Cardiovascular Risk Factors Involved in Hemorrhagic Transformation After Intravenous Thrombolytic Therapy in Patients with Acute Ischemic Stroke

Abstract

In line with AHA/ASA guidance, intravenous alteplase has served as the standard first-line reperfusion treatment in acute ischemic stroke (AIS). Hemorrhagic transformation (HT) is a common spontaneous complication after thrombolytic therapy for AIS with increased mortality. Restoration of flow in an occluded artery can precipitate blood-brain barrier breakdown and heighten the risk of HT. However, the pathogenesis of HT is multifactorial, and identifying patients at high risk after recanalization therapy (RT) has a defining role in ensuring optimal treatment. At the same time, it is still under debate how these patients can best be identified based on clinical and biological characteristics. Preventing HT will become increasingly essential. In this review, our primary objective was to identify research focused on the cardiovascular risk factors predicting HT after AIS treated with thrombolytics, as this may help develop targeted treatment strategies and diminish the risk of HT.

Keywords: acute ischemic stroke; hemorrhagic transformation; risk factors; thrombolytic therapy.

Figure 1

Hemorrhagic transformation after ischemic stroke. Each type of hemorrhagic complication is associated with an increased risk of subsequent complications; thus, accurate imaging definitions are necessary. On CT scans, they are normally classified into four categories: hemorrhagic infarction types 1 and 2 (HI1 and HI2); parenchymal hemorrhage types 1 and 2 (PH1 and PH2). HI1 presents as scattered, punctate hyperdense petechiae, whereas HI2 shows a more confluent hyperdensity extending across the infarcted territory. PH1 consists of a homogeneous hematoma involving < 30% of the infarcted area, typically accompanied by mild mass effect (documented by interrupted arrow). PH2 denotes a uniform hematoma occupying > 30% of the infarcted territory, typically associated with marked mass effect (documented by continuous arrows and exemplified by the reduction in cerebral gyri, compression of the ventricular system, and herniation phenomena).

Figure 2

Structural and functional alterations of the blood–brain barrier (BBB) in cerebral ischemia. (A) Under physiological conditions, the BBB is maintained by the coordinated interaction between cerebral endothelial cells, pericytes, and astrocytic endfeet, supported by intact tight junctions and a stable extracellular matrix. (B) Cerebral ischemia or hemorrhagic transformation following thrombolysis may disrupt this balance. The release of matrix metalloproteinases (MMPs) affects not only the pericytes, causing them to detach, but also produces astrocytic endfeet damage, tight junction degradation, and extracellular matrix remodeling. This is followed by the infiltration with activated immune cells, pro-inflammatory mediators, and red blood cells, which promote extravasation. Mitochondrial damage further contributes to cellular dysfunction and the progression of injury.

Figure 3

Age and blood-barrier dysfunction. As the body ages, molecular and cellular changes such as gut dysbiosis, chronic inflammation, and cellular senescence contribute to endothelial dysfunction and imbalances in the coagulation and fibrinolytic systems. These mechanisms are further aggravated by common comorbidities in the elderly (e.g., cardiovascular diseases, kidney disease, diabetes) and polypharmacy. PAI-1 (Plasminogen Activator Inhibitor-1) GAGs (Glycosaminoglycans).