The plasma protein fibrinogen stabilizes clusters of red blood cells in microcapillary flows

Abstract

The supply of oxygen and nutrients and the disposal of metabolic waste in the organs depend strongly on how blood, especially red blood cells, flow through the microvascular network. Macromolecular plasma proteins such as fibrinogen cause red blood cells to form large aggregates, called rouleaux, which are usually assumed to be disaggregated in the circulation due to the shear forces present in bulk flow. This leads to the assumption that rouleaux formation is only relevant in the venule network and in arterioles at low shear rates or stasis. Thanks to an excellent agreement between combined experimental and numerical approaches, we show that despite the large shear rates present in microcapillaries, the presence of either fibrinogen or the synthetic polymer dextran leads to an enhanced formation of robust clusters of red blood cells, even at haematocrits as low as 1%. Robust aggregates are shown to exist in microcapillaries even for fibrinogen concentrations within the healthy physiological range. These persistent aggregates should strongly affect cell distribution and blood perfusion in the microvasculature, with putative implications for blood disorders even within apparently asymptomatic subjects.

Optical tweezers study of red blood cell aggregation and disaggregation in plasma and protein solutions

“…This might be a limitation of the flow-chamber experiments, as in the latest work using an AFM, it was shown that RBCs do interact with each other in a solution of fibrinogen alone. 19 A monotonic increase in interaction energy along with an increase in fibrinogen concentration was observed. The interaction between RBCs in a fibrinogen solution (4 mg∕ml) was also qualitatively observed by Bronkhorst et al 23 using OT.…”

“…19,23,32 Our results give more specific information that most likely fibrinogen is the protein responsible for the disaggregation kinetics of RBCs, while for spontaneous aggregation, it has no effect when present alone or only with albumin in the solution. It was shown by the disaggregation force measurements that RBC interaction is strong even if fibrinogen is the sole protein in the solution.…”

“…During last two decades RBC interactions been studied in plasma and protein solutions using AFM and OT. [19][20][21][22][23] The interaction forces between RBCs were found to be on the order of dozens of pN. In particular, OT offers the possibility to assess the aggregation mechanics further by allowing the study of interaction kinetics with a large degree of freedom that is challenging to achieve using other methods.…”

Clusters of red blood cells in microcapillary flow: hydrodynamic versus macromolecule induced interaction

“…1). The physical origin of this cluster formation can be either the long-ranged hydrodynamic interaction [2][3][4][5][6] or a short-range aggregation mechanism, which is caused by the plasma macromolecules 7 . The latter relates to the so-called rouleaux formation 8 .…”

“…In former studies on cluster formation, either no macromolecules were added and only hydrodynamic effects were present 6 , or the effects of the macromolecules were tested in channels that were smaller than the RBC diameter with the effect of hydrodynamic attraction minimized 7 . In this study, we allow both mechanisms to take effect and we observe that both are relevant, but they form clusters of notably different geometrical forms.…”