title: Oversulfated heparin by-products induce thrombin generation in human plasmas through contact system activation.
abstract: Thrombin generation is thought to be mediated predominantly by the tissue factor or ''extrinsic'' coagulation pathway. An alternate pathway to thrombin generation (the ''intrinsic'' pathway or contact system) has been observed when blood or plasma comes in contact with artificial surfaces. Here we present evidence for a new route to thrombin formation that begins with the activation of the contact system protein prekallikrein by oversulfated heparin (OS-HB). Kallikrein, instead of activated factor X, cleaves prothrombin to form thrombin. Thrombin then cleaves fibrinogen to form fibrin clots. Moreover, we show that OS-HB by-products induce kallikrein- and thrombin-like activities in normal human plasma and in human plasma devoid of coagulation factor X or downstream contact system components factor IX or factor XI. Oversulfated heparin by-product-induced thrombin generation may have had a role in the adverse reactions associated with the recent clinical use of contaminated heparin.
authors.affiliation: Department of Pathology and Immunology, and Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.lastname: Yi Qian
authors.lastname: Jing Pan
authors.lastname: Xiaodong Zhou
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hourcade
authors.forename: M Kathryn
authors.initials: MK
authors.lastname: Liszewski
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.lastname: Hong Lu
authors.lastname: Lijuan Zhang
mesh_terms: D000707:Anaphylaxis / Q000097:blood / Q000139:chemically induced; D000925:Anticoagulants / Q000032:analysis / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D002809:Chondroitin Sulfates / Q000009:adverse effects / Q000032:analysis / Q000494:pharmacology*; D020147:Coagulation Protein Disorders / Q000097:blood; D004196:Disease Outbreaks; D004340:Drug Contamination; D004789:Enzyme Activation / Q000187:drug effects; D005340:Fibrinogen / Q000187:drug effects; D006493:Heparin / Q000032:analysis / Q000494:pharmacology*; D006801:Humans; D007610:Kallikreins / Q000097:blood; D010714:Phosphatidylethanolamines / Q000494:pharmacology; D011288:Prekallikrein / Q000187:drug effects / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D012822:Silicon Dioxide / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis*
chemical_list: D000925:Anticoagulants; D010714:Phosphatidylethanolamines; D012822:Silicon Dioxide; D011516:Prothrombin; D005340:Fibrinogen; D006493:Heparin; D002809:Chondroitin Sulfates; D011288:Prekallikrein; D007610:Kallikreins; D013917:Thrombin