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Abstract
Introduction Although there have been a few reports of coiling intracranial aneurysms in patients with sickle cell disease (SCD), there are no reports of intracranial stent placement in this patient population. A patient in whom stent placement was utilized as monotherapy to treat a blister-like aneurysm is described and the implications of SCD and endovascular treatment are discussed.
Case report A 37-year-old man with SCD presented with diffuse subarachnoid hemorrhage. Angiography confirmed a 2 mm irregular aneurysm on the posterior cerebral artery which was treated with an oversized Neuroform 3 stent that was placed across the aneurysm neck by the senior author (KRB). Follow-up CT angiography showed no residual aneurysmal filling. The patient was discharged home in a stable condition, and he continues to do well 4 weeks following the procedure with no recurrence of the aneurysm.
Discussion This report reviews hypercoagulability in SCD and the treatment options for intracranial aneurysms in patients with SCD. Additionally, the reported case suggests that intracranial stent placement may be a viable option for treating complex intracranial aneurysms in SCD patients.
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Introduction
Intracranial aneurysms are rare in patients with sickle cell disease (SCD). They are implicated in 2% of cases of intracranial hemorrhage in this patient population.1 There is limited information regarding coiling and no previous reports of intracranial stenting for cerebral aneurysms in these patients.2 ,3
SCD is a hemoglobinopathy associated with chronic hemolysis and vaso-occlusive episodes in multiple organ systems. Neurologic complications are a significant concern, with the most severe being ischemic and hemorrhagic stroke. The first neurologic manifestations of SCD were documented in 1923.4 Stroke was first reported in 1940, and the first case of intracerebral hemorrhage was documented in 1939.5 ,6 The age adjusted incidence of cerebrovascular accident is much higher in children with SCD (0.61 per 100 patient years) and remains the leading cause of mortality in SCD patients in all age groups.7
Hypercoagulability is a concerning characteristic of SCD and poses significant complications, such as pulmonary embolism.8 Surgery is known to promote acute phase reactions which will increase plasma levels of fibrinogen via interleukin 6.8 ,9 SCD is a hypercoagulable disease with increased plasma levels of thrombin, upregulated tissue factor expression, activation of the fibrinolytic system and depletion of anticoagulant proteins.10 It is not unusual for patients with SCD to present with new and old thrombi in the pulmonary vasculature on autopsy.11 In fact, patients are at increased risk for developing pulmonary embolism, pregnancy related venous thromboembolism and venous thromboembolism.10 Due to concerns regarding hypercoagulability, little is known about stent placement in these patients. We report on an SCD patient with a complex intracranial aneurysm who was treated with a single oversized Neuroform 3 stent (Boston Scientific Corporation, Natick, Massachusetts, USA).
Case report
A 37-year-old right-handed man with SCD requiring frequent exchange transfusions for sickle cell crises presented with the worst headache of his life. Head CT revealed diffuse subarachnoid hemorrhage (SAH) (figure 1A). Patient examination was remarkable only for headache and nuchal rigidity. CT angiography and formal angiography confirmed the culprit lesion to be an approximately 2 mm irregular aneurysm originating at the left P1–P2 junction on the posterior cerebral artery (figure 1B). Exchange transfusion was performed once prior to any intervention to keep the hemoglobin S fraction <30% of total blood volume. An elective ventriculostomy was placed prior to the attempted coiling. An attempt at primary coiling revealed that there was a small thalamoperforator intricately associated with the aneurysm and there was a small amount of transient self-limited contrast extravasation (figure 2A). Primary coiling was aborted. The patient remained neurologically intact. The patient was monitored in the neurointensive care unit for 48 h. On the day of the stenting procedure, he was then loaded with a total of 600 mg of Plavix and started on aspirin, and an oversized Neuroform 3 stent (3.0 mm ×15 cm) was placed across the neck of the aneurysm by the senior author (KRB). Some immediate stagnation of flow into the aneurysm was seen (figure 2B). During the stenting procedure, an intravenous heparin bolus was administered to maintain an activating clotting time >200 s. A heparin drip was continued for 24 h following the procedure. Follow-up CT angiography revealed no further filling of the aneurysm (figure 3A, B). Plavix was not continued following the procedure, given the increased risks of dual antiplatelet therapy in acute SAH patients. A platelet function assay revealed adequate platelet suppression. Aspirin was continued. When the ventriculostomy was removed 3 days following the stenting procedure, no platelets were administered. The protocol for vasospasm prophylaxis did not differ because the patient had SCD. It did differ because this was a blister-like aneurysm and therefore caution was used for hypertensive therapy. Hypertensive therapy was reserved for the situation in which the patient would develop clinically symptomatic vasospasm. The patient's systolic blood pressure was kept at <140 mm Hg throughout hospitalization because he did not develop clinical vasospasm. He was subsequently discharged home in a stable condition. He continues to do well 7 weeks following his procedure, with repeat CT angiography demonstrating no residual aneurysm and patency of the left posterior cerebral artery (figure 4A, B).
(A) Non-contrast head CT demonstrates subarachnoid hemorrhage and enlargement of the temporal horns. (B) Three-dimensional angiography demonstrates complex aneurysm at the P1–P2 junction opposing the posterior communicating artery. Note the ‘tit’ pointing toward the right.
(A) Anteroposterior left vertebral artery angiogram shows the aneurysm (arrow) with a prominent perforating artery near the neck. (B) Immediate post-stent placement there is stasis within the aneurysm. Arrows mark the stent markers.
(A, B) Sequential CT angiography maximum intensity projection images demonstrate no residual aneurysm filling.
(A, B) Sequential CT angiography maximum intensity projection images demonstrate no residual aneurysm filling at 2 months, with patency of the left posterior cerebral artery.
Discussion
At short term follow-up, antiplatelet treatment with aspirin alone has been sufficient to prevent potential thrombotic events associated with the intracranial stent in this patient. The decision to leave the patient on aspirin alone was made in close collaboration with the hematology team because it resulted in sufficient suppression of platelet function. Continuing both the aspirin and Plavix in this patient was not felt to be a good option in the setting of acute SAH. A platelet function assay was performed the day following the procedure which showed adequate platelet function suppression. It was understood however that the effects of the Plavix may have continued to contribute to this result, however, in the setting of acute SAH, dual antiplatelet therapy was not felt to be a good option. In the senior author's experience (KRB), numerous patients thus far have been managed with aspirin monotherapy following self-expanding stent placement with no significant adverse events.
Craniotomy and clipping of the aneurysm was included in the possible options in treating this aneurysm but given the increased vascularity of the patient skull due to longstanding SCD, duration of the possible operation and potential approaches, which included either a cranio-orbital trans-Sylvian approach or a left subtemporal approach, microsurgical treatment was felt to have higher risks in this patient. However, although this area could be approached, the optimal treatment for posterior circulation aneurysms is evolving to be endovascular treatment.
SCD is due to a homozygous mutation at the sixth amino acid in the β globin chain, resulting in the expression of valine instead of glutamic acid. The change in phenotype renders deoxygenated hemoglobin insoluble and susceptible to polymerization. The effects of this alteration are red cell sickling, hemolysis, vascular remodeling, inflammation and thrombosis, which can lead to widespread organ damage.12 Strokes are common in SCD patients due to both vasculopathy such as stenotic distal internal carotids and proximal middle cerebral arteries, and local thrombus formation.13 ,14 SCD patients at highest risk of stroke have severe anemia, elevated reticulocyte counts and lower hemoglobin F levels.15
The etiology of stroke in SCD is multifaceted. Due to chronic anemia and hypoxemia, cerebral blood flow is considerably greater than normal and the ability of blood vessels to further dilate when exposed to hypoxic stress is limited, thus resulting in cerebral ischemia.14 Additionally, released hemoglobin binds to nitric oxide resulting in microvascular dysfunction.16 Hemoglobin polymerization is considered a causative factor for intravascular hemolysis, endothelial dysfunction, red blood cell (RBC) membrane changes, vaso-occlusion, and inflammatory and hypercoagulable states.14 ,17 Repeated cycles of sickling will alter phosphatidylserine exposure on RBC membranes which in turn interacts with the coagulation and fibrinolytic pathways. More recent studies suggest that the released hemoglobin is the primary factor contributing to the prethrombotic state.10 The combination of RBC hemolysis and reperfusion injury can increase plasma tissue factor levels and inflammatory mediators. These mediators will in turn activate endothelial cells and inflammatory cells, including neutrophils and monocytes.18 Sickled RBCs also express increased levels of surface adhesion markers and readily bind to activated endothelial cells.17 There is also considerable evidence suggesting platelets are chronically activated in SCD patients. Specifically, platelet derived soluble CD40L is elevated and can contribute to B cell, tissue factor and ICAM-1 production.19 These inflammatory and thrombogenic mechanisms highlight the arteriopathy involved with stroke in SCD. Other rare etiologies of cerebrovascular accident include fat embolization, venous sinus thrombosis, moyamoya-type fragile collaterals and aneurysms.12
Arterial damage from hemodynamic stress and turbulent flow is common in SCD and can result in degeneration of the internal elastic lamina and smooth muscle layer of the vascular wall. This promotes aneurysm formation.20 ,21 SCD patients have aneurysmal hemorrhages earlier in life compared with the general public. These hemorrhages are usually not linked to common risk factors, including hypertension, renal disease and connective tissue disease.22 There have been several reports documenting intracranial aneurysms associated with SCD. Brandao et al 23 reported 50 cases of cerebral aneurysms published in the English literature.21 Of those described, 32.7% were located in the posterior circulation and 58% had multiple aneurysms. Additionally, most were smaller than intracranial aneurysms found in the general public, ranging from 3 to 7 mm.23
SCD patients oftentimes have complex intracranial aneurysms (CIAs). CIAs have no standard definition but typically comprise of giant aneurysms and can involve technically difficult locations, arterial trunks and branches, and have complex wall anatomy.24 Andaluz et al 25 has expanded the definition to include those with branches closely associated with the aneurysm. The group conducted a 12 year retrospective review and determined that 9.68% of aneurysms fit their criteria for CIA, 66.6% of CIAs presented as SAH and CIA–SAH outcomes were worse than the overall SAH population. The most frequent location was the middle cerebral artery. Treatment options for CIAs consisted of both microsurgical and endovascular treatments which are providing options for previously inoperable cases with similar rates of procedural complications.25
Both surgical and endovascular management of intracranial aneurysms in SCD patients have their respective risks, and treatment is complicated by several factors associated with SCD. Patients are at increased risk of vaso-occlusive crisis associated with hypoxia, hypovolemia, acidosis and radiologic contrast media.26 SCD patients may be at increased risk because of the contrast used in endovascular treatments but Firth et al 20 reported that transfusions and proper hydration can minimize these risks. Additionally, intravascular procedures have their inherent risks which can be complicated further by the hypercoagulable state of SCD patients. Vicari et al 3 suggest that with adequate preoperative management, specifically exchange transfusion to reduce hemoglobin S, SCD patients can be treated safely with endovascular approaches. Newer endovascular technology is providing better treatment options for CIAs that pose higher morbidity with microsurgery.25 There are, however, no clinical trials comparing different treatments of cerebral aneurysms in patients with SCD.
The placement of intracranial stents for cerebral aneurysms in SCD patients has not been previously reported. In the literature, there has only been one report of intravascular stent placement in an SCD patient with superior vena cava syndrome, which was complicated by an aortic laceration.27 Alhadad et al 28 suggest that stenting iliocaval vein segments with or without catheter directed thrombolysis is a valid treatment for acute thrombosis and acute iliocaval vein occlusion. Sixty-three per cent of patients in their review had hypercoagulable disorders and required closer monitoring and use of antithrombotics. There have been only a few antithrombotic agents that have been effective in SCD patients to prevent sickle crises. Heparin has been shown to decrease adhesion of sickled RBCs to P-selectin but there are no clinical trials testing its efficacy.29 Currently, there is a phase I/II study of eptifibatide, a glycoprotein IIb/IIIa inhibitor, in acute pain episodes in SCD patients. In a pilot study, eptifibatide was shown to decrease soluble CD40L plasma levels and markers for inflammation in SCD patients.30 The treatment of intracranial aneurysms in SCD patients can be challenging. Our short term experience with this patient suggests that intracranial stent placement in patients with SCD may be an option. Fundamental to this however, is close collaboration with the hematology team to optimize all patient conditions to minimize SCD related risks.
References
Footnotes
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Competing interests None.
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Patient consent Obtained.
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Ethics approval The study had a Yale HIC exemption.
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Provenance and peer review Not commissioned; externally peer reviewed.