Flow Diversion for Intracranial Aneurysms in Patients with Hematologic Disorders

Demographics

In total, 11 patients with 29 total aneurysms were treated at a single institution (Table 1). The median age at time of treatment was 50 years (interquartile range: 41–56). Of all patients, 81.8% (n=9) were female sex. Pre-operatively, all patients were on antiplatelet regimens. One patient with Factor V Leiden was on both anticoagulation and dual anti-platelet therapy (DAPT). Most patients were on preoperative DAPT using aspirin and either ticagrelor or clopidogrel. One patient was on single antiplatelet therapy at the recommendation of their hematologist. Six patients had pre-operative aspirin response unit (ARU) values and 10 had pre-operative VerifyNow P2Y12 response unit (PRU) values. The mean ARU was 505 (range: 379–652) and mean PRU was 112 (range: 7–213), both considered therapeutic at our institution. Two patients had a family history of aneurysms, and 4 patients had a history of subarachnoid hemorrhage (SAH). All the patients who presented with a SAH initially had their aneurysm treated with coiling, and 2 of these patients had SCD. In our total sample of 11 patients, 3 had SCD, 2 had SCT, 1 had alpha-thalassemia trait, and 5 had various coagulopathies.

Table 1.

Demographics of analytic sample

Aneurysms

Out of the 29 total aneurysms, 17 were treated with FD. Of the 17 treated with FD, 15 were paraophthalmic (88.2%), 1 was anterior communicating (ACOM), and 1 was anterior choroidal (Table 2). The aneurysms were treated with Pipeline Flex (n=10, 50.0%), Pipeline Flex Shield (n=7, 35.0%), and FRED X (n=3, 15.0%) with multiple adjacent aneurysms often getting treated by multiple FD in a telescoping fashion. One patient had their aneurysm treated previously with coils and was later treated with FD and more coils. One patient had their aneurysm treated only with coils and FD concurrently. The median number of FD initially deployed were 2. The average diameter of the aneurysms treated with FD was 5.03 mm (standard deviation: 3.88 mm).

Table 2.

Aneurysm and treatment characteristics

Outcomes

Patients with SCD (n=3) had the largest number of aneurysms per patient with 12 total aneurysms (41.4%, Table 2). Patients with SCD were also the only group in our cohort to experience adverse outcomes post-operatively after receiving FD (Table 3). Two of the 3 patients with SCD experienced a stroke post-operatively (Fig. 1). One patient had multiple ischemic strokes undergoing hemorrhagic conversion and permanent neurological deficits. The other patient had transient aphasia and homonymous hemianopsia that resolved prior to discharge. One of the 11 patients had a distinct FD treatment of a different aneurysm and was included as 2 separate treatments to make a total of 12. Three patients did not receive any follow-up angiograms after their procedure. Of those that did, 7 patients with 8 treated aneurysms had complete occlusion (OKM score C or D), whereas 2 patients with 2 treated aneurysms had adequate occlusion (OKM score B). Furthermore, the average time to OKM score D was 16.8 months or 1.4 years with the longest taking 5 years post-operatively. Three patients had inadequate occlusion on follow-up and underwent additional stent placement on a later date (Fig. 2), which occurred an average of 7.7 months from initial treatment.

Table 3.

Patient breakdown and HDs outcomes

Fig. 1.

Left supraclinoid aneurysms treated with flow diverters in sickle cell disease patient with post-procedural stroke. (A) 3D reconstruction of the aneurysms. (B) Angiography working angle demonstrating the multiple aneurysms. (C) Post-flow diverter placement working angle. (D) 3D reconstruction of the flow diverter post-stenting. (E, F) Magnetic resonance imaging (MRI) demonstrating the post-procedural ischemic stroke, which eventually underwent hemorrhagic conversion and lead to the patient having permanent neurological deficits.

Fig. 2.

Left superior hypophyseal artery aneurysm requiring additional flow diverting stents placement. The patient had a left superior hypophyseal aneurysm with inadequate O’Kelly-Marotta grading scale scores on follow-up angiograms necessitating placement of additional flow diverting stents. (A) 3D reconstruction of the aneurysm. (B) Angiography working angle demonstrating the aneurysm. (C) 3D reconstruction of the flow diverter post-stenting. (D) Angiography of follow-up residual aneurysm. (E) Angiography demonstrating resolution of the left superior hypophyseal artery aneurysm.

Sickle Cell Disease and Sickle Cell Trait

SCD is associated with a higher prevalence of IA often leading to SAH [10,11]. While the exact risk of aneurysm rupture in SCD is unclear, studies have reported that patients tend to present with rupture at a younger age and with smaller aneurysms compared to the general population [12]. Prior reports estimate that 6% of adults and 4% of children with SCD develop IA at some point within their lifetime [13] with 1 study showing that 52.6% of these patients had multiple aneurysms [10]. Therefore, identifying effective treatment strategies for this population is critical.

SCD arises from a beta-globin gene mutation leading to the polymerization of HbS, resulting in erythrocytes taking on a characteristic “sickle” shape, hemolysis, and increased blood viscosity [14]. This contributes to the high rates of stroke and sickle cell crises [15]. Therefore, SCD is a very common cause of stroke and consequent hemorrhage in children and adults [16,17]. Given the concern for thrombosis associated with endovascular procedures involving FD, microsurgical clipping has historically been favored for aneurysm treatment in patients with SCD [18]. In our subset of patients, Pipeline Flex Shield, Pipeline Flex, and FRED X were used in various combinations in patients with SCD and SCT. While patients with SCT did not suffer any adverse events, 2 out of the 3 patients with SCD in this series experienced ischemic strokes following FD placement. It is important to note that one of these patients also had concomitant antiphospholipid syndrome.

To our knowledge, there are only 2 reports that have described the use of FD in SCD [7,18]. Dmytriw et al. [7] demonstrated the use of a Pipeline device in treating a ruptured dissecting, fusiform aneurysm without complications. Gallas et al. [18] reported a delayed right hemispheric hemorrhage following FD for an ophthalmic artery aneurysm, which led to mortality. Additionally, Ediriwickrema et al. [19] described a case utilizing a Neuroform 3 (Boston Scientific) stent in a patient with SCD with a single aneurysm. In our study, all patients with SCD had multiple aneurysms and 2 had a history of SAH previously treated with endovascular coiling. These 2 patients were the only in our cohort experiencing adverse clinical outcomes after FD treatment, with both experiencing a stroke. One patient had multiple and progressive ischemic strokes that underwent hemorrhagic conversion and experienced significant permanent neurological deficits. The other patient had transient aphasia and homonymous hemianopsia that resolved prior to discharge. Of note, for both patients, the aneurysms treated with FD were separate from the previously coiled aneurysms. Both patients also received multiple flow diverting stents in a telescoping fashion to treat their aneurysms. While the literature has not suggested that multiple flow diverting stents increase the risk for stroke, there is a paucity in the literature on their safety in patients with HDs.

Prior literature has demonstrated high rates of aneurysm occlusion via FD at 6 months, with studies reporting the average time to aneurysm occlusion as 6.92 months to 14.7 months and complete occlusion rates of 73% to 95.6% [20,21]. However, in our cohort, the occlusion rates were lower, with the average time to OKM score of D of 16.8 months and only 33.3% occlusion at 6 months. Two patients still had not reached adequate occlusion at the time of last follow-up (OKM score B). Specifically, among patients with SCD, the average occlusion time was 8 months, though 1 aneurysm remained patent at 2 years. The prolonged time to aneurysm occlusion is likely due to impaired endothelialization, as SCD has been found to be associated with endothelial dysfunction due to decreased endogenous nitric oxide and decreased endothelial progenitor cells [22,23]. These mechanisms disrupt the functionality of FD, thereby decreasing the ability of the aneurysm to occlude.

FD have become the treatment of choice for many IA due to their low risk profile and high efficacy shown in multiple prospective trials. While surgical clipping has been traditionally performed in SCD patients, prolonged anesthesia times poses risks of vaso-occlusive crises [24]. Furthermore, patients with repeated episodes of acute chest syndrome can have decreased pulmonary function [25], which can lead to perioperative hypoxia and therefore may predispose patients to recurrent vaso-occlusive events during surgery [24]. Given the drawbacks of open surgery, many authors have pursued endovascular treatment of aneurysms in patients with SCD. Endovascular procedures offer shorter procedure times and therefore less anesthesia, decreasing the risk for vaso-occlusive crises. In addition, patients with SCD often have multiple aneurysms [10], therefore a FD can potentially treat all adjacent aneurysms at once, reducing the need for multiple operations. However, our findings suggest that there may be significant stroke risks involved with the placement of intraluminal metal. Therefore, the optimal treatment of patients with SCD is unclear, but endovascular coiling may represent a safer alternative in some cases by offering the advantages of shorter procedure times without the need for intraluminal metal.

Alpha-Thalassemia Trait and Coagulopathies

This study is the first to report on the efficacy of FD in patients with alpha-thalassemia trait and various coagulopathies such as thrombocythemia. Alpha-thalassemia trait, also called alpha-thalassemia minor, involves the deletion of 2 alpha-globin genes, which results in a mild anemia. In our cohort, the 1 patient with alpha-thalassemia trait achieved complete occlusion of the aneurysm within 6 months.

Thrombocythemia is a myeloproliferative disorder consisting of the overproduction of platelets [26]. It is also associated with an increase in thrombosis which decreases available platelets to prevent excessive bleeding [26], and can lead to hemorrhagic events or occlusion of vessels by causing a prothrombotic state [27]. There have been a few reports in the literature of patients with thrombocythemia developing aneurysms, both extracranially [28] and intracranially [27]. Baek and Kim [27] report a case of a patient with thrombocythemia treated endovascularly with coils leading to an infarction but overall recovery of neurological deficits. Our sample included 2 patients with thrombocythemia. One patient lacked follow-up imaging while the other had inadequate occlusion of the aneurysm and required additional FD placement. The delayed occlusion may be attributed to dysfunctional platelet aggregation exacerbated by DAPT, which may limit intra-aneurysmal thrombus formation and endothelization of the vessel wall [29]. Future research is needed to understand the flow dynamics in this subset of patients. However, it is important to note that neither patient had a complication or thrombosis associated with placement of the FD.

This study also analyzed patients with Protein S deficiency, Factor V Leiden, and vWD with Factor XII deficiency. Each of these factors plays an important role in the coagulation cascade in the formation or breakdown of clots. Protein S is a co-factor for Protein C and physiologically causes the degradation of clotting factors Va and VIIIa, however its deficiency causes a hypercoagulable state. The increased production of clots and decreased breakdown of certain clotting factors can cause occlusion of the vessels and an increased risk of stroke [30]. Our patient with Protein S deficiency had to receive additional flow diverting stents due to inadequate occlusion of the aneurysm and required 5 years to complete aneurysm occlusion. Brouns et al. [31] reported that Protein S deficiency causes impairment of fibrin formation and platelet activation, which are crucial for aneurysm occlusion [32]. Factor V Leiden also causes a hypercoagulable state by decreasing the ability of Factor Va from being degraded by Protein C. There is debate in the literature regarding Factor V Leiden and IA risk, with some studies reporting an association between these conditions [33] as well as an increased risk for stroke [34]. Our patient was placed on both anticoagulant and antiplatelet agents prior to FD placement to decrease the risk of thromboembolic events. The patient did not experience any post-operative adverse events in the hospital; however, this patient did not receive any post-operative angiograms.

Finally, vWD is a deficiency of von Willebrand factor (vWF) which is involved in both the coagulation cascade and platelet plug formation. For the coagulation cascade, it is a carrier protein for Factor VIII, and vWF also plays a role in ensuring platelet adherence to the endothelial lining. For FD, platelet adherence to the vessel wall is crucial for formation of new intima and occlusion of the aneurysm. This patient also had Factor XII deficiency which also causes a decrease in coagulation. Due to the pathophysiology of these two conditions, it is not surprising that this patient needed to be re-treated due to inadequate aneurysm occlusion.

None of the patients with coagulopathies experienced any adverse effects from the use of FD; however, 2 of the patients had inadequate occlusion at the time of last follow-up angiogram. The patient with thrombocythemia received an OKM score of B at the most recent follow-up 6 months post-operatively and required an additional FD. The patient with Protein S deficiency also required an additional FD and had an OKM score of C at last follow-up 1 year after the initial FD placement and 6 months after the additional FD placement. Finally, our patient with vWD and Factor XII deficiency had multiple additional stents placed with a time to complete aneurysm occlusion (OKM score D) of 5 years.

While our patient with vWD did not have any adverse events, it is important to note the increased risk of hemorrhage in patients with vWD on DAPT [35]. Our patient had a time to complete occlusion of 5 years with additional FDs placed, necessitating a prolonged course of DAPT. While it can be effective in the short term, studies have shown that prolonged use can increase the risk of severe hemorrhage and must be used with caution in this population. Therefore, while FD can be a good treatment option, its necessity for the prolonged use of DAPT may limit its utility in this population and a discussion with the patient should be had about any potential risks.

Limitations

Our sample includes a small cohort of 11 patients and few patients with each individual HD. All HD besides SCD, SCT, and thrombocythemia had only 1 patient, making this study unable to be generalizable. Furthermore, not all patients received follow-up angiograms, therefore we were unable to fully assess the post-operative occlusion times in all patients across the various HD. While this is a small series, there is a paucity of literature on the topic of FD in HD, limiting ability for comparison. Our experience was one of a single-center, and therefore it is important to compare whether our experience is similar to those of other institutions with varying patient populations and protocols.