Platelets in sickle cell disease: biomarkers, mediators, and lessons from clinical trials

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Abstract

Sickle cell disease (SCD) is an inherited hemolytic disorder characterized by a mutation in β-globin, resulting in hemoglobin polymerization, red blood cell rigidity, and a persistently activated endothelium that promotes thromboinflammation. Platelets are recognized as central mediators of this thromboinflammatory milieu, integrating signals from hemostatic and innate immune pathways. In this review, we summarize the disease-specific mechanisms by which platelets are activated in SCD, including G-protein coupled receptor signaling, C-type lectin-like receptor-2 (CLEC-2)/glycoprotein VI–Bruton tyrosine kinase pathways, and responses to damage-associated molecular patterns such as free heme, and how these processes amplify leukocyte recruitment, inflammasome activation, and vascular occlusion. We highlight emerging platelet-associated biomarkers that correlate with disease severity and acute complications, including platelet-leukocyte aggregates, P-selectin, podoplanin–CLEC-2 signaling, and inflammatory cytokine pathways. Finally, we evaluate clinical trial data targeting platelet pathways, from early aspirin studies to more recent trials of P2Y purinoceptor-12 inhibitors and selectin-blocking agents, noting both the promise and limitations of these approaches. Together, these findings underscore the multifaceted contribution of platelets to SCD pathophysiology, and point toward ongoing questions regarding whether platelets primarily serve as biomarkers of disease activity or represent modifiable therapeutic targets capable of reducing the clinical burden of SCD.

SCD

Sickle cell disease (SCD) is currently the most common inherited blood disorder worldwide, occurring in >500 000 births annually.¹ This chronic blood disorder is characterized by a mutation in the HBB gene, leading to production of sickle hemoglobin β (HbS).^2,3 Subsequently, polymerization of HbS within red blood cells (RBCs) causes decreased deformability and increased risk of hemolysis. These sickle RBCs circulate within a chronically activated vascular endothelium, which is prone to adhere not only to the fragile RBCs, but also leukocytes and platelets.4, 5, 6 This thromboinflammation in SCD is a known contributor to morbidity in this patient population, causing complications related to thrombosis such as vaso-occlusive pain crises (VOC), stroke, venous thromboembolism, and acute chest syndrome.^7,8 Although previously considered separate systems, the pathophysiology of SCD demonstrates that both hemostatic functions and the innate immune systems are interrelated.^6,9,10 Platelets are key players in the balance of thrombosis and inflammation. In this review, we will discuss how platelet thromboinflammatory responses in SCD have been studied and targeted over the last decade.

Mechanisms of platelet activation

Platelets express a diverse array of receptors involved in activation that play important roles in thrombosis, inflammation, and angiogenesis, and have differing effects based on affinity and density. To best consider the role of platelets in SCD, we briefly outline these basic mechanisms of platelets in a healthy host. Here we will discuss the pathways by which platelets are activated by prothrombotic and proinflammatory mediators.

Thrombotic platelet activation

At baseline, platelets are maintained in a quiescent state by endothelial cells, via release of nitric oxide and prostaglandin I2, which bind to surface proteins on platelets to upregulate intracellular cAMP and prevent platelet activation.^5,11,12 Platelets become activated via adhesion receptors glycoprotein 1b alpha (GPIbα) and glycoprotein IIb/IIIa (GPIIb/IIIa), immunoreceptor tyrosine-based activation motif receptors (C-type lectin-like receptor-2 [CLEC-2] and glycoprotein VI [GPVI]), and G-protein coupled receptors (protease-activated receptors [PARs] and P2Y purinoceptor-12 [P2Y₁₂]).

Platelet GPIbα binds to von Willebrand Factor (VWF), which tethers circulating platelets to the damaged endothelium. Platelet integrin α_IIbβ₃ activation is crucial for stable adhesion to occur after VWF binds to GPIbα.^13,14 Collagen engagement with platelet integrin α2β1 and immunoreceptor tyrosine-based activation motif GPVI is also essential for platelet adhesion and plug formation.⁵

CLEC-2 receptor transmembrane signaling is initiated by ligands such as rhodocytin and podoplanin, which is expressed on lymphatic endothelial cells and monocytes. Podoplanin–CLEC-2 interactions are particularly relevant in highly inflammatory and prothrombotic settings such as cancer, where they contribute to platelet activation and thrombus formation. CLEC-2 signaling converges with GPVI receptor signaling, sharing a downstream signaling cascade with Bruton tyrosine kinase (BTK), ultimately triggering release of Ca²⁺ from the intracellular dense tubular systems and activation of protein kinase C. This coordinated signaling ultimately drives platelet activation, granule secretion, and aggregation.

Ca²⁺ and protein kinase C promote the secretion and/or amplification of platelet G-protein coupled receptor agonists. These agonists include ADP, which binds P2Y₁₂ and P2Y₁, thromboxane A2, which binds thromboxane prostanoid receptor, and epinephrine, which binds α_2A adrenergic receptors.¹⁵ Platelets also support thrombin generation, which activates PAR1 and PAR4 on the platelet surface. Current studies have focused on identifying the receptor pathways that may serve as novel therapeutic targets to decrease the prothrombotic and proadhesive activity of platelets in SCD.

Inflammatory platelet activation

Platelets also have distinct functions within the innate immune system and play key roles in systemic inflammation. Interactions between platelets and white blood cells are mediated by pattern recognition receptors, including toll-like receptors (TLRs) and components of the NLR family pyrin domain containing 3 (NLRP3) inflammasome.^16,17 Typically, these receptors are activated by pathogen-associated molecular patterns such as lipopolysaccharide, leading to more than just platelet activation, adhesion, and aggregation. They also promote neutrophil recruitment and inflammatory signaling at sites of injury or infection.

Platelets are also activated by damage-associated molecular patterns (DAMPs), such as free heme released during RBC hemolysis.¹⁶ Activated platelets can trigger the release of other DAMPs, such as DNA-associated nuclear proteins like histones and serine proteases, including neutrophil elastase during the formation of neutrophil extracellular traps.^18,19 These neutrophil extracellular traps stimulate activation of neutrophil αMβ2 integrin (Mac-1), which binds to platelet GPIbα, leading to platelet activation and surface expression of P-selectin (CD62). P-selectin is a selectin stored in α granules and is rapidly expressed on the surface of activated platelets.¹⁹ Leukocytes express its ligand P-selectin glycoprotein ligand-1, which leads to cross-linking between leukocytes and platelets. Platelet α-granules also contain platelet factor 4 (CXC chemokine ligand 4), which promotes neutrophil granule release; and RANTES (chemokine ligand 5), which forms heterodimers with platelet factor 4 and leads to monocyte recruitment.

BTK, the signaling molecule downstream of CLEC-2 and GPVI, has also been shown to activate the NLRP3 inflammasome leading to inflammasome assembly and interleukin-1β (IL-1β) production in platelets, mirroring canonical myeloid immune cell responses. Platelet NLRP3 activation further enhances platelet activation and aggregation by an autocrine feedback loop via IL-1β binding to IL-1 receptor-1 expressed on platelets.^20,21 Other inflammatory cytokines indicated in both acute and chronic inflammation are also implicated in platelet activation. Specifically, IL-6 signals through platelet-expressed glycoprotein 130, and there is emerging evidence that platelets can release IL-8.²²

SCD-specific platelet activation

SCD is characterized by hemolytic anemia, in which extracellular hemoglobin is released into circulation and subsequently oxidized to liberate heme. These hemolysis-derived products, along with downstream inflammatory mediators, create a sustained proinflammatory and prothrombotic milieu that contributes to platelet activation and vascular dysfunction. Rather than activation through a single pathway, platelet activation in SCD reflects engagement of a convergent network of receptors that integrate hemolytic, inflammatory, and adhesive signals (Figure 1).

Figure 1.

Pathways of platelet activation in SCD. Several disease-specific pathways have been identified in modulating platelet activation. GPIb-IX-V, glycoprotein Ib-IX-V complex; HMGB1, high-mobility group box 1. Figure created with biorender.com. Alfred J. (2026) https://biorender.com/b5le13k.

One key pathway is platelet GPIbα, a major adhesion receptor that directly binds hemoglobin. In paroxysmal nocturnal hemoglobinuria, adult hemoglobin A (HbA) has been shown to activate platelets via GPIbα. In SCD, HbS binds GPIbα with higher affinity than HbA, inducing multiple platelet activation responses, such as granule secretion, integrin GPIIb/IIIa activation, and platelet shape change.²³ These findings support a direct role of circulating hemoglobin species in initiating platelet activation in hemolytic states.

In parallel, inflammatory signaling pathways further amplify platelet reactivity. SCD has been linked to activation of inflammasome-associated signaling cascades, including NLRP3-dependent pathways. Inhibition of BTK downstream of the NLRP3 inflammasome-associated signaling axis reduces baseline platelet aggregation and interferes with thrombus formation in SCD mouse models.²⁴ These findings were confirmed by additional in vivo studies demonstrating reduced platelet-neutrophil aggregation in lung arterioles of mice with SCD, as well as in microfluidic assays using human SCD blood samples in vitro.²⁵ Moreover, blockade of IL-1 receptor signaling reduces platelet-mediated RBC sickling ex vivo, underscoring a functional role for cytokine-driven platelet activation in disease progression.²⁶

Central to inflammatory signaling in SCD is TLR4, which recognizes multiple DAMPs. Platelet TLR4 is canonically activated by bacterial lipopolysaccharide, which induces granule secretion and integrin-dependent platelet aggregation in pathologic settings such as sepsis.²⁷ In SCD, endogenous ligands such as the proinflammatory DAMP high-mobility group box 1 can bind and activate platelet TLR4, leading to platelet activation.²⁸ Importantly, high-mobility group box 1-TLR4 signaling enhances platelet responsiveness to ADP, by augmenting both ADP release and surface expression of the P2Y₁₂ receptor, thereby priming platelets for amplified ADP-dependent activation. TLR4 also serves as a receptor for heme, the product of hemolytic anemia in SCD. Heme induces TLR4-dependent mitochondrial reactive oxygen species production via protein kinase B (PKB, also known as AKT serine/theronine kinase) mediated inhibition of mitochondrial complex V.²⁹

Beyond TLR4-mediated pathways, hemolytic products also engage platelet CLEC-2. Cell-free heme has been shown to directly bind CLEC-2, leading to P-selectin expression, GPIIb/IIIa activation, and platelet aggregation.³⁰ Importantly, both podoplanin and CLEC-2 are elevated in adult patients with SCD, especially in those with HbSS genotype. Elevated CLEC-2–to–platelet ratios, along with increased D-dimer levels, further support enhanced pathway activation. Additionally, increased lymphocyte-platelet aggregates have been observed in patients with elevated podoplanin. These findings implicate the platelet CLEC-2 axis as a key contributor to the heightened thromboinflammatory state of SCD.³¹

It is established that platelets contribute to thrombin generation in SCD.³² However, the specific contribution of thrombin-dependent platelet activation via PAR1 and PAR4 has not been well defined in SCD. Because there is ongoing elevated thrombin generation in SCD, it stands to reason that this pathway could contribute to platelet activation in this context. Although the role of complement in the pathology of SCD is well established, and there is some evidence of platelet-mediated complement activation, this area remains less well defined in the context of SCD and represents an important area for future investigation.

Together, these pathways illustrate that platelet activation in SCD is not mediated by a single ligand-receptor interaction but instead reflects a coordinated network involving GPIbα, TLR4, and CLEC-2. This integrates hemolysis-derived signaling with inflammatory and immune cues, promoting platelet activation, leukocyte-platelet aggregate formation, and downstream thromboinflammatory complications that contribute to disease pathology.

Use of platelets as biomarkers of disease severity

Considering the wide variety of platelet activation mechanisms, investigations into platelet biomarkers as predictors of disease severity in SCD have boomed in the last decade. These findings are comprehensively summarized in Table 1, and key findings are discussed in detail as follows.

Table 1.

Summary of platelet-specific biomarkers of complications and disease severity in SCD

Parameter	End point	Population	Results	Reference
Platelet count
	ACS, aplastic crisis, and hyper hemolysis correlations with platelet count and disease severity	Retrospective cross-sectional chart review study of all adult patients with SCD (hospitalized; ICU subset included)	In severe SCD crisis, thrombocytopenia is more common than thrombocytosis. ICU day 1 platelet counts inversely correlate with severity scores, and are reduced in multiorgan failure and nonsurvivors. Platelet count >175 × 109/L predicts patient survival with high specificity and positive predictive value but lacks sensitivity.	33
	Change from steady state during VOC and ACS	Retrospective study of N = 45 (HbSS and HbSC) patients aged 5-25 years, with paired steady state and acute events samples (VOC ± ACS)	Platelet counts decreased significantly in acute events (VOC/ACS) compared with steady state, consistent with platelet consumption/sequestration. This suggests dynamic platelet involvement in acute SCD complications rather than persistently elevated counts.	34
Platelet ratios
PNR	Abnormal TCD (eg, stroke risk)	Retrospective study of pediatric HbSS cohort (N = 248, aged 5-25 years) at Children’s Hospital	PNR had stronger predictive power for abnormal TCD than either HbF or absolute neutrophil count	35
PNR and PLR compared with NLR	Disease severity based on anemia (Hb-based stratification; complications/transfusion burden)	Retrospective study of pediatric HbSS cohort (N = 45) aged 4-18 years in Nigeria	PNR and PLR were significantly lower in severe disease; NLR did not differ between moderate vs severe. Platelet count alone did not correlate with severity.	36
Platelet activation markers
P2Y12 expression	Platelet activation and signaling	Cross-sectional adult SCD cohort (N = 18 HbSS and HbS/β0) vs healthy controls (N = 47); steady state + HU	SCD platelets exhibit increased activation with upregulated P2Y12 expression; HMGB1 enhances platelet activation via TLR4-dependent signaling, supporting a mechanistic link between inflammation and platelet hyperreactivity in SCD.	28
Activated GIIb/IIIa	Association with PAH severity and hemolysis	Adult HbSS cohort (N = 33; 16 PAH, 17 non-PAH)	Platelet activation correlated with PAH severity (r = 0.58, P < .001) and reticulocyte count (r = 0.44, P = .02)	37
P-sel, GPIIb/IIIa, and mitochondrial function	Platelet activation and bioenergetics	Cross-sectional study of n = 24 adult patients with HbSS at steady state vs n = 19 healthy controls	SCD platelets exhibit increased activation (P-sel and GPIIb/IIIa) associated with mitochondrial dysfunction. Platelet activation is also correlated with markers of hemolysis.	38
CD39 (ENTPD1) polymorphism	Pulmonary thrombosis and platelet activation mediated by purinergic signaling	Adult SCD cohort (N ∼ 20 HbSS and HbS/β0) with genetic stratification (CD39 variant or reference); complemented by mouse model	CD39 dysfunction/variant enhances platelet-mediated pulmonary thrombosis via impaired purinergic signaling and increased thromboinflammation.	39
Platelet NLRP3 inflammasome activation	Platelet activation and inflammasome signaling	Adult SCD cohort (n = 24, HbSS) vs healthy controls (n = 20)	Platelets from patients with SCD show increased inflammatory activation and upregulated NLRP3 inflammasome signaling. Interestingly, SCD plasma induces platelet activation in healthy donor platelets that suggest HMGB1-TLR4 signaling is involved in platelet priming and hyperreactivity.	20
PNA
PNA and GPIIb/IIIa	Neutrophil activation, lung vascular injury, vaso-occlusion	Human patients with SCD (HbSS, steady state) vs controls, complemented by SCD mouse model	SCD is associated with significantly increased GPIIb/IIIa expression and more PNAs, and neutrophils exhibited elevated oxidative burst and Cd11b expression.	40
PNA	Leukocyte-RBC-platelet interactions and inflammatory aggregation	Adult HbSS cohort (N = 28; 22 on HU) vs healthy controls	There were more heterocellular aggregates involving RBCs, platelets, and neutrophils in patients with HbSS. Platelets function as scaffolds promoting multicellular adhesion and inflammation.	41

ACS, acute chest syndrome; HMGB1, high-mobility group box 1; HU, hydroxyurea; ICU, intensive care unit; NLR, neutrophil-to-lymphocyte ratio; NLRP3, NLR family pyrin domain containing 3; P-sel, P-selectin; PAH, pulmonary arterial hypertension; PLR, platelet-to-lymphocyte ratio; PNA, platelet-neutrophil aggregates; PNR, platelet-to-neutrophil ratio; TCD, transcrandial doppler.

Platelet counts

In adults with SCD, elevated steady state platelet counts are associated with a higher frequency of emergency room use. In fact, each 50 × 10⁹/L increase in platelet count is associated with a 22% higher likelihood of visiting the emergency department.⁵⁰ Conversely, among patients with SCD admitted to the intensive care unit, lower platelet counts on admission were observed in patients with in-hospital mortality than with survivors.³³ Because platelet counts are routinely obtained during standard hematology evaluations, including in low- and middle-resource settings, they represent a readily accessible biomarker for risk stratification. Deviations from an individual patient’s baseline platelet count may therefore provide an early indication of clinical change.

Platelet-to-cell ratios

Platelet-based inflammatory ratios, particularly platelet-neutrophil and platelet-lymphocyte ratios, have emerged as potential biomarkers of disease severity in SCD. A study using the Sickle Cell Assessment severity score demonstrated that increased platelet-neutrophil and platelet-lymphocyte ratios were both associated with greater disease severity.³⁶ In subsequent work, the same group evaluated the platelet-neutrophil ratio as a predictor of disease complications, and found that higher ratios were associated with a higher likelihood of developing avascular necrosis.⁵¹ Because these ratios can be derived from routine complete blood counts without additional testing or cost, they may offer clinically practical tools for identifying patients at higher risk for severe disease manifestations and for supporting longitudinal monitoring.

Platelet-leukocyte aggregates

P-selectin has been implicated in the formation of platelet-neutrophil aggregates, as both in vivo murine studies and in vitro human SCD studies showed reduced aggregate formation with P-selectin–blocking antibodies,⁴⁰ highlighting platelet-leukocyte interactions as a promising therapeutic target. Furthermore, it has been shown that inhibition of platelets with P-selectin antibodies has shown a reduction in neutrophil-erythrocyte aggregates in SCD.⁴¹ Another study also found that higher levels of P-selectin by flow adhesion was a prognostic biomarker for VOC in patients with SCD by patient report.⁵² Despite their clinical relevance, platelet-leukocyte aggregates and adhesion assays are not standard clinical assays because their measurement requires specialized flow cytometry protocols and rapid sample processing.

Platelet activation markers

Platelet P-selectin expression is upregulated in patients with HbSS compared with healthy controls, which positively correlated with platelet mitochondrial dysfunction and markers of hemolysis,³⁸ suggesting that the extent of platelet activation may reflect disease severity. Platelets from patients with SCD also exhibit higher levels of the activated form of integrin GPIIb/IIIa.^37,38 Indeed, platelet activation measured by GPIIb/IIIa positively correlated with disease severity and the incidence of pulmonary arterial hypertension, further supporting the use of platelet activation markers as biomarkers of disease severity. However, both P-selectin and activated GPIIb/IIIa are measured by flow cytometry, limiting their clinical applicability due to the need for specialized equipment and protocols, and lack of standardized clinical thresholds.

Clinical trials

While the body of literature linking outcomes for patients with SCD and platelet markers continues to grow, the markers with the strongest evidence have led to several clinical trials in the last several decades (Table 2).⁵³ The earliest clinical trials of antiplatelet therapies in SCD were conducted in the 1980s and focused primarily on aspirin. Because aspirin inhibits both platelet and endothelial prostacyclin, there was theory that this dual effect on platelet inhibition would successfully prevent SCD VOC; however, this did not hold true for an initial study, using 6 mg/kg per day for 3 or 6 months. 71% of these participants had ≤2 VOC during the 21 months of the study, and there was a marked decrease in VOC in the first 6 months in both placebo and aspirin groups, suggesting a longer treatment period or increased dose may show changes.⁴² However, a second trial, similarly designed but with a higher dose of 31 mg/kg per day for 5 months, found no impact on the incidence of painful events or hematological parameters. One of the scientific questions with this study was to ascertain if there was an HbS antisickling effect produced by aspirin, and this was also shown not to take place.⁴³ Both studies were performed before hydroxyurea became the standard of care for individuals with SCD, and provide foundational information for other antiplatelet trials. Although these studies did not demonstrate the benefit of aspirin in SCD, they motivated future studies investigating more targeted and mechanistically specific antiplatelet agents.

Table 2.

Recent trials using antiplatelet therapy for treatment of SCD

Trial	Antiplatelet tested	Population	Primary outcome	Reference
Aspirin Phase 2	Aspirin Irreversible cyclooxygenase inhibitor	Pediatric HbSS and HbSC cohort; ages 2-17 years (N = 49)	No significant difference in frequency or severity of VOC (pain) events	42
Aspirin Phase 2	Aspirin Irreversible cyclooxygenase inhibitor	Pediatric and adult HbSS, HbS/β0 HbSOArab, cohort; ages 4-31 years (N = 29)	No significant difference in frequency of VOC (pain) events	43
DOVE Phase 3	Prasugrel Irreversible P2Y12 inhibitor	Pediatric HbSS and HbS/β0 cohort; ages 2-17 years (N = 341)	No significant differences between groups in rates of VOC (ACS or pain)	44
HESTIA Phase 3	Ticagrelor Reversible P2Y12 inhibitor	Pediatric HbSS and HbS/β0 cohort; ages 2-17 years (N = 193)	No significant differences between groups in rates of VOC (ACS or pain)	45
RESET Phase 2	Rivipansel Pan-selectin inhibitor	Pediatric and adult cohort including HbSS, HbS/β0, HbSC, HbS/β+, and other HbS variants; median age 18 years (N = 345)	No differences between groups in time to discharge	46
Sevuparin Phase 2	Sevuparin P-selectin, thrombospondin, VWF inhibitor	Pediatric and adult cohort HbSS, HbSC, HbS/β0, or HbS/β+; ages 12-33 years (N = 144)	No significant change in readiness for discharge, defined as use of IV opioids	47
SUSTAIN Phase 2	Crizanlizumab humanized monoclonal P-selectin antibody	Pediatric and adult cohort of HbSS, HbSC, HbS/β0 HbS/β+, or other HbS variants; ages 16-65 years (N = 198)	Notable significant differences in annual rate of VOC (pain, ACS, hepatic or splenic sequestration, priapism) between placebo and treatment groups	48
STAND Phase 3	Crizanlizumab humanized monoclonal P-selectin antibody	Pediatric and adult cohort of HbSS, HbS/β0 HbS/β+, or other HbS variants; ages 12-85 years (N = 252)	No difference in the annualized rate of VOC	49

ACS, acute chest syndrome.

Two major trials have evaluated P2Y₁₂ inhibition in pediatric SCD. The phase 3 DOVE trial tested prasugrel, an orally available irreversible P2Y₁₂ inhibitor that prevents ADP-dependent platelet activation, for its ability to reduce the frequency of VOC in pediatric patients with SCD. Ultimately, prasugrel did not demonstrate a statistically significant reduction in VOC rates compared with placebo, although trends suggested patients not on hydroxyurea had lower rates of VOC, with the question remaining whether antiplatelet therapies could benefit those who did not benefit from hydroxyurea therapy. Additionally, there were nonsignificant trends toward reduced VOC observed in adolescent patients, suggesting that those with chronic endothelial damage might derive some therapeutic benefits, but this was a limited finding due to lower accrual rates in the younger patient groups. Of note, the actual platelet inhibition achieved by prasugrel in the DOVE trial was ∼25%, which was statistically significant but below the targeted 30% to 60% inhibition, leaving open the important question of whether greater platelet inhibition could have provided clinical benefit.⁴⁴ The phase 3 HESTIA3 study evaluated ticagrelor, an orally available reversible ADP P2Y₁₂ receptor antagonist, in preventing VOC in pediatric patients with SCD and, despite aiming for and achieving higher platelet inhibition than the DOVE trial, the study ended early because the VOC rate was higher for the ticagrelor group. There was also 1 fatal intracranial hemorrhage that occurred in the ticagrelor group and there was no synergistic benefit with hydroxyurea therapy.⁴⁵ Together, these studies suggest that ADP-mediated platelet inhibition alone may be insufficient to prevent VOC in pediatric SCD and pointed toward platelet selectin interactions with the endothelium.

One candidate was sevuparin, a novel short heparinoid modified to be nonanticoagulant by removing the antithrombin-binding domain, thereby eliminating the antifactor II and antifactor X activities, making its overall bleeding safety profile more acceptable. Sevuparin also inhibits P-selectin, thrombospondin, and VWF. A double-blind phase 2 study evaluated sevuparin for the treatment of acute VOC in patients aged >12 years with SCD and differed from previous studies by selecting different end points: readiness for discharge as determined by the patient or physician, and freedom from IV opioid use. Drug monitoring was performed using activated partial thromboplastin time and found to have an appropriate safety profile, with no major bleeding events. Unfortunately, the primary end points were not met, and there was speculation that given the VOC events were actively occurring, the antiadhesive nature of sevuparin was better suited as a preventative agent rather than a VOC abortive.⁴⁷

In 2023, the phase 3 double-blind, randomized control RESET trial for children and adults evaluated rivipansel, a pan-selectin inhibitor with predominant E-selectin inhibition and some P-selectin inhibition, for similar end points as the phase 2 sevuparin trial. After the loading dose of rivipansel, there was a statistically significant decrease in mean plasma E-selectin, but not P-selectin. Interestingly, individuals who reported a shorter period between the onset of VOC and initiation of rivipansel had the greatest reductions in time to readiness for discharge, time to discharge, and time to discontinuation of IV opioids, despite nonsignificance. Though the primary and secondary end points were not met, this study did reinforce the suggestion that antiplatelet antiadhesive treatments are likely more effective at preventing the cascade of inflammation in VOC.⁴⁶

P-selectin remains a compelling therapeutic target in SCD, as subsequent studies have demonstrated that more potent and selective inhibition can reduce VOC. In 2025, the STAND trial, a phase 3 study of pediatric and adult patients treated with crizanlizumab, a humanized monoclonal antibody against P-selectin, was poised as the most promising antiplatelet to date, given the SUSTAIN phase 2 results. The primary outcome demonstrated no difference in the annualized rate of VOC leading to a health care visit over the first year after randomization, although the SUSTAIN phase 2 trial had promising results.^48,49,53 Unfortunately, the STAND trial was conducted between 2019 and 2022, with difficulty accruing during the COVID-19 pandemic during 2020 and significant deviations from trial protocol because of unprecedented circumstances. Additionally, there was a high discontinuation rate from the placebo arm, possibly skewing the placebo group to a less severe phenotype and ultimately leading to nonsignificance for the primary outcome.

The disappointing performance of antiplatelet therapies likely reflects the multifactorial nature of vaso-occlusion, in which platelet activation is necessary but not sufficient to drive disease. Platelets interact with sickled erythrocytes, activated endothelium, leukocytes, coagulation, complement, and inflammatory mediators. Consequently, inhibition of a single platelet pathway may be insufficient once the thromboinflammatory cascade is established, emphasizing the need to identify upstream pathways or patient subsets most likely to benefit from targeted therapy (Figure 2). Another potential explanation is that the frequency and severity of vaso-occlusive episodes may not fully capture the vascular benefits of platelet-directed therapies. Instead, these therapies may exert a greater impact on the progression of chronic vasculopathy and end-organ damage, outcomes that are considerably more difficult to evaluate in clinical trials because they require long-term follow-up and validated surrogate end points.

Figure 2.

Platelet activation biomarkers and targets of clinical trials in SCD. Arrows denote disease-specific biomarkers of platelet activation. Blue arrows are biomarkers that have led to clinical trials, and purple arrows are biomarkers that are yet to be explored clinically. GPIb-IX-V, glycoprotein Ib-IX-V complex; HMGB1, high-mobility group box 1. Figure created with biorender.com. Alfred J. (2026) https://biorender.com/b5le13k.

Key knowledge gaps

In summary, clinical trials of antiplatelet therapies in SCD have not demonstrated consistent clinical benefits. Most trials relied on VOC frequency, readiness for discharge, and opioid use as primary end points. However, these outcomes may not adequately capture the early microvascular and endothelial processes that precede VOC. Future studies may require more sensitive or biologically proximal end points, such as specific VOC complications or organ-specific manifestations. Ensuring inclusion and stratification by SCD genotype severity is also key, given that phenotype is often dictated by the differences in genotype. Additionally, antiplatelet therapies may be an alternative or adjunctive therapy to standard of care hydroxyurea, though the question has been incompletely explored. Currently, hydroxyurea remains consistently the most effective therapy for SCD regarding anemia and VOC complications. Although the therapeutic benefits of hydroxyurea focus on HbF generation and therefore more stable RBCs, there remains the possibility that the primary side effect, namely marrow suppression leading to leukopenia and thrombocytopenia, could also be contributing to decreased VOC given the many ways platelets and white blood cells contribute to thromboinflammation in SCD. On the immediate horizon, both CRISPR-Cas9 and lentiviral-based gene therapies prioritize similar mechanisms to hydroxyurea, resulting in production of either more HbF or reduced concentrations of HbS, respectively. With the knowledge that HbS triggers downstream effects of platelet-related inflammation, it may be worthwhile to study changes in SCD platelet activity before and after these gene therapy products are administered.

These trials are further limited by uncertainty about the degree of platelet inhibition required for clinical benefit. P2Y₁₂ antagonists prasugrel and ticagrelor achieved ∼25% and 40% to 50% inhibition, respectively, yet neither improved the primary outcome of VOC frequency. These findings raise the possibility that ADP-mediated platelet aggregation alone may not suppress the platelet-endothelial and platelet-leukocyte interactions central to VOC. Moreover, the optimal timing of intervention has not yet been defined. It is unclear whether these therapies would be more effective as prophylactic agents or as early interventions during the onset of vaso-occlusion.

Collectively, these results suggest that classic antiplatelet approaches used in cardiovascular diseases do not translate directly to the thromboinflammatory biology of SCD. Current antiplatelet approaches in SCD have primarily targeted platelet aggregation pathways rather than the thromboinflammatory signaling networks linking platelets, endothelial cells, leukocytes, and coagulation. This raises the question whether platelets are primary mediators of vaso-occlusion or secondary amplifiers of endothelial dysfunction?

Within this framework, targeting upstream thrombin-mediated pathways, including PAR1 and PAR4, may offer a more comprehensive approach by simultaneously modulating platelet activation and endothelial responses such as cytokine and adhesion molecule expression. Given the chronic thrombin generation that characterizes SCD, surprisingly little is known about the contribution of PAR1- and PAR4-dependent platelet signaling to disease pathophysiology. To date, most antiplatelet strategies have focused on inhibiting ADP-P2Y₁₂ signaling or platelet adhesion through P-selectin, whereas thrombin-mediated platelet activation has received comparatively little attention. This knowledge gap is particularly notable because the gain-of-function PAR4 Thr120 variant is overrepresented in individuals of African ancestry, the population disproportionately affected by SCD. This variant has been associated with enhanced platelet activation, increased platelet-neutrophil interactions, and a higher risk of ischemic stroke, raising the possibility that PAR-directed therapies may benefit selected patient populations.⁵⁴

Unlike ADP or P-selectin, thrombin occupies a central position at the interface of coagulation, platelet activation, endothelial dysfunction, and inflammation. Moreover, thrombin generation remains elevated despite current disease-modifying therapies, suggesting that thrombin-PAR signaling represents a persistent pathogenic pathway that is not adequately addressed by existing treatments. Collectively, these observations identify thrombin-PAR signaling as an underappreciated therapeutic axis in SCD with the potential to simultaneously attenuate platelet activation, thromboinflammation, and vascular dysfunction. Among emerging approaches, parmodulins are particularly attractive because they reversibly modulate PAR1 signaling while preserving endothelial cytoprotective pathways and exhibit a lower bleeding risk than conventional PAR1 antagonists such as vorapaxar. Such strategies may better address the interconnected thromboinflammatory network underlying vaso-occlusion in SCD.

Conclusion

Platelets play a substantial role in both the baseline and acute thromboinflammatory states of SCD. Their diverse signaling pathways and the biological information these signals provide have opened new possibilities for patient monitoring and risk stratification, and there are pathways such as PAR1 and PAR4 modulation,^55,56 mitochondrial inhibition,³⁸ and generation of reactive oxygen species⁵⁷ that are currently being explored as methods of platelet modulation in SCD to attenuate thromboinflammation. Translational research, from cell culture studies to clinical trials, has identified potential strategies to target platelet-driven thromboinflammation; however, there is still ground to cover to translate these findings into interventions that meaningfully reduce the clinical symptom burden in patients with SCD. The key question remains whether platelets are a biomarker of disease or a modifiable target that can be leveraged to improve treatment and prevention of symptoms in this population.

Conflict-of-interest disclosure: The authors declare no competing financial interests.