Discussion

Our study demonstrates a 6.3% (SITS) and 10.0% (NINDS) sICH rate, as well as a 19.4% asymptomatic and 29.4% overall hemorrhage rate. Serologic markers that demonstrated association with post-EVT hemorrhage were: low lymphocyte count (SITS), high neutrophil count (NINDS, overall hemorrhage), low platelet-to-lymphocyte ratio (NINDS), and low total WBC (NINDS, asymptomatic hemorrhage). Other factors that showed previous association with post EVT hemorrhage were also seen in our study: diabetes mellitus, ^{Reference Enomoto, Shigeta and Ota19} higher number of passes, ^{Reference Hao, Yang and Wang4,Reference Enomoto, Shigeta and Ota19} onset to perfusion time, ^{Reference Hao, Yang and Wang4,Reference Bin, Yoon and Lee20} lower ASPECTS, ^{Reference Hao, Liu and Wang6,Reference Boisseau, Fahed and Lapergue21} and intravenous thrombolysis. ^{Reference Enomoto, Shigeta and Ota19,Reference Nogueira, Gupta and Jovin22} The neutrophil-to-lymphocyte ratio has previously been associated with early neurological deterioration, ^{Reference Nam, Kim and Lee23} post-thrombolysis hemorrhagic transformation, ^{Reference Liu, Lu and Yin24} and poor outcomes in acute ischemic stroke patients. ^{Reference Song, Zhao and Rajah25} However, it was not associated with post-EVT hemorrhage in our study using any of the definitions.

Blood–brain barrier disruption induced by the inflammatory response to acute ischemic stroke may play a role in post-EVT hemorrhage. Neutrophils are a source of matrix metalloproteinase (MMP)-9, which play a direct role in degrading tight junction proteins. Conceivably, higher neutrophil counts may lead to higher levels of MMP-9, potentially translating to a higher risk of HT. ^{Reference Kanazawa, Takahashi, Nishizawa and Shimohata26} The role of neutrophils is emphasized further by decrease in ischemic volume in rats undergoing middle cerebral artery occlusion after the administration of anti-neutrophil antibodies compared with those with a normal complement of neutrophils. ^{Reference Dawson, Ruetzler, Carlos, Kochanek and Hallenbeck27} These pathomechanisms may underlie a recent finding that high neutrophil count predicts poor clinical outcomes despite recanalization in patients with large vessel occlusion. ^{Reference Boisseau, Desilles and Fahed28} Large cohorts of patients undergoing intravenous thrombolysis ^{Reference Maestrini, Strbian and Gautier29} and endovascular thrombectomy ^{Reference Hao, Yang and Wang4} also demonstrated an increased risk of hemorrhagic transformation in patients with higher neutrophil counts and ratios. Circulating neutrophil transcriptomes have also been demonstrated to correlate with the presence of unruptured intracranial aneurysms. ^{Reference Tutino, Poppenberg and Li30–Reference Poppenberg, Tutino and Li32}

Diabetes has been associated with post EVT hemorrhage in past studies. ^{Reference Enomoto, Shigeta and Ota19,Reference Nogueira, Gupta and Jovin22} Chronic hyperglycemia in diabetic mice undergoing MCA occlusion has been demonstrated to aggravate HT by inciting mitochondrial dysfunction leading to endothelial cell death. ^{Reference Mishiro, Imai and Sugitani33} Classically, HT had been attributed to free radical damage from reperfusion injury. However, similar to our findings, a large multicenter study demonstrated that reperfusion status did not correlate with HT after EVT. ^{Reference Boisseau, Fahed and Lapergue21} More recent basic science research has focused on downstream microvascular thromboinflammation (DMT), a phenomenon characterized by leukocyte margination (mostly neutrophils) and thrombosis in the venules after proximal large vessel occlusion. DMT by inducing vascular leakage may account for microhemorrhages and incomplete reperfusion despite large vessel recanalization. ^{Reference Desilles, Syvannarath and Di Meglio34}

Hyperglycemia has been demonstrated to precipitate infarct growth and HT by exacerbating DMT through preactivating neutrophils in rats undergoing experimental large vessel occlusion. ^{Reference Desilles, Syvannarath and Ollivier35} Earlier studies noted that diabetic rats had a more robust neutrophil–endothelial cell interaction compared with nondiabetic ones in the setting of large vessel ischemia reperfusion injury models. ^{Reference Ritter, Davidson and Henry36} This interplay between diabetes and neutrophils may be the pathomechanism behind the association of both factors with post-EVT ICH in our study.

Higher WBC count has already been associated with less hematoma expansion in spontaneous ICH. ^{Reference Morotti, Phuah and Anderson37} However, its association with less post-EVT hemorrhage has not yet been described elsewhere. A higher platelet lymphocyte ratio has been associated with poorer clinical outcomes in patients undergoing thrombolysis and endovascular therapy ^{Reference Altintas, Altintas, Tasal, Kucukdagli and Asil38,Reference Xu, He and Li39} ; counterintuitively, our study demonstrates that a lower ratio is associated with sICH (NINDS). Similarly, the association of lower lymphocyte to our outcome of interest (SITS) is also a new finding.

Limitations of our study include its retrospective nature, lack of a core laboratory, and low sample size. Next, perfusion imaging and MRI data were not included in the analysis. The model also needs validation using a different large independent cohort. Furthermore, the models obtained by the study only have moderate accuracy. Lastly, the paper is exploratory in nature. It is a proof of concept of the association of serology markers to post-EVT hemorrhage.