@article{De Franceschi_2009, title={PATHOPHISIOLOGY OF SICKLE CELL DISEASE AND NEW DRUGS FOR THE TREATMENT}, volume={1}, url={https://www.mjhid.org/mjhid/article/view/2009.024}, abstractNote={<p class="MsoBodyText2" style="margin: 0cm 0cm 0pt; text-indent: 20.25pt; text-align: left;" align="left"><span style="font-size: small;"><span style="line-height: 150%; mso-ansi-language: EN-US; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-family: Times New Roman;">A homozygous mutation in the gene for </span></span><span style="line-height: 150%; font-family: Symbol; mso-ansi-language: EN-US; mso-bidi-font-size: 12.0pt; mso-ascii-font-family: ’Times New Roman’; mso-hansi-font-family: ’Times New Roman’; mso-char-type: symbol; mso-symbol-font-family: Symbol;" lang="EN-US"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">b</span></span><span style="line-height: 150%; mso-ansi-language: EN-US; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-family: Times New Roman;"> globin, a subunit of adult hemoglobin A (HbA), is the proximate cause of sickle cell disease (SCD). Sickle hemoglobin (HbS) shows peculiar biochemical properties, which lead to polymerizing when deoxygenated.<span style="mso-spacerun: yes;">  </span>HbS polymerization is associated with a reduction in cell ion and water content (cell dehydration), increased red cell density which further accelerate HbS polymerization. Dense, dehydrated erythrocytes are likely to undergo instant polymerization in conditions of mild hypoxia due to their high HbS concentration, and<span style="mso-spacerun: yes;">  </span>HbS polymers may be formed under normal oxygen pressure.</span></span></span></p><p class="MsoNormal" style="margin: 0cm 0cm 0pt; line-height: 150%;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">Pathophysiological studies have shown that the dense, dehydrated red cells may play a central role in acute and chronic clinical manifestations of sickle cell disease, in which intravascular sickling in capillaries and small vessels leads to vaso-occlusion and impaired blood flow in a variety of organs and tissue. The persistent membrane damage associated with HbS polymerization also favors the generation of <span style="mso-spacerun: yes;"> </span>distorted rigid cells and further contributes to<span style="mso-spacerun: yes;">   </span>vaso-occlusive crisis (VOCs) and cell destruction in the peripheral circulation. These damaged, dense sickle red cells also show a loss of phospholipid asymmetry with externalization of phosphatidylserine (PS), which is believed to play a significant role in promoting macrophage recognition with removal of erythrocytes (erythrophagocytosis). Vaso-occlusive events in the microcirculation result from a complex scenario involving the interactions between different cell types, including dense, dehydrated sickle cells, reticulocytes, abnormally activated endothelial cells, leukocytes, platelets and plasma factors such as cytokine and oxidized pro-inflammatory lipids.</span></span></p><p class="MsoNormal" style="margin: 0cm 0cm 0pt; line-height: 150%;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">Hydroxycarbamide (hydroxyurea) is currently the only drug approved for chronic administration in adult patients with sickle cell disease to prevent acute painful crises and reduce the incidence of transfusion and acute chest crises.</span></span></p><p class="MsoBodyTextIndent" style="margin: 0cm 0cm 0pt; text-indent: 0cm;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">Here, we will focus on consolidated and experimental therapeutic strategies for the treatment of sickle cell disease, including:</span></span></p><p class="MsoBodyTextIndent" style="margin: 0cm 0cm 0pt 36pt; text-indent: -18pt; tab-stops: list 36.0pt; mso-list: l0 level1 lfo1;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: ’Times New Roman’;" lang="EN-US"><span style="mso-list: Ignore;"><span style="font-size: small;">a)</span><span style="font: 7pt ";Times New Roman";;">      </span></span></span><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">agents which reduce or prevent sickle cell dehydration</span></span></p><p class="MsoBodyTextIndent" style="margin: 0cm 0cm 0pt 36pt; text-indent: -18pt; tab-stops: list 36.0pt; mso-list: l0 level1 lfo1;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: ’Times New Roman’;" lang="EN-US"><span style="mso-list: Ignore;"><span style="font-size: small;">b)</span><span style="font: 7pt ";Times New Roman";;">      </span></span></span><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">agents which reduce sickle cell-endothelial adhesive events</span></span></p><p class="MsoBodyTextIndent" style="margin: 0cm 0cm 0pt 36pt; text-indent: -18pt; tab-stops: list 36.0pt; mso-list: l0 level1 lfo1;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: ’Times New Roman’;" lang="EN-US"><span style="mso-list: Ignore;"><span style="font-size: small;">c)</span><span style="font: 7pt ";Times New Roman";;">      </span></span></span><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">nitric oxide (NO) or NO-related compounds</span></span></p><p class="MsoBodyTextIndent" style="margin: 0cm 0cm 0pt 36pt; text-indent: -18pt; tab-stops: list 36.0pt; mso-list: l0 level1 lfo1;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: ’Times New Roman’;" lang="EN-US"><span style="mso-list: Ignore;"><span style="font-size: small;">d)</span><span style="font: 7pt ";Times New Roman";;">     </span></span></span><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">anti-oxidant agents</span></span></p><p class="MsoBodyTextIndent" style="margin: 0cm 0cm 0pt; text-indent: 0cm;"><span style="line-height: 150%; font-family: ";Times New Roman";,";serif";; mso-bidi-font-size: 12.0pt;" lang="EN-US"><span style="font-size: small;">Correction of<span style="mso-spacerun: yes;">  </span>the abnormalities ranging from membrane cation transport pathways to red cell-endothelial adhesive events, might constitute new pharmacological targets for treating sickle cell disease.</span></span></p><p class="MsoNormal" style="margin: 0cm 0cm 0pt;"><span lang="EN-US"><span style="font-size: small; font-family: Times;"> </span></span></p><p> </p>}, number={1}, journal={Mediterranean Journal of Hematology and Infectious Diseases}, author={De Franceschi, Lucia}, year={2009}, month={Dec.}, pages={e2009024} }