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The signs and symptoms of loxoscelism are divided into cutaneous and systemic forms. The former is more frequent and includes signs of envenoming at the bite site or neighboring regions. Systemic loxoscelism, although much less frequent, is associated with complications, and can even lead to death. It may include intravascular hemolysis, acute renal failure, and thrombocytopenia. Loxosceles venoms are enriched with phospholipases D (PLDs), which are a family of isoforms found at intra-species and inter-species levels. Under experimental conditions, these enzymes reproduce the main clinical signs of loxoscelism, including an exacerbated inflammatory response at the bite site and dermonecrosis, as well as thrombocytopenia, intravascular hemolysis, and acute renal failure. The role of PLDs in cutaneous loxoscelism was described over forty years ago, when studies identified and purified toxins featured as sphingomyelinase D. More recently, the production of recombinant PLDs and discoveries about their structure and mechanism has enabled a deeper characterization of these enzymes. In this review, we describe these biochemical and functional features of Loxosceles PLDs that determine their involvement in systemic loxoscelism.<\/jats:p>","DOI":"10.3390\/toxins15010017","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T05:30:27Z","timestamp":1672205427000},"page":"17","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Systemic Loxoscelism, Less Frequent but More Deadly: The Involvement of Phospholipases D in the Pathophysiology of Envenomation"],"prefix":"10.3390","volume":"15","author":[{"given":"Luiza Helena","family":"Gremski","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81531-980, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna C\u00e2mara","family":"da Justa","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81531-980, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayanne Louise Costacurta","family":"Polli","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81531-980, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8454-7454","authenticated-orcid":false,"given":"Pedro Henrique de Caires","family":"Schluga","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81531-980, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Lucas","family":"Theodoro","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81531-980, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Carolina Martins","family":"Wille","sequence":"additional","affiliation":[{"name":"Department of Structural, Molecular Biology and Genetics, State University of Ponta Grossa (UEPG), Ponta Grossa 84030-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7967-6307","authenticated-orcid":false,"given":"Andrea","family":"Senff-Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81531-980, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio Sanches","family":"Veiga","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Federal University of Paran\u00e1 (UFPR), Curitiba 81531-980, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"ref_1","unstructured":"(2022, September 15). 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