de Maat, M. P. | Search bioRxiv

bioRxiv2025

Arterial Shear Rate Determines the Structure and Mechanical Properties of Whole-Blood Clots

BackgroundArterial thrombosis arises under high shear conditions and is a leading cause of ischemic stroke and myocardial infarction. The local hemodynamic environment during the formation of the thrombus influences its final composition, which in turn influences its mechanical characteristics and the associated risk of embolization. However, how arterial shear rates determine the local mechanical properties, structure and composition of clots remains poorly understood. ObjectiveTo investigate how physiological and pathological arterial shear rates shape blood clot composition, formation dynamics, and regional mechanical properties in a newly-developed microfluidic flow model. MethodsWe used a microfluidic flow model that allows real-time imaging of blood clot formation under controlled arterial shear rates (300, 1000, and 3500s-1). We visualized platelets and fibrin deposition using confocal microscopy and quantified composition-dependent spatial heterogeneities in clot stiffness with microindentation. ResultsPathologically high (3500 s-1) arterial shear rates promoted more rapid platelet aggregation and the formation of taller platelet-rich clots. Fibrin deposition started after about 6 minutes in all shear conditions and coincided with platelet aggregate stabilization at higher shear rates. Microindentation revealed that platelet- and fibrin-rich regions were significantly stiffer than red blood cell-rich regions. Clots formed at 3500s-1 had a > 3-fold higher average stiffness than those formed at 300s-1, reflecting their higher platelet content. ConclusionsThis study demonstrates that arterial shear rate governs clot growth and composition, translating into shear-dependent microscale mechanical properties. These findings provide new mechanistic insights into clot properties that are relevant for clot stability and vulnerability to embolization.

bioengineering↗

bioRxiv2018

Evaluation of the causal effect of fibrinogen on incident coronary heart disease via Mendelian randomization

BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.\n\nMethods and FindingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score incorporated data from 11 European-ancestry prospective cohorts to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI).\n\nIn single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.\n\nConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.\n\nAuthor SummaryInitial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.

genetics↗