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. Author manuscript; available in PMC: 2020 Sep 1.
Published in final edited form as: Curr Opin Hematol. 2019 Sep;26(5):336–342. doi: 10.1097/MOH.0000000000000526

Altered Functions of Platelets During Aging

Emilie Montenont 1, Matthew T Rondina 1,2,3, Robert A Campbell 1,2
PMCID: PMC7039178  NIHMSID: NIHMS1558976  PMID: 31348047

Abstract

Purpose of review:

Platelets are specialized effector cells that rapidly respond to sites of vascular injury. However, emerging data demonstrate that platelets possess diverse functions that also mediate inflammatory responses and neurological diseases. These functions are relevant to disease processes prevalent among older adults and likely influence susceptibility to thrombotic and inflammatory disorders.

Recent findings:

Platelet counts decrease in aged individuals while platelet reactivity increases. The platelet transcriptome is altered in aged individuals resulting in altered platelet function and exaggerated inflammation. Platelet signaling to monocytes in aging results in significantly more cytokines due to increased platelet-derived granzyme A. Platelet activation in aging appears to be driven, in part, due to increased reactive oxygen species and activation of the mammalian target of rapamycin pathway. Increased platelet hyperactivity in diseases associated with aging, such cardiovascular disease and sepsis, exaggerate inflammation and thrombosis. Non-canonical functions of platelets influence the development of neurological diseases including Alzheimer’s disease.

Summary:

While there have been advances dissecting the molecular mechanisms regarding aged-related changes in platelets, many knowledge gaps still remain. Studies filling these gaps are likely to identify new mechanisms driving aging-related changes in platelet gene expression and function, and contributing to injurious thrombo-inflammation in older adults.

Keywords: Platelets, aging, inflammation, thrombosis

Introduction

Platelets are one of the few human cells that live and function without a nucleus. Because they are anucleate, platelets have been traditionally viewed as simple cells that inherit a predictable, fixed, and relatively short-acting hemostatic toolset from their parent cell: the megakaryocyte (MK). While the hemostatic roles of platelets are well recognized, emerging data demonstrate that platelets possess diverse and dynamic functions that also mediate inflammatory and immune responses. This review will summarize selected, key aspects of aging-related changes in platelets in the context of thrombotic and inflammatory diseases in older adults.

Thrombotic and Inflammatory Disorders are Prevalent in Aging

Dysregulated platelet functions have been associated with cardiovascular diseases, including coronary artery disease (CAD), stroke, and venous thromboembolism (VTE). These disease processes are associated with aging. For example, CAD is the leading cause of death for adults ≥75 years (1). Older age is also a risk factor for VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) (2). Similar to CAD, individuals with VTE and PE tend to be older with rates of VTE approximately 1/10,000 in younger adults, but rising to 1/1,000 (~10-fold increase) in adults 75 years and older (3). Consequently, as the life expectancy increases and the proportion of older adults rises, the burden of thrombotic disease in the elderly will likely become even greater.

Aging is also accompanied by a decreased tolerance to physiological stress and, in many cases, increased local and systemic inflammatory responses (4–9). Sepsis, a systemic inflammatory syndrome in response to infection, remains a significant cause of morbidity and mortality in older adults (4–7, 9–12). Micro- and macro-vascular thrombosis is common in sepsis and may contribute to the increased morbidity and mortality in older adults who develop sepsis (13, 14). Dysregulated inflammation in aging also contributes to neurological diseases, including vascular disease (e.g. stroke) and Alzheimer’s disease (AD) (15, 16). While comorbid conditions, and frailty are implicated in the development of these diseases, emerging and established data support platelets as cellular contributors through direct and/or indirect mechanisms.

Platelet number and function change during aging

As platelets play critical roles in thrombosis and thrombosis increases with aging, it may be surprising to some that platelet counts decrease with age. Multiple studies have reported lower platelet counts in older individuals from various ethnic populations across the world. Interestingly, platelet counts remain stable in young to middle-aged subjects (20-60 years old), but drop by approximately 10% in older individuals (>70 years old) (17–20). Even though women have approximately ~15% more platelets than men, the gender difference in platelet count persists in aging (17, 20, 21). The mechanisms behind decreasing platelet count during human aging remains unknown. However, some investigators have suggested that a reduction in hematopoietic stem cell reserve during aging could be responsible for reduced platelet production (22) while others have observed a shift in the hematopoietic stem cell population towards a megakaryocytic bias (23). These differing results suggest future studies are necessary to determine if changes in the hematopoietic stem cell population are responsible for alterations in platelet counts during aging.

Although platelet counts decrease in aging, platelet reactivity generally increases. As such, the increased risk for thrombosis in older individuals is likely due, in part, to increased platelet activation. For example, β-thromboglobulin (β-TG) and platelet factor 4 (PF4), two cytokines that are released by activated platelets and promote thrombosis, are increased in plasma from older individuals (24, 25). Further, earlier investigations demonstrated lower doses of collagen and adenosine diphosphate (ADP) were necessary to reach half-maximal platelet aggregation in adults age 60 and older compared to younger individuals (26–29). Higher platelet aggregation in response to ADP was also reported in 16-month-old wild type mice (a murine age that is felt comparable to older humans), compared to young 4-month-old mice (30*). This suggests that in some settings models of murine aging, findings may be similar to humans. Indeed, aged murine models are pivotal in understanding many pathobiological changes in platelets during aging (Davizon-Castillo P, Rondina MT, and Di Paola J; unpublished data).

Additionally, flow cytometry-based assays have been developed to measure markers of platelet activation, including activation of integrin αIIβ3 (an abundant platelet integrin that promotes thrombosis) as well as P-selectin, a protein contained in the α-granules, which is released upon platelet activation and mediates platelet binding to leukocytes. While these canonical platelet activation indices are used commonly to phenotype platelets in clinical studies and experimental model systems, few studies have systematically examined integrin αIIβ3 activation and P-selectin expression in the context of human aging. Recently, Haynes et al examined platelet activation in the context of endothelial dysfunction and observed no relationship between endothelial cell damage and platelet activation in aged individuals (31). However, these studies were performed exclusively in an aged population. Our laboratory has preliminarily examined integrin αIIβ3 activation in adults across the age spectrum (including older adults with frailty) and observed increased activation of integrin αIIβ3 compared to younger subjects (Davizon-Castillo P, Rondina MT, and Di Paola J; unpublished data). These preliminarily findings suggest platelet integrin αIIβ3 activation is heightened in older individuals and also support the need for future studies examining the interplay of frailty (which is associated with thrombosis) and aging on platelet functional responses.

More recently, a group has developed a Dynamic Platelet Function Assay, using parallel plate flow chambers coated with immobilized human Von Willebrand Factor (vWF) to investigate the effect of aging on platelet adhesion and activation (32). Using platelets from 100 healthy donors (aged 19 to 82), aging was associated with unstable platelet interactions with vWF, an adhesive plasma glycoprotein which binds platelet GPIbα. However, only six subjects in this study were over 60 and further studies assessing these changes in a larger population of older adults are warranted. Age-related changes in platelet function are more profound in women, than in men, indicating that both age and gender may significantly impact platelet interactions with vWF (33).

Platelet-monocyte interactions promote inflammation in aging

In addition to platelet activation and aggregation, monocyte phenotype and function are different in older adults than in younger adults, resulting in increased platelet-monocyte interactions (PMA) and exaggerated inflammatory responses (34). PMAs are formed when monocytes bind to platelet P-selectin via their surface P-selectin glycoprotein ligand-1 (PSGL1). In addition to binding monocytes after activation, platelets secrete RANTES which binds to CCR5 on monocytes, driving downstream synthesis of pro-inflammatory gene products by monocytes such as interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. Interestingly, circulating RANTES, IL-6, IL-8 and MCP-1 increase with age (35, 36). Our group recently identified a novel mechanism driving higher levels of monocyte-derived cytokines in aged individuals. We observed that platelet-monocyte interactions from aged individuals triggered the release of significantly higher levels of IL-8 and MCP-1 (37*). To dissect the mechanism behind increased cytokine synthesis, we performed next-generation RNA-sequencing on platelets from older individuals (age>65 years) compared to young, gender matched controls (age<40 years). We discovered that there were significant changes in the platelet transcriptome from older individuals. One of the differentially regulated transcripts in platelets was granzyme A (GrmA), a serine protease not previously identified in human platelets. In other cells, GrmA is known to modulate pro-inflammatory cytokine profiles (38). Remarkably, platelet-derived GrmA from aged individuals induced increased IL-8 and MCP-1 synthesis in a toll-like receptor 4 (TLR4) and caspase-1 dependent manner. Whether GrmA is acting specifically and selectively on monocytes, platelets, or both remains to be determined. Although human platelets do not synthesize IL-8 and MCP-1, they express TLR4 on their surface which can activate caspase-1 leading to inflammasome activation (39, 40). Thus, altered signaling through these pathways may affect platelet-monocyte interactions and activation, leading to increased monocyte-driven cytokine synthesis in older adults. Our work stands as an example for the increasingly recognized role of platelets as effector cells during systemic and injurious inflammatory responses that occur more commonly in older adults.

The role of platelets in aging-related inflammation

Beyond their well-recognized role in hemostasis and vascular injury repair, platelets also possess a broad repertoire of immune receptors and ligands, many of which are activated and/or released upon activation. Many of these molecules are stored within platelet granules. Platelets contain two relatively abundant types of granules: α-granules, and dense granules. Α-granules are the largest, most numerous granules in platelets and contain chemokines that recruit and activate other immune cells, and induce endothelial cell inflammation through β-TG, coagulation factors and adhesion molecules (including P-selectin). In addition, α-granules contain many anti-microbial agents (41). Interestingly, a large number of platelet α-granule components are increased with aging (42). For example, plasma concentrations of platelet-derived coagulation factors V and XIII (which are stored in α-granules) are increased with age, correlating with a heightened risk for thrombotic events (43). Α-granules also release fibrinogen and vWF, adhesion molecules which bind to activated integrin αIIβ3 and promote further platelet activation, adhesion and aggregation. These proteins are also elevated in older subjects (43). Dense granules release small molecules such as ADP, serotonin, epinephrine and polyphosphate, all playing major roles in platelet aggregation, coagulation, and immune responses (42). While many studies have focused on changes in hemostatic function during aging, how the expression and release of anti-microbial proteins and polyphosphates in platelets during aging have not been well characterized. Changes in these immune functions of platelets may have significant consequences in the setting of aging where infection and inflammation are more prevalent, and warrant future investigation.

Besides degranulation, activated platelets generate a large number of microparticles. Microparticles are plasma membrane vesicles of 0.1 to 1μm in diameter that contains numerous bioactive molecules. Platelet microparticles (PMPs) can transfer growth factors, RNA, and even cell surface receptors to target cells such as monocytes and endothelial cells, promoting activation (44–46). For example, a study by our group demonstrated that platelet activation induced IL-1β production. IL-1β was then delivered by PMPs to endothelial cells, inducing activation and their adhesiveness for neutrophils (46). As aging is associated with increase platelet activation, alterations in levels of PMP could affect the function of other cells which come in contact with circulating PMPs.

Linking platelets and age-related diseases

Aging is the predominant risk factor for many thrombo-inflammatory diseases, including CAD and stroke. Platelets mediate key aspects of the development and progression of CAD and stroke, anti-platelet agents are a mainstay of treatment for patients with, or at risk for, CAD. Much clinical data has been published that link increased platelet activation and hyperreactivity with poor clinical prognosis and progression of CAD and stroke (47, 48). Activated platelets interact with endothelial cells of inflamed or atherosclerotic arteries and deposit platelet-derived cytokines PF4 or RANTES onto the surface of endothelial cells. This contributes to the recruitment of leukocytes into the plaque. Furthermore, platelet-leukocyte aggregates are an independent risk factor for CAD and promote the development of atherosclerotic lesions in mice. These experimental observations have been extended clinically with a recent meta-analysis linking platelet reactivity to major adverse cardiac events (49). These data suggest that, despite anti-platelet therapy, platelet activation and hyperreactivity in subjects with CAD is associated with progression of atherosclerosis and increased risk of cardiovascular events.

VTE risk increases with aging and is associated with increased platelet activation (50). Emerging data highlights that platelets mediate key aspects of VTE development. Recently, some of the molecular mechanisms and signaling pathways related to aging-dependent increased platelet activation and VTE were elucidated. In aged mice, signaling through the mammalian target of rapamycin complex 1 (mTORC1) was increased in platelets and MKs. In these aged mice, increased platelet activation was also observed (30*). To determine the role of mTORC1, the authors deleted RAPTOR, a mTORC1 specific component, in mice. They observed markedly smaller thrombi in a VTE model when RAPTOR was depleted. Mechanistically, they determined increased reactive oxygen species (ROS) generation during aging induced mTORC1 activation in MKs and platelets, resulting in increased platelet activation and VTE. Consistent with this, therapeutic administration of a ROS scavenger significantly decreased platelet activation in aged mice. Another recent study reported that activated platelets released high-mobility group box 1 protein (HMGB1). The increase in HMGB1 promoted VTE by coordinating the crosstalk between platelets and leukocytes, including increased neutrophil extracellular trap formation, platelet aggregation, and monocyte activation (51, 52). In addition to platelet activation, the formation of PMA in aged individuals may also contribute to the development of VTE. Shih et al recently observed that increased PMA formation was predictive of VTE in older individuals after orthopedic surgery (50). These studies suggest altered platelet hyperactivity during aging may promote VTE through multiple different mechanisms.

In addition to altered hemostatic functions, platelets contribute significantly to inflammatory and infectious pathologies in older individuals. As an example, septic syndromes, including severe sepsis and septic shock, are the 10th leading cause of death among older adults. Septic syndromes are characterized by extensive platelet activation, adhesion, and aggregation (53, 54). As a result, platelet mediators (IL-1β, tissue factor, PF4, β-TG, P-selectin, etc.) are released into the systemic milieu, contributing to exaggerated inflammation, micro- and macro-vascular thrombosis, organ failure, and death. Increased formation of PMAs in older septic patients also significantly correlates with mortality and inflammation, whereas neither were associated with mortality in younger patients (55). Given that platelets play a significant role in the pathophysiology of sepsis, studies have also examined the role of antiplatelet therapy in improving outcomes. While still controversial, several animal models and clinical studies have demonstrated significant decreases in mortality associated with antiplatelet use during sepsis(56–59).

In addition to stroke, platelets also play a major role in aging-related neurologic disorders, including Alzheimer’s disease (AD). AD is characterized by neurotoxic amyloid-ß (Aβ) plaque and aggregate formation in the brain and cerebral blood vessels known as cerebral amyloid angiopathy (CAA) (60). Clinical studies have found that platelet activation in patients with AD was elevated compared to AD-free controls (61). In addition, platelet deposition was higher around amyloid deposits of cerebral vessels of AD transgenic mice. suggesting that platelets may help orchestrate the development of CAA (62). Platelets are an abundant source of the amyloid precursor protein (APP) and also possess the complete enzymatic machinery necessary to process APP proteins into amyloid-ß (Aß) peptides. Interestingly, incubation of platelets with Aß leads to platelet activation and enhanced generation of reactive oxygen species (ROS) (62). Others have demonstrated an age specific effect of Aß peptides on platelets, with Aß peptides inducing increased mitochondrial dysfunction in platelets from older subjects compared to younger subjects. These studies suggest a link between increased platelet activity, mitochondrial dysfunction and AD (63, 64). Additionally, APP may also regulate thrombosis. For example, APP knockout (KO) mice develop much larger thrombi than control animals in a VTE model. APP-KO mice also had increased circulating platelet-leukocyte aggregates, and neutrophils from APP-KO mice had a greater tendency to form extracellular traps (NETs, which in some settings are pro-thrombotic). These results indicate that platelet APP may not only play a role in the AD pathophysiology, but also other cardiovascular diseases (65*).

Conclusions

In conclusion, aging is associated with an altered platelet transcriptome and dysregulated platelet functions, leading to platelet hyperreactivity and increased interactions with other cells, thereby contributing to an increased risk of injurious thrombo-inflammatory events (Figure 1). While changes in the hemostatic functions of platelets contribute significantly to aging related thrombosis, newly discovered functions of platelets may dramatically affect inflammatory diseases associated with aging, including sepsis and AD. Over the past few years, our understanding of the molecular and phenotypic changes in platelets associated with aging have made significant advances. However, these changes remain only partially understood. As the population ages, ongoing research is needed to fill knowledge gaps and identify novel therapies that safely and effectively reduce the burden of thrombo-inflammatory disease in older adults.

Figure 1. Altered platelet functions during aging.

Figure 1.

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Aging is associated increased reactive oxygen species (ROS) generation in platelets due to mitochondrial dysfunction. ROS activates the mTOR signaling pathway resulting in increased platelet activation. In older individuals, platelet activation is characterized by increased αIIβ3 integrin activation. Degranulation upon activation induces the releases of coagulation factors and inflammatory mediators. Increased P-selectin expression and release of granzyme A from platelets promotes the formation of platelet-monocyte aggregations and secretion of pro-inflammatory cytokines. These cytokines and platelet-derived cytokines released from granules and PMP promote endothelial activation and increased systemic inflammation. Together, these events contribute to increased systemic inflammation and elevated risk for atherothrombotic events in aging.

Key Points.

  1. Platelets play a significant role in many diseases associated with aging, including cardiovascular disease as well as inflammatory and neurological syndromes.

  2. Platelet activation increases during aging resulting in increased activation of platelet integrins and release of chemokines and cytokines.

  3. Increased platelet activation in aging is due, in part, to increased reactive oxygen species and mitochondrial dysfunction activating the mTORC1 pathway.

  4. Platelet-monocyte interactions in the setting of aging result in increased monocyte-dependent cytokine secretion due to platelet-derived granzyme A.

  5. Inflammatory and neurological diseases in aging are driven by increased platelet activation.

Acknowledgements

We would like to thank Ms. Diana Lim for her creativity and excellent assistance with the figure and Ms. Toni Blair for her editorial assistance.

Financial Support and sponsorship

Disclosures of Funding Source: This work was supported by the National Institute of Health (HL126547, HL142804, AG059877, and AG048022 to M.T.R., K01AG059892 to R.A.C). This work was also supported in part by Merit Review Award Number I01 CX001696 from the United States (U.S.) Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service. This material is the result of work supported with resources and the use of facilities at the George E. Wahlen VA Medical Center, Salt Lake City, Utah.

Footnotes

Conflict of Interest.

None

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