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Mechanism of the anticoagulant action of heparin

Summary

The anticoagulant effect of heparin, a sulfated glycosaminoglycan produced by mast cells, requires the participation of the plasma protease inhibitor antithrombin, also called heparin cofactor. Antithrombin inhibits coagulation proteases by forming equimolar, stable complexes with the enzymes. The formation of these complexes involves the attack by the enzyme of a specific Arg-Ser bond in the carboxy-terminal region of the inhibitor. The complexes so formed are not dissociated by denaturing solvents, which indicates that a covalent bond may contribute to their stability. This bond may be an acyl bond between the active-site serine of the enzyme and the arginine of the cleaved reactive bond of the inhibitor. However, the native complexes dissociate slowly at near-neutral pH into free enzyme and a modified inhibitor, cleaved at the reactive bond. So, antithrombin apparently functions as a pseudo-substrate that traps the enzyme in a kinetically stable complex.

The reactions between antithrombin and coagulation proteases are slow in the absence of heparin. However, optimal amounts of heparin accelerate these reactions up to 2 000-fold, thereby efficiently preventing the formation of fibrin in blood. The accelerating effect, and thus the anticoagulant activity, is shown by only about one-third of the molecules in all heparin preparations, while the remaining molecules are almost inactive. The highly active molecules bind tightly to antithrombin, i.e. with a binding constant of slightly below 108 M−1 at physiological ionic strength, while the relatively inactive molecules bind about a thousand-fold more weakly. The binding of the high-affinity heparin to antithrombin is accompanied by a conformational change in the inhibitor that is detectable by spectroscopic and kinetic methods. This conformational change follows an initial, weak binding of heparin to antithrombin and causes the tight interaction between polysaccharide and inhibitor that is prerequisite to heparin anticoagulant activity. It has also been postulated that the conformational change leads to a more favourable exposure of the reactive site of antithrombin, thereby allowing the rapid interaction with the proteases.

Heparin also binds to the coagulation proteases. Recent studies indicate that this binding is weaker and less specific that the binding to antithrombin. Nevertheless, for some enzymes, thrombin, Factor IXa and Factor XIa, an interaction between heparin and the protease, in addition to that between the polysaccharide and antithrombin; apparently is involved in the accelerated inhibition of the enzymes. The effect of this interaction may be to approximate enzyme with inhibitor in an appropriate manner. However, the bulk of the evidence available indicates that binding of heparin to the protease alone cannot be responsible for the accelerating effect of the polysaccharide on the antithrombin-protease reaction.

Heparin acts as a catalyst in the antithrombin-protease reaction, i.e. it accelerates the reaction in non-stoichiometric amounts and is not consumed during the reaction. This ability can be explained by heparin being released from the antithrombin-protease complex for renewed binding to antithrombin, once the complex has been formed. Such a decresed affinity of heparin for the antithrombin complex, compared to the affinity for antithrombin alone, has been demonstrated.

The structure of the antithrombin-binding region in heparin has been investigated following the isolation of oligosaccharides with high affinity for antithrombin. The smallest such oligosaccharide, an octasaccharide, obtained after partial random depolymerization of heparin with nitrous acid, was found to contain a unique glucosamine-3-O-sulfate group, which could not be detected in other portions of the high affinity heparin molecule and which was absent in heparin with low affinity for antithrombin. The actual antithrombin-binding region within this octasaccharide molecule has been identified as a pentasaccharide sequence with he predominant structure: →N-acetyl-D-glucosamine(6-O-SO3)→D-glucoronic acid→D-glucosamine(N-SO3;3,6-di-O-SO3)→L-iduronic acid(2-O-SO3)→D-glucosamine(N-SO3;6-O-SO3). In addition to the 3-O-sulfate group, both N-sulfate groups as well as the 6-O-sulfate group of the N-acetylated glucosamine unit appear to be essential for the interaction with antithrombin. The remarkably constant structure of this sequence, as compared to other regions of the heparin molecule, suggests a strictly regulated mechanism of biosynthesis.

The ability of heparin to potentiate the inhibition of blood coagulation by antithrombin generally decreases with decreasing molecular weight of the polysaccharide. However, individual coagulation enzymes differ markedly with regard to this molecular-weight dependence. Oligosaccharides in the extreme low-molecular weight range, i.e. octa- to dodecasaccharides, with high affinity for antithrombin have high anti-Factor Xa-activity but are virtually unable to potentiate the inhibition of thrombin. Furthermore, such oligosaccharides are ineffective in preventing experimentally induced venous thrombosis in rabbits. Slightly larger oligosaccharides, containing 16 to 18 monosaccharide residues, show significant anti-thrombin as well as antithrombotic activities, yet have little effect on overall blood coagulation. These findings indicate that the affinity of a heparin fragment for antithrombin is not in itself a measure of the ability to prevent venous thrombo-genesis, and that the anti-Factor Xa activity of heparin is only a partial expression of its therapeutic potential as an antithrombotic agent.

The biological role of the interaction between heparin and antithrombin is unclear. In addition to a possible function in the regulation of hemostasis, endogenous heparin may serve as a regulator of extravascular serine proteinases. Mouse peritoneal macrophages have been found to synthesize all the enzymes that constitute the extrinsic pathway of coagulation. Moreover, tissue thromboplastin is produced by these cells in response to a functional interaction with activated T-lymphocytes. The inhibition of this extravascular coagulation system by heparin, released from mast cells, may be potentially important in modulating inflammatory reactions.

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References

  1. 1.

    McLean, J., 1916. Am. J. Physiol. 41: 250–257.

  2. 2.

    Howell, W. H. and Holt, E., 1918. Am. J. Physiol. 47: 328–341.

  3. 3.

    Charles, A. F. and Scott, D. A., 1933. J. Biol. Chem. 102: 431–435.

  4. 4.

    Yosisawa, Z., 1964. Biochim. Biophys. Res. Commun. 16: 336–341.

  5. 5.

    Horner, A. A., 1977. Fed. Proc. 36: 35–39.

  6. 6.

    Toledo, O. M. S. and Dietrich, C. P., 1977. Biochim. Biophys. Acta 498: 114–122.

  7. 7.

    Frommhagen, L. H., Fahrenbach, M. M., Brockman, J. B., Jr. and Stokstad, E. L. R., 1953. Proc. Soc. Exp. Biol. Med. 82: 280–283.

  8. 8.

    Cássaro, C. M. F. and Dietrich, C. P., 1977. J. Biol. Chem. 252: 2254–2261.

  9. 9.

    Jorpes, E., Holmgren, H. and Wilander, O., 1937. Zeitschr. Mikr.-Anat. Forsch. 42: 279–301.

  10. 10.

    Schiller, S. and Dorfman, A., 1959. Biochim. Biophys. Acta 31: 278–280.

  11. 11.

    Yurt, R. W., Leid, R. W., Jr., Austen, K. F. and Silbert, J. E., 1977. J. Biol. Chem. 252: 518–521.

  12. 12.

    Berlin, G. and Enerbäck, L., 1978. J. Histochem. & Cytochem. 26: 14–21.

  13. 13.

    Jaques, L. B. and Waters, E. T., 1941. J. Physiol. 99: 454–466.

  14. 14.

    Jacobsson, K.-G. and Lindahl, U., 1979. Thromb. Haemostas. 42: 84.

  15. 15.

    Howell, W. H., 1925. Am. J. Physiol. 71: 553–562.

  16. 16.

    Quick, A. J., 1938. Am. J. Physiol. 123: 712–719.

  17. 17.

    Brinkhous, K. M., Smith, H. P., Warner, E. D. and Seegers, W. H., 1939. Am. J. Physiol. 125: 683–687.

  18. 18.

    Seegers, W. H., Johnson, J. F. and Fall, C., 1954. Am. J. Physiol. 176: 97–103.

  19. 19.

    Monkhouse, F. C., France, E. S. and Seegers, W. H., 1955. Circ. Res. 3: 397–402.

  20. 20.

    Waugh, D. F. and Fitzgerald, M. A., 1956. Am. J. Physiol. 184: 627–638.

  21. 21.

    Blombäck, B., Blombäck, M. and Olsson, P., 1963. Thromb. Diath. Haemorrh. 9: 368–386.

  22. 22.

    Abildgaard, U., 1968. Scand. J. Clin. Lab. Invest. 21: 89–91.

  23. 23.

    Rosenberg, R. D. and Damus, P. S., 1973. J. Biol. Chem. 248: 6490–6505.

  24. 24.

    Rosenberg, R. D., 1977. Fed. Proc. 36: 10–18.

  25. 25.

    Barrowcliffe, T. W., Johnson, E. A. and Thomas, D., 1978. Br. Med. Bull. 34: 143–150.

  26. 26.

    Comper, W. D., 1981. Heparin (and Related Polysaccharides), Gordon & Breach, New York.

  27. 27.

    Jackson, C. M. and Nemerson, Y., 1980. Ann. Rev. Biochem. 49: 767–811.

  28. 28.

    Abildgaard, U., 1967. Scand. J. Clin. Lab. Invest. 19: 190–195.

  29. 29.

    Lane, J. L., Bird, P. and Rizza, C. R., 1975. Br. J. Haematol. 30: 103–115.

  30. 30.

    Abildgaard, U., 1979. In: The Physiological Inhibitors of Blood Coagulation and Fibrinolysis (Collen, D., Wiman, B. and Verstraete, M., eds.), pp. 31–33, Elsevier/North-Holland, Amsterdam.

  31. 31.

    Tollefsen, D. M. and Blank, M. K., 1981. J. Clin. Invest. 68: 589–596.

  32. 32.

    Yin, E. T., Wessler, S. and Stoll, P. J., 1971. J. Biol. Chem. 246: 3712–3719.

  33. 33.

    Damus, P. S., Hicks, M. and Rosenberg, R. D., 1973. Nature (London) 246: 355–357.

  34. 34.

    Rosenberg, J. S., McKenna, P. W. and Rosenberg, R. D., 1975. J. Biol. Chem. 250: 8883–8888.

  35. 35.

    Kurachi, K., Fujikawa, K., Schmer, G. and Davie, E. W., 1976. Biochemistry 15: 373–377.

  36. 36.

    Stead, N., Kaplan, A. and Rosenberg, R. D., 1976. J. Biol. Chem. 251: 6481–6488.

  37. 37.

    Highsmith, R. F. and Rosenberg, R. D., 1974. J. Biol. Chem. 249: 4335–4338.

  38. 38.

    Mahoney, W. C., Kurachi, K. and Hermodson, M. A., 1980. Eur. J. Biochem. 105: 545–552.

  39. 39.

    Jesty, J., 1978. Arch. Biochem. Biophys. 185: 165–173.

  40. 40.

    Marciniak, E., 1973. Br. J. Haematol. 24: 391–400.

  41. 41.

    Miletich, J. P., Jackson, C. M. and Majerus, P. W., 1978. J. Biol. Chem. 253: 6908–6913.

  42. 42.

    Miller-Andersson, M., Borg, H. and Andersson, L.-O., 1974. Thromb. Res. 5: 439–452.

  43. 43.

    Kurachi, K., Schmer, G., Hermodson, M. A., Teller, D. C. and Davie, E. W., 1976. Biochemistry 15: 368–373.

  44. 44.

    Nordenman, B., Nyström, C. and Björk, I., 1977. Eur. J. Biochem. 78: 195–203.

  45. 45.

    Furugren, B., Andersson, L.-O. and Einarsson, R., 1977. Arch. Biochem. Biophys. 178: 419–424.

  46. 46.

    Koide, T., 1979. J. Biochem. 86: 1841–1850.

  47. 47.

    Collen, D., Schetz, J., deCock, F., Holmer, E. and Verstraete, M., 1977. Eur. J. Clin. Invest. 7: 27–35.

  48. 48.

    Murano, G., Williams, L., Miller-Andersson, M., Aronson, D. L. and King, C., 1980. Thromb. Res. 18: 259–262.

  49. 49.

    Petersen, T. E., Dude k-Wosciechowska, G., Sottrup-Jensen, L. and Magnusson, S., 1979. In: The Physiological Inhibitors of Blood Coagulation and Fibrinolysis (Collen, D., Wiman, B. and Verstraete, M., eds.) pp. 43–54, Elsevier/North-Holland, Amsterdam.

  50. 50.

    Franzén, L. E., Svensson, S. and Larm, O., 1980. J. Biol. Chem. 255: 5090–5093.

  51. 51.

    Mizuochi, T., Fujii, J., Kurachi, K. and Kobata, A., 1980. Arch. Biochem. Biophys. 203: 458–465.

  52. 52.

    Carrell, R. W., Boswell, D. R., Brennan, S. O. and Owen, M. C., 1980. Biochem. Biophys. Res. Commun. 93: 399–402.

  53. 53.

    Hunt, L. T. and Dayhoff, M. O., 1980. Biochem. Biophys. Res. Commun. 95: 864–871.

  54. 54.

    Lindahl, U., 1976. In: MTP International Reviews of Science; Organic Chemistry, Series Two — Carbohydrate Chemistry (Aspinall, G. O., ed) Vol. 7, pp. 283–312, Butterworths, London.

  55. 55.

    Lindahl, U. and Höök, M., 1978. Ann. Rev. Biochem. 47: 385–417.

  56. 56.

    Rodén, L., 1980. In: The Biochemistry of Glycoproteins and Proteoglycans (Lennartz, W. J., ed.) pp. 267–371, Plenum, New York.

  57. 57.

    Lindahl, U., Höök, M., Bäckström, G., Jacobsson, I., Riesenfeld, J., Malmström, A., Rodén, L. and Feingold, D. S., 1977. Fed. Proc. 36: 19–24.

  58. 58.

    Jacobsson, I. and Lindahl, U., 1980. J. Biol. Chem. 255: 5094–5100.

  59. 59.

    Riesenfeld, J., Höök, M. and Lindahl, U., 1980. J. Biol. Chem. 255: 922–928.

  60. 60.

    Feingold, D. S., Rodén, L., Forsee, T., Jacobsson, I., Jensen, J., Lindahl, U., Malmström, A. and Prihar, H., 1981. In: Biology of Heparin (Lundblad, R. L., Brown, W. V., Mann, K.G. and Roberts, H.R., eds.) pp. 157–171, Elsevier/North-Holland, New York.

  61. 61.

    Robinson, H. C., Horner, A. A., Höök, M., Ögren, S. and Lindahl, U., 1978. J. Biol. Chem. 253: 6687–6693.

  62. 62.

    Ögren, S. and Lindahl, U., 1971. Biochem. J. 125: 1119–1129.

  63. 63.

    Horner, A. A., 1972. Proc. Natl. Acad. Sci. U.S.A. 69: 3469–3473.

  64. 64.

    Ögren, S. and Lindahl, U., 1975. J. Biol. Chem. 250: 2690–2697.

  65. 65.

    Young, E. and Horner, A. A., 1979. Biochem. J. 180: 587–596.

  66. 66.

    Horner, A. A. and Young, E., 1979. In: Glycoconjugates; Proceedings of the Fifth International Symposium (Schauer, R., Boer, P., Buddecke, E., Kramer, M. F., Vliegenthart, J. F. G. and Wiegandt, H., eds.) pp. 63–64, Thieme, Stuttgart.

  67. 67.

    Örgen, S. and Lindahl, U., 1976. Biochem. J. 154: 605–611.

  68. 68.

    Jesty, J., 1979. J. Biol. Chem. 254: 10044–10050.

  69. 69.

    Feinman, R. D., 1979. In: The Physiological Inhibitors of Blood Coagulation and Fibrinolysis (Collen, D., Wiman, B. and Verstraete, M., eds.) pp. 55–66, Elsevier/North-Holland, Amsterdam.

  70. 70.

    Danielsson, Å. and Björk, I., 1982. Biochem. J., (in press).

  71. 71.

    Villanueva, G. B. and Danishefsky, I., 1979. Biochemistry 18: 810–817.

  72. 72.

    Owen, W. G., 1975. Biochim. Biophys. Acta 405: 380–387.

  73. 73.

    Jesty, J., 1979. J. Biol. Chem. 254: 1044–1049.

  74. 74.

    Fish, W. W. and Björk, I., 1979. Eur. J. Biochem. 101: 31–38.

  75. 75.

    Longas, M. O. and Finlay, T. H., 1980. Biochem. J., 189: 481–489.

  76. 76.

    Björk, I., Jackson, C. M., Jörnvall, H., Lavine, K. K., Nordling, K. and Salsgiver, W. J., 1982. J. Biol. Chem. 257: 2406–2411.

  77. 77.

    Björk, I., Danielsson, Å., Fenton, J. W., II, and Jörnvall, H., 1981. FEBS Lett. 126: 257–260.

  78. 78.

    Jörnvall, H., Fish, W. W. and Björk, I., 1979. FEBS Lett. 106: 358–362.

  79. 79.

    Griffith, M. J. and Lundblad, R. L., 1981. Biochemistry 20: 105–110.

  80. 80.

    Danielsson, A. and Björk, I., 1980. FEBS Lett. 119: 241–244.

  81. 81.

    Stroud, R. M., Krieger, M., Koeppe, R. E., II, Kossiakoff, A. A. and Chambers, J. L., 1975. In: Proteases and Biological Control (Reich, E., Rifkin, D. B. and Shaw, E., eds.) Cold Spring Harbor Conference on Cell Proliferation, Vol. 2, pp. 13–32, Cold Spring Harbor Laboratory, Cold Spring Harbor.

  82. 82.

    Walsh, C., 1979. Ezymatic Reaction Mechanisms. pp. 67–71, 94–97, Freeman, San Francisco.

  83. 83.

    Wallgren, P., Nordling, K. and Björk, I., 1981. Eur. J. Biochem. 116: 493–496.

  84. 84.

    Fish, W. W., Orre, K. and Björk, I., 1979. FEBS Lett. 98: 103–106.

  85. 85.

    Björk, I. and Fish, W.W., 1982. J. Biol. Chem. (in press).

  86. 86.

    Villanueva, G. B. and Danishefsky, I., 1977. Biochem. Biophys. Res. Commun. 74: 803–809.

  87. 87.

    Einarsson, R. and Andersson, L.-O., 1977. Biochim. Biophys. Acta 490: 104–111.

  88. 88.

    Einarsson, R., 1976. Biochim. Biophys. Acta 446: 124–133.

  89. 89.

    Piepkorn, M. W., Lagunoff, D. and Schmer, G., 1978. Biochem. Biophys. Res. Commun. 85: 851–856.

  90. 90.

    Piepkorn, M. W., Lagunoff, D. and Schmer, G., 1980. Arch. Biochem. Biophys. 205: 315–322.

  91. 91.

    Markwardt, F. and Walsman, P., 1959. Hoppe-Seylers Z. Physiol. Chem. 317: 64–77.

  92. 92.

    Gitel, S. N., 1975. In: Heparin. Structure, Function and Clinical Implications (Bradshaw, R. Å. and Wessler, S., eds.) pp. 243–247, Plenum Press, New York.

  93. 93.

    Björk, I. and Nordenman, B., 1976. Eur. J. Biochem. 68: 507–511.

  94. 94.

    Kowalski, S. and Finlay, T. H., 1979. Thromb. Res. 14: 387–397.

  95. 95.

    Carlström, A.-S., Liedén, K. and Björk, I., 1977. Thromb. Res. 11: 785–797.

  96. 96.

    Andersson, L.-O., Engman, L. and Henningsson, E., 1977. J. Immunol. Methods 14: 271–281.

  97. 97.

    Jordan, R., Beeler, D. and Rosenberg, R. D., 1979. J. Biol. Chem. 254: 2902–2913.

  98. 98.

    Lam, L. H., Silbert, J. E. and Rosenberg, R. D., 1976. Biochem. Biophys. Res. Commun. 69: 570–577.

  99. 99.

    Höök, M., Björk, I., Hopwood, J. and Lindahl, U., 1976. FEBS Lett. 66: 90–93.

  100. 100.

    Andersson, L.-O., Barrowcliffe, T. W., Holmer, E., Johnson, E. A. and Sims, G. E. C., 1976. Thromb. Res. 9: 575–583.

  101. 101.

    Nordenman, B. and Björk, I., 1978. Biochemistry 17: 3339–3344.

  102. 102.

    Nordenman, B., Danielsson, Å. and Björk, I., 1978. Eur. J. Biochem. 90: 1–6.

  103. 103.

    Danielsson, Å. and Björk, I., 1978. Eur. J. Biochem. 90: 7–12.

  104. 104.

    Rosenberg, R. D., Jordan, R. E., Favreau, L. V. and Lam, L. H., 1979. Biochem. Biophys. Res. Commun. 86: 1319–1324.

  105. 105.

    Danielsson, Å. and Björk, I., 1981. Biochem. J. 193: 427–433.

  106. 106.

    Radoff, S. and Danishefsky, I., 1981. Thromb. Res. 22: 353–365.

  107. 107.

    Nordenman, B. and Björk, I., 1981. Biochim. Biophys. Acta 672: 227–238.

  108. 108.

    Björk, I. and Nordling, K., 1980. Eur. J. Biochem. 102: 497–502.

  109. 109.

    Blackburn, M. N. and Sibley, C. C., 1980. J. Biol. Chem. 255: 824–826.

  110. 110.

    Villanueva, G. B., Perret, V. and Danishefsky, I., 1980. Arch. Biochem. Biophys. 203: 453–457.

  111. 111.

    Longas, M. O., Ferguson, W. S. and Finlay, T. H., 1980. J. Biol. Chem. 255: 3436–3441.

  112. 112.

    Finlay, T. H. and Ferguson, W. S., 1981. Thromb. Haemostas. 46: 81

  113. 113.

    Olson, S. T. and Shore, J. D., 1981. J. Biol. Chem. 256: 11065–11072.

  114. 114.

    Olson, S. T., Srinivasan, K. R., Björk, I. and Shore, J. D., 1981. J. Biol. Chem. 256: 11073–11079.

  115. 115.

    Rosenberg, R. D., Armand, G. and Lam, L., 1978. Proc. Natl. Acad. Sci. U.S.A. 75: 3065–3069.

  116. 116.

    Lindahl, U., Bäckström, G., Höök, M., Thunberg, L., Fransson, L.-Å. and Linker, A., 1979. Proc. Natl. Acad. Sci. U.S.A. 76: 3198–3202.

  117. 117.

    Rosenberg, R. D. and Lam, L., 1979. Proc. Natl. Acad. Sci. U.S.A. 76: 1218–1222.

  118. 118.

    Hopwood, J., Höök, M., Linker, Å. and Lindahl, U., 1976. FEBS Lett. 69: 51–54.

  119. 119.

    Thunberg, L., Bäckström, G., Grundberg, H., Riesenfeld, J. and Lindahl, U., 1980. FEBS Lett. 117: 203–206.

  120. 120.

    Ototani, N. and Yosisawa, Z., 1981. J. Biochem. 90: 1553–1556.

  121. 121.

    Casu, B., Oreste, P., Torri, G., Zopetti, G., Choay, J., Lormeau, J.-C. and Petitou, 1981. Biochem. J. 197: 599–609.

  122. 122.

    Choay, J., Lormeau, J.-C., Petitou, M., Sinaÿ, P., Casu, B., Oreste, P., Torri, G. and Gatti, G., 1980. Thromb. Res. 18: 573–578.

  123. 123.

    Leder, I. G., 1980. Biochem. Biophys. Res. Commun. 94: 1183–1189.

  124. 124.

    Lindahl, U., Bäckström, G., Thunberg, L. and Leder, I. G., 1980. Proc. Natl. Acad. Sci. U.S.A. 77: 6551–6555.

  125. 125.

    Meyer, B., Thunberg, L., Lindahl, U., Larm, O. and Leder, I. G., 1981. Carbohyd. Res. 88: C1-C4.

  126. 126.

    Riesenfeld, J., Thunberg, L., Höök, M. and Lindahl, U., 1981. J. Biol. Chem. 256: 2389–2394.

  127. 127.

    Thunberg, L., Bäckström, G. and Lindahl, U., 1982. Carbohyd. Res. 100: 393–410.

  128. 128.

    Gentry, P. W. and Alexander, B., 1973. Biochem. Biophys. Res. Commun. 50: 500–509.

  129. 129.

    Machovich, R., Blásko, G. and Pálos, L. A., 1975. Biochim. Biophys. Acta 379: 193–200.

  130. 130.

    Danishefsky, I., Tzeng, F., Ahrens, M. and Klein, S., 1976. Thromb. Res. 8: 131–140.

  131. 131.

    Nordenman, B. and Björk, I., 1977. Thromb. Res. 11: 799–808.

  132. 132.

    Nordenman, B. and Björk, I., 1978. Thromb. Res. 12: 755–765.

  133. 133.

    Holmer, E., Söderström, G. and Andersson, L.-O., 1979. Eur. J. Biochem. 93: 1–5.

  134. 134.

    Longas, M. O., Ferguson, W. S. and Finlay, T. H., 1980. Arch. Biochem. Biophys. 200: 595–602.

  135. 135.

    Griffith, M. J., Kingdon, H. S. and Lundblad, R. L., 1978. Biochem. Biophys. Res. Commun. 83: 1198–1205.

  136. 136.

    Nordenman, B. and Björk, I., 1980. Thromb. Res. 19: 711–718.

  137. 137.

    Li, E. H. H., Orton, C. and Feinman, R. D., 1974. Biochemistry 13: 5012–5017.

  138. 138.

    Griffith, M. J., Kingdon, H. S. and Lundblad, R. L., 1979. Arch. Biochem. Biophys. 195: 378–384.

  139. 139.

    Smith, G. F. and Sundboom, J. L., 1981. Thromb. Res. 22: 103–114.

  140. 140.

    Smith, G. F., 1977. Biochem. Biophys. Res. Commun. 77: 111–117.

  141. 141.

    Hatton, M. W. C. and Regoeczi, E., 1977. Thromb. Res. 10: 645–660.

  142. 142.

    Bartl, K., 1978. Thromb. Res. 13: 1141–1142.

  143. 143.

    Griffith, M. J., Kingdon, H. S. and Lundblad, R. L., 1979. Biochem. Biophys. Res. Commun. 87: 686–692.

  144. 144.

    Jordan, R. E., Oosta, G. M., Gardner, W. T. and Rosenberg, R. D., 1980. J. Biol. Chem. 255: 10073–10080.

  145. 145.

    Smith, G. F. and Craft, T. J., 1976. Biochem. Biophys. Res. Commun. 71: 738–745.

  146. 146.

    Stürzebecher, J. and Markwardt, F., 1977. Thromb. Res. 11: 835–846.

  147. 147.

    Griffith, M. J., 1979. J. Biol. Chem. 254: 3401–3406.

  148. 148.

    Laurent, T. C., Tengblad, A., Thunberg, L., Höök, M. and Lindahl, U., 1978. Biochem. J. 175: 691–701.

  149. 149.

    Pomerantz, M. W. and Owen, W. G., 1978. Biochim. Biophys. Acta 535: 66–77.

  150. 150.

    Machovich, R. and Arányi, P., 1978. Biochem. J. 173: 869–875.

  151. 151.

    Li, E. H. H., Fenton, J. W., II, and Feinman, R., 1976. Arch. Biochem. Biophys. 175: 153–159.

  152. 152.

    Jordan, R. E., Oosta, G. M., Gardner, W. T. and Rosenberg, R. D., 1980. J. Biol. Chem. 255: 10081–10090.

  153. 153.

    Machovich, R., 1975. Biochim. Biophys. Acta 412: 13–17.

  154. 154.

    Machovich, R., Staub, M. and Patthy, L., 1978. Eur. J. Biochem. 83: 473–477.

  155. 155.

    Machovich, R., Regoeczi, E. and Hatton, M. W. C., 1980. Thromb. Res. 17: 383–391.

  156. 156.

    Oosta, G. M., Gardner, W. T., Beeler, D. L. and Rosenberg, R. D., 1981. Proc. Natl. Acad. Sci. U.S.A. 78: 829–833.

  157. 157.

    Holmer, E., Lindahl, U., Bäckström, G., Thunberg, L., Sandberg, H., Söderström, G. and Andersson, L.-O., 1980. Thromb. Res. 18: 861–869.

  158. 158.

    Thunberg, L., Lindahl, U., Tengblad, A., Laurent, T. C. and Jackson, C. M., 1979. Biochem. J. 181: 241–243.

  159. 159.

    Holmer, E., Kurachi, K. and Söderström, G., 1981. Biochem. J. 193: 395–400.

  160. 160.

    Yin, E. T., Wessler, S. and Stoll, P. J., 1971. J. Biol. Chem. 246: 3703–3711.

  161. 161.

    Kakkar, V. V., Field, E. S., Nicolaides, A. N., Flute, P. T., Wessler, S. and Yin, E. T., 1971. Lancet 2: 669–671.

  162. 162.

    Wessler, S., 1974. Thromb. Diathes. Haemorrh. 33: 81–86.

  163. 163.

    Gitel, S. N., Stephenson, R. C. and Wessler, S., 1977. Proc. Natl. Acad. Sci. U.S.A. 74: 3028–3032.

  164. 164.

    Thomas, D. P., Merton, R. E., Lewis, W. E. and Barrowcliffe, T. W., 1981. Thromb. Haemostas. 45: 214–218.

  165. 165.

    Carter, C. J., Kelton, J. G., Hirsch, J. and Gent, M., 1981. Thromb. Res. 21: 169–174.

  166. 166.

    Thomas, D. P., Barrowcliffe, T. W., Lindahl, U., Thunberg, L., Merton, R. E., Hiller, K. F. and Eggleton, C. A., 1981. Thromb. Haemostas 46: 185.

  167. 167.

    Holmer, E., Mattsson, C., Nilsson, S., Söderström, G. and Svahn, C.-M., 1981. Thromb. Haemostas. 46: 117.

  168. 168.

    Glimelius, B., Busch, C. and Höök, M., 1978. Thromb. Res. 12: 773–782.

  169. 169.

    Höök, M., Lindahl, U., Hallén, Å. and Bäckström, G., 1975. J. Biol. Chem. 250: 6065–6071.

  170. 170.

    Thunberg, L., Bäckström, G., Wasteson, Å. Robinson, H. C., Ögren, S. and Lindahl, U., 1982. J. Biol. Chem., (in press).

  171. 171.

    Seljelid, R., Bäckström, G. and Lindahl, U., 1980. Exp. Cell. Res. 129: 478–481.

  172. 172.

    Østerud, B., Lindahl, U. and Seljelid, R., 1980. FEBS Lett. 120: 41–43.

  173. 173.

    Østerud, B., Bögwald, J., Lindahl, U. and Seljelid, R., 1981. FEBS Lett. 127: 154–156.

  174. 174.

    Levy, G. A. and Edgington, T. S., 1980. J. Exp. Med. 151: 1232–1244.

  175. 175.

    Geczy, C. L. and Hopper, K. E., 1981. J. Immunol. 126: 1059–1065.

  176. 176.

    Lindahl, U., Kolset, S.O., Bögwald, J., Østerud, B. and Seljelid, R., 1982. Biochem. j., (in press).

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Björk, I., Lindahl, U. Mechanism of the anticoagulant action of heparin. Mol Cell Biochem 48, 161–182 (1982). https://doi.org/10.1007/BF00421226

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Keywords

  • Heparin
  • Oligosaccharide
  • Antithrombin
  • Sulfated Glycosaminoglycan
  • Reactive Bond