Lyophilizing thrombin powder-based treatment for hemostasis during coil embolization of ruptured cerebral aneurysm: Two case reports

Abstract

Background

Rupture of cerebral aneurysm is an inevitable complication during embolization, followed by subsequent acute subarachnoid hemorrhage or intracranial hematoma, and results in the aggravation of a patient’s condition. In particular, for patients who have had a ruptured aneurysm, urgent treatment strategies are required during operation. The most common hemostatic methods seen in clinical practices are as follows: after lowering the blood pressure, we continue to embolize the aneurysms with detachable coils as soon as possible or inject with Glubran/Onyx embolization liquids, as well as use a balloon catheter to temporarily block the blood supply. If the conditions are permissible, a balloon guiding catheter may even be used to restrict the proximal blood flow. At times, due to limitations of these methods, neurosurgeons are requested to perform craniotomy to treat the hemostasis. However, the delayed transition often leads to rapid deterioration of the patient’s condition and even death due to cerebral hernia.

Case description

We herein presented two cases of ruptured cerebral aneurysms to provide an alternative method for hemostasis and to save the lives of patients as much as possible. In an extremely urgent situation (conventional treatment is ineffective), we successfully saved the patient’s life by injecting lyophilizing thrombin powder (LTP) solution into the aneurysmal sac and the parent artery through a microcatheter.

Conclusions

To our knowledge, this is the first report of successful hemostasis during coil embolization of ruptured cerebral aneurysm with LTP. Further prospective studies are needed to confirm the safety and efficacy of LTP in cerebrovascular interventional therapy.

Introduction

The prevalence rate of cerebral aneurysms is approximately 1–2%,^1,2 and the incidences of morbidity and mortality of ruptured cerebral aneurysms have been reported to be relatively high. However, the mortality rate is doubled in patients with ruptured cerebral aneurysms. Nevertheless, the advanced approaches of interventional therapy have saved many lives, especially those of patients who have had cerebral aneurysm embolization and benefited from it. A ruptured aneurysm is a common complication that almost remains inevitable during interventional surgery.³ The patient’s condition deteriorates when an aneurysm ruptures, and hence it requires urgent and effective treatment to stop the bleeding as soon as possible. The most common methods used in clinical practice include lowering the blood pressure and immediately embolizing the ruptured aneurysm with the use of metal coils.⁴ Liquid embolic materials such as Glubran/Onyx⁵ and a balloon catheter for temporary blockage of blood flow in the forward direction^3,6 are considered as alternative treatment options. Also, protamine, an antagonist to heparin, is required for the reversal of systemic heparinization in patients.⁷

These methods are sometimes challenging to stop the bleeding due to shortage of equipment for interventional therapies and massive bleeding during ruptured aneurysm, as well as tedious and time-consuming operation steps. This in turn possibly wastes the best time window for the treatment, allowing the neurosurgeons to perform craniotomy and intracranial aneurysm clipping to control the hemostasis. Two patients were admitted to our medical center between March 2017 and July 2018 who underwent the aneurysmal embolization under general anesthesia and had ruptured aneurysm during the operation. In both cases, the bleeding was uncontrollable by the use of conventional methods such as remedial coil embolism. For the sake of the patients’ lives, we first injected 100U lyophilizing thrombin powder (LTP) solution with 1-mL syringe (500U LTP dissolved in 5 mL saline) into the lumen of an aneurysm and the parent artery was under the surveillance of digital subtraction angiography (DSA) within five seconds. The hemorrhage recurrence was then checked by using DSA. If bleeding still persisted, the same method was applied by injecting 50–100U LTP solution, and then the dosage in the follow-up treatments was determined by examining the DSA results. Surprisingly, the ruptured aneurysms stopped bleeding following LTP treatment during the assessment of vascular anatomy in both the patients, and the occlusion of aneurysms was succeeded without affecting the blood flow in the parent artery and its distal branches. Dyna-CT or Xper-CT was performed immediately after the operation to guide the follow-up treatment. Both patients were intensively treated and provided with rehabilitation training after surgery, and thus were saved. Hence, we considered LTP treatment to be feasible and practical for ruptured cerebral aneurysms during embolization, thereby becoming a promising hemostatic approach in clinical practice.

Case report

Case I

A 78-year-old woman was admitted to our hospital due to sudden headache and left oculomotor nerve palsy five months ago (Figure 1). DSA and clinical manifestations demonstrated rupture of ophthalmic arterial segment and posterior communicating segment aneurysms of the left internal carotid artery (ICA) as the responsible lesions. DSA also indicated aneurysms in the posterior communicating segment of the right ICA and severe stenosis in the terminal section of the right common carotid artery (CCA). However, due to their non-liability, clinicians suggested conduction of treatment in two stages. Therefore, a stent-assisted coil embolization of the left ICA ophthalmic artery and posterior communicating segment aneurysms was performed five months ago under general anesthesia. The operation was successful but the patient had incomplete paralysis in the left oculomotor nerve. The patient after being discharged from the hospital was treated with aspirin 100 mg per day in combination with clopidogrel 75 mg per day and rosuvastatin calcium 10 mg per day. The modified Rankin Scale (mRS) score was 1 at 90 days’ follow-up. Based on the symptoms of the right ICA insufficiency, we decided to re-treat the patient with stent angioplasty for the right carotid artery and stent-assisted coil embolization for posterior communicating artery (PCoA) aneurysms of the right ICA. Besides, the patient did not agree to a craniotomy by neurosurgeons. Under general anesthesia, we inserted an 8F sheath into the femoral artery, which was flushed with heparin saline. An 8F guiding catheter was advanced into the right CCA. DSA indicated severe stenosis in the terminal segment of the right CCA with a stenosis rate of 85%. Using the FilterWire embolic protection device, a 9 × 30 mm Carotid Wallstent was accurately implanted into the stenotic segment. DSA re-examination showed that the stenosis was significantly decreased, and the rate of residual stenosis was 15%. The 8F guiding catheter was then introduced through the stent towards the C1 segment of the right ICA, followed by angiography as well as 3D angiography. The results indicated that the right PCoA aneurysm was approximately 2.3 × 1.9 mm, and angiomatoid protuberance in the distal segment of this aneurysm was 1.5 × 1.0 mm in size. We then introduced the Headway21 microcatheter into the M1 of the right middle cerebral artery (MCA) using the Traxcess14 microwire, and this was used to guide the tip of the modified Echelon10 microcatheter into an aneurysm. A 3.5 × 20 mm LVIS stent was delivered through the Headway21 microcatheter by covering the neck of the aneurysm. Then, a 2 mm–4 cm 3D coil was carried along the Echelon10 microcatheter until the third loop had extended beyond the aneurysmal boundary. After that, the DSA confirmed the extensive extravasation of the contrast agent as well as the rupture of the aneurysm. Then compression of the right CCA was performed immediately, while reducing the blood pressure, by quickly inserting the coils and detaching them; that is, the cerebral aneurysm was embolized by fast and consecutive deployment of 2 mm–4 cm, 2 mm–6 cm, 2 mm–2 cm, 2 mm–2 cm and 2 mm–8 cm coils through the Echelon10 microcatheter. DSA still showed apparent extravasation of the contrast agent, and then delivered 2 mL of LTP solution immediately through the microcatheter. After that, no further extravasation as well as patency of the parent artery was indicated by DSA. Following observation for ten minutes, re-examination with DSA also confirmed no extravasation of the contrast agent, as well as the patency of the distal segment of the ICA with sufficient blood supply and without thrombosis. Immediate examination using Xper-CT showed no midline shift and brain hernia other than subarachnoid hemorrhage (SAH), with Fisher grade 3. After the operation, the patient was sent to the neurology intensive care unit (NICU) for further observation. Aspirin and clopidogrel were suspended for two days. Next day, the patient underwent lumbar cistern drainage through a catheter to prevent vasospasm, control the elevated intracranial and cerebral pressures and support symptomatic treatment among other comprehensive therapies. Seven days after the operation, the patient had a Glasgow coma scale (GCS) score of 13, meningeal irritation sign (+) and Hunt-Hess grade III. On day 30, the GCS score was 15 and mRS was 2, with weak-positive neck resistance, and Hunt-Hess grade I, and no apparent SAH was observed on computed tomography.

Figure 1.

(a) Deployment of a 9 × 30 mm Carotid Wallstent (Boston Scientific, USA) across the right carotid stenotic area. (b, c) Right posterior communicating aneurysm with distal angiomatoid protuberance; a stent-assisted coil embolization for left posterior communicating aneurysm was performed five months ago without recurrence. (d, e, f) The coil has passed beyond the aneurysmal boundary, indicating aneurysmal rupture during surgery. (g) Massive contrast agent overflow showed immediate remedial embolism. (h) Successive delivery of five coils did not achieve complete hemostasis. (i) Lyophilizing thrombin powder was injected into the aneurysmal sac through a microcatheter, and then the bleeding was stopped. (j) Subarachnoid hemorrhage (SAH) was observed on computed tomography (CT). (k, l) Follow-up CT at 30 days showed no SAH.

Case II

A 64-year-old woman with type 2 diabetes mellitus was initially admitted to the Endocrinology Department of our hospital and an aneurysm was found in the right MCA using computed tomography angiography (Figure 2). By combined consultation and after transferring to our department, DSA confirmed the localization of an aneurysm that was about 8 mm × 8mm in the M1 segment of the right MCA, as well as severely tortuous sections in both the right CCA and respective ICA intracranial vessels, indicating poor accessibility with interventional operations. We thus suggested the conduction of craniotomy, but the patient refused a surgical approach, demanding an aneurysmal embolization in our department. An 8F sheath flushed with heparin saline was inserted into the femoral artery of the patient under general anesthesia. An 8F guiding catheter was then advanced into the right CCA. Using the coaxial technique, we added a 6F Navien intermediate catheter to support the 8F guiding catheter with the help of a loach guidewire. The 6F Navien was placed on the upper segment of the petrous ICA, followed by an 8F guiding catheter to the ICA C1 segment. With proper positioning, Navien angiography in combination with 3D-DSA revealed the location of an aneurysm in the right M1 with the same size. However, when the tip of the Echelon10 microcatheter along the Traxcess14 microwire was introduced through the neck of the aneurysm, the heart rate was suddenly accelerated to 110 bpm and the blood pressure was increased rapidly to 196/124 mmHg under electrocardiogram monitoring. Immediately, angiography showed extensive extravasation of the contrast agent and rupture of the aneurysm. We then decided to instantly deposit a 6 mm–20 cm coil through an Echelon10 microcatheter into the aneurysmal sac to stop the bleeding. After detachment of the coil, DSA showed massive bleeding from the aneurysm. After that, we inserted a 6 mm–20 cm coil through the microcatheter. However, due to blood overflow from the ruptured aneurysm into the right lateral fissure and temporal lobe, the resistance caused by the occupying effect of the bleeding gradually prevented the coil from entering the aneurysmal sac. The tip of the microcatheter was then pushed out of the aneurysm. Thus, we stopped the delivery of the loops through the microcatheter. LTP solution was injected with three aliquots of 2.5 mL by using Echelon10 to the aneurysm and the parent artery, followed by re-examination using DSA each time. After the third drug treatment, DSA confirmed reduced extravasation of the contrast agent, followed by immediate insertion of the microcatheter combined with a 6 mm–20 cm coil, decreasing the resistance. Following coil detachment as mentioned above, we performed aneurysmal embolization by quickly and consecutively using six coils (5 mm–15 cm, 5 mm–15 cm, 4 mm–12 cm, 4 mm–12 cm, 3 mm–8 cm and 3 mm–8 cm) and then sequentially releasing them, turning the aneurysm into dense embolization. Re-examination using DSA showed no extravasation of the contrast agent, hemostasis of the ruptured aneurysm, as well as patency of the right ICA and M1 with no occlusion. A Dyna-CT head scan post-procedure identified right lateral fissure and temporal lobe acute hemorrhage other than SAH. Urgent consultation with neurosurgeons indicated that it was necessary to perform a bone flap decompression and hematoma removal with craniotomy. After the operation, the patient was sent to neurology intensive care unit (NICU) for brain hematoma drainage, lumbar cistern drainage, vasospasm prevention, control elevated intracranial pressures, anti-inflammatory treatment, nutritional support, and rehabilitation training among other comprehensive therapies, leading to improvement of the patient’s condition. On day 90, the GCS score was 15 and mRS score was 4. The mRS on follow-up at one year was 3.

Figure 2.

(a, b, c, d) Anteroposterior, lateral digital subtraction angiography (DSA), and 3D-DSA presented right middle cerebral artery (MCA) M1 aneurysm; a severely tortuous right internal carotid artery (ICA). (e) A 6F Navien was advanced to the petrous segment; an 8F guiding catheter was placed into the C2. (f) DSA confirmed the extensive extravasation of the contrast agent as well as the ruptured aneurysm. (g) After the third lyophilizing thrombin powder treatment, DSA confirmed reduced extravasation of the contrast agent. (h, i) A total of eight coils were used to embolize an aneurysm. DSA showed no extravasation of the contrast agent, hemostasis of the ruptured aneurysm, as well as the patency of right ICA and MCA M1 segment with no occlusion. (j, k, l) Dyna-CT showed subarachnoid hemorrhage (SAH), right lateral fissure and temporal lobe hematoma. (m, n, o) Follow-up computed tomography at 90 days showed complete absorption of SAH; post-operative status of right craniotomy.

Discussion

It has been reported that the incidence rate for perforation of an aneurysm during aneurysmal embolization ranged between 2% and 8.8%.^3,4,8 Moreover, the hemorrhage risk for recurrent rupture of an aneurysm has become even more apparent.^4,9 Most aneurysmal fractures occur during the progression of microcatheter into an aneurysm, and during the progression of microwire or coils into the aneurysmal sac.^4,10 Then intraoperative treatment for aneurysmal rupture is extremely urgent as the mortality rate is as high as 40%, inevitably leading to a tremendous loss of neurological function and even costing the patients’ lives.³ Remedial embolization is considered to be the most efficient way for treating ruptured aneurysms, but at times remain ineffective when using only coils due to multiple issues, such as the occurrence of a ruptured aneurysm if the microcatheter is not in place, as well as a large laceration. From the above cases, active and extensive illness was confirmed by DSA, possibly resulting from a relatively large tear. In the above-mentioned cases, the patients were not treated with systemic heparinization before a surgical operation. Thus, we instantly inserted coils for remedial embolization without using protamine to neutralize the heparin. However, Case I had the following issues: continuous delivery of five coils did not achieve hemostasis, whereas LTP treatment showed achievement of hemostasis. Case II had the following problems: the coils were no longer able to be inserted when the coiling of the second one was being added, and the tip of the microcatheter was also rejected from the aneurysmal sac into the parent artery due to gradual increase in resistance, which might be due to subsequent cerebral swelling following aneurysm rupture and hematoma in the lateral fissure and temporal lobe. A similar method was applied by injecting LTP using a microcatheter to stop bleeding and to reduce hematoma volume, thus creating favorable conditions for subsequent insertion of coils.

Since 1997, there have been many case reports regarding LTP-mediated embolization for the treatment of false aneurysms through local injection by ultrasound guidance,^11–14 which turned out to be effective. However, there are no reports related to LTP treatment against hemostasis during embolization of a cerebral aneurysm. This might be possibly due to potential complications by LTP injection, which may result in severe occlusion and disability of the patients. The two cases described herein were extremely urgent and complicated due to the consequences of bleeding and difficulty in achieving normal hemostasis. Time is brain, and life is priceless. Hence, it is necessary to save the lives of patients through quick and effective hemostasis. We used this method in two cases, which turned out to be useful and efficient in achieving hemostasis without the occurrence of severe occlusion in the distal part of the parent vessel, leading to life-saving outcomes in patients with good prognosis. LTP solution is a liquid hemostatic agent, and thus it can be easily diffusible to access the localization of a ruptured aneurysm.

The main component of LTP includes thrombin, with prothrombin as the precursor that is extracted from pig or bovine blood. Sterile and lyophilizing products of thrombin are produced after activating prothrombin, and they are applicable for oral or local hemostasis. Hence, they are commonly seen during the operation of small blood vessels that are not easily suture-ligated for hemostasis, as well as gastrointestinal and traumatic bleeding. The pharmacological activity involves the conversion of fibrinogen to fibrin, and then the fibrin is subsequently applied to the wound cavity, resulting in blood coagulation and hemostasis. In these cases, we applied LTP to stop bleeding without apparently affecting the parent artery and distal main artery. Also, there was no extensive arterial occlusion observed. These results suggested the possibility of using LTP for the management of ruptured cerebral aneurysm. Typically, the initial ruptures of cerebral aneurysm gradually cease the bleeding by themselves. Based on a report in 2006, the hemostatic mechanism of a ruptured cerebral aneurysm mainly occurs due to the formation of platelet thrombus following laceration outside the aneurysmal cavity, and in turn a large amount of fibrin leaked out from the aneurysmal sac into the platelet thrombus to strengthen the structure, thus forming surface sealing of the laceration and achieving the initial hemostatic effect.¹⁵ Based on the pathological examination and appearance of the aneurysms during surgery, a hypothesis has been put forward for spontaneous hemostasis in the acute rupture of cerebral aneurysm by Ishikawa et al.¹⁵ The hypothesis described three ways for hemostasis of cerebral aneurysm: extraluminal platelet embolus/fibrin net on the aneurysmal sac, thrombosis/platelet plug formation within the cavity, and clotting formation at the bottom of the aneurysm. A brief mechanism of the physiological hemostasis and coagulation should be reviewed. When a vascular injury occurs, a small amount of platelets becomes attached to the exposed collagen in the vascular endothelium within seconds. This is an initial step in thrombus formation, and the hot spots of thrombus formation at the injury site to which the activated platelets adhere are in turn identified and localized. Next, more and more platelets are constantly glued upon the platelets that are bound to the collagen from the bloodstream. Also, the coagulation system is locally initiated in the damaged blood vessels to achieve rapid blood coagulation through the formation of interwoven network architecture, where the insoluble fibrin converts the soluble fibrinogen in the plasma, further strengthening the hemostatic system. When the aneurysm ruptures, the tissue factors are released and then expose the collagen of the ruptured vascular wall, activating the exogenous coagulation system as well as the endogenous coagulation system. The exogenous coagulation system is considered to play a critical role in the initiation of physiological coagulation, which is induced by tissue factors.

Meanwhile, the endogenous coagulation system plays a critical role in the maintenance and consolidation of the coagulation reaction. The tissue factors are anchored onto the cell membrane, contributing to the response of physiological coagulation of the damaged vessels. The thrombus formation is thus limited to the lesion site without damaging the patency of the uninjured area. In brief, it is indeed the converging process that involves multiple factors, indicating that the means of physiological coagulation are intricately organized in space and time. First, the intact vascular endothelial cells prevent blood coagulation from excessive outspreading. Second, fibrin and thrombin are strongly affinitive to each other. During the coagulation process, 90% of activated thrombin is absorbed by the fibrin network, which not only accelerates the local reaction of coagulation, but also avoids the diffusion of thrombin to other areas.

Furthermore, the extra activated clotting factors that enter the bloodstream are diluted by blood flow, followed by subsequent inactivation by anticoagulants and phagocytosis by monocyte-derived macrophages in the plasma. In summary, under extremely critical conditions such as active bleeding from ruptured cerebral aneurysms, it is probably considered to be safe to inject LTP into the aneurysmal sac and parent artery using a microcatheter. The premise is within a specific range of concentrations and doses. To conclude, it requires further investigation in animal models to explore the effective dosage, effects of concentration, maximal tolerated dose, and reduced incidence rates of drug complications.

In conclusion, from the experience of the two above-mentioned cases, it is indeed feasible and practical to execute alternate plans to achieve local hemostasis with LTP during interventional operation of a ruptured cerebral aneurysm. In such critical moments, LTP remains useful for treating rapid arterial hemostasis, minimizing the loss and saving the patient’s life by winning valuable time for follow-up treatments. Besides, LTP is not only easy to start with, but is also relatively inexpensive and continuously available, providing a promising approach in real-life clinical practice.

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.