Characterization of high molecular weight plasma protein complexes induced by clotting factor rFXIII-treatment in the cynomolgus monkey

Journal of Thrombosis and Haemostasis : JTH
R Schaal-JensenM B Oleksiewicz


In cynomolgus monkeys, suprapharmacological doses of clotting recombinant factor XIII (rFXIII) cause a generalized coagulopathy, associated with formation of circulating high molecular weight protein complexes (HMEX). HMEX consist of plasma protein substrates cross-linked by FXIII transglutaminase activity. To characterize HMEX, with a view to develop safety biomarker assays. Cynomolgus monkeys received single i.v. injections with vehicle or rFXIII at 1, 3 and 10 mg kg(-1). Plasma HMEX were analyzed by sodium dodecylsulfate-polyacrylmide gel electrophoresis, silver staining, Western blotting and quantitative dissociation-enhanced lanthanide fluoroimmunoassay. Plasma FXIII antigen was analyzed by quantitative ELISA. Human HMEX were made in vitro, by spiking plasma with thrombin-activated rFXIII. Maximal circulating HMEX levels were reached within 1 h of rFXIII treatment, and remained stable over 24 h. HMEX above 250 kDa contained fibrinogen alpha-chains and fibronectin. Fibrinogen gamma-chain was detected only in HMEX below 250 kDa. The total plasma concentration of HMEX was in the low microg mL(-1) range, distributed on less than 20 main species. Human and cynomolgus HMEX were similar. HMEX formation increased with rFXIII dose ...Continue Reading


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Related Concepts

Blood Coagulation
Blood Coagulation Factor
Serum Proteins
Dose-Response Relationship, Drug
Factor XIII A-Chain
Macaca fascicularis
Proteins, Recombinant DNA

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