Two main pathogenetic factors are responsible for the development of HL: first, a rapid blast proliferation leading to a high leukemic tumor burden; second, disruption in normal hematopoietic cell adhesion leading to a reduced affinity to the bone marrow.17 The high number of leukocytes may cause 3 main complications: disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. DIC is caused by high cell turnover and associated high levels of released tissue factor, which then triggers the extrinsic pathway via factor VII.18 TLS may occur as a result of spontaneous or treatment-induced cell death. Leukostasis is explained by 2 main mechanisms. The rheological model is based on a mechanical disturbance in the blood flow by an increase of viscosity in the microcirculation.19,20 The fact that myeloid blasts are larger than immature lymphocytes or mature granulocytes and that leukemic blasts are considerably less deformable than mature leukocytes explains the higher incidence of leukostatic complications in AML as opposed to ALL, chronic myeloid leukemia, or chronic lymphocytic leukemia.8,21-23 However, the observation that there is no clear correlation between the leukocyte count and the severity and frequency of leukostatic complications6,24,25 points toward additional cellular mechanisms involved in the genesis of leukostasis such as interactions between leukemic cells and the endothelium,26,27 mediated by adhesion molecules.28 Bug et al described a significant association between expression of CD11c and a high risk of early death in leukocytosis.29 Stucki and coworkers observed a secretion of tumor necrosis factor-α and interleukin-1β by leukemic myeloblasts leading to change in the makeup of adhesion molecules on the endothelial cells.30 Several molecules such as intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin were shown to be upregulated. By this mechanism, leukemic cells can promote their own adhesion to the endothelium and create a self-perpetuating loop in which more and more blast cells migrate and attach to the endothelium.30 Additionally, cytokine-driven endothelial damage, subsequent hemorrhage, hypoxic damage, and AML blast extravasation followed by consecutive tissue damage by matrix metalloproteases might contribute to the pathogenesis of leukostasis.31-34 Important mechanisms of leukostasis are shown in Figure 3.35-37
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
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While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
Finally, it must be emphasized that regardless of theoretical potential to protect from COVID-19 or preliminary favorable outcomes, drug treatment for COVID-19 patients must be prescribed only after consistent demonstration of efficacy in randomized clinical trials. After proven efficacy, use of drug must be restricted for patients in the specific stage of COVID-19 for which drug has demonstrated efficacy, since drugs can lead to opposite results, as demonstrated with dexamethasone, which while reduced mortality in critically ill patients, subgroup analysis suggested that its use in mild and non-hospitalized patients led to increased mortality [64]. Drugs must prove efficacy in terms of reduction of hospitalization, need of intensive care, mechanical ventilation, and death, and prevention of long-term pulmonary, musculoskeletal, and other physical and mental consequences, in order to be clinically used. 2ff7e9595c
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