Aortic aneurysm is associated with consumption coagulopathy [10]. Cases of complicated AAA with chronic disseminated intravascular coagulopathy have been reported [21,22]. Chronic disseminated intravascular coagulopathy was cured by surgical repair in an elderly patient with AAA over the next 14 days [23]. Although no significant differences were found between acutely symptomatic non-ruptured and ruptured AAA [24], platelet count was significantly lower in patients with AAA compared with healthy controls [25], suggesting an increase in platelet destruction, most likely through activation within the aneurysm sac [26,27]. Patients with AAA had higher baseline spontaneous platelet aggregation compared with normal controls [28]. The relationship between platelet count and aortic aneurysm size is controversial. A clinical study reported that platelet count decreased as aneurysm size increased, and platelet count was lower in patients with a large AAA (diameter > 55 mm) [29]. In contrast, no significant differences in platelet count were found between patients with a large AAA and small AAA in another study [30]. The correlation between platelet indices, such as platelet count, mean platelet volume, the platelet/large cell ratio, and platelet distribution width, are important factors for understanding platelet heterogeneity [31]. In addition to the decrease in platelet count, mean platelet volume, the mean platelet volume-to-platelet count ratio, the mean platelet volume-to-lymphocyte ratio, and the red cell distribution width-to-platelet count ratio were significantly higher in patients with AAA [32].

Pathophysiological evidence from patients and animal models indicates ILT formation in the lumen in AAA [33]. The ILT is often structured in three layers in AAA patients: luminal, medial, and abluminal. The luminal ILT layer, which is in contact with blood, is biologically active and enriched in platelets, neutrophils, and red blood cells. The ILT rarely embolizes but does not resolve once it occurs. Eccentric distribution of the ILT was associated with continuous AAA expansion, and a thicker ILT volume was associated with a higher growth rate [34]. Inflammatory cells and cytokines were reported to accumulate in the ILT and play an important role in AAA progression [35,36]. The evolution of ILT can lead to vessel wall weakness through high concentrations of reactive oxygen species, proteases, and cytokines. A study showed that ILT thickness correlated with matrix metalloproteinase 9 (MMP9) expression [37]. Roxana et al. reported that local C3 retention, consumption, and proteolysis in the ILT could induce polymorphonuclear leukocyte chemotaxis and activation, associated with a decrease in systemic complement concentration and activity in later stages of AAA [38].

Adenosine diphosphate is an important activator of platelets [40]. It exerts its activity through three major purinergic receptors: P2Y12, P2Y1, and P2X1. They are important for changes in platelet shape and aggregation, TxA2 generation, procoagulant activity, adhesion to immobilized fibrinogen, and thrombus formation under shear conditions. P2Y12 receptors are also important for the potentiation of platelet activation that is mediated by other physiological agonists, including collagen, vWF, and TxA2, resulting in sustained platelet activation [39,41]. P2Y12 receptor antagonists, such as clopidogrel and ticagrelor, inhibit platelets by selectively and irreversibly binding to P2Y12 receptors and blocking the ADP-dependent pathway of platelet activation. In a rat model that implanted a segment of the sodium dodecyl sulfate-decellularized guinea pig aorta, the P2Y12 receptor antagonist AZD6140 inhibited platelet activation and prevented the development of AAA by inhibiting ADP-induced platelet aggregation and limiting biological activity of the ILT [42]. Administration of the P2Y12 inhibitor clopidogrel significantly suppressed aortic expansion, elastic lamina degradation, inflammatory cytokine expression, and aortic aneurysm rupture in an established animal model of AAA that was induced by Ang II infusion in hypercholesterolemic mice [43]. Clopidogrel bisulfate reduced death among patients with AAA [44]. However, a multicenter randomized, double-blind, controlled trial of ticagrelor and placebo reported different results. Patients who were randomized to ticagrelor did not exhibit a reduction in AAA growth compared with controls during the 12-month follow-up period. This was the first interventional trial on AAA growth using AAA volume as the primary outcome measure other than rupture [45]. In response to the limited clinical studies of the effects of ADP receptor antagonists on AAA, a Phase 2 clinical trial is currently verifying the efficacy of ticagrelor in patients with a small AAA (ClinicalTrials identifier: NCT02070653).

P-selectin (CD62P) is an adhesion receptor for neutrophils and macrophages that is expressed on both endothelial cells and platelets [46]. In platelets, P-selectin is stored in α granules and mobilized to the external plasma membrane within minutes after activation. The expression of P-selectin on activated platelets is important for the recruitment of leukocytes to thrombi and induction of fibrin production during hemostasis. Because detection is relatively easy, soluble P-selectin was assayed as a marker of platelet activity. Soluble P-selectin significantly increased in plasma in patients with AAA [36]. Likewise, P-selectin significantly increased in an animal model of AAA that was established by xenografting a segment of the sodium dodecyl sulfate-decellularized guinea-pig aorta (xenogenic matrix) onto the abdominal aorta in rats [36]. P-selectin deficiency attenuated AAA formation in elastase aortic perfusion mice, with diminished aortic wall degradation and preserved elastin and collagen [47]. P-selectin glycoprotein ligand-1 (PSGL-1) acts as a critical regulator of inflammatory cells infiltration by mediating the adhesion of leukocytes. PSGL-1 deficiency reduced the incidence and severity of AAA by inhibiting inflammatory cell migration and recruitment under conditions of aortic aneurysm [48].

Integrin αIIbβ3 is expressed at high levels in platelets and their progenitors. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, it switches from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which drives essential platelet functions, such as spreading, aggregation, clot retraction, and thrombus consolidation [49]. The inhibition of integrin αIIbβ3 by treatment with the Fab fragment abciximab for 6 weeks reduced both thrombus area and aneurysmal enlargement in a rat xenograft model of AAA compared with treatment with irrelevant immunoglobulins [36].

GPIb is a major glycoprotein on the platelet surface. Like the integrin αIIbβ3, GPIb undergoes reversible translocation as a function of platelet activation [50]. As an extramembranous portion of GPIb, glycocalicin was higher in patients with AAA than in patients who underwent carotid endarterectomy, indicating that GPIb was cleaved from the platelet membrane after platelet activation and turnover [26].

TxA2 is produced from arachidonate through the aspirin-sensitive cyclooxygenase 1 (COX-1) pathway in activated platelets and involved in multiple biological processes via its cell-surface thromboxane prostanoid (TP) receptor. TxA2 binds to TP, leading to changes in platelet shape, phospholipase A2 activation, the platelet degranulation of dense granules and alpha granules, and platelet aggregation [51]. The release of TxA2 amplifies the initial stimulus for platelet activation and helps recruit additional platelets. TxB2 (the hydrolysis product of TxA2) was the main prostanoid that was produced by tissue from AAA in humans [52]. Preliminary promising results indicated that the TxA2 inhibitor BM-573 suppressed aneurysmal growth in rats [53].

Aspirin (acetylsalicylic acid) irreversibly inhibits platelet COX-1, blocking TxA2 production in platelets and decreasing platelet aggregation. The administration of aspirin dramatically reduced the rupture of AAA that was induced by a high-fat diet and Ang II infusion in Ldlr^−/− mice. Aspirin also reduced platelet and macrophage recruitment, resulting in a decrease in MMP activity, and reduced plasma concentrations of PF4, cytokines, and components of the plasminogen activation system in abdominal aortas in mice [44]. Patients with AAA are recommended to receive low-dose aspirin or a P2Y12 receptor antagonist for the secondary prevention of AAA progression or rupture [54,55].

PDGF is a potent mitogen for cells that is partially synthesized and stored in alpha granules of platelets and released upon platelet activation. There are five different isoforms of PDGF that activate cellular responses through two different receptors (PDGFRα and PDGFRβ), known as PDGF-AA (PDGFA), PDGF-BB (PDGFB), PDGF-CC (PDGFC), PDGF-DD (PDGFD), and PDGF-AB [56]. PDGFA was reported to increase in human AAA tissue in a membrane-based complementary DNA expression array [57]. PDGF A and B chains were strongly stained on small vessels in aneurysmal walls of atherosclerotic AAA in patients, whereas the weaker expression of PDGF A and B chains was observed in endothelial cells of vessel walls around inflammatory cells in the aneurysmal wall of inflammatory AAA [58]. PDGFD was shown to mediate adventitial inflammation, which provided a direct link between perivascular adipose tissue dysfunction and AAA formation in Ang II-infused obese mice [59].

Both CD40L and CD40 exist in platelets [60]. CD40L is cryptic in unstimulated platelets but rapidly presents to the platelet surface after platelet activation. CD40L that is expressed on the cell surface is subsequently cleaved, generating a soluble fragment, termed sCD40L. Studies of the cellular distribution of CD40L indicated that >95% of circulating CD40L was produced by platelets [61,62]. The ligation of platelet CD40 with sCD40L increased platelet P-selectin expression and granule release and enhanced platelet-leukocyte adhesion [63]. The abundance of both CD40L and CD40 increased in media of thrombus-free and thrombus-covered human AAA samples. The CD40L–CD40 axis has been implicated in aneurysm formation. CD40L deficiency reduced inflammatory chemokine/cytokine expression, MMP activity, and macrophage infiltration, lowering the incidence of AAA and risk of rupture [64].

Platelets regulate leukocyte recruitment indirectly via the release of chemokines upon platelet activation. Platelet factor 4 (PF4/CXCL4) and RANTES (CCL5) are two main chemokines that are located within alpha granules of platelets. CXCL4 has been shown to form functional heterodimers with CCL5 to promote the recruitment of neutrophils, macrophages, and T cells [65]. CXCL4 and CCL5 levels increased in plasma in AAA patients, with high levels in luminal layers of ILTs [66]. Platelets and neutrophils co-localized in luminal ILT layers of AAA [66], and plasma levels of CXCL4 and CCL5 were positively associated with macrophage recruitment in murine AAA models [44]. The inhibition of CXCL4-CCL5 heterodimers by the peptide inhibitor MKEY before or after the induction of experimental AAA was reported to efficiently prevent the development of AAA or halt its progression, respectively [67].

Ficolin-3 (H-ficolin) is one of the most abundant and efficient recognition molecules in the lectin pathway of the complement system, which was identified in platelet-derived microvesicles [68]. Ficolin-3 levels in microvesicles that were obtained from plasma-activated platelets and AAA tissue were associated with the presence and progression of AAA compared with healthy ones [69]. High levels of ficolin-3 in the AAA thrombus could be involved in complement-coagulation crosstalk and the immune-inflammatory response that is associated with AAA.

Myeloperoxidase, which is partially released by activated platelets, was localized both on the surface of and inside platelets. Etienne et al. found that myeloperoxidase was significantly elevated in experimental saccular aneurysms compared with fusiform aneurysms in a decellularized xenograft model in rats [70], and it caused oxidative damage by producing superoxide in a chronic remodel of AAA [71].

vWF is a large, multimeric glycoprotein that is found in blood plasma, platelet granules, and subendothelial connective tissue that mediates the adhesion of platelets to subendothelial connective tissue [72]. A prospective study found that vWF activity in plasma correlated with AAA thrombus size [73]. Another study found that 14-3-3ζ that was stored in dense granules was secreted by activated platelets in the abdominal aorta in patients with aneurysm, based on an organellar proteomics method [74]. Serum levels of thrombospondin-1 and clusterin, which are secreted by platelets, were negatively associated among 1003 AAA patients [75].

Labeled platelets and visualization method reveal the role of the platelet activation in aneurysm progression in another way. Accompanied by platelet activation, phosphatidylserine that is exposed on platelet membranes is a mediator that links platelet vesicles to aneurysm progression. Radiolabeled 99mTc-annexin-V specifically binds phosphatidylserine and has been used to assess the renewal activity of ILT in an in vivo experimental model of AAA and ex vivo in human ILT [84]. 99mTc-fucoidan is an imaging agent for the in vivo detection of biological activity that is associated with P-selectin overexpression on activated platelets in humans and rats with AAA [85,86]. Biodegradable microcapsules that are made of polycyanoacrylate and polysaccharide that are functionalized with fucoidan had high binding activities by targeting arterial thrombi that overexpressed P-selectin in human activated platelets and rat AAA thrombotic wall [87].

Surgical repair, including traditional open surgical repair and EVAR, is indicated for AAA with a diameter greater than 5.5 cm in men and 5.0 cm in women, growth of more than 0.5 cm in 6 months, or AAA-related symptoms, such as rupture, dissection, and pain [88]. Low platelet count at the time of hospital admission predicts poor outcome in patients who undergo the emergency repair of a ruptured AAA [89,90]. Platelet count and platelet activity significantly increased after AAA repair [25,91]. Platelet count decreased significantly in patients who underwent EVAR during the first few days postsurgery, returning to preoperative levels by 1-week to 1-month post-EVAR [92,93,94]. Vascular surgeons encounter an endovascular-specific problem, the so-called endoleak, which reduces the curability of EVAR. In EVAR in 249 patients, platelet count after EVAR in patients with malignant type II endoleak was lower than in patients without malignant endoleak [95]. A lack of aneurysm shrinkage by 7 days and 6 months after EVAR was significantly associated with ongoing multiagent antiplatelet therapy with clopidogrel, ticlopidine, cilostazol, and aspirin [96].

Transfusion during open surgery is essential to increase platelet count and function in response to massive blood loss and platelet disorders. Patients with ruptured AAA who received proactive transfusion therapy with platelets had a higher platelet count when they were admitted to the intensive care unit compared with the control group [97]. Patients with ruptured AAA who received more platelets and plasma intraoperatively had lower 30-day mortality compared with control patients [98]. Patients who were scheduled to undergo the open repair of a ruptured AAA, however, received no significant benefit from the early administration of platelets with regard to postoperative complications and mortality [99]. Platelet transfusion was an independent marker of thrombotic complications in patients with ruptured AAA [100].