In all 60 patients, the responses to IVT were shown in 35 patients classified into the IVT-responsive and the rest 25 patients into IVT-unIVT-responsive groups. The comparison between the two groups were presented in Table 3 and Table 4. In general demographics, age were significantly younger in the IVT-unresponsive group (IVT-responsive; 66.2±11.9 vs. IVT-unresponsive; 59.3±14.2, p=0.045).
Risk factor for ischemic stroke and prior antiplatelet use did not affect the response to IVT. M2 were more common in the IVT-responsive group (n=5, 14.3% vs. n=1, 4.0%), however, a statistical significance on thrombus location was not shown between the two groups. Subtype of stroke was not different in the two groups. Baseline stroke severity, represented with NIHSS, was higher in the IVT-responsive group (16.8±4.0 vs. 13.8±5.1, p=0.012). Consequently, mRS at 3 months was worse on the IVT-responsive group (n=18, 51.4% vs. n=21, 84.0%, p=0.012).
Table 4 presented with radiological, histopathological and treatment parameters between the IVT-responsive and IVT-unIVT-responsive groups. The vessel signs on CT and MR scan were not different between the two groups (HAS; n=14, 40.0% vs. n=10, 40.0%, p=1.000, SVS on MR; n=24, 68.6% vs.
n=18, 72.0%, p=0.775), and the clot burden score also did not show difference (5.60±2.7 vs. 5.96±2.2, p=0.709). Thirty-three patients were thrombus-available—16 in the IVT-responsive group and 17 in the IVT-unresponsive group. In histopathological analysis, RBC-dominant patients were more common in IVT-responsive group (n=8, 50.0% vs. n=1, 5.9%) and fibrin-dominant or mixed patients were more common in IVT-unresponsive group (n=8, 50.0% vs. n=16, 94.1%; p=0.007), however, the ratio of component did not differ between the two groups. Treatment parameters related with EVT were balanced in the two groups.
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Table 3. Comparison of demographics and baseline characteristics between the IVT-responsive and IVT-unresponsive groups
HTN = hypertension, DM = diabetes mellitus, ICA = internal carotid artery, LAA = large artery atherosclerosis, CE = cardioembolism, NIHSS = National Institutes of Health Stroke Scale, mRS = modified Rankin scale;
*independent t-test, †Pearson’s chi-square test, ‡Fisher’s exact test IVT-responsive
Cryptogenic embolism 8 (22.9) 4 (16.0)
Baseline NIHSS, median (range) 17 (7-24) 12 (5-22) 0.012*
mRS 0-2 at 3 months, n (%) 18 (51.4) 21 (84.0) 0.012†
Mortality at 3 months, n (%) 2 (5.7) 0 (0.0) 0.501‡
１３
Table 4. Comparison of radiological and treatment parameters between the IVT-responsive and IVT-unresponsive groups
ASPECT = Alberta Stroke program early CT score, SVS = susceptibility vessel sign, CBS = clot burden score, IVT
= intravenous thrombolysis; *independent t-test, †Pearson’s chi-square test, ‡Fisher’s exact test, §Mann-Whitney U test; a: exclusion of 10 IVT-responsive patients due to recanalization after IVT use (only diagnostic angiography)
IVT-responsive
Baseline CBS, mean±SD 5.60±2.7 5.96±2.2 0.709§
ΔCBS -2.51±1.85 1.24±2.18 0.000*
Histopathological analysis, % 16 patient available 17 patients available
RBC ratio 50.52±13.34 43.12±10.35 0.084§
Fibrin/platelet ratio 46.31±12.60 52.22±8.71 0.125§
WBC ratio 3.18±1.39 4.65±3.55 0.130§
Thrombus group, n (%) 0.007‡
RBC dominant group 8 (50.0) 1 (5.9)
Fibrin-dominant or mixed group 8 (50.0) 16 (94.1)
Endovascular therapy, n (%)a 25 patients available 0.246‡
Retrieval stent 16 (64.0) 15 (60.0)
Aspiration 1 (4.0) 5 (20.0)
Combined 8 (32.0) 5 (20.0)
Time parameters, min, mean±SD
Onset to IVT time 125.06±54.49 110.76±79.09 0.064§
Onset to puncture time 214.92±65.18 197.40±77.59 0.283§
CT to puncture time 98.52±24.37 98.40±22.38 0.689§
Median procedure time a 72.84±45.62 67.44±36.85 0.756§
Onset to reperfusion time a 291.84±75.54 264.84±86.42 0.245*
Successful reperfusion, n (%) 33 (94.3) 23 (92.0) 1.000‡
Symptomatic hemorrhage, n (%) 7 (20.0) 1 (4.0) 0.123‡
１４ C. Predictors of the response to IVT
Logistic regression analysis was performed to detect influential factors on the response to IVT (Table 5). Multiple logistic regression was executed in thrombus-available and IVT-received 33 patients.
In univariate analysis, age, hypertension, and RBC dominance had a significant effect on outcome (age;
OR=1.086, 95% confidence interval, 1.011-1.166, p=0.024, hypertension; 5.280, 1.196-23.317, p=0.028, RBC dominance; 16.000, 1.694-151.110, p=0.027). Baseline NIHSS and clot burden score did not show significant relationship. After adjustment of age and hypertension, RBC dominance was an only variable influencing the good response to IVT (15.816; 1.368-182.897, p=0.027).
１５
Table 5. Logistic regression analyses of the relations between clinical covariates and the response to IVT (n=33)
Variables Univariate analysis Multivariable analysis
Odds ratio (95% CI) P value Odds ratio (95% CI) P value
Age 1.086 (1.011-1.166) 0.024 1.078 (0.973-1.194) 0.153
HTN 5.280 (1.196-23.317) 0.028 1.724 (0.210-14.189) 0.612
DM 3.692 (0.342-39.837) 0.282 .. ..
Histological feature (RBC dominance) 16.000 (1.694-151.110) 0.016 15.816 (1.368-182.897) 0.027 HTN = hypertension, DM = diabetes mellitus, LAA = large artery atherosclerosis, CE = cardioembolism, NIHSS = National Institutes of Health Stroke Scale, ASPECT = Alberta Stroke program early CT score, SVS = susceptibility vessel sign
１６ D. Patient characteristics according to RBC ratio
We analyzed the characteristics of all thrombus-available 56 patients, including who were did not receive IVT treatment. The patients were divided into the three groups according to the RBC ratio. The cut-off value for lower tertile group was 37%, and the value for middle tertile group was 49% (Figure 3).
The patient characteristics according to the RBC ratio are shown in Table 6. Age, sex, risk factor profiles, subtype of stroke, and stroke severity were not different among the groups except hypertension (lower 1/3;
n=5, 27.8% vs. middle 1/3; n=7, 36.8% vs. higher 1/3; n=14, 73.7%, p=0.012). However, vessel signs and symptomatic hemorrhage was more prevalent in patients with higher tertile than in those with lower levels (HAS; n=6, 33.3% vs. n=4, 21.1% vs. n=12, 63.2%; p=0.024, SVS; n=9, 50.0% vs. n=15, 78.9% vs.
n=19, 100.0%; p=0.002, symptomatic hemorrhage; n=0, 0.0% vs. n=2, 10.5% vs. n=4, 21.1%; p=0.040).
Figure 4 presented radiological and histopathological findings of the representative cases from RBC-dominant and fibrin-RBC-dominant patients.
１７
Figure 3. The arrangement of RBC ratio in all thrombus-available 56 patients
１８
Table 6. Patient characteristics stratified by RBC ratio in all thrombus-available 56 patients
HTN = hypertension, DM = diabetes mellitus, LAA = large artery atherosclerosis, CE = cardioembolism, ICA = internal carotid artery, NIHSS = National Institutes of Health Stroke Scale, ASPECT = Alberta Stroke program early CT score, SVS = susceptibility vessel sign, CBS = Clot burden score, IVT = intravenous thrombolysis;
†Pearson’s chi-square test, ‡Fisher’s exact test,║Oneway Analysis of Variance; a: only in patients received IVT RBC ratio, %
Age, yrs, mean±SD 63.17±15.76 62.53±17.42 70.79±10.92 0.177║
Sex, female, n (%) 5 (27.8) 11 (57.9) 7 (36.8) 0.159†
１９
Figure 4. Representative cases from RBC-dominant (A) and fibrin-dominant or mixed groups (B) (A) Early vessel signs are seen on nonenhance CT and gradient echo image of MR scan (red arrows).
Initial CT angiography and digital subtraction angiography showed improvement of clot burden score (2 6 points). The color of gross specimen was categorized into dark red visually, and histological compositions were analyzed into RBC 65.0%, fibrin 33.7%, and WBC 1.3%.
(B) Patient from fibrin-dominant or mixed group did not show early vessel signs and response to IVT (clot burden score 4 3 points). The color of gross specimen was categorized into scarlet, and histological compositions were comprised in RBC 27.2%, fibrin 69.2%, and WBC 3.6%.
２０
IV. DISCUSSION
This study shows the histological composition of thrombus might lead to the different clinical characteristics, especially the response to IVT. In RBC dominant group, early vessel signs and the good response to IVT were more prevalent compared with fibrin-dominant or mixed group. After adjustment of other factors, the response to IVT was influenced by RBC dominance, most importantly. According to the RBC ratio, the vessel signs and symptomatic hemorrhage were more prevalent in patients with higher tertile RBC ratio group.
We could obtain entire thrombi from patients with cardioembolism, higher clot burden, and SVS on MR. Atrial fibrillation and the involvement of internal carotid artery (ICA) were more prevalent in thrombus-available group without significance. In comparison between the thrombus-available and thrombus-unavailable groups, various and combined EVT modalities were used in thrombus-unavailable patients. These process could be affect the integrity of thrombi, consequently, we could not obtain intact thrombi. The response to IVT did not show significance, it might be resulted from mixed characteristics of the patients. The presence or absence of intact thrombi did not affect to clinical and interventional outcome. We could scientifically confirm the experiences from the clinical field from this study.
In our study, the most relevant factor influencing the response to IVT was RBC dominance from the histopathological analysis. Although there was no statistical difference, IVT-responsive group was more prevalent M2 occlusion and symptomatic hemorrhage. In IVT-unresponsive group, the patients were younger and have more fibrin-dominant thrombi. Compared with previous studies, vessel signs and clot burden were not different according to IVT responsiveness. It may be due to small sample size of our data. Traditionally, thrombi were categorized into white—platelet-fibrin rich and red—RBC-rich clots.
Red clots tend to form in low flow circumstance, whereas white clots adhere to roughened places in fast flow. (Caplan, 2006) During the formation of thrombus, incorporation of RBCs deemed to be mediated through a loose entrapment than that of platelets.(Brown et al., 1977) Therefore, thrombolytic agents may act by lysing the fibrin bridges in red thrombi, and do not have a lytic effect on white clots. In myocardial infarction, usually attributed to platelet-rich clots, the effect of IVT was limited in contrast to an acute
２１
ischemic stroke. (O'Gara et al., 2013) Therefore, primary percutaneous coronary intervention was recommended than IVT in patients with acute myocardial infarction.
To find the factors related with RBC ratio, we arranged the patients with available thrombi according to the RBC ratio. Consequently, we analyzed clinical and radiological characteristics among the patients divided into three groups according to the RBC ratio. As the RBC ratio increased, the proportion of patients with vessel signs and symptomatic hemorrhage increased. There was a tendency of good response to IVT related with increase of RBC ratio. Clinical outcome at 3 months was worse with increase of RBC ratio, related with symptomatic hemorrhage. RBC dominance was related with vessel signs on imaging studies and might be related with symptomatic hemorrhage. This is line with previous studies, and worse outcome in patients with vessel signs is generally accepted. (Qureshi et al., 2006) Even the response to IVT was more prevalent in RBC-dominant group, considering clinical outcome and symptomatic hemorrhage, the use of IVT should be cautious in patients with vessel signs.
This study has several limitations. This is a retrospective study with small sample size. We try to reduce bias using prospectively collected registry and following a flow chart. Although single center study, in our best knowledge, this is a first study to evaluate the response of IVT focused on the patients who were available for histologic analysis of retrieved thrombi. Inhomogeneity due to the use of various EVT modalities could affect the results of our study. In future, prospective multi-center study are needed.
２２
V.
CONCLUSION
This study shows the histological composition of thrombus might lead to the different clinical characteristics, especially the response to IVT. The RBC dominance can be an important factor affecting the response to IVT comparable with clinical or radiological findings in this study. These findings might affect clinical outcome through increased symptomatic hemorrhage related with increased RBC ratio. The response to IVT appears to be influenced by histopathological features of retrieved thrombi and clinical implication will be further evaluated.
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