We were able to specifically demonstrate the feasibility of measuring platelet pathophysiology in postmortem blood.[32]

We then showed the following in SIDS subjects compared with control cases[32]: (1) increased levels of plasma and intraplatelet 5-HT, (2) decreased levels of platelet 14-3-3ζ protein, (3) decreased levels of the platelet surface adhesion receptor glycoprotein (GP) IX, and (4) in this independent cohort, confirmation of our previous finding[31] of elevated serum 5-HT. Moreover, a correlation was observed between platelet surface GPIX and levels of both serum and plasma 5-HT. Thus, the differences between SIDS and controls in both platelet and brainstem 5-HT and 14-3-3 biomarkers suggest a global dysregulation of these pathways in SIDS.

Unrecognized infection and neuroinflammation may be present in a subset of SIDS[34] and, as we recently reviewed,[32] platelets may represent a link between the periphery and neuroinflammation.[35] [36] [37] [38] In the setting of epilepsy, platelets themselves are reported to directly contribute to neuroinflammation by modulating brain 5-HT.[39] Specifically, platelet degranulation near the blood–brain barrier may directly affect the brain endothelium and factors released by platelets, including 5-HT, may alter neuronal activity.[39] Therefore, the presently reported platelet biomarker abnormalities raise the possibility that platelets in SIDS may also contribute to neuroinflammation.[32]

The presence in SIDS of both platelet and brainstem 5-HT and 14-3-3 abnormalities suggest the potential for platelets to be used as a model system to study 5-HT and 14-3-3 interactions in SIDS.[32] Moreover, platelet and serum biomarkers may aid in the forensic determination of SIDS and, unlike neurons, have the potential to be an easily accessible predictor of SIDS risk in living infants. Thus, the study of platelet physiology[1] can sometimes lead researchers in unexpected and fruitful new directions.



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Artikel online veröffentlicht:
18. Juni 2024

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