Selected ARHGEF3 Gene Polymorphisms Associated With Platelet Hyperaggregability in Patients With Venous Thromboembolism

Abstract

So called “sticky platelet syndrome” (SPS) is an inherited thrombophilic thrombocytopathy characterized by platelet hyperaggregability to low concentrations of adenosine diphosphate and/or epinephrine using light transmission aggregometry and is a recognized cause of otherwise unexplained venous thromboembolism (VTE). Variants within the ARHGEF3 gene have previously been implicated in platelet-related traits, suggesting its potential role in thrombosis associated with SPS. We investigated the association between eight selected single nucleotide polymorphisms (SNPs) within the ARHGEF3 gene and the risk of VTE in 49 patients with SPS and VTE compared with 70 healthy controls. Genetic associations were evaluated using allelic, genotype-based (dominant and recessive models), and haplotype analyses, with stratification according to SPS subtype. In the overall SPS cohort, the minor allele of rs9851853 was significantly more frequent in patients with SPS and VTE compared to controls. SNP rs4681767 showed a borderline allelic association in the overall cohort but reached statistical significance in patients with SPS type II. Genotype-based analyses revealed significant associations for rs9851853 under the dominant model and for rs4681767 and rs1354034 under the recessive model, predominantly in the SPS type II subgroup. Haplotype analysis identified distinct risk- and protective haplotypes within the ARHGEF3 locus. The TAT haplotype was associated with an increased risk of VTE, whereas the CAC haplotype conferred a protective effect, more significantly in SPS type II patients. Our findings indicate that genetic variability within the ARHGEF3 gene, particularly rs9851853, rs4681767, and rs1354034, may modulate thrombotic susceptibility in patients with SPS, especially in the epinephrine-sensitive SPS type II.

Keywords

platelet hyperaggregability sticky platelet syndrome venous thromboembolism single nucleotide polymorhphism

Introduction

At the turn of the 19th and 20th centuries, the characteristics of platelets and their role in hemostasis began to be recognized.¹ Early investigations were primarily focused on bleeding disorders. Later, platelets disorders associated with thromboembolism, termed thrombophilic thrombocytopathies, were described.² Among these entities, the term “sticky platelet syndrome” (SPS) was originally coined by a team led by professor Eberhard F. Mammen, first mentioned in a conference paper in 1983 and then more fully described in a 1988 report.³ In this paper he and various colleagues described a cohort of patients with coronary artery disease, transient ischemic attacks and/or strokes and idiopathic ischemic optic neuropathy who have a platelet population which is in vitro hyperaggregable with low concentrations of epinephrine (EPI) and/or adenosine diphosphate (ADP) and hyperresponsive to surface contact. It is said to be a largely undiagnosed autosomal-dominant trait and a common cause of hereditary thrombophilia.⁴ According to aggregation pattern, three types of the syndrome can be identified. Type II is most common (hyperaggregability to epinephrine (EPI) alone), followed by type I (hyperaggregability to adenosine diphosphate (ADP) and EPI), whereas type III (hyperaggregability to ADP alone) is rare.⁵ Aggregation in response to other agonists (collagen, arachidonic acid, ristocetin, and thrombin) remains normal.^6,7 SPS is defined its clinical and laboratory features not by genetic testing, although it is generally regarded as an inherited disorder.⁸ Clinical symptoms of SPS include venous and arterial thrombosis,⁹ migraine,¹⁰ graft versus host disease and pregnancy complications.^2,11 Arterial thrombosis has been described as the most common clinical manifestation of the syndrome, followed by venous thrombosis including deep vein thrombosis and pulmonary embolism as the second most common.¹² The etiology of SPS is still uncertain. Although SPS phenotype, including familiar occurrence, is clearly defined, the exact genetic cause is still not sufficiently explained.⁸ It has been suggested that the defects of the platelet membrane glycoproteins (GP) and/or the intracellular signals pathways involved in platelet activation and aggregation are responsible for the disorder.^13,14 This led to further investigations into the cellular and molecular mechanisms underlying platelet hyperaggregability. Ngwa et al identified a novel locus (rs1354034) and gene ARHGEF3 in genome-wide association studies (GWAS) of platelet aggregation phenotypes, which had not previously been reported.¹⁵ Gene ARHGEF3, located on chromosome 3p14.3, encodes a protein that acts as a RhoA‐specific guanine nucleotide exchange factor that has emerged as an important regulator in diverse biological processes. Genetic variants positioned upstream of the ARHGEF3 gene have been robustly associated with changes in mean platelet volume, underscoring its contribution to platelet function and vascular homeostasis.^16,17 Based on this results, we analysed the numbers of SNPs from the gene ARHGEF3 including mentioned SNP. The aim of this study was to evaluate the potential association between selected SNPs of ARHGEF3 gene in patients with SPS manifesting as VTE compared to control individuals and to determine the relationship between these SNPs and risk for venous thromboembolism (VTE) in patients with SPS.

Material and Methods

Study Population and Inclusion/Exclusion Criteria

The local Ethical Committee of Jesenius Faculty of Medicine in Martin approved the study (Number EK 36/2025). All study participants agreed to participate in the project and signed a written informed consent in accordance with Declaration of Helsinki.

Patients with verified VTE were enrolled in the study and were referred to undergo thrombophilia screening as a part of VTE differential diagnosis. Initially, they were examined and tested at the National Center of Hemostasis and Thrombosis in Martin University Hospital. Two study populations were analyzed. The patient group considered of individuals with confirmed diagnosis of SPS and documented history of VTE. The control group comprised randomly selected healthy individuals without personal history of VTE and with normal platelet aggregability after stimulation by low doses of EPI and/or ADP agonists. Exclusion criteria included age at VTE onset more than 50 years, the presence of other congenital or acquired thrombophilic conditions, chronic inflammatory or malignant disease, anatomical abnormalities of the venous system (e.g. May-Turner syndrome, clinically significant varicose veins), and a personal or family history of chromosomal abnormalities. The diagnosis of SPS was confirmed or disproved by light transmission aggregometry (LTA) according to the method by Mammen^6,7 in all subjects, while all of them had initial platelet count within the reference range. The testing was performed on patients without any antiplatelet therapy at least 7 days before testing, they were omitting the use of other drugs which affects platelet activity. At the time of testing patients were free of the occurence of acute thromboembolic events (>3 months). Diagnosis of VTE included deep vein thrombosis (DVT) in both typical (veins of lower extremity) and atypical locations (veins of upper extremity, retinal vein, cerebral venous sinuses, splanchnic veins, etc.) verified by Doppler ultrasonography or computed tomography (CT), and pulmonary embolism (PE) verified by computed tomography angiography (CTA), in the absence of known risk factors for VTE.

Diagnostics of SPS

Venous blood was collected in the morning between 6:30 - 7:30 a.m. from the forearm vein into tubes containing 3.2% buffered sodium citrate (anticoagulant–blood ratio 1:9) for the assessment of platelet aggregation. The blood samples were processed and analyzed within 2 h after sampling. Platelet aggregability was tested with platelet-rich plasma, assessed photometrically using LTA (AggRAM, Helena Laboratories, Beaumont, TX, USA) according to the method described by Mammen.⁶ Each blood sample was tested using three low concentrations of ADP (2.34, 1.17, and 0.58 mmol/L) and EPI (11.0, 1.1, and 0.55 mmol/L. SPS was classified into type I, II and III. Testing of platelet aggregation was performed 2 times to confirm the diagnosis.

DNA Analysis

Antecubital venous blood used for DNA analysis was collected into tubes containing 5.4 mg K2EDTA (spray-coated). Blood samples were processed within 2 h after collection and stored, at – 20 °C. DNA was extracted from peripheral blood leukocytes. Isolation of genomic DNA from whole blood was performed with MagNA Pure LC DNA Isolation Kit I (Roche Diagnostics, Mannheim, Germany) on MagNA Pure LC 2.0 Instrument (Roche Diagnostics, Mannheim, Germany) according to the instructions. SNP genotyping used High resolution melting (HRM) analysis on LightCycler 480 II (Roche Diagnostics, Mannheim, Germany). The selection and designing of primer sequences were performed by Primer3 software.¹⁵

Gene Analysis

Eight SNPs located in the ARHGEF3 gene (rs17288922, rs13062174, rs9851853, rs6445826, rs4681767, rs1948722, rs1354034, and rs1039384) were included in the analysis. Linkage disequilibrium (LD) patterns among the analyzed variants were evaluated based on HapMap CEU population data and are illustrated in Figure 1.

Figure 1.

Linkage disequilibrium map of SNPs of the ARHGEF3 gene

Statistics

Association analysis was performed using PLINK (v1.9). Single-variant associations were evaluated under both dominant and recessive genetic models using logistic regression adjusted for sex. Haplotype-based associations were tested using Pearson’s chi-square test. Haplotype frequencies were estimated using the expectation–maximization algorithm implemented in PLINK. A p-value < 0.05 was considered statistically significant.

Results

We examined 49 SPS patients with history of VTE, with a mean age at the onset of thrombosis of 34.4 ± 9.0, thirty-one women (63.3%) and eighteen men (36.7%) and 70 healthy control subjects with the age of 36.1 ± 9.2, thirty-eight women (54.29%) women and thirty-two men (45.71%). We found 19 patients with SPS type I (38.8 %), 29 patients with SPS type II (59.2 %) and one patient with SPS type III (2 %) by classifying according to Mammen´s criteria. Overall, 8 SNPs within ARHGEF3 gene were analyzed. Seven selected polymorphisms were recognised in intronic regions (rs9851853, rs6445826, rs1039384, rs1948722, rs1354034, rs17288922, rs13062174), one (rs4681767) was located within the regulatory region. In the overall SPS cohort, the frequency of the minor allele for rs9851853 was significantly higher in patients with SPS and VTE compared to the control group (0.174 vs 0.086, OR 2.239, 95% CI 1.016-4.931) see Table 1. While the allelic association of SNP rs4681767 showed borderline significance in the overall cohort (0.459 vs 0.336, OR 1.680, 95% CI 0.989-2.854, p= 0.059), a statistically significant association was observed in the SPS type II subgroup (0.535 vs 0.336, OR 2.272, 95% CI 1.217-4.240, p=0.011) (Table 1).

Table 1.

Frequency of Examined Allels Within ARHGEF3 in Patients With SPS and VTE Compared to Control Group

SNPs	Minor allele	Frequency (SPS)	Frequency (Controls)	P (Fisher)	OR	CI (95%)
All SPS cases	n=49	n=70
rs4681767	T	0.459	0.336	0.059	1.680	0.989-2.854
rs9851853	G	0.174	0.086	0.046	2.239	1.016-4.931
rs6445826	C	0.510	0.450	0.598	1.173	0.699-1.968
rs1039384	G	0.255	0.221	0.642	1.204	0.658-2.204
rs1948722	T	0.082	0.050	0.418	1.689	0.592-4.822
rs1354034	T	0.418	0.329	0.173	1.470	0.862-2.508
rs17288922	A	0.204	0.186	0.741	1.124	0.587-2.154
rs13062174	A	0.480	0.414	0.354	1.303	0.775-2.191
SPS type II		n=29	n=70
rs4681767	T	0.535	0.336	0.011	2.272	1.217-4.240
rs9851853	G	0.172	0.086	0.086	2.222	0.901-5.479
rs6445826	C	0.483	0.450	0.436	1.130	0.709-2.418
rs1039384	G	0.276	0.221	0.464	1.339	0.665-2.699
rs1948722	T	0.103	0.050	0.208	2.192	0.704-6.831
rs1354034	T	0.448	0.329	0.144	1.660	0.888-3.106
rs17288922	A	0.207	0.186	0.843	1.144	0.532-2.458
rs13062174	A	0.535	0.414	0.158	1.623	0.877-3.005

Abbreviations: A, adenine; C, cytosine; CI, confidence interval; G, guanine; OR, odds ratio; SPS, sticky platelet syndrome; T, thymine.

Note. p-values ≤ 0.05 are shown in bold.

Logistic regression analyses were performed under dominant and recessive genetic models to further assess genotype-based associations. Summary of genotype-based association analysis under dominant and recessive models in patients with SPS and VTE is given in Table 2. In the overall SPS cohort, SNP rs9851853 showed a significant association with SPS patients and VTE under the dominant model (OR 2.849, 95% CI 1.191–6.815, p = 0.019), whereas no significant association was observed under the recessive model. Additionally, rs4681767 was significantly associated with SPS patients and VTE under the recessive model (OR 5.726, 95% CI 1.486–22.07, p = 0.011). In the SPS type I subgroup, no statistically significant associations were detected for any of the analyzed SNPs under either the dominant or recessive genetic model. In contrast, in the SPS type II subgroup, rs9851853 remained significantly associated with SPS patients and VTE under the dominant model (OR 2.823, 95% CI 1.038–7.676, p = 0.042). Moreover, rs4681767 demonstrated a strong association with SPS patients and VTE under the recessive model (OR 10.050, 95% CI 2.481–40.71, p = 0.001). A significant association under the recessive model was also observed for rs1354034 (OR 3.394, 95% CI 1.029–11.19, p = 0.045). No other SNPs showed statistically significant associations in this subgroup (Table 2).

Table 2.

Genotype-Based Association Analysis Under Dominant and Recessive Models in Patients With SPS and VTE

SNP	Dominant			Recessive
SNP	P	OR	CI (95%)	P	OR	CI (95%)
All SPS Cases
rs4681767	0.331	1.477	0.672-3.245	0.011	5.726	1.486-22.07
rs9851853	0.019	2.849	1.191-6.815
rs6445826	1.000	1.000	0.445-2.244	0.303	1.583	0.660-3.797
rs1039384	0.639	1.194	0.508-2.510	0.601	1.467	0.348-6.170
rs1948722	0.477	1.500	0.490-4.588
rs1354034	0.503	1.292	0.610-2.732	0.070	2.735	0.921-8.115
rs17288922	0.835	1.086	0.502-2.347	0.654	1.457	0.281-7.537
rs13062174	0.326	1.509	0.664-3.427	0.510	1.375	0.533-3.546
SPS type II
rs4681767	0.215
rs9851853	0.042	2.823	1.038-7.676
rs6445826	0.807	0.889	0.346-2.281	0.093	2.308	0.871-6.114
rs1039384	0.564	1.294	0.538-3.107	0.420	1.904	0.398-9.098
rs1948722	0.321	1.875	0.542-6.481
rs1354034	0.441	1.425	0.579-3.506	0.045	3.394	1.029-11.19
rs17288922	0.876	1.076	0.431-2.682	0.593	1.654	0.261-10.46
rs13062174	0.230	1.876	0.671-5.242	0.177	2.043	0.723-5.769

Abbreviations: CI, confidence interval; OR, odds ratio.

Note. p-values ≤ 0.05 are shown in bold.

The haplotype analysis identified several haplotypes within ARHGEF3 gene associated with either increased risk or protective effect. Based on the LD analysis, two haplotype blocks were identified within the ARHGEF3 gene region. The first block was formed by rs4681767 and rs9851853. For haplotype-based association analysis, an effective haplotype was constructed using these two variants together with rs1354034, representing the second haplotype block. In the overall SPS patients with VTE cohort, the CAC haplotype was significantly associated with a reduced risk of SPS patients with VTE (OR 0.486, p = 0.030), while the TAT haplotype showed a borderline association with increased risk (OR 3.160, p = 0.058). In the SPS type II subgroup, the TAT haplotype demonstrated a significant risk-increasing effect (OR 5.810, p = 0.011), whereas the CAC haplotype remained significantly protective (OR 0.291, p = 0.007). The results of haplotype analysis are shown in the Table 3. Figure 2 provides a visual overview of the experimental setup and findings.

Table 3.

Results of Haplotype Analysis

Haplotype	Frequency (all SPS)	Frequency (controls)	P Value	OR	Frequency (SPS II)	P Value	OR
TGT	0.045	0.019	0.180	3.860	0.042	0.287	3.210
TAT	0.124	0.063	0.058	3.160	0.171	0.011*	5.810
CAT	0.249	0.247	0.965	1.010	0.236	0.858	0.933
TGC	0.129	0.067	0.074	2.490	0.131	0.113	2.510
TAC	0.161	0.187	0.528	0.763	0.191	0.938	1.040
CAC	0.292	0.417	0.030**	0.486	0.230	0.007**	0.291

Abbreviations: A, adenine; C, cytosine; G, guanine; OR, odds ratio; SPS, sticky platelet syndrome; T, thymine.

Order of SNPs in haplotype: rs4681767, rs9851853 and rs1354034.

Note. p-values ≤ 0.05 are shown in bold.

*Significantly elevated haplotypes

**Significantly decreased haplotypes.

Figure 2.

Visual summary of the article

Discussion

VTE which include DVT and PE, is a leading cause of cardiovascular mortality, exceeded only by stroke and myocardial infarction.¹⁸ VTE is associated also with significant risk of recurrence and chronic complication including pulmonary hypertension and postthrombotic syndrome.¹⁹ VTE is multifactorial disease provoked by clinical risk factors and acquired or inherited predispositions to thrombosis.^20,21 Platelet activation in VTE is mediated by multiple agonists interacting with specific membrane receptors.²² According to Bick the SPS represents a common cause of otherwise unexplained VTE.²³

In our study, we analyzed 8 SNPs within ARHGEF3 gene and we examined the association between selected SNPs and the risk of VTE in patients with SPS compared with healthy controls. To date, there are no published studies investigated these ARHGEF3 variants in the context of SPS and VTE. The ARHGEF3 gene was selected as a candidate gene based on prior genetic evidence suggesting its involvement in platelet-related phenotypes.¹⁵ We identified three variants (rs9851853, rs4681767 and rs1354034) associated with increased thrombotic risk, with the strongest associations observed in patients with SPS type II.

SNP rs1354034, previously identified by GWAS as a locus associated with platelet hyperaggregability,²⁴ did not show a statistically significant allele association with SPS patients and VTE in our cohort, either in the overall population or in the SPS type II subgroup. However, genotype-based analysis revealed a significant association under the recessive genetic model in patients with SPS type II, where homozygous carriers of the minor allele T exhibited an increased risk in SPS patients with VTE. This finding suggests that the effect of rs1354034 may be model-dependent and become evident only in specific clinical subgroups characterized by a more pronounced thrombotic phenotype. Furthermore, rs1354034 contributed to haplotypes that showed strong risk-modifying effects in combination with rs4681767 and rs9851853. Notably, the TAT haplotype, which includes the rs1354034 risk allele, was significantly associated with increased VTE risk in SPS type II patients, whereas the CAC haplotype exerted a consistent protective effect. These results indicate that rs1354034 may not act as an independent risk variant but rather modulates thrombotic susceptibility through epistatic interactions within the ARHGEF3 locus. Such haplotype-dependent effects are biologically plausible given the role of ARHGEF3 in RhoA signaling and platelet cytoskeletal rearrangement, processes critical for platelet activation and aggregation.^15,17 Together, our findings support the relevance of rs1354034 in shaping thrombotic risk in SPS, particularly within genetically and clinically defined subgroups, and underscore the importance of haplotype-based approaches in uncovering complex genetic contributions to VTE.

SNP rs9851853 and rs4681767 showed distinct patterns of association with SPS patients and VTE. In the overall cohort, rs9851853 exhibited a significant allelic association, with the minor allele G being more frequent among SPS patients with VTE compared to controls. This association remained significant under the dominant genetic model and persisted in the SPS type II subgroup, whereas no significant association was observed in SPS type I patients. In contrast, rs4681767 demonstrated a borderline allelic association in the overall cohort but reached statistical significance in the SPS type II subgroup. Genotype-based analyses further revealed a significant association for rs4681767 under the recessive model, with a markedly increased risk observed in SPS type II patients. No significant associations for rs4681767 were detected under the dominant model or in the SPS type I subgroup. Notably, these SNPs are located upstream of ARHGEF3 within putative regulatory regions, likely affecting gene expression and thereby modulating platelet function and thrombotic susceptibility.

Both rs9851853 and rs4681767 substantially contributed to haplotype-based associations within the ARHGEF3 locus. These two variants formed a core linkage disequilibrium block and, together with rs1354034, defined the effective haplotypes used for association testing. In the overall SPS cohort with VTE, haplotypes carrying the major allele A of rs9851853 in combination with rs4681767 alleles showed differential risk effects, with the CAC haplotype being significantly associated with a reduced risk of SPS patients with VTE, while the TAT haplotype demonstrated a borderline risk-increasing effect. In the SPS type II subgroup, haplotype-based analysis revealed stronger associations, with the TAT haplotype showing a significant increase in VTE risk and the CAC haplotype remaining consistently protective. No significant haplotype associations were observed in SPS type I patients. These findings underscore the importance of considering haplotype context in addition to single-SNP effects and provide further evidence that regulatory variation within ARHGEF3 may modulate thrombotic susceptibility, potentially via RhoA-dependent platelet signaling pathways as described in prior functional studies.¹⁵

There are several limitations to our study. Relative small sample size, particularly in subgroup and haplotype analyses, may have limited statistical power and contributed to borderline or non-significant associations for some variants. The retrospective study design may have introduced selection bias and limits the ability to draw causal inferences. Additionally, platelet aggregability is sensitive to preanalytical conditions, which may affect the assessment of platelet hyperaggregability and the lack of standardized LTA protocols for SPS diagnostics can compromise diagnostic accuracy and limit cross-study comparability.^25-27 The lack of functional validation and prospective follow-up limits conclusions regarding biological mechanisms and predictive value of the identified variants.

Conclusions

In conclusion, our findings suggest that genetic variation within the ARHGEF3 gene rs4681767, rs9851853, and rs1354034 may act as modulators of thrombotic susceptibility in patients with SPS and VTE, particularly in SPS type II. These variants may contribute to the SPS phenotype not as primary causal factors, but rather as additional genetic modifiers that contribute to inter-individual variability in platelet reactivity and thrombotic risk. Although these results provide new insight into genetic background of thrombotic susceptibility in SPS, further research in larger, independent cohorts coupled with functional studies is required to validate these associations and clarify their biological relevance.

Footnotes

ORCID iD

Skerenova Maria

Ethical Considerations

The study was approved by the local Ethical Committee of Jesenius Faculty of Medicine in Martin (Number EK 36/2025). All participants provided written informed consent prior to participating.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported by project Vega 1/0059/25.

Declaration of Conflicting Interests

The autors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data that support the findings of this study are available.*

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