{"title":"Lessons Learned from Animal Models of Inherited Bleeding Disorders.","authors":"Timothy C Nichols","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Advances in treatment of hemophilia and von Willebrand disease (VWD) depend heavily on the availability of well-characterized animal models. These animals faithfully recapitulate the severe bleeding phenotype that occurs in humans with these inherited bleeding disorders. Research in these animal models represents important early and intermediate steps of translational research aimed at addressing current limitations in treatment such as the development of inhibitory antibodies to coagulation factors VIII and IX (FVIII, FIX) or von Willebrand factor (VWF), the life-long need for frequent venous access, the expense of therapy, and the ongoing need for improved ex vivo coagulation assays and in vivo methods for assessing hemostasis. The primary strengths of research that utilizes these highly relevant animal models include the development of better and safer treatments for hemophilia and VWD. Careful consideration of the strengths and limitations of the specific models is essential for optimizing chances for successful translation of advances to clinical medicine that benefits humans and animals.</p>","PeriodicalId":90175,"journal":{"name":"Hematology education. European Hematology Association. Congress. Education Program","volume":"8 1","pages":"39-46"},"PeriodicalIF":0.0,"publicationDate":"2014-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457463/pdf/nihms650889.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33369233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fabian Stavenuiter, Eveline A M Bouwens, Laurent O Mosnier
{"title":"Down-regulation of the clotting cascade by the protein C pathway.","authors":"Fabian Stavenuiter, Eveline A M Bouwens, Laurent O Mosnier","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The protein C pathway provides important biological activities to maintain the fluidity of the circulation, prevent thrombosis, and protect the integrity of the vasculature in response to injury. Activated protein C (APC), in concert with its cofactors and cell receptors, assembles in specific macromolecular complexes to provide efficient proteolysis of multiple substrates that result in anticoagulant and cytoprotective activities. Numerous studies on APC's structure-function relation with its cofactors, cell receptors, and substrates provide valuable insights into the molecular mechanisms and presumed assembly of the macromolecular complexes that are responsible for APC's activities. These insights allow for molecular engineering approaches specifically targeting the interaction of APC with one of its substrates or cofactors. Thus far, these approaches resulted in several anticoagulant-selective and cytoprotective-selective APC mutants, which provide unique insights into the relative contributions of APC's anticoagulant or cytoprotective activities to the beneficial effects of APC in various murine injury and disease models. Because of its multiple physiological and pharmacological activities, the anticoagulant and cytoprotective protein C pathway have important implications for the (patho)physiology of vascular disease and for translational research exploring novel therapeutic strategies to combat complex medical disorders such as thrombosis, inflammation, ischemic stroke and neurodegenerative disease.</p>","PeriodicalId":90175,"journal":{"name":"Hematology education. European Hematology Association. Congress. Education Program","volume":"7 1","pages":"365-374"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985519/pdf/nihms513449.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32270199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}