Hepatocyte growth factor in serum after injection of unfractionated and low molecular weight heparin in healthy individuals C ARINA S EIDEL , 1 H ENRIK H JORTH -H ANSEN, 1 B JØRN B ENDZ , 2 MAGNE B ØRSET, 1 P ER MORTEN S ANDSET, 2 J OHN -B JARNE H ANSEN, 3 A NDERS S UNDAN 1 AND A NDERS WAAGE 41 Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, 2 Haematological Research Laboratory, Medical Clinic, Ulleva ˚l University Hospital, Oslo, 3 Institute of Clinical Medicine, University of Tromsø, Tromsø, and 4 Section of Haematology, University Hospital, Norwegian University of Science and Technology, Trondheim, Norway Received 9 November 1998; accepted for publication 15 February 1999 Summary. Soluble heparin displaces the cytokine hepatocyte growth factor (HGF) from heparan sulphate proteoglycans on the cell surface and in the extracellular matrix into the circulation. We examined serum HGF elevation after heparin injections, and whether there is a difference between unfractionated heparin (UH) and low molecular weight heparin (LMWH) in their ability to increase serum HGF. 20 healthy individuals were randomized to a single injection of intravenous or subcutaneous UH or LMWH. There was a significant increase in HGF from pretreatment values. This HGF was bioactive. When these preparations were compared on the basis of their serum concentrations (anti-factor Xa activity or molar concentrations), the increase in HGF was greater in individuals receiving UH than LMWH. When UH or LMWH were administered over a 5 d period, the increase in HGF, as well as the difference between treatments to induce HGF, remained stable throughout the treatment. In five patients treated with continuous intravenous heparin infu- sion HGF was increased throughout the treatment period of 5–7d. In summary, the rise in bioactive HGF after heparin treatment was stable during continued treatment. UH was more potent in inducing HGF increase than LMWH, both after a single injection and after several days of treatment. Keywords: hepatocyte growth factor, heparin, dalteparin, volunteers, serum. Hepatocyte growth factor (HGF) is a pleiotropic cytokine with mitogenic, motogenic and morphogenic effects on several cell types (Zarnegar & Michalopoulos, 1995). Of particular interest is the effect of HGF on bone (Grano et al, 1996; Fuller et al, 1995; Sato et al, 1995) and its ‘scatter’ activity, i.e. its ability to disperse coherently growing epithelial cells (Stoker et al, 1987). Because of its ability to cause blood vessel formation and to promote cell prolifera- tion, invasion and motility, HGF is proposed to be involved in the process of cancer growth and metastasis (Stoker et al, 1987; Bussolino et al, 1992; Bellusci et al, 1994). These diverse biological activities are a result of HGF binding to, and activating, its high affinity tyrosine kinase receptor c-met (Bottaro et al, 1991). In addition, HGF binds heparin and heparan sulphate proteoglycans (HSPGs), although with a 10-fold lower affinity (Zioncheck et al, 1995; Naka et al, 1993; Schwall et al, 1996). Soluble heparin molecules can bind and displace HGF from heparan sulphate proteoglycans on the cell surface (Naka et al, 1993; Zarnegar et al, 1990) and in the extracellular matrix. The two heparin preparations which are in clinical use: unfractionated heparin (UH) and low molecular weight heparin (LMWH), differ in several respects which could influence their ability to cause displacement of the molecule: Firstly, the mean molecular weight of UH is 12–15 kilodaltons (kD), whereas that of LMWH is 4–6 kD (Hirsh & Levine, 1992). These preparations also differ in their degree of sulphatation, which in addition to molecular size may influence their affinity to HGF (Lyon et al, 1994). Secondly, the heparin preparations differ in affinity to serum proteins and endothelial cells (Barzu et al, 1984; van Rijn et al, 1987; Young et al, 1992). Thirdly the elimination of British Journal of Haematology , 1999, 105, 641–647 641  1999 Blackwell Science Ltd Correspondence: Dr Carina Seidel, Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Medisinsk Teknisk Senter, N-7005 Trondheim, Norway.