A systems approach to hemostasis: 2. Computational analysis of molecular transport in the thrombus microenvironment

Abstract

• Hindered diffusion becomes the dominant force of molecular movement in a thrombus.• The thrombus core acts as a selective molecular prison.Hemostatic thrombi formed after a penetrating injury have a heterogeneous architecture in which a core of highly activated, densely packed platelets is covered by a shell of lessactivated, loosely packed platelets. In the first manuscript in this series, we show that regional differences in intrathrombus protein transport rates emerge early in the hemostatic response and are preserved as the thrombus develops. Here, we use a theoretical approach to investigate this process and its impact on agonist distribution. The results suggest that hindered diffusion, rather than convection, is the dominant mechanism responsible for molecular movement within the thrombus. The analysis also suggests that the thrombus core, as compared with the shell, provides an environment for retaining soluble agonists such as thrombin, affecting the extent of platelet activation by establishing agonist-specific concentration gradients radiating from the site of injury. This analysis accounts for the observed weaker activation and relative instability of platelets in the shell and predicts that a failure to form a tightly packed thrombus core will limit thrombin accumulation, a prediction tested by analysis of data from mice with a defect in clot retraction. (Blood.

Defective release of α granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models

“…Thrombin activity in this model extends as a gradient from the site of vascular injury [73][74][75][76] and is necessary for full platelet activation and a granule secretion. 51,77 Our results indicate that ADP signaling reinforces platelet activation at the edge of this gradient where thrombin activity starts to decline.…”

Platelets and hemostasis: a new perspective on an old subject

“…7 Tight packing slows the movement of soluble molecules in the gaps between platelets, which shrink as the thrombus retracts. 10,11 The core is where most of the fibrin is found and where clot retraction would be expected to have the greatest impact ( Figure 1B). As packing density increases, transport becomes dominated by diffusion rather than convection, slowing movement to an even greater extent ( Figure 1C).…”

“…As packing density increases, transport becomes dominated by diffusion rather than convection, slowing movement to an even greater extent ( Figure 1C). [10][11][12] Regional differences in packing density also affect the distribution of platelet agonists. The result is the appearance of concentration gradients in which the distribution of each agonist is also affected by its physical properties and binding to other molecules.…”

“…11,15 Studies performed in silico extend the observational studies and provide hypotheses that can be tested in vivo and in vitro. 10,16,17 Most of the studies summarized in Figure 1 were performed in the mouse microvasculature using a laser or a sharpened probe to make small holes in arterioles and venules. To what extent are the results applicable to people?…”

Platelets stop us leaking

“…A consequence of the tightly packed core is restricted permeation of plasma-borne molecules through the core, and therefore greater local thrombin activity resulting in fibrin formation and increased platelet activation. [6][7][8][9] Indeed, inhibition of thrombin disrupts thrombus core structure, while the size of the thrombus shell is reduced in the presence of adenosine 59-diphosphate (ADP) receptor antagonists. 6 In this issue, Welsh et al have explored which features of the heterogeneous architecture of platelet thrombi explain their ability to seal blood vessels to achieve "plasma stasis," and determined whether the use of antiplatelet and anticoagulant agents which impair thrombus structure interfere with the formation of a vascular seal.…”