Thrombus remnant despite intra-arterial thrombolysis for thrombus formation during endovascular treatment of ruptured cerebral aneurysms: Does it harm?

Abstract

Background

The fate and safety of thrombus remnant despite intra-arterial thrombolysis for unexpected thrombus formation has rarely been reported.

Methods

From January 2010 to May 2015, 131 consecutive patients with ruptured intracranial aneurysms were treated by endovascular methods at our institution. Among the 21 patients (16%) treated by intra-arterial thrombolysis for the thrombus formation during the procedure, nine patients (nine aneurysms) suffered from thrombus remnant. We reviewed the clinical and radiologic outcomes of patients with thrombus remnant as well as intraoperative and postoperative management of thrombus formation.

Results

Thrombus formation occurred near the coiled aneurysm in eight patients, and distal embolic occlusion was observed in one patient. All nine patients were initially managed by intra-arterial thrombolysis with tirofiban. One patient with persistent distal embolic occlusion and two patients with distal migration of the thrombus after intra-arterial thrombolysis were additionally treated with stent retriever. One patient with occlusion of the parent artery near the coiled aneurysm despite intra-arterial thrombolysis was partially recanalized by permanent deployment of a stent retriever. Delayed cerebral angiography showed no increase in size of thrombus remnant in any patients. After the procedure, thrombus remnant was managed by intravenous tirofiban. Follow-up CT angiography on the first postoperative day showed patent arterial flow, and ischemic complication related with thromboembolism did not occur in any patients. One patient suffered from hemorrhagic complication.

Conclusion

If the patency of parent artery is maintained and the size of the thrombus remnant does not increase on delayed angiography after intra-arterial thrombolysis, postoperative thromboembolic events rarely occur.

Introduction

Thromboembolism is the most frequently reported complication during or after endovascular treatment of ruptured intracranial aneurysm^1–4 and it can result in periprocedural morbidity and mortality. In most case series, the rate of rescue therapy for thromboembolic complications ranges between 5% and 10%.^3–12

Many protocols have been suggested to prevent the formation of thrombus such as heparinized saline, systemic heparinization, and preoperative antiplatelet treatment.^{1,4,6,8,13–16} Despite all these measures, thrombosis can still occur and there is no consensus on an optimal protocol to prevent thromboembolic complications during endovascular treatment of intracranial aneurysm. Especially in the setting of endovascular treatment of a ruptured aneurysm, the use of a preventive protocol is limited, and unexpected thromboembolism is encountered more frequently. Until recently, many studies have suggested the use of thrombolytic agents or mechanical thrombectomy as a rescue therapy for intraprocedural thrombus formation.^{3–5,11,13,17–19}

However, in our experience, thrombus remnants (TR) occasionally exist despite the rescue treatment during coil embolization of ruptured intracranial aneurysms. At present, there have been no studies dealing with the safety of TR during endovascular treatment of ruptured intracranial aneurysms. Therefore, we report our experience with regard to the management of TR and investigated the clinical and radiological consequences when TR persisted after incomplete rescue treatment.

Methods

Patient population and aneurysmal characteristics

From January 2010 to May 2015, 131 consecutive patients who presented with ruptured intracranial aneurysms were treated by endovascular coil embolization at our institution. Among these 131 patients, thromboembolism occurred during the procedure in 21 patients. Thromboembolism occurred in 8 of 17 patients (47%) treated by the stent-assisted coiling technique, 10 of 79 patients (13%) treated by the single-microcatheter technique, and 3 of 35 patients (7%) treated by the double-microcatheter technique. In 12 of these 21 patients, thrombi or emboli were resolved completely by intra-arterial thrombolysis with tirofiban (a nonpeptide glycoprotein (Gp) IIb/IIIa antagonist) with or without mechanical thrombectomy. Of these 12 patients, seven patients with thrombus formation near the coiled aneurysm were fully recanalized by intra-arterial thrombolysis with tirofiban. The remaining five patients with distal embolic occlusion were successfully recanalized by only intra-arterial thrombolysis with tirofiban (n = 2) or adjuvant mechanical thrombectomy with stent retriever (n = 3). In 12 patients who were treated by the rescue therapy, one patient suffered from a hemorrhagic complication (focal hemorrhage at the frontal lobe) and one patient suffered from an ischemic complication (infarction at the territory of the middle cerebral artery (MCA)). Finally, we identified the remaining nine patients who suffered from TR after incomplete thrombolysis.

The mean patient age at the time of the procedure was 60.8 ± 12.7 years (range, 43–80 years). Seven patients were women. The treated aneurysms were located on the anterior communicating artery in two cases, MCA in two cases, posterior communicating artery in two cases, anterior choroidal artery in one case, basilar artery in one case, and the distal anterior cerebral artery in one case. Maximal diameters of aneurysms treated ranged from 3.3 to 10.5 mm (mean, 5.5 ± 2.2 mm). Most aneurysms were wide necked (5/9, 55%), with depth-to-neck ratios <1.5.

Coil embolization

All endovascular procedures were performed with the patients under general anesthesia using a relatively consistent scheme at our institution. Systemic anticoagulation with heparin was started after formation of the first coil frame. Heparin was usually administered as a 2000 - to 3000-IU bolus intravenously followed by 1000 IU/h. In all cases (n = 9), heparin was administered to achieve an activated clotting time (ACT) of approximately twice normal. ACT was checked every 30 minutes. The total amount of infused heparin during a procedure ranged from 2000 to 5000 IU. Dosages administered ranged from 25 to 100 IU/kg. In cases with unfavorable and wide-necked aneurysmal configuration that required stent-assisted coil embolization, antiplatelet treatment with 300 mg of clopidogrel and 300 mg of aspirin was administered orally after stent deployment. In cases with large intraventricular hemorrhage, if extra-ventricular drainage was planned, a mono-antiplatelet agent was given.

Management of thromboembolism during procedure

When thrombus formation was encountered during coil embolization, we continued coil deployment until satisfactory protection of the ruptured point was achieved. Partially occluded parent artery with flow was monitored closely every five minutes. If the thrombus formation increased or the parent artery was completely occluded, we started intra-arterial tirofiban infusion immediately. Dosages of 0.2 to 0.5 mg were infused intra-arterially via a microcatheter near the clot. When the arterial flow did not improve and thrombus was not resolved, additional infusion was performed with a maximum dosage of 0.75 mg. In case of embolic occlusion of a distal artery, intra-arterial thrombolysis or mechanical thrombectomy with a stent retriever (Solitaire AB or FR, Covidien, Irvine, CA, USA) was performed. Despite the use of maximum dosage of intra-arterial tirofiban infusion, if the parent artery near the aneurysm was not recanalized, permanent deployment of a stent retriever was performed because temporary deployment and retrieval of thrombus could result in herniation of coils into the parent artery.

If TR was observed despite the rescue treatment, we performed 20 minutes’ delayed cerebral angiography in a single session to confirm the stability of the thrombus. We stopped the procedure after confirmation of unchanged or decreased size of TR.

After the procedure, TR was managed by intravenous infusion of tirofiban (0.1 µg/kg/min for eight hours) to prevent thromboembolic complications in all cases. Antiplatelet medications were not routinely administered except in the case of stent-assisted coil embolization or coil protrusion.

Angiographic and clinical outcome

The degree of arterial recanalization was graded as follows: Grade A, complete clot dissolution; Grade B, incomplete clot dissolution without flow stagnation; and Grade C, incomplete clot dissolution with flow stagnation.¹⁴ Grade B was also assigned when not all branches were recanalized in cases of embolic occlusion.

All patients underwent computed tomography angiography (CTA) within one day after the procedure to evaluate the patency of the artery containing TR and to detect ischemic or hemorrhagic complications. After discharge, magnetic resonance angiography (MRA) or conventional digital subtraction angiography (DSA) was recommended at six months’ postembolization.

At six months after discharge, clinical outcomes were evaluated with the Glasgow Outcome Scale (GOS), in which GOS 5 indicates good recovery (resumption of normal life despite minor deficits), GOS 4 represents moderate disability (disabled but independent), GOS 3 indicates severe disability (conscious but disabled and dependent for daily care), GOS 2 indicates persistent vegetative state (unresponsive and speechless), and GOS 1 indicates death.²⁰

Results

Endovascular coiling and thrombus treatment

The stent-assisted coiling technique was the most frequently used (5/9, 55.5%). The double-microcatheter technique was used in two cases (2/9, 22.2%), and single-microcatheter technique was also used in two cases (2/9, 22.2%). All implanted stents for coiling were Enterprise stents (Codman, Raynham, MA, USA) (Table 1).

Table 1.

Procedural characteristics and outcome of the patients with thrombus remnant^a.

Patient no.	Sex/Age (year)	HH grade	Aneurysm location	Ratio	Procedure	Clot type (location)	IA tirofiban	Additional mechanical thrombectomy	Recanalization grade	Arterial patency (CTA after one day)	GOS
1	F/64	2	PcomA	1.58	Stent assisted (Enterprise)	Embolus (MCA)	0.75 mg	Stent retriever (Solitaire)	B	Patent	5
2	F/64	1	MCA	1.68	Single microcatheter	Thrombus	0.75 mg		B	ICH	4
3	F/47	2	AcomA	1.73	Double microcatheter	Thrombus	0.5 mg		B	Patent	4
4	F/80	3	PcomA	1.29	Stent assisted (Enterprise)	Thrombus (distal migration)	0.6 mg	Stent retriever (Solitaire)	B	Patent	3
5	F/64	2	MCA	1.96	Stent assisted (Enterprise)	Thrombus (distal migration)	0.75 mg	Stent retriever (Solitaire)	B	Patent	4
6	F/59	2	AchA	1.47	Stent assisted (Enterprise)	Thrombus	0.6 mg		B	Patent	4
7	M/54	2	BA	1.1	Stent assisted (Enterprise)	Thrombus	0.5 mg	Stent deployed (Solitaire inside the Enterprise)	B	Patent	5
8	M/58	4	AcomA	0.95	Double microcatheter	Thrombus	0.5 mg		B	Patent	1
9	F/43	3	ACA	1.24	Single microcatheter	Thrombus	0.3 mg		B	Patent	3

^aAchA: anterior choroidal artery; AcomA: anterior communicating artery; BA: basilar artery; CTA: computed tomography angiography; HH, Hunt Hess grade; IA: intra-arterial; MCA: middle cerebral artery; PcomA: posterior communicating artery; Ratio: depth to neck ratio of aneurysm; ICH: intracerebral hemorrhage; M: male; F: female; GOS: Glasgow Outcome Scale.

Thrombus formation occurred at the interface between the parent artery and aneurysm neck in eight cases. Distal embolic occlusion was observed in one case. All patients were initially managed by intra-arterial thrombolysis with tirofiban. The mean dose of intra-arterially infused tirofiban was 0.56 ± 0.29 mg (range, 0.3–0.75 mg). One patient with persistent distal embolic occlusion and two patients with distal migration of thrombus after intra-arterial thrombolysis were additionally treated by mechanical thrombectomy. In these cases, distal arterial occlusion was partially recanalized by stent retriever. One patient who showed persistent occlusion of the parent artery near the coiled basilar top aneurysm despite intra-arterial thrombolysis was partially recanalized by permanent deployment of the stent retriever (Figure 1). Although all cases suffered from TR despite the rescue treatment described above, delayed cerebral angiography after 20 minutes showed no increase in size of the thrombus. According to the grading system, nine cases were Grade B.

Figure 1.

A 54-year-old man presented with subarachnoid hemorrhage and intraventricular hemorrhage. Cerebral angiography showed a large wide-necked basilar top aneurysm (a). Thrombus formation (arrow) along the deployed stent and occlusion of the basilar artery was detected during the stent-assisted coiling (b). Despite intra-arterial infusion of tirofiban (0.5 mg), the parent artery was not recanalized. Solitaire stent was permanently deployed inside the enterprise stent, and resulted in partial recanalization of the parent artery with thrombus remnant (arrow) (c). Computed tomography angiography on the first postoperative day showed patent arterial flow to both posterior cerebral arteries (arrow) (d). Follow-up cerebral angiography at six months after coil embolization showed stable coiled aneurysm and patent arterial flow without thrombus (e).

Angiographic and clinical outcomes

In all cases, postoperative CTA performed on the first postoperative day showed good patency of the involved artery, and ischemic complication related with thromboembolism was not observed. Postoperative hemorrhagic complication (intracerebral hemorrhage at the temporal lobe) was detected in one case. This patient underwent surgical removal of the hematoma and was discharged with moderate disability. At six months after discharge, mean GOS score was 3.67 ± 1.22 (range, 1–5). Two patients (both were initial Hunt and Hess Grade III) were moderately disabled as a result of the effects of initial bleeding. One patient (initial Hunt and Hess Grade IV) died from septic shock.

Eight cases had late follow-up images (MRA in five cases, DSA in three cases). The mean follow-up period was 6.51 ± 1.78 months (range, 4.8–8.3 months). All cases demonstrated stable coil mass and good patency of the involved artery.

Discussion

Thromboembolic complications during endovascular treatment of intracranial aneurysms are estimated to occur in 2% to 15% of patients.^4,5,7,11,17 The causes of thrombus formation are reported as the presence of foreign materials in the aneurysm and in the parent artery, the electric current used for the detachment of coils, the changes in blood flow, the hypercoagulable state after subarachnoid hemorrhage and vessel injury.^2,4,17,21,22 Thromboembolism can result in partial or total occlusion of vascular branches and may result in transient or permanent neurologic symptoms.

In our series of 131 patients with 131 intracranial ruptured aneurysms, we demonstrated that 21 patients (16.0%) suffered from thromboembolic events. These results show a higher incidence of thromboembolism as compared with that in previous studies.^4,5,7,11,17 A relatively high incidence of thromboembolism in our report can be explained by the fact that we included only ruptured cerebral aneurysms, while previous reports included unruptured cerebral aneurysms.^4,5,7,11,17 Altay et al. reported that diffusion-positive lesions were more common in patients with ruptured aneurysms (33/65, 51%) than in those with unruptured aneurysms (40/133, 30%) by using periprocedural diffusion-weighted imaging.⁶ Similarly, Brooks et al. and Hadeishi et al. described higher rates of diffusion-positive lesions in patients with ruptured aneurysms compared to those with unruptured aneurysms regardless of the technique used.^8,23

According to previous studies, a higher incidence of thromboembolic events in patients with ruptured aneurysms was closely related to vasospasm and hypercoagulability.^12,24 The presence of blood in the subarachnoid space catalyzed the release of tissue factor into the systemic blood circulation, thus activating thrombin, which leads to fibrin and platelet aggregation, and thereby making the patients with ruptured aneurysms more prone to thromboembolic events.^6,22,25,26 Thus, thromboembolism during endovascular treatment may result from endovascular material (catheters, balloons, stent, microcoils, etc.), or spontaneous activation of the coagulation system in patients with ruptured aneurysms.

Despite the numerous preoperative and intra-operative protocols to prevent thromboembolism, thromboembolic complications can occur and lead to stroke, which contribute to the morbidity and mortality of endovascular procedures. Traditionally, intraprocedural thrombus formation was treated with pharmacologic rescue, by using intra-arterial or intravenous administration of Gp IIb/IIIa inhibitors or fibrinolytics to recanalize the artery and to avoid permanent neurologic deficits.^{4,5,7,10,17,18} Recently, some authors performed local mechanical thrombectomy or forced-suction thrombectomy for recanalization.^10,18,19 Kadziolka et al. reported a case of mechanical thrombectomy with stent retriever and manual aspiration as a rescue treatment of distal MCA occlusion during endovascular treatment of proximal MCA aneurysms.¹⁸ The rescue treatment described above generally appears to be a safe and effective treatment modality in patients who develop thromboembolism during endovascular treatment of intracranial aneurysms.

However, despite adequate rescue therapy for thromboembolism, we experienced nine cases of TR among 21 patients during endovascular treatment of ruptured intracranial aneurysms. In cases of distally migrated thrombus or embolus in large vessels, we performed mechanical thrombectomy. The intra-arterial thrombolytic agents have a potential to aggravate hemorrhagic complications, especially in cases of incomplete coiling or in patients with concomitant intracerebral hemorrhage, while mechanical thrombectomy does not influence the coagulability in patients. Mechanical thrombectomy can be considered in these specific situations, and special care should be taken to avoid movement of the coils.

In all cases with TR, arterial flow was maintained and the size of thrombi or emboli did not increase on delayed cerebral angiography. We started intravenous tirofiban infusion after endovascular treatment because we feared further aggravation of thrombus formation. The patency of the involved artery was well maintained on postoperative CTA or MRA and thromboembolic events did not occur. In our experience, intra-arterial thrombolysis followed by intravenous injection of tirofiban may be an effective treatment modality for the management of thromboembolic complications occurring during endovascular treatment of ruptured aneurysms. The limitations of the study are the retrospective nature of the reported observations and the small number of patients included. Postoperative follow-up CTA or MRA could not show the accurate status of TR. Further prospective study with a large number of patients and follow-up DSA are needed.

Conclusion

Our results indicate that TR with patent arterial flow in the occluded artery after adequate rescue treatment might be safe in patients who develop thromboembolism during endovascular treatment of intracranial ruptured aneurysms. Further studies are necessary to make an accurate estimate of the fate of TR.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.