The Effect of Clot Volume and Permeability on Response to Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke

https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104541Get rights and content

Abstract

Background and Aims

The characteristics of clot causing acute ischemic stroke, such as size, content, and location, are among the main determinants of response to intravenous tissue plasminogen activator [IV tPA]. Clot heterogeneity and permeability are under-recognized features that might provide additional information in predicting the efficacy of IV tPA.

Methods and Patients

Patients with proximal middle cerebral artery occlusion treated with “IV tPA alone” were included. The mean Hounsfield's unit (HU) value, as objective measure of clot attenuation, and its standard deviation (SD), as proposed measure of clot heterogeneity, were obtained. The difference in HU values between CT Angiography and CT was defined as “clot permeability”, or “perviousness’. The size (length and volume-mm3) of pre-clot pouch and occluding clot along with ASPECT score and Maas’ silvian and leptomeningeal collateral score were measured.

Results

The study included 84 cases (44 women, age: 68 ± 14 years, pretPA NIHSS: 16 ± 5). Patients with excellent response to tPA (31%) had lower thrombus volume (37.54 ± 32.37 versus 63.49 ± 37.36, P = .009) and heterogeneity (4.05 ± 1.49 versus 5.35 ± 2.34, P = .011), along with higher clot permeability (48 ± 35.48 to 31.32 ± 18.62, P = .006). However, significance of permeability did not survived in the regression analysis with adjustment for NIHSS (β:−.296, P = .003); clot volume (β:−.240, P = .014) and collateral status (β:.346, P < .001). In patients with good prognosis, clot volume was significantly lower (37.76 ± 30.08 versus 67.57 ± 37.83, P < .001), whereas permeability was significantly higher (43.97 ± 32.33 versus 31.13 ± 19.01, P = .026). However, this effect did not persist in the regression analysis after adjustment for NIHSS (β:−.399, P < .001), collateral status (β: .343, P < .001) and clot volume (β:−.297, P = .001). Clot permeability was significantly higher (45.78 ± 36.34 versus 33 ± 20.2, P = .045) and heterogeneity was lower (4.1 ± 1.55 to 5.27 ± 2.32, P = .028) in patients with dramatic response to tPA (27%). In patients responding positively to IV tPA (48%), clot permeability was numerically higher (39.85 ± 31.79 to 33.47 ± 19.28, P = .268), while clot volume (48.15 ± 34.5 to 62.07 ± 39.62, P = .093) was lower. Clot volume, permeability and heterogeneity did not show a significant difference in any (38.1%) or symptomatic (8.3%) bleeders after IV tPA. The chance of IV tPA to be beneficial increased in patients with clot volume lower than 45 mm3, with an increased likelihood of this benefit to be observed within the first day after IV tPA. Our detailed explorative ROC analysis was not able to detect a volume threshold above which the positive effect of IV tPA disappeared.

Conclusion

Clot volume is critical for the effectiveness of IV tPA in acute ischemic stroke. Clot permeability and heterogeneity may modify its effect. CT technologies, which are readily available when evaluating a stroke patient in an emergency setting, provide us with useful parameters regarding the size, permeability and heterogeneity of the clot.

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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