A method for producing a protein having an antithrombotic activity, which comprises replacing, in a protein that has an amino acid sequence having a homology of not less than 30% to the amino acid sequence of SEQ ID NO: 1 and forms a higher order structure composed of a first .beta. strand (.beta.1), a first a helix (.alpha.1), a second .alpha. helix (.alpha.2), a second .beta. strand (.beta.2), a loop, a third .beta. strand (.beta.3), a fourth .beta. strand (.beta.4) and a fifth .beta. strand (.beta.5) in this order from the amino terminus, at least one amino acid residue in a region from .alpha.2 to .beta.2 and/or a region from .beta.3 to .beta.4 so that electric charge of the amino acid residue is changed towards positive direction.