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Compared with the idealized isotropic coal seam, the effectively cracking distances of deep-hole pre-splitting blasting in different directions have significant difference in the structural anisotropy of coal seam. In this paper, based on the test results of coal mechanical parameters in different coring directions, the blasting crack distances in these coring directions of coal seam are theoretically calculated and analyzed, and then a new method of blasthole layout in coal seam is designed and the blasting crack effect is investigated according to the test data of gas drainage. The research results show that both compressive strength and tensile strength of the direction of perpendicular to bedding are larger than that in other directions, especially parallel to bedding. The blasting crack distances of calculation results are in great agreement with that of underground in-situ measurement, so the blasting crack zone caused by the differences of mechanical properties in different directions can be approximately treated as an ellipse. Comparing the conventional method of blasthole layout, the blasting crack effect with new method has greatly enhanced the methane concentration and gas drainage quantity. Pure methane quantities with the new method and conventional method are about 2.8 times and 1.67 times as large as that before blasting, and pure methane quantity with the new method is about 1.46 times that with the conventional method. Therefore, considering the anisotropic characteristics of coal seams, the reasonable blasthole layout plays an important role for enhancing gas drainage in low permeability and outburst working face.