“Time lost is clot resolution lost”: the neglected perspective of the therapeutic time window for ischemic stroke

 Are you even measuring 100% recovery?

“What's measured, improves.” So said management legend and author Peter F. Drucker 

 

In this research in mice the needed time frame for tPA delivery is 3 minutes for full recovery. CAN YOU DO THAT? Since no one can do that, what are the followup procedures that will still deliver 100% recovery?

Electrical 'storms' and 'flash floods' drown the brain after a stroke

 

Don't allow your hospital to use the tyranny of low expectations to drive their goals for stroke recovery. The only goal in stroke is 100% recovery. You may need to scream at your stroke medical 'professionals' to get them to understand that. 

The latest here:

“Time lost is clot resolution lost”: the neglected perspective of the therapeutic time window for ischemic stroke

Manuela De Michele^1*, Svetlana Lorenzano², Lucia Bertuccini³, Francesca Iosi³ and Danilo Toni²

• ¹Emergency Department, Sapienza University of Rome, Rome, Lazio, Italy
• ²Department of Human Neurosciences, Sapienza University of Rome, Rome, Lazio, Italy
• ³Core Facilities, National Institute of Health (ISS), Rome, Lazio, Italy

“Time is brain,” a mantra adapted from the cardiological “time is muscle,” was first proposed 30 years ago (1), and it is still a valid concept, stressing the need for urgent intervention in acute ischemic stroke (AIS). The suffering but still viable neurons residing in the ischemic penumbra are at high risk of being included in the necrotic core over time. Hence, “time is brain” was also translated into the statement “time lost is penumbra lost,” highlighting even better the concept of the penumbral tissue lost during the therapeutic time window. In fact, it is well established that the efficacy of both intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) gradually declines and the chance of recanalization and of reaching a good outcome is much higher during the 1st h after stroke onset, the so-called “golden hour” (2). More recently, the wider use of advanced neuroimaging made it clear that this evolution takes place at different paces, depending on the collateral circulation status (3).

Another issue to that rates of near-complete or complete recanalization of LVO in the AIS amount to a maximum of 32% with IVT (10–15 and 25–50% for internal carotid artery and proximal middle cerebral artery occlusion, respectively) (4, 5) and of 56–59.9% with MT (6). Therefore, for patients with LVO, bridging therapy is recommended (7).

Reasons for this recanalization “resistance” are not completely known. Clot burden, good collaterals (that can deliver more rTPA in the clot via backflow), timing from stroke onset, and thrombus composition have been advocated (8). In case of recanalization failure after MT, other important determinants are the pressure gradient across the thrombus and the stickiness of the thrombus itself (due to the combined force of friction and adhesion on the vessel wall) (9). Notably, it has been observed that the achievement of recanalization with a single thrombectomy device pass, the “first-pass effect,” is associated with a better outcome (6).

In 2014, in a single-center prospective study, Muchada et al. (10) showed that the effect of IVT on early recanalization detected by transcranial doppler sonography declined over time. Treatment initiation after 270 min was an independent predictor of lack of recanalization in distal MCA occlusion, whereas there was a trend toward lower recanalization in proximal MCA occlusion treated after 90 min. In the related editorial comment, Tsivgoulis and Alexandros (11) proposed the motto “time is clot” for thrombolytic therapy. After 1 year, Kim et al. (12) reported a linear inverse relationship between time from symptom onset to treatment and the degree of thrombus resolution after rtPA administration, assessed by a thin section non-contrast computed tomography scan performed at 1 h after IVT. In the same study, it was observed, by using an animal model of stroke, that the effect of rTPA depended on the thrombus age (12). The authors concluded their study by reviving the sentence “time is clot” for thrombolytic treatment but it did not gain a foothold and was early neglected. Afterward, growing evidence from research on retrieved thrombi during MT has been brought back into the spotlight, with the occluding clot as one of the main actors of the acute phase of IS.

It is now clear that, whether it has an atherothrombotic or an embolic origin, the clot is a tissue with specific characteristics evolving over time, whose probability to be resolved by thrombolytic therapy or removed by MT quickly declines pari passu (12). In this perspective, two variables are particularly relevant: length of thrombus and its composition.

Thrombi exceeding the length of 8 mm seem to have almost no chance to be recanalized by IVT (13).

Recent data on the composition of retrieved thrombi suggest that stroke clots can be categorized into platelet-rich thrombi and red blood cells (RBC)-rich thrombi with, in the middle, a wide range of more heterogeneous thrombi having a mixed coexisting platelet-rich and RBC-rich areas (14, 15).

RBC-rich clots and areas consist of densely packed RBC surrounded by a thin fibrin network, while platelet-rich clots and areas are much more complex and organized with dense fibrin strings, von Willebrand factor (VWF), platelets, DNA from neutrophil extracellular traps (NETs), and sparse leukocytes. Interestingly, networks of extracellular DNA and leukocytes have been more frequently found within the platelet-rich areas and at the interface between the platelet-rich and the RBC-rich areas but not within the RBC-rich areas (15).

Although it is not possible to analyze the histological characteristics of clots lysed and dissolved by rTPA, RBC-rich thrombi appear more susceptible to be lysed and more easily to be retrieved by thrombectomy devices compared to the other types of thrombi (16, 17). RBC-rich clots are also associated with non-cardioembolic stroke and with hyperdense MCA sign on non-contrast CT scan or blooming artifact on brain MRI (14, 18). In 2021, Gunning et al. demonstrated that fibrin-rich thrombi had a significantly higher coefficient of friction between the clot and the vessel wall than RBC-rich thrombi, thus contributing to the difficulty in retrieval by MT (19). In this regard, it has been observed that clots retrieved in earlier passes have higher RBC content in comparison with clots retrieved in later passes that are conversely, rich of fibrin, platelets, and other components (20). Interestingly, in this study, the extracted clot area was larger in the earlier than in later passes (20), supporting the fact that RBC-rich thrombi and RBC-rich areas inside the same thrombus are less sticky and more easily retrievable compared to fibrin-rich thrombi and fibrin-rich areas. However, it is not possible to rule out a direct effect of passes on the clot itself.

By using scanning electron microscopy (SEM), it is possible to identify two different time-related structural thrombotic patterns, one formed by dense fibrin mesh with sparse cellular elements suggesting a matured clot and another one characterized by looser fibrin strands and intact RBC suggesting a fresh and evolving clot (21). Figure 1 clearly shows these two patterns from the same thrombus retrieved by the proximal MCA of an adult patient treated in our center with bridging therapy 3 h after symptoms onset and analyzed by SEM.

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