Elsevier

Annals of Vascular Surgery

Volume 88, January 2023, Pages 42-50
Annals of Vascular Surgery

Selected Papers from the Editorial Board
Identifying Sex Dimorphism in Peripheral Artery Disease with Platelet Mapping

https://doi.org/10.1016/j.avsg.2022.08.006Get rights and content

Highlights

  • Females with PAD have worse outcomes with fewer risk factors.

  • Patients in this study had lower rates of HTN and heart disease.

  • Platelet function testing showed females had a lower rate of platelet inhibition.

Background

Clinical outcomes in women with peripheral artery disease (PAD) after revascularization procedures are worse compared to men, yet there is little in the existing literature as why this may be the case. Platelet Mapping is an emerging point-of-care viscoelastic technology that measures the comprehensive properties of a blood clot, including fibrin-platelet interactions. This prospective observational study aimed to characterize the clinical and Platelet Mapping profiles of female and male patients undergoing lower extremity revascularization, and to correlate Platelet Mapping distribution to thrombotic potential.

Methods

All patients with a diagnosis of PAD undergoing named vessel open or endovascular revascularization to re-establish inflow, outflow, or both, during December 2020 and January 2022 were prospectively included. Patients were followed clinically for thrombosis for up to 1 year. Platelet Mapping assays were performed in 3 clinical phases: preoperative, postoperative inpatient, and postoperative outpatient. Inferential analysis between female and male patient was performed. The quartile distribution of Platelet Mapping metrics associated with thrombosis was used to infer to thrombotic potential.

Results

One hundred seven patients were enrolled, of which 37 (34.6%) were female. Female patients had significantly lower rates of uncontrolled diabetes (2.7% vs. 18.6%), hypertension requiring combination therapy (37.8% vs. 58.6%), chronic kidney disease (27.0% vs. 51.4%), coronary artery disease (29.7% vs. 57.1%), and myocardial infarction (16.2% vs. 35.7%) (all P < 0.05). Platelet reactivity was significantly higher in female patients with greater platelet aggregation (75.9 ± 23.3 vs. 63.5 ± 28.8) and lower platelet inhibition (23.8 ± 23.4 vs. 36.8 ± 28.9) (all P < 0.01). This trend was consistent over time when stratified by the postoperative inpatient and postoperative outpatient clinical phases. There was no statistically discernible difference in the use of antiplatelet therapy between groups, yet female patients continued to exhibit greater platelet reactivity when analyzed by the type of pharmacologic regimen (platelet aggregation on mono-antiplatelet therapy: 80.6 ± 21.0 in women versus 69.4 ± 25.0 in men; platelet aggregation on dual antiplatelet therapy: 67.9 ± 23.8 in women versus 44.8 ± 31.8 in men) (all P < 0.01). Twenty-one patients experienced postoperative graft/stent thrombosis within the study period. In relation to the overall study population, patients with thrombosis had Platelet Mapping metrics above the 50th percentile of overall platelet aggregation distribution.

Conclusions

There is a growing appreciation for the differences in etiology, disease progression, and outcomes of cardiovascular conditions as they relate to sex. In this cohort, traditional cardiovascular risk factors were in lower prevalence in female patients. Platelet reactivity was found to be higher across clinical phases and antiplatelet regimens. High platelet reactivity was also associated with an increased incidence of thrombosis after lower extremity revascularization. These hypothesis-generating findings provide the basis for further exploration of sex-specific coagulation profiling in PAD patients.

Introduction

There is a growing appreciation for the differences in etiology, disease progression, and outcomes of cardiovascular conditions as they relate to sex.1 The prevalence and burden of peripheral artery disease (PAD) is equal, if not higher, in women compared to men.2,3 Clinical outcomes following lower extremity revascularization are worse in women, with higher rates of wound complications, major amputations, and mortality.4 Disease progression is also worse, with women experiencing a faster functional decline and greater loss of mobility over time.5

However, women are notably underrepresented in existing PAD studies, contributing to a significant gap in clinical and physiologic knowledge regarding the etiology and natural history of female-specific disease.6 What is known is paradoxical: traditional cardiometabolic risk factors associated with cardiovascular disease are less prevalent in females and at the same time females are more sensitive than males to the effects of certain risk exposures.7, 8, 9, 10 Importantly, there is an emerging consensus that there may be ineffectively measured, or yet unidentified, key risk factors for PAD in women.1 This highlights the importance of understanding sexual dimorphism in cardiovascular biology, in which sex-biased gene expression results in phenotypic divergence of disease.11

Thromboelastography (TEG), an established viscoelastic method for hemostasis testing, with wide adoption within the cardiac and transplant populations, may provide some insight. Unlike other assays that aim to quantify platelet reactivity, TEG with Platelet Mapping provides clot analysis with and without thrombin, offering the opportunity to not only study platelet function, but also may overcome the confounding effect of direct oral anticoagulant medications on platelet function, which is yet to be established.12

We hypothesize that quantifying platelet variability from eventually be used, in conjunction with other thromboelastographic metrics, to detect dysregulation in clotting parameters and establish cohort-specific antithrombotic management. This prospective observational study aimed to establish differences in platelet reactivity between sexes in those PAD patients undergoing lower extremity revascularization.

Section snippets

Study Population

Patients scheduled for lower extremity revascularization procedures within the Vascular Surgery department at a large tertiary care center were prospectively enrolled between December 2020 and January 2022. Open surgical, endovascular, and hybrid procedures were included. Procedure types included re-establishing in-line flow inflow insufficiency, outflow insufficiency, or combined cases involving both inflow and outflow pathology. Exclusion criteria were inability to provide informed consent,

Demographics, Comorbid Conditions, and Procedure Details

One hundred seven patients were analyzed, of which 70 were male and 37 were female. Age at the time of enrollment, race/ethnicity, body mass index, and tobacco use did not differ significantly between groups. Diabetes was stratified as controlled (HbA1c < 7%) or uncontrolled (HbA1c ≥ 7%). The prevalence of uncontrolled diabetes in male patients was significantly higher compared to female patients (18.6% vs. 2.7%, P = 0.03). Patients with hypertension were stratified as those requiring only 1

Discussion

Women face a disproportionate burden from many types of cardiovascular disability and mortality, including a greater lifetime risk of cerebrovascular events, a greater risk of death following MI, and poorer outcomes after lower extremity revascularization procedures compared to men.8,13, 14, 15 Because PAD affects millions across the United States, and is now recognized as a global pandemic, it is imperative that we work to understand this inequality.2

Given the historic male predominance in

Conclusion

Although female patients with PAD currently experience the same treatment paradigms as male patients, it is known that the natural history, disease progression, and response to intervention are significantly worse. In this cohort of patients undergoing lower extremity revascularization, females had a significantly lower prevalence of traditional cardiometabolic risk factors for PAD. On the other hand, high platelet reactivity in women, with increased platelet aggregation and diminished platelet

References (20)

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Cited by (3)

  • Peripheral Artery Disease in Women

    2022, Journal of Critical Limb Ischemia

Funding: Grant support for this research was provided by Haemonetics, Boston, MA.

Disclosure: The authors have no conflicts of interest to report.

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