The Effect of Clot Volume and Permeability on Response to Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke
Introduction
Intravenous tissue plasminogen activator (IV tPA) has been used successfully for the treatment of acute ischemic stroke for a quarter of a century.1 However, its effect on proximal cerebral artery occlusions is not at the desired level, therefore it is currently combined with thrombectomy/thrombo-aspiration in these cases.2 The volume and content of the clot, in fact are more critical determinants of IV tPA responsiveness in comparison to its exact location. Plain computed tomography (CT) and CT angiography (CTA), which are routinely used in evaluation of acute stroke patients, allow us to have information about not only the presence of the occluding clot and its location and length, but also its composition. In this context, “clot density”, defined directly by the degree of clot attenuation with Hounsfield unit (HU) measurement, and the presence of “hyperdense artery sign” or “burden of clot”, evaluated either by a scoring system, or direct measurement have been discussed in the germane literature for a long time. It has been shown in at least some studies that each of these parameters has significant prognostic importance, together with collateral status, which is independent of time of treatment application, clinical severity and degree of tissue ischemia.3, 4, 5, 6, 7
Several recent studies have been interested in the difference between thrombus attenuation between CT and CTA as a marker of contrast penetration into the clot, and defined it as “clot perviousness”.8, 9, 10, 11, 12, 13, 14, 15, 16, 17 This parameter was considered wisely as a measure of clot looseness. Some studies suggest that it is easier to mechanically remove the clots with high perviousness value, and this feature is an important predictive marker for good response to endovascular therapy.13,11 Contrast penetrability may, of course, be considered to be an, perhaps more, important parameter for the penetration of tPA molecules into the clot. This was previously investigated in a study and its importance was therein demonstrated.15 We are interested in this subject and examined the interaction between IV tPA and clot perviousness. We propose a seemingly more dependable way of definition of perviousness with using whole clot histogram instead of averaging HU of visually selected 3 ROIs from the clot area used in the previous study. We also described a practical method for clot heterogeneity determination and studied its relationship with tPA responsiveness.
Section snippets
Patients
A total of 84 consecutive acute stroke patients with CT-angiography documented proximal segment middle cerebral artery occlusion, treated solely with intravenous tPA, over the last 8 years, were included into the study. As details can be found in our other publications,5,6 the patients were obtained from our prospective departmental stroke register. Our stroke management protocol utilizes a stepwise etiological work-up including transthoracic echocardiography, 24-hour Holter monitoring, cranial
Results
This study included a total of 84 patients (52% female; mean age: 68 ± 14 years). The mean pre-IV tPA NIHSS was 15.6 ± 5.4; and median onset-to-needle time was 155 ± 52 minutes.
At the end of the third month, 26 (31%) of 84 patients had mRS less than 2, and 35 (42%) had mRS less than 3. Thrombus volume was almost the half (37.54 versus 63.49 mm3, P = .009) with lower heterogeneity (4.05 versus 5.35 HU, P = .011) in patients with excellent outcome (mRS 0-1) with IV tPA, who are younger, more
Discussion
We could not able to demonstrate a significantly positive link between clot perviousness and response to IV tPA. In univariate analyses, degree of perviousness was correlated to good prognosis, but in the multivariate model this association was lost. We found that thrombus size, as evaluated either by volume or simply by length, was significantly correlated to responsiveness to systemic thrombolysis and prognosis in acute stroke patients. This is, of course, an expected finding25 to some
Conflict of Interest
The authors declare that there is no conflict of interest.
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Cited by (20)
Histological composition of retrieved emboli in acute ischemic stroke is independent of pre-thrombectomy alteplase use
2022, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :In general, much of the literature has converged to the conclusion that the presence of a hyperdense artery sign which is short and pervious to contrast portends a higher recanalization rate with tPA and better functional outcomes.5,9,11,17 This is based on the idea that tPA is probably more efficacious for RBC rich clots which are generally hyperdense and which generally do not have much fibrin and platelets.5,9,11,17 Clot perviousness to contrast on CTA is thought to represent increased clot porosity and thus improved tPA delivery to the clot itself and improved thrombolysis.
Associations of thrombus perviousness derived from entire thrombus segmentation with functional outcome in patients with acute ischemic stroke
2021, Journal of BiomechanicsCitation Excerpt :This implies that high-density thrombus parts on NCCT also showed a higher increase in attenuation on CTA, which may suggest that high-density thrombi are more pervious. This is in line with previous studies showing that high-density thrombi are more responsive to IV-rtPA and showing that IV-rtPA is more successful in pervious thrombi (Bilgic et al., 2020; Dutra et al., 2019; Kappelhof et al., 2021; Niesten et al., 2014; Santos et al., 2016a). The higher manual TAI value might also arise from partial volume effect.
Large Artery Atherosclerotic Clots are Larger than Clots of other Stroke Etiologies and have Poorer Recanalization rates
2021, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :This suggests that LAA cases are more prone to distal embolization, likely due to their large, soft, friable composition, and that in cardioembolic and cryptogenic patients, the clots are smaller and likely stiffer, fibrin and platelet-rich clots that are less prone to fragmentation. Recombinant tissue plasminogen activator (tPA) is the current FDA approved thrombolytic treatment for AIS and has been demonstrated to reduce the clot burden in responsive patients, however, the length and volume of the clot are critical to the effectiveness of tPA.18, 19 This study demonstrates that the administration of tPA was associated with a smaller extracted clot Area.
Isolated Sulcal Effacement and Response to Intravenous Thrombolysis in Acute Ischemic Stroke
2020, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :In our study, favorable outcome rate was 38% with IV tPA. This is lower than thrombectomy, but of course clearly higher than the IV tPA success in the major vessel occlusions reported in the literature.14,15 However, in regression models, we could not detect ISE as an independent prognostic indicator, most probably due to its close connection to other good prognostic factors such as younger age, low NIHSS, high ASPECT and good collateral score.
Ischemic Stroke Thrombus Perviousness is Associated with Distinguishable Proteomic Features and Susceptibility to ADAMTS13-Augmented Thrombolysis
2023, American Journal of Neuroradiology
Notice: The complete de-identified dataset is available from the corresponding author on a reasonable request.