High thrombus platelet content is associated with a lower rate of first pass effect in stroke treated by endovascular therapy

Abstract

Background and purpose:

First pass effect (FPE), the occurrence of complete reperfusion after one pass with no rescue attempt during endovascular therapy (EVT), is associated with the best clinical outcome after an acute ischemic stroke (AIS). Previous studies evaluating FPE occurrence according to EVT technical strategies, occlusion locations, or thrombus composition have provided controversial results. Here, we performed a correlation analysis between FPE occurrence and AIS thrombus cellular composition, as assessed using quantitative biochemical assays.

Patients and methods:

Homogenates of AIS thrombi from 250 patients were prepared by mechanical grinding. Platelet, red blood cell (RBC), and leukocyte contents of AIS thrombi were respectively estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. FPE was defined as a modified Thrombolysis in Cerebral Infraction (mTICI) score of 2C or 3 after a single EVT device pass.

Results:

AIS thrombi successfully removed after a single pass were poorer in GPVI (0.098 ± 0.023 vs 0.111 ± 0.024 ng/mg, p < 0.001) compared to those whose removal had required several passes. GPVI content was also significantly associated with a higher number of device passes and a longer procedure time. No such significant correlation was found with DNA and heme content.

Discussion and conclusion:

Thrombus platelet content may hamper thrombus removal by EVT. This result suggests that adjunctive therapies or functionalization of retrieval devices targeting platelets may improve EVT efficacy.

Keywords

Platelets thrombosis endovascular therapy first pass effect biomarker

Introduction

Endovascular therapy (EVT) is now the standard-of-care for acute ischemic stroke (AIS) patients with anterior circulation large vessel occlusion (LVO).¹ Although EVT has dramatically improved the rate of early recanalization, more than 40% of EVT still do not achieve complete recanalization defined as a final modified Thrombolysis In Cerebral Infarction (mTICI) score of 2C or 3.² Moreover, complete recanalization after a single EVT pass (first pass effect, FPE), which has been reported to be associated with the best clinical outcome, occurs in 25%–40% of EVT-treated patients.^3,4

There is an increasing number of studies investigating possible associations between the composition and structural features of AIS thrombi and per-procedural outcomes.⁵ In particular, fibrin/platelet-rich thrombi have been reported to require a higher number of EVT passes to achieve recanalization, as compared to RBC-rich thrombi.^6,7 Determination of thrombus composition in these previous studies was, however, based on non-specific and semi-quantitative histological evaluations (i.e. H&E or Scarlett Martius staining), thus precluding any definitive conclusion regarding the role of platelet content in hindering thrombus extraction. This question is of crucial importance in the setting of the emergence of new antiplatelet agents which could be infused during the EVT procedure to facilitate the thrombus extraction and avoid immediate or early artery reocclusion.⁸

In this study, we evaluated the relationships between FPE occurrence and platelet, RBC and white blood cell (WBC) content of AIS thrombi, as determined using cell-type specific quantitative assays performed on whole thrombus homogenates.

Methods

Standard protocol approvals, registrations, and patient consents

Consecutive thrombi were collected in two centers at the end of EVT. The EVT procedure (stent-retriever or contact aspiration alone) was chosen at the interventionalist’s discretion.

Patient data were collected prospectively using a standardized questionnaire (Endovascular Treatment in Ischemic Stroke registry, URL: https://www.clinicaltrials.gov; Unique identifier: NCT03776877).

All patients were provided with a written explanation of the study. The patients or their representatives were given the opportunity to refuse participation. The local Ethics Committee approved this research protocol (CPP Nord Ouest II, ID-RCB number: 2017-A01039-44).

Radiological outcomes

Two experienced neuro-interventionists (FD, JPD), blinded to the follow-up images and clinical data, reviewed images by consensus to determine the recanalization status after the first pass and at the end of EVT procedure according to the mTICI score. FPE was defined as a mTICI score of 2C or 3 after a single pass.

Preparation of thrombus homogenates

Thrombi weighting more than 10 mg were included in this study in order to recover enough homogenate volume for the different assays. Thrombus homogenates were prepared with stainless steel beads (5 mm, Qiagen, 69989) in cold PBS (30 μL/mg thrombus) supplemented with protease inhibitor (1%, Sigma, P8340), using a tissue lyser (25 Hz, 4 min, TissueLyser II, Qiagen). Thrombi not completely grinded went through a second passage in the tissue lyser. The thrombus homogenates were then recovered after centrifugation (14,000g × 20 min, 4°C) to eliminate non-soluble debris.

Quantification of RBC and DNA content

RBC content was estimated by measurement of heme concentration in thrombus homogenates using a formic acid-based colorimetric assay, as described previously.⁹ DNA was quantified using the Molecular Probes Quant iT Picogreen dsDNA Assay kit (Life Technologies).

Quantification of platelet content

Platelet content was estimated by measuring GPVI levels in thrombus homogenates using an immunoassay according to the following protocol. Ninety-six wells standard binding plate from MesoScale Discovery (Rockville, MD) were coated overnight at 4°C with 2 μg/mL sheep anti-human GPVI polyclonal antibody (Bio Techne, France, AF3627). After 1 h of incubation at room temperature with 5% MesoScale Discovery Blocker A (R93AA-1) and three washes with 150 μL PBS/0.05% Tween, 25 μL of thrombus homogenate or standard were added, and the plate was incubated for 1 h at room temperature, 500 rpm. Standard curve was obtained with Recombinant Human GPVI protein (Bio techne, France, 3627-GP, 0.097–25 ng/mL). After three PBS Tween washes, 25 μL of biotinylated sheep anti-human GPVI antibody (Bio Techne, France, BAF3627, 0.5 μg/mL in 1% MesoScale Discovery Blocker A) was added to each well and the plate was incubated 1 h at room temperature. Finally, 25 μL of streptavidin Sulfo-TAG/well was added after three PBS Tween washes, and the plate was incubated 1 h at room temperature. A MesoScale Quickplex Plate Scanner was used of quantification.

Statistical analysis

Quantitative variables were expressed as mean (standard deviation, SD), or median (interquartile range, IQR) for non-normal distribution. Normality of distributions was assessed graphically and by using the Shapiro-Wilk test. Categorical variables were expressed as frequencies and percentages. Main patient’s characteristics were described according to FPE status (primary outcome) and magnitude of the between-group differences were assessed by calculating the standardized differences; absolute value of standard differences of 0.2, 0.5, and 0.8 were interpreted as small, medium and large.¹⁰

The thrombus cell marker content concentrations (GPVI, DNA, and Heme) were compared according to FPE status (primary outcome) by using student t test after applying a log-transformation for DNA for overall study sample and in each first-line EVT strategy subgroups (Contact Aspiration – CA or Stentretriever – SR). Strength of associations were assessed by calculating odds ratio (OR) with theirs 95% confidence interval (CIs) per one standard deviation increase in thrombus cell marker content concentrations by using univariate logistic regression models. Associations were further adjusted for pre-specified factors (center, site of occlusion, use of intravenous (IV) tPA therapy prior to EVT and first-line EVT strategy) regarding the potential effect on FPE status, as well as on baseline between-group differences (standardized difference >20% in absolute values) by using multivariable logistic regression models. As secondary analyses, we assessed the association of each thrombus cell marker content with other angiographic outcomes by using binomial negative regression models for number of passes (a count outcome), ordinal logistic regression models for reperfusion grade (a five-level ordinal outcome), and linear regression models for reperfusion time (a quantitative outcome, after applying a log-transformation to satisfy the normality of residuals). From the regressions coefficients, we derived effects sizes and their 95% CIs per one per one standard deviation increase in thrombus cell marker content concentrations (incidence rate ratio in number of passes, common OR per one-grade improvement in reperfusion grade, and change in log-transformed reperfusion time value).

Statistical testing was conducted at the two-tailed α-level of 0.05. No correction for multiple testing were done regarding the exploratory nature of the present study and results should be interpreted with caution. Data were analyzed using the SAS software version 9.4 (SAS Institute, Cary, NC).

Results

From June 2016 to November 2018, a total of 729 thrombi were retrieved in 1209 consecutive AIS patients treated by EVT in our institutions. Retrieved thrombi weighting more than 10 mg were available in 250 of these patients and were homogenized and analyzed for RBC, platelet and leukocyte content, as estimated by quantification of heme, GPVI, and DNA, respectively.

Patient and treatment characteristics of the 250 included patients, overall and according to FPE occurrence are reported in Table 1. They are similar to the characteristics of patients randomized in recent EVT clinical trials. The median number of passes was 2 (range 1–12) and FPE was achieved in 36.4% (n = 91).

Table 1.

Patients characteristics with cell marker content of retrieved thrombi, overall and according to First Pass Effect (FPE) status.

Characteristics	Overall (n = 250)	First pass effect		Standardized differences (%)
Characteristics	Overall (n = 250)	No (n = 159)	Yes (n = 91)	Standardized differences (%)
Demographics
Age, years	70.1 ± 15.5	69.4 ± 15.7	71.1 ± 15.1	10.8
Men	129/250 (51.6)	81/159 (50.9)	48/91 (52.7)	3.6
Medical history
Hypertension	144/247 (58.3)	95/158 (60.1)	49/89 (55.1)	−10.3
Diabetes	42/248 (16.9)	25/158 (15.8)	17/90 (18.9)	8.1
Hypercholesterolemia	79/247 (32.0)	43/157 (27.4)	36/90 (40.0)	26.9
Current smoking	50/238 (21.0)	36/152 (23.7)	14/86 (16.3)	−18.6
Coronary artery disease	31/345 (12.7)	20/157 (12.7)	11/88 (12.5)	−0.7
Previous stroke or TIA	34/246 (13.8)	22/159 (13.8)	12/87 (13.8)	−0.1
Previous antithrombotic medications	103/244 (42.2)	62/155 (40.0)	41/89 (46.1)	12.3
Antiplatelet agents	47/240 (19.6)	33/155 (21.3)	14/85 (16.5)
Anticoagulant agents	48/240 (20.0)	29/155 (18.7)	19/85 (22.4)
Antiplatelet and anticoagulant agents	4/240 (1.7)	0/155 (0.0)	4/85 (4.7)
Current stroke event
NIHSS score^a	17 (12–20)	18 (13–21)	16 (12–20)	−23.2
Pre-stroke mRS ⩾1	23/248 (9.3)	10/159 (6.3)	13/89 (14.6)	27.5
Site of occlusion				67.9
MCA isolated	160/250 (64.0)	90/159 (56.6)	70/91 (76.9)
Intracranial and/or extracranial ICA	78/250 (31.2)	65/159 (40.9)	13/91 (14.3)
Vertebro-basilar	12/250 (4.8)	4/159 (2.5)	8/91 (8.8)
Cardioembolic etiology	142/250 (56.8)	89/159 (56.0)	53/91 (58.2)	28.1
Treatment characteristics
Intravenous t-PA therapy	131/250 (52.4)	82/159 (51.6)	49/91 (53.8)	4.6
General anesthesia	35/242 (14.5)	25/153 (16.3)	10/89 (11.2)	−14.8
First-line EVT strategy
Stent retriever	47/250 (18.8)	26/159 (16.4)	22/91 (23.1)	38.8
Contact aspiration	137/250 (54.8)	98/159 (61.6)	39/91 (42.8)
Stent retriever and contact aspiration	66/250 (26.4)	35/159 (22.0)	31/91 (34.1)
Onset to groin puncture, min^b	240 (186–291)	245 (185–295)	225 (188–280)	−12.8
Number of passes	2 (1–3)	2 (2–4)	NA	NA
Groin puncture to recanalization, min^c	40 (28–58)	49 (35–68)	29 (22–40)	NA
Final recanalization grade (mTICI)
0	7/250 (2.8)	7/159 (4.4)	0/91 (0.0)	NA
2a	11/250 (4.4)	11/159 (6.9)	0/91 (0.0)
2b	61/250 (24.4)	61/159 (38.4)	0/91 (0.0)
2c	69/250 (27.6)	41/159 (25.8)	28/91 (30.8)
3	102/250 (40.8)	39/159 (24.5)	63/91 (69.2)
Cell marker content
GPVI^d (ng/mg thrombus)	0.106 ± 0.024	0.111 ± 0.024	0.098 ± 0.023	−54.3
DNA^e (ng/mg thrombus)	33 (14–94)	31 (13–92)	40 (15–114)	16.7
Heme (µg/mg thrombus)	221 ± 112	223 ± 110	218 ± 115	−8.5

DNA: deoxyribonucleotidic acid; EVT: endovascular treatment, FPE: first pass effect; GPVI: glycoprotein VI; ICA: internal carotid artery; IQR: interquartile range; MCA: middle cerebral artery; NIHSS: National Institutes of Health Stroke Scale; rt-PA: recombinant tissue plasminogen activator; TIA: transient ischemic attack; mRS: modified Rankin Scale; mTICI: modified treatment in cerebral infarction; SD: standard deviation.

Values expressed as number (%) or mean ± SD or median (IQR).

Three missing values (one in FPE group).

Two missing values (zero in FPE group).

Three missing values (zero in FPE group).

Twenty-two missing values (seven in FPE group).

One missing value (zero in FPE group).

Thrombus cellular content and EVT procedural outcomes

As shown in Figure 1, thrombus GPVI concentration differed significantly between patients with and without FPE. No such significant difference was found with DNA and heme thrombus concentration. The mean GPVI level was significantly lower among patients with FPE (0.098 ± 0.023 µg/mg thrombus) compared to patients without FPE (0.111 ± 0.024 µg/mg thrombus), with a medium effect size (standardized mean difference = −0.54; 95% CI −0.82 to −0.27). In univariate logistic regression model, a one standard deviation increase in GPVI was associated with an OR of FPE of 0.57 (95% CI 0.42–0.77). The association remained significant after adjustment on pre-specified factors (center, use of IV tPA therapy, first-line EVT strategy, and occlusion site), and on baseline differences (hypercholesterolemia, pre-stroke rankin >1, NIHSS score, and cardioembolic etiology), with an adjusted OR of 0.55 (95% CI 0.39–0.76; p < 0.001). Similarly, the difference in thrombus GPVI concentration according to FPE was observed when the analysis was restricted to the 160 patients with MCA occlusion (Supplemental Figure I with an unadjusted and adjusted ORs of 0.65 (95% CI 0.44–0.97) and 0.59 (95% CI 0.38–0.91).

Figure 1.

Distribution (Tukey’s box plot) of glycoprotein VI: GPVI (a), DNA (b), and Heme (c) assessed in retrieved thrombi according to first pass effect status. Boxes show the 25th, 50th, and 75th, and whiskers indicates values outside the lower and upper quartile with a length equal to 1.5 interquartile range. p-Values for comparison (Student t test) are reported; calculated on log-transformation values for DNA.

As shown in Table 2, higher GPVI levels were associated with an increased number of passes (incidence rate ratio per one standard deviation increase = 1.11; 95% CI 1.01–1.23), a longer reperfusion time (regression coefficient per one standard deviation increase, 0.14; 95% CI 0.06–0.21), and a lower reperfusion grade (common OR per one-grade improvement = 0.69; 95% CI 0.54–0.89). No such significant correlations were found with DNA or heme thrombus concentration. Similar effects sizes were obtained in multivariate analysis, or when analysis was restricted to patients with thrombi located to MCA (Supplemental Table I).

Table 2.

Association of cell marker contents with angiographic outcomes (first pass effect, number of device passes, final recanalization grade (mTICI), and EVT procedure time).

Outcomes	Thrombus content
Outcomes	GPVI	DNA	HEME
Unadjusted effect sizes
First pass	0.57 (0.42–0.77)	1.13 (0.86–1.47)	0.95 (0.73–1.23)
Number of passes	1.11 (1.01–1.23)	1.04 (0.94–1.15)	0.94 (0.85–1.04)
Recanalization grade	0.69 (0.54–0.89)	1.04 (0.83–1.32)	0.94 (0.75–1.19)
EVT procedure time	0.14 (0.06–0.21)	−0.004 (−0.08–0.07)	−0.04 (−0.11–0.03)
Adjusted effect sizes^a
First pass effect	0.55 (0.39–0.76)	1.18 (0.88–1.57)	0.91 (0.68–1.21)
Number of passes	1.09 (0.99–1.21)	1.03 (0.93–1.13)	0.95 (0.86–1.05)
Recanalization grade	0.69 (0.53–0.89)	1.09 (0.86–1.38)	0.89 (0.69–1.14)
EVT procedure time	0.14 (0.06–0.22)	−0.010 (–0.08 to 0.07)	–0.04 (–0.12 to 0.04)

EVT: endovascular treatment; GPVI: glycoprotein VI; DNA: deoxyribonucleotidic acid.

Values are effects size (95% confidence interval) calculated per one standard deviation increase in thrombus content (after applying log-transformation for DNA). Effects sizes were derived from logistic regression models for first pass effect (as odd ratio), negative binomial regression for number of passes (as incidence rate ratio), ordinal logistic regression model for recanalization grade (as common odd ratio for one grade increase), and linear regression model for EVT procedure time (as regression coefficient on log-transformed value).

Adjusted for center, occlusion site, intravenous thrombolysis, first-line EVT approach, admission NIHSS score, pre-stroke mRs >1, cardioembolic etiology and hypercholesterolemia.

As shown in Figure 2, thrombus GPVI concentration between patients with or without FPE according to the first-line EVT strategy differed significantly in the CA group (p = 0.004) and was at the limit of the significance in the SR group (p = 0.055). Once again, no such significant difference was found with DNA and heme thrombus concentration.

Figure 2.

Distribution (Tukey’s box plot) of GPVI (a), DNA (b), and Heme (c) according to first pass effect status and first-line EVT strategy. Boxes show the 25th, 50th, and 75th, and whiskers indicates values outside the lower and upper quartile with a length equal to 1.5 interquartile range. p-Values for comparison (Student t test) between patients with and without FPE in patients are reported; calculated on log-transformation values for DNA.

Discussion

In the present study, we explored the possible relationships between EVT procedure outcomes and thrombus cellular composition, as determined using quantitative assays. Our results indicate that, as compared to RBC and WBC, platelets are the only cell type that impacts FPE occurrence, especially when a front-line contact-aspiration strategy is used. In fact, whereas FPE occurrence was associated with a lower platelet content, it was not related to either RBC or WBC content.

Our findings are in accordance with a recent study in which platelet-rich thrombi were shown to lead to a lower recanalization rate.¹¹ Furthermore, recent results from in vitro simulation of EVT also indicate that platelet thrombus content could impair EVT, notably by increasing thrombus stiffness and friction.^12,13 In line with other published series,^14,15 we report a different impact of thrombus platelet content according to the front-line strategy used, as this variable affected significantly the FPE rate in the CA but not in the SR group. In addition, and contrarily to others, who used a semi-quantitative technique⁷ or in vitro model,¹⁶ we did not find any difference in RBC content according to FPE status. Altogether, these results suggest that platelets are major actors of EVT resistance among the usual cellular components of AIS thrombi.

We and others^17,18 have described that, in AIS thrombi retrieved by EVT, platelets usually colocalize with fibrin, neutrophils, neutrophil extracellular traps (NETS), and von Willebrand factor (vWF), notably in the thrombus outer shell. In an in vitro study, friction was found to be higher in fibrin-rich thrombi containing less than 20% of RBC.¹⁹ Stiffness was influenced by a balance between large fibrin fibers size and branching,²⁰ and enhanced by activated platelets, which kink and connect fibrin fibers.²¹ The latter elements might be regarded as key factors explaining the resistance to EVT in platelets-rich thrombi.⁵

NETs and vWF are possibly also involved in resistance to EVT.^22,23 In fact, activated platelets stimulate NET formation,²⁴ which contributes to thrombus stabilization.²⁵ Furthermore vWF interacts directly with NETs,²⁶ and it is worth noting that platelet-derived vWF is regarded as more resistant to enzymatic degradation than vWF from the plasma pool.²⁷ Last but not least, thrombus NETs,²³ vWF and fibrin²⁸ content were also described as strong factors of tPA resistance. These components may thus be rendering both recanalization treatments of LVO less effective. Taken together, these results support the notion that new therapeutic agents targeting platelets, vWF, and NETs could help to improve tPA-induced thrombolysis but also FPE occurrence after EVT. This may be of particular interest since platelet-rich thrombi could be identified on imaging^29,30 or blood biomarkers,³¹ or even during the EVT procedure.³²

As the goal of EVT should be to achieve FPE, this study supports the use of new treatments targeting platelets or the consequences of their interactions with leukocytes (i.e. the formation of NETs). Interestingly such treatments are currently under evaluation in various randomized trials (i.e. REPERFUSE: NCT04667078, ACTISAVE: NCT05070260 and NETS-TARGET: NCT04785066).

Our study suffers from several limitations. First, our analysis was restricted to thrombi that had not been dissolved after IV tPA therapy. Second, our thrombus homogenization method and the subsequent quantitative analyses were aimed at releasing and measuring blood cell markers, but no quantification of insoluble thrombus fibrillar components like vWF and fibrin was performed. Third, only thrombi weighing more than 10mg were included. In addition, no formal sample size calculation was performed and potential differences might then have been overlooked due to a lack of adequate statistical power. In an a posteriori power calculation for our primary aim (comparison of thrombus cell marker content between 91 FPE(+) and 159 FPE(-) patients), an effect size (absolute standardized difference) of 0.4 (two-sided test, alpha = 0.05, 80% of power) was detected, a value with a medium effect.

Conclusion

Our study shows that higher platelet content in thrombi retrieved by EVT is associated with a lower rate of FPE and a higher number of devices passes during EVT. These results suggest that new EVT devices and adjuvant treatments targeting platelets could help the development of tailored combined reperfusion strategies (i.e. drug and device combination guided by thrombi features).

Supplemental Material

sj-docx-1-eso-10.1177_23969873221108740 – Supplemental material for High thrombus platelet content is associated with a lower rate of first pass effect in stroke treated by endovascular therapy

Supplemental material, sj-docx-1-eso-10.1177_23969873221108740 for High thrombus platelet content is associated with a lower rate of first pass effect in stroke treated by endovascular therapy by François Delvoye, Lucas Di Meglio, Arturo Consoli, Mialitiana Solo Nomenjanahary, Sébastien Dupont, Julien Labreuche, Benjamin Maier, Michel Piotin, Raphael Blanc, Simon Escalard, Perrine Boursin, Mylène Hamdani, Hocine Redjem, Stanislas Smajda, Solène Hébert, Candice Sabben, Alain Maertens de Noordhout, Martine Jandrot-Perrus, Bertrand Lapergue, Mikael Mazighi, Benoit Ho-Tin-Noé and Jean-Philippe Desilles in European Stroke Journal

Footnotes

Declaration of conflicting interests

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

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: By public grants overseen by the French National Research Agency (ANR) as part of the investments for the future program (PIA) under grants agreement No. ANR-18-RHUS-0001 (RHU Booster).

Ethical approval

The local Ethics Committee approved this research protocol (CPP Nord Ouest II, ID-RCB number: 2017-A01039-44).

Informed consent

All patients were provided with a written explanation of the study. The patients or their representatives were given the opportunity to refuse participation.

Guarantor

Benoit Ho-Tin-Noe (BHTN).

Contributorship

FD, JPD, BHTN, MM, AMdN researched literature and conceived the study. FD, JPD, BHTN, MM, LDM, BM, AMdN were involved in protocol development. FD, JPD, MM, BM, MP, RB, SE, PB, MH, HR, SS, SH, CS, AC, BL were involved in gaining ethical approval, patient recruitment, samples collection. FD, JPD, MM, MSN, SD, MJP, BHTN were involved in sample analysis and interpretation of the results. JL worked as our biostatistician. FD, LDM, JPD wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

ORCID iD

François Delvoye

Registration

URL: . Unique identifier: NCT03268668.

Supplemental material

Supplemental material for this article is available online.

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