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The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso\u2010occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (\n                    <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n                    ) depletion are involved in endothelial damage. New insights in\n                    <jats:styled-content style=\"fixed-case\">SCA<\/jats:styled-content>\n                    pathophysiology and vascular biology have shown that cell\u2010derived microparticle (\n                    <jats:styled-content style=\"fixed-case\">MP<\/jats:styled-content>\n                    ) generation is also involved in the vaso\u2010occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and\n                    <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n                    . New therapeutic interventions should address these aspects of\n                    <jats:styled-content style=\"fixed-case\">SCA<\/jats:styled-content>\n                    pathogenesis. To date, the only\n                    <jats:styled-content style=\"fixed-case\">US<\/jats:styled-content>\n                    \u2010\n                    <jats:styled-content style=\"fixed-case\">FDA<\/jats:styled-content>\n                    \u2010approved therapy to prevent painful vaso\u2010occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L\u2010glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on\n                    <jats:styled-content style=\"fixed-case\">SCA<\/jats:styled-content>\n                    .\n                  <\/jats:p>","DOI":"10.1111\/ejh.13212","type":"journal-article","created":{"date-parts":[[2019,1,21]],"date-time":"2019-01-21T09:20:01Z","timestamp":1548062401000},"page":"319-330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":111,"title":["Insight into the complex pathophysiology of sickle cell anaemia and possible treatment"],"prefix":"10.1111","volume":"102","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2645-8496","authenticated-orcid":false,"given":"Andrea","family":"Piccin","sequence":"first","affiliation":[{"name":"Department of Paediatric Haematology Our Lady's Children's Hospital Dublin Ireland"},{"name":"Internal Medicine V University of Medicine Innsbruck Austria"},{"name":"Transfusion Service San Maurizio Regional Hospital Bolzano Italy"},{"name":"Irish Blood Transfusion Service Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciaran","family":"Murphy","sequence":"additional","affiliation":[{"name":"Irish Blood Transfusion Service Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elva","family":"Eakins","sequence":"additional","affiliation":[{"name":"Irish Blood Transfusion Service Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Beatrice","family":"Rondinelli","sequence":"additional","affiliation":[{"name":"Transfusion Service Ao San Camillo Forlanini Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Daves","sequence":"additional","affiliation":[{"name":"Transfusion Service San Maurizio Regional Hospital Bolzano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Vecchiato","sequence":"additional","affiliation":[{"name":"Transfusion Service San Maurizio Regional Hospital Bolzano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Wolf","sequence":"additional","affiliation":[{"name":"Internal Medicine V University of Medicine Innsbruck Austria"},{"name":"Medical Clinic 3, Oncology, Hematology Immunoncology and Rheumatology, University Hospital Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrina","family":"Mc Mahon","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology Our Lady's Children's Hospital Dublin Ireland"},{"name":"University College Dublin (UCD) Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen P.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology Our Lady's Children's Hospital Dublin Ireland"},{"name":"University College Dublin (UCD) Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,2,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.06.036673"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025635118305"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03173886"},{"key":"e_1_2_6_5_1","volume-title":"The Causes of Evolution","author":"Haldane JBS","year":"1932"},{"key":"e_1_2_6_6_1","first-page":"68","article-title":"Disease and evolution","volume":"19","author":"Haldane JBS","year":"1949","journal-title":"Ricerca Sci"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(54)90101-7"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.4857.290"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0759"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.73.4.990"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(85)90175-5"},{"key":"e_1_2_6_12_1","unstructured":"DoverGJ PlattOS.Hematolology of Infancy and Childhood edited by Nathan and Oski'sSaunders 2003; (19) 790\u2010841."},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(82)90432-6"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.3109\/03630267709003417"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V70.5.1245.1245"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(75)90345-9"},{"issue":"9","key":"e_1_2_6_17_1","doi-asserted-by":"crossref","first-page":"3462","DOI":"10.1016\/S0021-9258(18)50782-1","article-title":"Deoxygenated sickle hemoglobin. 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