Per-Pass Analysis of Thrombus Composition in Patients With Acute Ischemic Stroke Undergoing Mechanical Thrombectomy
Abstract
Background and Purpose—
Mechanical thrombectomy may involve multiple attempts to retrieve the occluding thrombus. This study examined the composition of thrombus fragments retrieved with each pass of a device during the thrombectomy procedure. Second, the per-pass composition was compared with procedural and clinical data including angiographic outcome and stroke etiology.
Methods—
Thrombi were retrieved from 60 patients with acute ischemic stroke, where thrombus fragments retrieved in each pass were segregated as individual samples and maintained throughout the histological analysis as independent samples. All samples were stained with hematoxylin and eosin and Martius Scarlet Blue. The relative composition of red blood cells, fibrin, and white blood cells in thrombus fragments from each pass was quantified.
Results—
Over the 60 cases, thrombus material was retrieved in 106 of 138 passes. The number of passes required to complete the cases ranged from 1 to 6 passes. The analysis of thrombus fragments retrieved in each pass provided a greater insight into the thrombectomy procedure progression than the overall thrombus composition; the red blood cell content of thrombus fragments retrieved in passes 1 and 2 was significantly higher than that retrieved in passes 3 to 6. The removal of thrombus material in a total of 1, 2, or 3 passes was associated with the highest percentage of final modified Thrombolysis in Cerebral Infarction score of 2c-3. There was no association between modified Thrombolysis in Cerebral Infarction score and per-pass thrombus composition.
Conclusions—
The differentiation achieved through the per-pass analysis of acute ischemic stroke thrombi provides a greater insight into the thrombectomy procedure progression than the combined per-case thrombus analysis. Insights gained may be a useful consideration in determining the treatment strategy as a case evolves and may be useful for the development of new devices to increase rates of 1-pass recanalization.
Introduction
Mechanical thrombectomy is increasingly being used for the treatment of large vessel occlusions1 and has enabled the analysis of acute ischemic stroke (AIS) thrombi. The procedure can involve multiple attempts or passes to retrieve the occluding thrombus and subsequently increase the chances of a poorer patient outcome. The composition of the thrombus itself may be a decisive factor in predicting the recanalization rate. Red blood cell (RBC)–rich thrombi were shown to be associated with higher successful recanalization rates,2 lower rates of fragmentation,3 and required fewer number of passes at retrieval.4,5 RBC-rich thrombi have increased viscosity and deformability6 and reduced elasticity and stiffness.7 These combined characteristics may increase the effectiveness of thrombectomy in retrieving this thrombus type. Clarifying the association between thrombus composition and pass number may in the future be important for device selection, refining the procedural technique, and to help develop technologies to successfully retrieve difficult thrombi. Numerous studies to date have examined the histopathology of thrombi retrieved from patients with AIS, with thrombi retrieved in separate passes analyzed as an entirety. To our knowledge, no studies have examined the composition of thrombi retrieved in individual passes.
The aim of this study was to evaluate thrombus composition over multiple passes and correlate this with procedural and patient factors such as revascularization outcome and stroke etiology.
Methods
The data that support the findings of this study are available from the corresponding author on reasonable request.
Patient Selection
Thrombi retrieved from 60 patients with AIS admitted to Beaumont Hospital (Dublin, Ireland) between March 2017 and July 2017 were histopathologically analyzed. A waiver of consent was approved by the hospital ethics committee for the collection of the thrombus material. Patients were enrolled consecutively during this time period, with the exception of a 2-week period in June. Only patients who underwent thrombectomy and had thrombus material removed in ≥1 pass were included in the study. Patients <18 years of age were excluded from the study.
The following procedural data were collected: r-tPA (recombinant tissue-type plasminogen activator) administration (yes/no), suspected etiology, modified Thrombolysis in Cerebral Infarction (mTICI) score after every pass, and technique applied for each pass (stentriever or direct aspiration). Trial of ORG 10172 in Acute Stroke Treatment classification system was applied to define suspected etiology of AIS based on diagnostic and clinical information available for each patient. These included (1) atheroembolic, (2) cardioembolic, (3) other determined etiology, and (4) undetermined or cryptogenic etiology.8 Cases classified as cryptogenic in nature were confirmed following diagnostic workup. Final mTICI score was confirmed by consensus review where the reviewers were blinded to the clinical and histological outcome. Details on the thrombectomy procedure for the retrieval of the thrombus fragments are outlined in the online-only Data Supplement.
Histopathologic Analysis
During the procedure, thrombus fragments retrieved in each pass were fixed in separate containers of 10% neutral buffered formalin and traceability maintained throughout subsequent analysis. If multiple fragments were retrieved in a single pass, then the fragments were combined as a single sample. All samples were processed histologically in a tissue processor (RGV/1 processor), embedded in paraffin wax and cut along the longest plane on a microtome into 4-µm-thick sections. Two sections were obtained from each of the initial, middle, and terminal segments of the paraffin blocks. One set of sections (initial, middle, and terminal) was stained with hematoxylin and eosin, while the remaining set was stained with Martius Scarlet Blue. Sections were visualized and scanned using an Olympus vs120 slide scanner at ×20 magnification. Martius Scarlet Blue–stained slides were reviewed by an experienced pathologist (M.F.). Color-based segmentation of Martius Scarlet Blue–stained slides in Orbit software9 was used to determine the relative quantitative fraction of RBCs, fibrin, and white blood cells (WBCs) for each pass; RBCPASS, fibrinpass, and WBCPASS, respectively. In this study, material identified as thrombus was only included in the analysis; nonthrombus material was rarely identified.
Separately, Image J software was used to calculate the area of the thrombus fragments in each pass using a gross image of the clot taken before histological processing. The combined area of the thrombus fragments from each pass was calculated (APASS1, APASS2,…APASS6), as well as the combined area of all fragments from the entire case (ATOTAL=APASS1+APASS2+…APASS6).
The fractional contribution of RBCs in a pass to the entire thrombus load removed during the case was determined using calculation (Equation 1), and the overall contribution of RBCs in all passes to the entire thrombus load removed was determined using calculation (Equation 2). The fractional contributions of fibrin and WBCs were calculated in a similar way.
(1)
(2)
Statistical Analysis
Statistical analysis was performed using Minitab (version 17.3.1). The statistical difference in RBC, WBC, and fibrin composition between passes 1 and 6 was calculated using a 1-way ANOVA. Passes 4 to 6 were combined for the statistical analysis because of the small sample size in these later passes. When comparing thrombus composition with etiology and final mTICI score, a 1-way ANOVA was applied to identify significant differences. P values <0.05 were considered significant.
Results
Clinical and Interventional Data
Between March 2017 and July 2017, thrombus fragments were collected from 60 patients with AIS. The main clinical characteristics from the cases are displayed in Table I in the online-only Data Supplement. r-tPA was administered to 38 patients (63.3%). Cryptogenic etiology, at an occurrence of 36.7%, was the largest category classified under Trial of ORG 10172 in Acute Stroke Treatment criteria. Stentrievers from 3 different manufacturers were used to retrieve the thrombus fragments. These included Trevo (Stryker), Embotrap (Cerenovus), and Catch (Balt), listed in order of their frequency of use. Over the 60 cases, a total of 138 separate passes were performed with thrombus material retrieved in 106 of these passes (76.8% of passes). Embolization of thrombus fragments to a new territory was noted in 2 cases (3% of cases). Balloon guide catheters were applied in 8.0% (11 passes) of passes. Distal aspiration catheters were used in 95% of cases. In the majority of cases (n=42 cases), the thrombus was retrieved directly into the aspiration catheter. The technique of retracting the device and aspiration catheter as a unit into the guide catheter was used less frequently (in 7 cases).
Histopathology Findings
Materials from the 106 passes were processed histologically and stained with hematoxylin and eosin and Martius Scarlet Blue. Staining revealed high interpass variation and intrapass variation in the distribution of fibrin and RBCs as illustrated in Figure 1.
Per-Case Thrombus Composition
The combined thrombus burden that includes all fragments removed from each pass is depicted in Figure 2A for each case. Similar to other studies of thrombi removed by thrombectomy, a broad distribution in the RBC and fibrin composition was noted. The WBC composition was consistently marginal across all cases. The mean composition of thrombi combined from all passes was 48% RBCs, 47% fibrin, and 5% WBCs (Table I in the online-only Data Supplement). In cases consisting of a total of 1, 2, 3, or 4 to 6 passes, there was no significant difference in the RBC (P=0.412), fibrin (P=0.409), and WBC (P=0.675) compositions of the overall thrombus burden between the 4 groups, as shown in Figure 2B and Table I in the online-only Data Supplement.
Per-Pass Thrombus Composition
Figure 3 represents the RBC, fibrin, and WBC composition of thrombus fragments retrieved in each pass over the 60 cases. Thirty-two (23.2%) of 138 passes failed to retrieve at least some thrombus material. Of the cases that required just 1 or 2 passes to remove the thrombus fragments, only 12.2% of these cases involved an attempt where thrombus material was not removed (5 of 41 cases). In more complex cases involving 3 to 6 passes, 84.2% of these cases involved at least 1 pass where thrombus fragments were not removed (16 of 19 cases; Figure 3). Thrombus fragments retrieved in all passes succeeding a failed attempt had a mean (±SD) RBC, fibrin, and WBC composition of 31% (±19.20%), 64% (±18.16%), and 5% (±3.71%), respectively.
A statistical analysis of thrombus components per pass (Figure 4) shows that the mean RBC composition of material retrieved in passes 1 and 2 was significantly higher (P=0.001) than the RBC composition in pass 3 and passes 4 to 6 combined (Table I in the online-only Data Supplement). The inverse pattern was observed for fibrin composition, with thrombus fragments retrieved in passes 1 and 2 associated with a significantly lower (P=0.001) fibrin composition (Table I in the online-only Data Supplement) when compared with thrombus fragments retrieved in passes 3 and passes 4 to 6 combined (Table I in the online-only Data Supplement). The RBC and fibrin composition of thrombus fragments retrieved in pass 1 when compared with those retrieved in pass 2 did not differ significantly (RBC comparison, P=0.764; fibrin comparison, P=0.817). Likewise, when the RBC and fibrin composition of thrombus fragments retrieved in pass 3 and passes 4 to 6 combined were compared with each other, no significant difference in composition was noted (RBC comparison, P=0.987; fibrin comparison, P=0.855). The WBC composition did not differ significantly between any of the groups (P=0.505).
When less-complex cases consisting of 1 and 2 passes only were excluded from the analysis as illustrated in Figure I in the online-only Data Supplement, similar findings were observed. This confirms that in complex cases consisting of multiple passes, the thrombus fragments retrieved after pass 2 have a significantly greater fibrin composition in comparison to the first 2 passes.
Stentriever/Direct Aspiration Technique
A stentriever was used for 90% of passes (124 passes), with a direct aspiration (DA) by catheter technique used in the remaining 10% of passes (14 passes; Table I in the online-only Data Supplement). Following 5 of the DA passes, the technique was converted to stentriever for the remainder of the passes (36%). Additionally, DA failed to retrieve thrombus material in 2 passes (14%). Among the 124 stentriever passes, 30 passes failed to retrieve thrombus material (24%). In summary, 50% of DA passes either failed to retrieve thrombus or converted to stentriever, whereas 25% of stentriever passes failed to retrieve thrombus or converted to DA.
The average RBC, fibrin, and WBC composition of thrombus fragments retrieved using stentriever and DA is displayed in Table II in the online-only Data Supplement. The higher RBC (P=0.004) and lower fibrin (P=0.003) composition of fragments retrieved by DA versus stentriever was statistically significant. No thrombus fragments with >56.4% fibrin were retrieved by DA, whereas thrombus fragments retrieved by stentriever encompassed the full range of thrombus composition seen in the study (Table II in the online-only Data Supplement).
Thrombus Composition and Occlusion Location
Eighteen cases (30%) involved occlusions of the internal carotid artery (ICA) alone or occlusions of the ICA extending into the middle cerebral artery (Table I in the online-only Data Supplement). The average number of passes required to retrieve thrombus fragments from the various occlusion locations and the composition of these fragments is displayed in Table III in the online-only Data Supplement.
Occlusions of the ICA only and ICA and middle cerebral artery collectively were associated with a significantly greater (P=0.001). RBC composition in comparison to occlusions not involving the ICA and a significantly lower (P=0.001) fibrin composition (Table III in the online-only Data Supplement).
r-tPA Administration
r-tPA was administered to 38 patients (63.3%). The average number of passes required to retrieve thrombus fragments from patients who received r-tPA before thrombectomy was not significantly different from those who did not receive r-tPA but were associated with thrombus fragments with a significantly greater RBC composition (P=0.037) and significantly lower fibrin composition (P=0.029) in comparison to those who did not receive the drug (Table IV in the online-only Data Supplement).
Stroke Etiology and Thrombus Composition
The correlation of thrombi retrieved from patients with the Trial of ORG 10172 in Acute Stroke Treatment classifications of cardioembolic, cryptogenic, atheroembolic is shown in Figure 5. The composition of the full thrombus load recovered in the procedure (Figure II in the online-only Data Supplement) does not show a remarkable difference between groups. The average RBC and fibrin composition of the entire thrombus load retrieved from cardioembolic, atheroembolic, and cryptogenic stroke patients is shown in Table I in the online-only Data Supplement. The RBC (P=0.286) and fibrin (P=0.269) composition of the overall thrombus load removed did not differ significantly between the 3 different etiology groups.
Examination of the thrombus composition in each pass (Figure 5) revealed additional information. The ratio of fibrin to RBCs in passes 1 and 2 was similar in cardioembolic and cryptogenic etiology (51% and 45% RBCs, respectively; Table I in the online-only Data Supplement). Thrombi retrieved in passes 1 and 2 from atheroembolic etiology had a higher RBC composition (63%). This difference was statistically significant when compared with cases of cryptogenic stroke (P=0.003), but while trending in the same direction, it was not statistically different when compared with cardioembolic etiology (P=0.077).
There was no significant difference in the RBC (P=0.479), fibrin (P=0.537), and WBC (P=0.416) composition of fragments retrieved in passes 3 to 6 between the 3 etiology groups. There was a clear significant increase in the fibrin composition between the first 2 passes and the later passes among all etiology groups. Further analysis, just focusing on the 30% of cases that had >2 passes, showed the same trend in composition as described above for all cases (Table I in the online-only Data Supplement).
Comparison of Angiographic Outcome With Pass Number
Final angiographic reperfusion rates for the sixty cases were 90% mTICI ≥2b, 73.3% mTICI ≥2c and 53.3% mTICI 3 score (Table I in the online-only Data Supplement). The removal of all thrombus material in passes 1 to 3 was associated with a higher percentage of final mTICI 2c-3 scores in comparison with thrombi that required 4 to 6 passes for retrieval; in cases consisting of a total of 1, 2, 3, or 4 to 6 passes, the rate of final mTICI ≥2c was 78.3%, 77.8%, 85.7%, and 50%, respectively, whereas the rate of final mTICI ≥2b was 87%, 88.9%, 100%, and 91.7%, respectively. The full distribution of recanalization outcomes is shown in Table I in the online-only Data Supplement.
The mean fraction of RBCs and fibrin composition was calculated for cases with a final mTICI of 2b, 2c, and 3. Cases with a final mTICI of 0, 1, and 2a were excluded in this analysis because it was assumed that an insufficient representative quantity of thrombi was removed in these cases (n=1, 1, and 4 cases, respectively). There was no significant association between RBC (P=0.173) and fibrin (P=0.182) composition with final mTICI score of 2b, 2c, or 3. Although there was a trend toward an increasing RBC and decreasing fibrin content with increasing mTICI scores. The respective mean RBC and fibrin compositions for cases with a final mTICI of ≥2b were as follows: mTICI 2b, 37±14.7% and 58±15.2%; mTICI 2c, 42±22.4% and 52±19.4%; and mTICI 3, 54±18.7% and 42±17.6%. Similarly, there was no significant correlation between mTICI score after each pass and the RBC (P=0.193) and fibrin (P=0.229) composition of the fragments retrieved in that pass.
Discussion
Because the thrombus itself is the target of current endovascular therapies, a greater understanding of thrombus composition is key to determining the success of endovascular therapy. Currently, little is known about thrombus composition before endovascular therapy, and, therefore, a similar treatment approach is undertaken with all thrombi. Several studies have analyzed AIS thrombus composition histologically and recognized the heterogeneity of these thrombi.10–13 However, these studies did not examine the thrombus fragment composition removed in individual passes. In contrast to these studies, the work reported here provides evidence of the impact that thrombus composition has on the complexity of the thrombectomy procedure by reporting on the per-pass analysis of thrombus composition in AIS.
To enable the results from this study to be compared with previously published studies, the combined compositional data from all passes for each case were also examined. Significant heterogeneity in RBC and fibrin composition was observed between thrombi among the 60 cases (Figure 2A). The results also showed that regardless of the total number of passes required to retrieve the thrombus, there was not a significant difference in the overall thrombus burden composition (Figure 2B). However, in comparison to the fractional compositional analysis of the thrombus fragments retrieved in each pass of multipass cases, consisting of ≥3 passes, it was demonstrated that later passes were predominantly associated with fibrin-rich thrombus fragments (Figure I in the online-only Data Supplement). In this analysis, the portion of the thrombus fragments removed in the first 2 passes tended to have a higher RBC fraction. The fibrin-rich nature of the thrombus fragments retrieved in later passes may point to differences in the cohesiveness of the thrombi, with thrombi preferentially fragmenting along the boundaries in the clot between RBC- and fibrin-rich areas, such as in the histological section provided in Figure 1C. One possible mechanism for the formation of this heterogeneity in thrombus composition was reported by Qazi et al,14 who suggested that thrombi in AIS consist of 2 components: the initial thrombus/embolus that is either from a proximal source or forms in situ and a secondary thrombus that forms as a result of blood stasis around the original thrombus/embolus. The secondary clot formation around the original thrombus is possibly RBC dominant in nature as it has been shown that clots forming in a static environment have a predominance of RBCs.15 Thrombus fragments retrieved after ≥2 passes and in passes succeeding the failed attempt had a much greater fibrin content to those retrieved in previous passes. This analysis further suggests that the fibrin-dominant portions of the overall thrombus contributed to the resistance to removal.
Gunning et al16 described how fibrin-dominant clots have a greater coefficient of friction than RBC-dominant clots. This may suggest a greater resistance to retrieval of these clot types. In another study of fibrin-rich thrombi, it was demonstrated the sequential compression of fibrin-dominant clots resulted in an increase in the coefficient of friction that may result in compounding the difficulty of removing the clot when multiple passes are used.17
In general, a greater insight into per-pass thrombus composition will help to understand why successful recanalization is achieved in only 70% to 80% of cases18 and, therefore, to develop devices that can successfully retrieve these difficult thrombi in fewer passes. Studies have correlated thrombus composition with imaging characteristics on computed tomography and magnetic resonance imaging. The presence of a hyperdense artery sign and susceptible vessel sign on computed tomography and magnetic resonance imaging, respectively, is indicative of RBC-dominant thrombi, whereas the absence of these characteristics is suggestive of fibrin-rich thrombi.19 Predicting thrombus composition from imaging characteristics and correlating it with knowledge regarding per-pass composition could help to estimate the number of passes that are likely to be required to retrieve the thrombus and subsequently predict recanalization outcome before the procedure and facilitate device/technique selection.
The overall RBC composition of thrombi from patients who receive r-tPA was significantly higher in comparison to thrombi retrieved from patients who did not receive the drug. This finding is in keeping with the results obtained by Qureshi et al.20 As r-tPA acts on the thrombus to lyse the fibrin fibers within, this finding may be explained by the lysis of fibrin within the thrombi retrieved from patients who received r-tPA.
Accurate identification of the underling etiology is important for administering the most appropriate treatment for secondary stroke prevention. The combined thrombus-compositional analysis, which includes all passes in a single case, showed that there was no significant difference between etiology groups (Figure II in the online-only Data Supplement). A breakdown of thrombus composition per pass suggests that atheroembolic clots are associated with a significant preferential removal of RBC-dominant fragments in passes 1 and 2 in comparison to later passes (Figure 5). This finding could have important implications on procedural planning, in particular if there is pretreatment evidence of an atheroembolic source of the thromboembolism, such as a freshly ruptured atherosclerotic plaque from computed tomography. However, in multiple-pass cases, regardless of the underlying etiology, thrombus fragments remaining after the second pass are likely to be fibrin rich in nature. Thrombus fragments retrieved in passes 1 to 2 and 3 to 6 in cases that were classified as cryptogenic demonstrated the same pattern in RBC and fibrin content as cardioembolic thrombi (Figure 5). This is in line with the findings by Sporns et al21 and Boeckh-Behrens et al.13 The results further strengthen the theory that stroke classified as cryptogenic following complete diagnostic workup is likely to be cardioembolic in origin.
In this study, it was shown that a lower final pass number was associated with better angiographic outcomes; cases with a total of 1, 2, and 3 passes were associated with the greatest proportion of final mTICI 2c-3 (73.3% of passes) compared with cases with >3 passes. The work reported here did not find a relationship between mTICI score and thrombus composition. The reasons for poor revascularization are multifaceted, and additional contributing factors may include occlusion location, length of the thrombus, variations in the vascular architecture, and vessel tortuosity.
Study Limitations
This work has some limitations that merit consideration. The patient population size was relatively small, so some comparisons were not possible with small sample sizes. In particular, there were only 12 cases that consisted of >3 passes. The majority of cases (37.6%) were classified as cryptogenic. This is an important limiting factor that should be considered, in particular when comparing thrombus composition to etiology. Furthermore, the variation in procedural techniques and the combination of devices applied to retrieve the thrombus fragments is a confounding factor that may potentially affect the rates of recanalization. Standard clinical practice was followed in the center, and a minimum number of retrieval attempts were not stipulated before ending the procedure. Such a stipulation may have provided additional data to analyze for more accurate results. Finally, only those thrombi that were not successfully lysed by r-tPA and that were retrieved by thrombectomy were available for analysis. This impedes the analysis of thrombi that failed to be retrieved or those that were susceptible to thrombolysis. Despite these limitations, this study demonstrates the value of analyzing the per-pass composition of thrombi and should encourage future studies to undertake a similar approach.
Conclusions
This novel study suggests that thrombus fragments retrieved in individual passes differed significantly in their histopathologic characteristics. Fragments retrieved in passes 1 and 2 were associated with a much lower fibrin composition in comparison to fragments retrieved in passes 3 to 6. The insights gained in this study of per-pass thrombus composition may be useful in determining the treatment strategy as the case evolves and to inform the development of new technologies to retrieve difficult thrombi in a fewer number of passes.
Acknowledgments
First, the authors would like to acknowledge all the staff in the Radiology Department, Beaumont Hospital, for collecting the samples and data. The authors would also like to acknowledge Sinead Duff (Radiology Department, Beaumont Hospital) and Roisin Walsh (Royal College of Surgeons in Ireland, Beaumont Hospital) for their assistance with data collection, Dr Karen Doyle (National University of Ireland, Galway) and Andy Douglas (National University of Ireland, Galway) for the use and training in the use of the slide scanner, and finally Jasmin Kreiser (Cerenovus, Galway) for her assistance in determining the thrombus areas.
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© 2019 American Heart Association, Inc.
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History
Received: 24 October 2018
Revision received: 16 January 2019
Accepted: 4 February 2019
Published online: 11 April 2019
Published in print: May 2019
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Disclosures
Drs Duffy and McCarthy, and M. Gilvarry are employees of Cerenovus, Galway, Ireland. Dr Thornton reports consultancy fees from Neuravi. S. Thomas reports funding for nursing educational purposes. The other authors report no conflicts.
Sources of Funding
This study was funded by Cerenovus, Galway, Ireland.
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