Pathogenetic mechanisms in leukostasis. Sludging of circulating myeloblasts causes mechanical obstruction of small vessels and consecutive malperfusion in the microvasculature (eg, in organs such as brain and lungs). Apart from the mechanical obstruction, myeloblasts adhere to the endothelium by inducing endothelial cell adhesion receptor expression including E-selectin, P-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Myeloblasts can promote their own adhesion to unactivated vascular endothelium by secreting tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), or additional stimulating factors (sequence of events represented by steps 1 to 3).³⁰  Additional changes after cytokine-driven endothelial cell activation can be a loss of vascular integrity and modification of endothelial phenotype from antithrombotic to prothrombotic phenotype.^35,36  Endothelial disintegration allows myeloblast migration and blood extravasation and microhemorrhages. Tissue invasion of myeloblasts is mediated by metalloproteinases (MMPs; particularly MMP-9), which are expressed on the cellular surface and secreted into the extracellular matrix.^31,33,34,37