Background: Platelet contractility plays a crucial role in clot contraction to provide rigidity and stability to thrombi. Clot contraction has been studied extensively in static conditions, but there are fewer studies that evaluate how shear flow can affect platelet contraction. In particular, there have been limited studies evaluating the role of secondary platelet aggregation on platelet contraction under flow.

Aims: Here, we wanted to evaluate how inhibition ADP and thromboxane A2 (TXA2) would affect clot contraction.

Methods: We ran PPACK-treated whole blood ± acetylsalicylic acid (ASA), 2-MethylthioAMP (2-MeSAMP), and/or MRS-2179 over collagen (100 s-1) for 7.5 minutes, then stopped flow to observe contraction for 7.5 minutes. We developed two automated methods of quantifying platelet contraction: (1) a one dimensional, “global” measurement of clot length in the direction of flow, and (2) a two dimensional, “local” measurement of the change in area coverage of platelets in a clot.

Results: Figure 1: Global platelet contraction is reduced by both ADP and TXA2 inhibition, while local platelet contraction is only reduced by TXA2 inhibition.
We found that platelet fluorescence intensity (FI) decreased and global platelet contraction was inhibited when ASA, 2-MeSAMP, or MRS-2179 were added to inhibit TXA2 or ADP production. We observed a correlation between platelet FI and global platelet contraction (R2= 0.72). Unlike global platelet contraction, local platelet contraction was more pronounced across all conditions; however, we observed that in conditions with ASA, there was significantly reduced local platelet contraction relative to conditions without ASA. We also evaluated P-selectin FI to determine how highly activated platelets were affected by ADP and TXA2 inhibition. P-selectin FI was significantly reduced by ADP and TXA2 inhibition. There was limited global and local contraction in P-selectin+ platelets across all conditions.

Conclusions: Our results demonstrate that global platelet contraction is inhibited by ASA, 2-MeSAMP, and MRS-2179, while ASA has a more pronounced inhibitory effect on local platelet contraction. These results are significant in understanding how different platelet antagonists affect clot contraction and ultimately clot resolution.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/inhibition-of-adp-and-thromboxane-a2-production-results-in-decreased-global-platelet-contraction-but-thromboxane-a2-inhibition-plays-a-greater-role-in-limiting-local-platelet-contraction/