Intra-Aneurysmal Thrombosis as a Possible Cause of Delayed Aneurysm Rupture after Flow-Diversion Treatment

Rupture-Risk Assessment before Treatment

All patients belonged to a relatively high-risk group, most presenting with a combination of multiple risk factors for rupture. Eleven aneurysms were symptomatic before treatment, and symptomatic aneurysms have a relative risk for rupture of 8.3 compared with asymptomatic ones.⁷ Most patients had hypertension. With a mean aneurysm size of 22 mm and with all lesions being >15 mm, the rupture risk further increased.⁸

For saccular aneurysms, a high AR (>1.6) has been shown to correlate with aneurysm rupture.⁹ In our series, the mean AR for the 9 saccular aneurysms was 3.1 and was ≥1.8 in all cases. In a study by Ujiie et al,¹⁰ an AR of >1.6 correlated with slow flow in the dome area, resulting in low wall shear stress. This is known to cause aggregation of blood cells along the intimal surface,¹⁰ endothelial dysfunction, and cell loss.¹¹ This result, in turn, leads to intimal damage, thrombosis, and intramural inflammation with further degeneration of the aneurysm wall.¹² In principle, these processes, leading to degeneration of the aneurysm wall and eventual rupture, may also have important biologic effects on the aneurysm wall after treatment. Although most large and giant aneurysms, like in our series, tend to have a high AR, this indirect sign of aneurysm wall vulnerability and fragility may become more relevant when addressing the delayed rupture risk of aneurysms smaller than those from this series.

Treatment Effects with FD Implantation

FD implantation resulted in significant flow changes in all cases; however, inflow jets as recorded before treatment were still present immediately after treatment in most patients. With in vitro studies and numeric simulations of FD hemodynamic effects, such a lack of flow change has been observed with inertia-driven flow (when the arterial flow points to inside the aneurysmal sac) compared with shear-driven flow.¹³ Therefore, FD effects in an individual patient depend on local flow conditions and are mainly governed by parent vessel geometry and aneurysm configuration. A possible undesirable effect of insufficient flow diversion may be the induction of a detrimental intra-aneurysmal flow pattern. FD treatment could therefore lead to a sudden change in flow pattern, with consequent increased stress to areas that were not previously exposed to strain. This might play a leading role in rupture if there is no or only partial thrombosis.

Treatment with FDs changed the intra-aneurysmal hemodynamics resulting, in all cases, in complete or significant thrombus formation in the aneurysm cavity. The reduced but persisting intra-aneurysmal flow could provide a basis for continuous thrombus renewal. This is known to favor autolytic aggressive thrombus formation.¹⁴

Role of Intra-Aneurysmal Thrombus in Delayed Aneurysm Rupture

Thrombus developed in the aneurysm sac in all cases after FD treatment, suggesting that in some circumstances, intraluminal thrombus may contribute to the pathophysiologic cascade ending in rupture in both untreated and treated aneurysms. In clinical studies, besides increased de-endothelialization and aneurysm wall infiltration by leukocytes,^15,16 the presence of fresh and organizing luminal thrombus was identified as a key factor leading to aneurysm wall degradation and correlating with aneurysm rupture.¹⁵

On the other hand, thrombus formation is the first step leading to permanent aneurysm repair through cicatrization and reverse remodeling of the vessel wall. Coil and FD treatment have demonstrated well their great potential to induce this pathway of cure through thrombosis.^1,2 It is unclear why thrombosis may lead to cure in some cases, whereas in others, it appears to trigger increased autolysis, which may overload the biologic defense mechanisms of the vessel wall and result in aneurysm rupture.

Similar pathologic processes are observed and have been extensively investigated in AAAs. In AAAs, mural thrombus forms along the aneurysm wall in permanent contact with the flowing blood and undergoes continuous thrombolysis and renewal.¹⁴ Mural thrombi within AAAs are characterized by an absence of organization and cell colonization¹⁷ and are associated with a thinner arterial wall, more extensive elastolysis, a lower attenuation of smooth muscle cells in the media, and a higher level of immunoinflammation in the adventitia.¹⁴ By aggregating platelets continuously entrapping circulating white blood cells and absorbing plasma components, the mural thrombus acts as a source of secreted proteases within the aneurysm, leading to further chemical degradation and weakening of the aneurysm wall with subsequent evolution of the aneurysm.¹⁷ The volume of mural thrombus correlates with protease activity both in the thrombus itself and within the aneurysm wall,¹⁸ suggesting that the bigger the thrombus, the more important its biochemical effects.

It is tempting to apply these observations to intracranial aneurysms. All the aneurysms in our series contained a significant volume of thrombus following FD treatment, which filled most or the entire volume of the aneurysm cavity. In the 2 cases examined histopathologically, thrombus without significant organization or cellular colonization was identified, as described in AAA. That thrombosis may precipitate rupture was also suggested in patient 11, in whom, as described above, delayed rupture occurred only after thrombus developed.

In contrast, clinical observations of aneurysms following spontaneous partial thrombosis do not suggest that thrombosis significantly increases the risk of rupture.¹⁹ However the biologic consequences of stepwise thrombosis may not be the same as those for a large thrombus developing rapidly. One could suggest that depending on the quality, quantity, and evolution of the thrombus, the aneurysm wall might be exposed to varying thrombus-induced autolytic activities, though this possibility is hypothetic. Furthermore, in the presence of a large thrombus, defense mechanisms opposing autolysis and wall degradation may be overwhelmed by a large enzymatic overload. Whether cicatrization and reverse remodeling or rupture occur may depend on the balance between pro- and antiautolytic activities in the aneurysm wall. Our observations support this hypothesis because the ruptured aneurysms in our series were large and thin-walled and contained extensive thrombus that developed during a short period.

The temporary swelling and increased volume of a thrombosed aneurysm following FD treatment or PAO²⁰ might also be explained by a similar mechanism, though following gradual rather than rapid thrombosis (the latter favoring rupture).

Cicatrization and reverse remodeling with a decrease in aneurysm volume are thought to start only after complete thrombosis.²¹ According to our hypothesis, by promoting thrombus within the aneurysm sac and by isolating it from the circulation, FD devices facilitate this process. Cicatrization and reverse remodeling are favored when thrombus in the aneurysmal cavity stops the continuous process of renewal, an event that becomes more likely following sealing of the luminal surface of the thrombus by a layer of neointimal tissue and in-growth of mesenchymal cells.

Major Common Features of the Ruptured Aneurysms

The main goal of this analysis was to suggest a mechanism to explain the observed delayed aneurysm wall degradation and rupture. We have identified 4 features in our series that may be associated with an increased risk of delayed rupture:

• 1) Large and giant aneurysms, potentially able to contain large rapidly accumulated thrombi

• 2) Symptomatic aneurysms suggesting recent growth and wall instability

• 3) Saccular aneurysms with an AR of > 1.6

• 4) Morphologic characteristics predisposing to an inertia-driven inflow, not necessarily addressed by a FD device.

In this series, at least 3 of the 4 features were present in all patients, and in 7 patients, all 4 features were present. Needless to say, our study was not designed and does not enable us to assess the relative risk of delayed rupture in the presence of ≥1 of these features. Nevertheless, delayed-rupture events for all aneurysms with the above-mentioned characteristics remain rare after this form of treatment; however, to date, no scientifically reliable registry data are available to address the exact incidence. We suggest that for delayed rupture to occur, a complex interaction of multiple factors is required. For intracranial aneurysms, these factors and interactions have, as yet, been only partially unraveled.

Proposed Treatment Strategy to Avoid Ruptures

On the basis of our observations and our hypothesis, we suggest that measures to prevent the buildup of unstable thrombus exhibiting high and aggressive autolytic characteristics following flow diversion may reduce the incidence of delayed rupture. This might be achieved with aneurysm filling, with the addition of coils, or by increasing the flow-diverting effect of the implants. Coils may exhibit favorable effects in stabilizing thrombus, different from stagnation through flow diversion alone. Deconstructive methods like PAO remain a very valuable and safe solution when hemodynamically tolerated. We should not forget the high natural bleeding risk in this specific group of patients with large and giant aneurysms and should balance the treatment risk accordingly.

The major limitations of this study are the retrospective nature of the analysis, the lack of exact data on the incidence of aneurysm ruptures after FD treatment, and the lack of a control group that would make comparison with other similar aneurysms not rupturing after FD treatment possible.