Rethinking the Collateral Vasculature Assessment in Acute Ischemic Stroke: The Comprehensive Collateral Cascade : Topics in Magnetic Resonance Imaging

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Rethinking the Collateral Vasculature Assessment in Acute Ischemic Stroke

The Comprehensive Collateral Cascade

Faizy, Tobias Djamsched MD; Heit, Jeremy Josef MD, PhD

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Topics in Magnetic Resonance Imaging 30(4):p 181-186, August 2021. | DOI: 10.1097/RMR.0000000000000274
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Acute ischemic stroke (AIS) due to large vessel occlusion (AIS-LVO) is caused by an embolic or thromboembolic occlusion of a cervical or cerebral artery.1 This vessel occlusion results in disruption of blood flow to the brain and subsequent oxygen deficiency within the dependent brain tissue. All AIS-LVO treatments seek to restore blood flow to the brain by dissolving or removing the clot blocking blood flow to the brain. Intravenous thrombolysis with tissue plasminogen activator has been the predominant treatment of AIS for over 2 decades. More recently, several landmark randomized trials have demonstrated that a minimally invasive surgery called thrombectomy proved useful to effectively remove the blood clot from the artery in the brain and result in improved functional outcomes compared to standard medical therapies.2–8

In order to evaluate whether a patient is suitable for endovascular thrombectomy, the brain tissue and its blood supply need to be examined by means of computer tomography or magnetic resonance (MR) imaging. AIS-LVO patients most likely to benefit from thrombectomy have a LVO of the internal carotid artery or middle cerebral artery, a relatively small ischemic core, and salvageable brain tissue (penumbra) that is larger than the ischemic core at the time of baseline imaging evaluation.1,9 The neuroimaging protocols used to identify thrombectomy treatment candidates vary between centers and based upon the time of symptom onset before imaging. Recent advances in neuroimaging have led to a greater understanding of ischemic stroke pathophysiology and superior identification of patients who are most likely to have a favorable response to thrombectomy and favorable clinical outcomes. In many patients, the presence of robust pial arterial collaterals (PACs) that deliver blood flow to the ischemic brain tissue is used to guide thrombectomy treatment decisions.2

In this review, we aim to summarize recent research into the comprehensive collateral cascade (CCC). The CCC concept builds upon the concept that patients with robust PAC overlying the ischemic brain are more likely to respond favorably to thrombectomy treatment, and it provides a more complete understanding of cerebral blood flow in the context of AIS-LVO. We focus on novel imaging biomarkers that allow for delineation of specific components of the CCC and how a more comprehensive assessment of the cerebral blood flow leads to a better prediction of thrombectomy efficacy and treatment response.


Brain tissue fate during AIS-LVO depends upon the ability to deliver blood flow to the ischemic brain. When cerebral perfusion is hampered and cerebral blood flow falls below a threshold of 10 to 15 mL blood/100 g brain tissue per minute, the brain suffers infarction and brain edema formation.10–12 The extent of infarction and edema formation in ischemic tissue is directly linked to the robustness of cerebral perfusion, which is a strong determinant of tissue fate and clinical outcomes in patients with AIS-LVO.10–12 Patients who exhibit good PAC are more likely to protect the brain from rapid infarction, and adequate PAC presence on computed tomography angiography (CTA) is often used as a selection criteria for thrombectomy treatment.2,13

The presence of numerous PAC is certainly a validated method to assess arterial collateral network in the context of AIS-LVO, but PAC do not necessarily provide evidence that the brain tissue itself has adequate blood flow to prevent cerebral infarction before revascularization by thrombectomy is achieved. In essence, robust PAC indicates that there are a large number of arteries that may deliver blood to ischemic brain, but they do not determine whether the blood is effectively transmitted from the arteries to the brain tissue itself. In support of this hypothesis, the DEFUSE 3 investigators found that PAC did predict patient outcome after thrombectomy in late time windows.14 This finding suggests that a more comprehensive understanding of collateral blood flow through the ischemic brain tissue is needed to understand this discrepancy.

To determine whether the ischemic brain has sufficient blood flow to avoid infarction, additional imaging studies that assess tissue-level collaterals (TLCs) or blood flow are required. They hypoperfusion intensity ratio (HIR) has emerged as a strong measure of TLC and a superior predictor of patient outcome after thrombectomy outcome compared to PAC.14 HIR is determined from time-to-maximum of the residue function (Tmax) maps that are obtained from computed tomography (CT) or MR perfusion studies.15–18 HIR is defined as the volumetric ratio of ischemic brain tissue with Tmax >10 seconds divided by Tmax >6 seconds, and a lower HIR (HIR ≤0.4) is consistent with more robust TLC.17,18 Because HIR is derived from perfusion imaging studies of the brain tissue itself, it provides information about blood flow through the ischemic brain tissue itself, which is likely why HIR is a better predictor of patient outcome than the more simplistic PAC determination on CTA.

It is intuitive that a patient with AIS-LVO with favorable PAC and favorable TLC (HIR ≤0.4) has good delivery of blood to ischemic brain through large arteries and smaller arterioles. However, what if exit of this blood flow from the ischemic brain was hindered by poor filling of the cortical veins that drain this tissue? It is possible that increased interstitial pressure due to ischemic stroke or thrombosis of the capillary bed or draining venules might lead to an effective outflow obstruction to limits cerebral perfusion even in the presence of robust PAC and TLC.19,20 Emerging data have shown the importance of robust venous outflow (VO) in patients with AIS-LVO.21–25 In these studies, patients with more extensive filling of cortical veins overlying the ischemic brain tissue in patients with AIS-LVO had the best treatment response to thrombectomy and the best clinical outcomes after treatment.21,22,24,25 VO is currently best measured using the 6-point cortical vein opacification score (COVES) (Fig. 1).

COVES determination. Delineation of the COVES on CT angiography in a 64-year-old patient with occlusion of the left middle cerebral artery (MCA). COVES is acquired by assessing the degree of contrast opacification in 3 major cortical veins, which represent the venous drainage of the MCA territory. Green arrows point to the superficial middle cerebral vein (SMCV, A), to the vein of Labbé (B), and to the sphenoparietal sinus (C). This patient exhibited a favorable COVES profile on the affected left hemisphere, with normal contrast opacification inside all of the assessed veins.

Collectively, these data suggest that a more comprehensive understanding of blood flow in patients with AIS-LVO will lead to a better understanding of an individual patient's pathophysiology, which may lead to a more tailored and precise treatment approach. We have recently described the CCC, which combines information about the quality of PAC bringing blood to ischemic brain, the robustness of TLC as the blood flows into capillaries, and how well VO occurs.26 We will now discuss 3 critical stages of the CCC in more detail. These stages are PAC, TLC, and VO.

Pial Arterial Collaterals Assessment

Patients with this favorable treatment profile typically have good collateral blood flow to the ischemic brain via a robust PAC network. Patients with good PACs are able to temporarily preserve blood flow to otherwise critically hypoperfused brain areas, which protects the brain from immediate infarction.27 In addition, patients with robust PACs are more likely to exhibit complete vessel recanalization after thrombectomy treatment, and long-term functional outcome in these patients was found to be better compared to patients with poor PACs.27–31

During endovascular treatment triage, PAC status is usually assessed on CTA, which provides a semiquantitative assessment of the number of pial collaterals overlying the ischemic brain that fill with contrast (Fig. 2). The ESCAPE trial selected patients for thrombectomy based upon favorable PAC identified on multiphase CTA, which provides a temporal component to PAC assessment.2 Some sites continue to use the presence of favorable collaterals on multiphase CTA as an important criterion to determine thrombectomy treatment eligibility.

Favorable and unfavorable pial arterial collaterals on CT angiography. Poor (A) and robust (B) arterial collaterals in patients with acute ischemic stroke with large vessel occlusions. A, A 74-year-old woman with occlusion of the first segment of the right middle cerebral artery (MCA) has poor filling of pial arterial collaterals distal to the occlusion (red circle). B, An 82-year old man with occlusion of the distal segment of the left MCA has robust pial arterial collaterals distal to the occlusion (green circle).

Tissue-level Collateral Assessment

The presence of robust PAC on CTA or multiphase CTA is a useful tool for the selection of patients with AIS-LVO who may benefit from thrombectomy. It is important to remember that the presence of robust PAC indicates that the arteries are present and filling sufficiently to deliver blood flow to the ischemic brain, but robust PAC does not actually measure whether this blood flow is reaching and permeating the brain tissue. In order to understand how well collateral blood flow reaches and permeates the ischemic brain, TLC must be evaluated. TLC is best characterized by CT or MR perfusion imaging.

Perfusion imaging is widely available and thus increasingly performed for the physiological evaluation of brain tissue,32 and most radiologists, neurologists, and neurointerventionalists are familiar with the use of perfusion imaging to identify the ischemic core and penumbra in patients with AIS-LVO.1 Recent studies have also demonstrated that CT and MR perfusion may be used to assess TLC in patients with AIS-LVO.14–18,24,25 As introduced earlier, HIR is a measure of TLC that is derived from Tmax imaging maps, and HIR represents the volume of ischemic brain tissue with a time-to-maximum of the residue function (Tmax) delay of >10 seconds divided by the volume of brain tissue with a Tmax delay of >6 seconds.18 Patients with robust blood flow through PAC into the ischemic brain tissue will have a larger percentage of delayed Tmax in the >6 seconds range and less tissue with a Tmax >10 seconds. Therefore, a lower HIR indicated favorable TLC, and HIR ≤0.4 has been correlated with endovascular treatment success, reduced ischemic core growth, and more favorable functional outcomes in patients with AIS-LVO, regardless of the CTA collateral status.14

An additional advantage of using CT or MR perfusion to identify patients with AIS-LVO with favorable TLC before thrombectomy treatment is that HIR is fully automated and more quantitative than PAC assessment on CTA or multiphase CTA. In addition, HIR may be measured by either CT or MR perfusion techniques, whereas there is not an accurate way to assess PAC on time-of-flight MR angiography sequences.

Venous Outflow Assessment

Tissue perfusion is not only governed by the inflow of arterial blood to the brain tissue but also by its outflow into the cerebral veins. Consideration of hemodynamics in the brain cannot focus solely on arterial delivery of blood without including other determinants of blood flow, such as downstream resistance due to tissue pressure or capillary and venous characteristics.19 Similar to the logic that the presence of robust PAC does not necessarily indicate that blood flow is adequately perfusing the ischemic brain, the presence of robust blood flow that permeates the brain tissue (TLC) does not necessarily mean that the blood flow transits through the tissue and exits through the draining veins adequately. One can envision how increased interstitial pressure due to edema or microvascular thrombosis due to static capillary blood flow might result in impaired venous egress and an effective blood flow outlet obstruction. In order to understand how well collateral blood flow exits from the ischemic brain, VO must be evaluated.

In the last couple of years, CT-based assessment of parameters associated with the degree of venous filling or VO during AIS have gained increasing attention. The rationale behind targeting the venous component of the cerebral vasculature as a potential new biomarker for collateral blood flow was based upon the presumption that VO may adequately reflect both PAC and TLC as it represents the final component of the collateral cascade after blood has permeated the brain tissue.

Bhaskar et al33,34 reported a novel angiographic pattern called the delay in “late venous phase cortical vein filling (LCVF)” on CTA images. The authors investigated the association between LCVF and IC status in patients with AIS eligible for treatment with intravenous tissue plasminogen activator and found that delayed LCVF strongly correlated with poor IC status.34 In a second study, Bhaskar et al33 reported that delayed LCVF was more often found in patients with proximal vessel compared to distal vessel occlusions, and that delayed LCVF was also a strong predictor of poor functional outcome in patients AIS. The authors concluded that the assessment of venous drainage patterns and flow dynamics associated with the downstream venous system may be useful in the prognostic management of patients with acute stroke.

A different approach to assess VO on CTA images during treatment triage in patients with AIS-LVO was proposed by Parthasarathy et al. The authors evaluated the contrast filling in 4 major veins, which represent the drainage of cortical and deep brain structures, namely the vein of Labbe, the vein of Trolard, the superficial middle cerebral vein, and vein of Rosenthal and combined their findings to the “Prognostic Evaluation based on Cortical vein (PRECISE)” score.35 The authors found that the PRECISE score was an independent predictor of functional outcome in patients with AIS-LVO during treatment triage.35

More recently, the COVES has been introduced by Jansen et al21 as a novel scoring system for the assessment of principal veins of the middle cerebral artery territory. The COVES differs from the PRECISE score in that only 3 major veins (vein of Labbe, superficial middle cerebral vein, sphenoparietal sinus), which reflect the cortical venous drainage of the middle cerebral artery territory, are included into the scoring system. A study by Hoffman et al22 demonstrated that COVES, but not PRECISE, was found to be an independent predictor of functional outcome of patients with AIS-LVO during endovascular treatment triage. Furthermore, Jansen et al reported that patients with a COVES ≥1 exhibited a better collateral profile and higher ASPECTS on baseline imaging compared to patients with a COVES of 0. The authors concluded that venous assessment of the cerebral vasculature may serve as a surrogate marker for local microcirculation function and that the proposed COVES could potentially be a stronger predictor of endovascular treatment benefit than arterial collateral vessel status because it better reflects microcirculation function.

In summary, the results of the here presented studies provide increasing evidence of a strong association between collateral blood flow to the ischemic brain tissue and subsequent venous drainage. These findings suggest that unhampered blood flow through the brain tissue into the draining cortical veins may be a strong independent predictor of clinical outcome of AIS-LVO patients and thus the parameters of venous blood flow may serve as a robust surrogate for patient treatment selection in the future. Prospective randomized trials are, however, required to determine the optimal threshold for COVES dichotomization, which best predicts IC status, robust tissue microperfusion, and favorable clinical outcomes in patients with AIS-LVO.


Over the last decade, technological advances in the field of medical imaging and neuroscience have led to a better understanding of the mechanisms that affect and alter cerebral perfusion in the event of an AIS. Several novel imaging biomarkers, such as PAC and TLC, have been introduced to help radiologists and clinicians facilitate thrombectomy treatment decisions. Reductionism within the scientific method, however, tends to focus attention on specific targets within most medical disciplines, which may inadvertently compartmentalize our thinking and obscure an appreciation of “the bigger picture.”19 There is a need for a more comprehensive understanding of the mechanisms that affect the cerebral vasculature and blood transit through the brain during AIS. As many of the current vascular models are unable to accurately display and characterize the complex pathophysiology behind collateral blood flow to ischemic brains, a more comprehensive understanding of alternative blood flow patterns would help to a more holistic approach for the assessment of ischemic brain pathophysiology (Fig. 3).

Comprehensive collateral cascade (CCC) in patients with acute ischemic stroke. Schematic overview of the 3 major collateral blood flow pathways: pial arterial collaterals (A–C), tissue-level collaterals (D–F), and venous outflow (G–I). A maximum intensity projection image from an MR angiogram demonstrates occlusion of the proximal left middle cerebral artery (A, D, G). A favorable CCC profile (B, E, H) is schematized by robust pial arterial collaterals (B), robust tissue-level collateral flow to the capillary bed (E; arteries in red, veins in blue), and robust venous outflow (H; arteries in red, veins in blue). By contrast, an unfavorable CCC profile (C, F, I) is schematized by poor pial arterial collaterals (B, dashed red lines), poor tissue-level collateral flow to the capillary bed (F; arteries in dashed red, veins in dashed blue), and poor venous outflow (I; arteries in red, veins in dashed blue).

In support of this idea, Dr. David Liebeskind recently stated that “The nature of current stroke research and practice is largely reductionist, offering a logical sequence of hypothesis-driven investigations or medical decisions. This reductionist approach is characterized by the focus on specific targets or dominant factors, maintenance of homeostasis, risk factor modification, and additive treatment strategies. For example, ischemic stroke therapies have only indirectly addressed the key pathophysiology, or ischemia, by targeting clots in the setting of AIS. […] Collaterals remove the focus in acute stroke from the clot, to consider alternative blood flow pathways and the complex dynamics of the arterial and venous circulation.”36

Similar to the concept of a CCC, Dr. Liebeskind noted that an analysis of cerebral hemodynamics in patients with stroke should not solely focus on arterial delivery of blood without including other determinants of blood flow, such as downstream resistance due to tissue pressure or capillary and venous characteristics.19 This larger view of collateral flow led to the concept of the “collaterome.”19 The collaterome is a conceptual framework that considers cerebral blood flow as a complex macrovascular and microvascular circulation system, which includes arteries, arterioles, capillaries, venules, and veins. The collaterome emphasizes the importance of this complex cerebral vascular architecture, blood flow dynamics, tissue perfusion, and how it influences adjacent neuron function.20,37 The optimal manner in which to characterize the collaterome in patients with stroke remains to be determined.


In this review, we have described the imaging biomarkers (PAC, TLC, and VO) that we believe show promise for the assessment of specific components of the CCC and collaterome. It would be desirable to combine distinct parameters of each component of the collateral cascade into a more CCC model, which may provide deeper insights into individual mechanisms and flow dynamics that govern cerebral microvascular perfusion during AIS. With the flourishing advances in the field of AI and machine learning, we are confident that these complex and dynamic processes may be targetable through medical imaging and that a proper assessment of the CCC may enhance our understanding of cerebral blood flow patterns in patients with AIS. We expect that knowledge generated from such studies will lead to improved thrombectomy treatment decisions and improved outcomes in patients with AIS-LVO.


1. Heit JJ, Zaharchuk G, Wintermark M. Advanced neuroimaging of acute ischemic stroke: penumbra and collateral assessment. Neuroimaging Clin N Am 2018; 28:585–597.
2. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372:1019–1030.
3. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018; 378:708–718.
4. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372:11–20.
5. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018; 378:11–21.
6. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372:1009–1018.
7. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372:2296–2306.
8. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372:2285–2295.
9. Warach SJ, Luby M, Albers GW, et al. Acute stroke imaging research roadmap III imaging selection and outcomes in acute stroke reperfusion clinical trials: consensus recommendations and further research priorities. Stroke 2016; 47:1389–1398.
10. Broocks G, Hanning U, Flottmann F, et al. Clinical benefit of thrombectomy in stroke patients with low ASPECTS is mediated by oedema reduction. Brain 2019; 142:1399–1407.
11. Broocks G, Flottmann F, Ernst M, et al. Computed tomography-based imaging of voxel-wise lesion water uptake in ischemic brain: relationship between density and direct volumetry. Invest Radiol 2018; 53:207–213.
12. Broocks G, Flottmann F, Scheibel A, et al. Quantitative lesion water uptake in acute stroke computed tomography is a predictor of malignant infarction. Stroke 2018; 49:1906–1912.
13. Broocks G, Kemmling A, Meyer L, et al. Computed tomography angiography collateral profile is directly linked to early edema progression rate in acute ischemic stroke. Stroke 2019; 50:3424–3430.
14. De Havenon A, Mlynash M, Kim-Tenser MA, et al. Results from DEFUSE 3: good collaterals are associated with reduced ischemic core growth but not neurologic outcome. Stroke 2019; 50:632–638.
15. Guenego A, Fahed R, Albers GW, et al. Hypoperfusion intensity ratio correlates with angiographic collaterals in acute ischaemic stroke with M1 occlusion. Eur J Neurol 2020; 27:864–870.
16. Olivot JM, Mlynash M, Inoue M, et al. Hypoperfusion intensity ratio predicts infarct progression and functional outcome in the DEFUSE 2 cohort. Stroke 2014; 45:1018–1023.
17. Guenego A, Marcellus DG, Martin BW, et al. Hypoperfusion intensity ratio is correlated with patient eligibility for thrombectomy. Stroke 2019; 50:917–922.
18. Guenego A, Mlynash M, Christensen S, et al. Hypoperfusion ratio predicts infarct growth during transfer for thrombectomy. Ann Neurol 2018; 84:616–620.
19. Liebeskind DS. The collaterome: a novel conceptual framework of systems biology in cerebrovascular disorders. Brain Circulation 2015; 1:3–8.
20. Liebeskind DS. Imaging the collaterome: a stroke renaissance. Curr Opin Neurol 2015; 28:1–3.
21. Jansen IGH, Van Vuuren AB, Van Zwam WH, et al. Absence of cortical vein opacification is associated with lack of intra-arterial therapy benefit in stroke. Radiology 2018; 286:731.
22. Hoffman H, Ziechmann R, Swarnkar A, et al. Cortical vein opacification for risk stratification in anterior circulation endovascular thrombectomy. J Stroke Cerebrovasc Dis 2019; 28:1710–1717.
23. Faizy T, Kabiri R, Leipzig M, et al. O-034 Intraarterial clot localization in patients with acute ischemic stroke affects the venous microperfusion profile. J NeuroIntervent Surg 2020; 12: (suppl 1): A23–A24.
24. Faizy T, Kabiri R, Leipzig M, et al. O-027 favorable venous microvascular profile is associated with smaller ischemic lesion growth and smaller final core infarction volume in patients with acute ischemic stroke due to large vessel occlusion. J NeuroIntervent Surg 2020; 12: (suppl 1): A19–A20.
25. Faizy T, Kabiri R, Leipzig M, et al. O-002 favorable venous microperfusion profile correlates with pial arterial collateral status and clinical outcome in acute stroke patients with large vessel occlusion. J NeuroIntervent Surg 2020; 12: (suppl 1): A1–A2.
26. Faizy TD, Mlynash M, Kabiri R, et al. The cerebral collateral cascade: comprehensive blood flow in ischemic stroke. Brain 2021; under review.
27. Bang OY, Saver JL, Kim SJ, et al. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Stroke 2011; 42:693–699.
28. Liebeskind DS, Tomsick TA, Foster LD, et al. Collaterals at angiography and outcomes in the Interventional Management of Stroke (IMS) III trial. Stroke 2014; 45:759–764.
29. Sheth SA, Liebeskind DS. Collaterals in endovascular therapy for stroke. Curr Opin Neurol 2015; 28:10–15.
30. Bang OY, Saver JL, Buck BH, et al. Impact of collateral flow on tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychiatry 2008; 79:625–629.
31. Lima FO, Furie KL, Silva GS, et al. The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. Stroke 2010; 41:2316–2322.
32. Heit JJ, Sussman ES, Wintermark M. Perfusion computed tomography in acute ischemic stroke. Radiol Clin North Am 2019; 57:1109–1116.
33. Bhaskar S, Bivard A, Stanwell P, et al. Association of cortical vein filling with clot location and clinical outcomes in acute ischaemic stroke patients. Sci Rep 2016; 6:38525.
34. Bhaskar S, Bivard A, Parsons M, et al. Delay of late-venous phase cortical vein filling in acute ischemic stroke patients: Associations with collateral status. J Cereb Blood Flow Metab 2017; 37:671–682.
35. Parthasarathy R, Kate M, Rempel JL, et al. Prognostic evaluation based on cortical vein score difference in stroke. Stroke 2013; 44:2748–2754.
36. Liebeskind DS. Mapping the collaterome for precision cerebrovascular health: theranostics in the continuum of stroke and dementia. J Cereb Blood Flow Metab 2018; 38:1449–1460.
37. Liu L, Ding J, Leng X, et al. Guidelines for evaluation and management of cerebral collateral circulation in ischaemic stroke 2017. Stroke Vasc Neurol 2018; 3:117–130.

collaterals; collaterome; perfusion; stroke; thrombectomy

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