Download PDF
Thromb Haemost 2003; 89(01): 9-12
DOI: 10.1055/s-0037-1613536
Review Article
Schattauer GmbH

Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation

Michael W. Mosesson
1   The Blood Research Institute of the Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin, USA
› Author Affiliations
Further Information

Publication History

Received 24 September 2002

Accepted after revision 01 November 2002

Publication Date:
09 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Thrombin substrate binding is mediated through fibrinogen recognition “exosite 1” in thrombin, resulting in fibrinopeptide cleavage to form fibrin. In addition, thrombin exhibits “non-substrate” binding to fibrin, an activity termed “Antithrombin I”. Antithrombin I (AT-I) is characterized by two classes of throm-bin binding sites, the first of “low affinity” in the fibrin E domain, and the other of high affinity, that is situated between C-terminal residues 414 and 427 of a variant γ chain termed γ’ 1-427L. Plasma fibrinogen molecules containing γ ’ chains (“fibrino-gen 2”) are virtually all heterodimers containing one γA chain (platelet-binding) and one γ’ chain. The remaining fibrinogen (~ 85%) is homodimeric, lacks high affinity thrombin-binding potential, and is termed “fibrinogen 1” (γA/γA). Thrombin generation in recalcified fibrinogen-depleted or congenital afibrinogenemic plasma is increased. Repletion with fibrino-gen 1 has a modest effect in normalizing thrombin generation, whereas repletion with fibrinogen 2 (γA/γ’) has a more marked effect. A post-translational γ’ chain derivative, γ’ 1-423P, accounts for 3%-34% of the γ’ chain population, lacks thrombin binding potential, and arises by proteolytic processing at the expense of γ’ 1-427L chains. Little is known about its effect on plasma AT-I activity under normal or pathological circumstances. In summary, fibrin formation (Antithrombin I) inhibits throm-bin generation in clotting blood by sequestering thrombin, and “high-affinity” thrombin-binding (i.e., via γ’ chains) plays a dominant role in this process. AT-1 should be considered when assessing the pathogenesis of thromboembolic disease.

Keywords

Fibrin - thrombin - antithrombin - thrombin inhibition
 

  • References

  • 1 Fenton II JW, Olson TA, Zabinski MP, Wilner GD. Anion-binding exosite of human α-thrombin and fibrin(ogen) recognition. Biochemistry 1988; 27: 7106-12.
    CrossrefPubMedGoogle Scholar
  • 2 Stubbs MT, Bode W. A player of many parts: The spotlight falls on thrombin’s structure. Thromb Res 1993; 69: 1-58.
    CrossrefPubMedGoogle Scholar
  • 3 Seegers WH, Nieft M, Loomis EC. Note on the adsorption of thrombin on fibrin. Science 1945; 101: 520-1.
    CrossrefPubMedGoogle Scholar
  • 4 Seegers WH. Multiple protein interactions as exhibited by the blood-clotting mechanism. J Phys Colloid Chem 1947; 51: 198-206.
    PubMedGoogle Scholar
  • 5 Seegers WH, Johnson JF, Fell C. An anti-thrombin reaction related to prothrombin activation. Am J Physiol 1954; 176: 97-103.
    CrossrefPubMedGoogle Scholar
  • 6 Liu CY, Nossel HL, Kaplan KL. Defective thrombin binding by abnormal fibrin associated with recurrent thrombosis. Thromb Haemost 1979; 42: 79 (abs).
    PubMedGoogle Scholar
  • 7 Meh DA, Siebenlist KR, Mosesson MW. Identification and characterization of the thrombin binding sites on fibrin. J Biol Chem 1996; 271: 23121-5.
    CrossrefPubMedGoogle Scholar
  • 8 Mosesson MW, Finlayson JS, Umfleet RA. Human fibrinogen heterogeneities. III. Identification of γ chain variants. J Biol Chem 1972; 247: 5223-7.
    PubMedGoogle Scholar
  • 9 Wolfenstein-Todel C, Mosesson MW. Carboxy-terminal amino acid sequence of a human fibrinogen γ chain variant (γ’). Biochemistry 1981; 20: 6146-9.
    CrossrefPubMedGoogle Scholar
  • 10 Kloczewiak M, Timmons S, Lukas TJ, Hawiger J. Platelet receptor recognition site on human fibrinogen. Synthesis and structure-function relationship of peptides corresponding to the C-terminal segment of the γ chain. Biochemistry 1984; 23: 1767-74.
    CrossrefPubMedGoogle Scholar
  • 11 Vali Z, Scheraga HA. Localization of the binding site on fibrin for the secondary binding site of thrombin. Biochemistry 1988; 27: 1956-63.
    CrossrefPubMedGoogle Scholar
  • 12 Siebenlist KR, DiOrio JP, Budzynski AZ, Mosesson MW. The polymerization and thrombin-binding properties of des-(B beta 1-42)-fibrin. J Biol Chem 1990; 265: 18650-5.
    PubMedGoogle Scholar
  • 13 Binnie CG, Lord ST. A synthetic analog of fibrinogen α27-50 is an inhibitor of thrombin. Thromb Haemost 1991; 65: 165-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Meh DA, Siebenlist KR, Brennan SO, Holyst T, Mosesson MW. The amino acid sequences in fibrin responsible for high affinity throm-bin binding. Thromb Haemost 2001; 85: 470-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Meh DA, Mosesson MW, Siebenlist KR, Simpson-Haidaris PJ, Brennan SO, DiOrio JP, Thompson K, Di Minno G. Fibrinogen Naples I (Bβ A68T) non-substrate thrombin binding capacities. Thromb Res 2001; 103: 63-73.
    CrossrefPubMedGoogle Scholar
  • 16 Koopman J, Haverkate F, Lord ST, Grim-bergen J, Mannucci PM. Molecular basis of fibrinogen Naples associated with defective thrombin binding and thrombophilia. J Clin Invest 1992; 90: 238-44.
    CrossrefPubMedGoogle Scholar
  • 17 Farrell DH, Lovely RS, Moaddel M, Stafford AR, Weitz JI. Fibrinogen γ’ chain binds thrombin exosite II. Blood 2000; 96: 448a-9a.
    PubMedGoogle Scholar
  • 18 Francis CW, Kraus DH, Marder VJ. Structural and chromatographic heterogeneity of normal plasma fibrinogen associated with the presence of three gamma-chain types with distinct molecular weights. Biochim Biophys Acta 1983; 744: 155-64.
    CrossrefPubMedGoogle Scholar
  • 19 Francis CW, Keele EM, Marder VJ. Purification of three gamma-chains with different molecular weights from normal human plasma fibrinogen. Biochim Biophys Acta 1984; 797: 328-35.
    CrossrefPubMedGoogle Scholar
  • 20 Francis CW, Muller E, Henschen A, Simpson PJ, Marder VJ. Carboxy-terminal amino acid sequences of two large variant forms of the human plasma fibrinogen γ chain. Proc Natl Acad Sci USA 1988; 85: 3358-62.
    CrossrefPubMedGoogle Scholar
  • 21 Shariat-Madar Z, Mahdi F, Schmaier AH. Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem 2002; 277: 17962-9.
    CrossrefPubMedGoogle Scholar
  • 22 Liu CY, Nossel HY, Kaplan KL. The binding of thrombin by fibrin. J Biol Chem 1979; 254: 10421-5.
    PubMedGoogle Scholar
  • 23 de Bosch NB, Mosesson MW, Ruiz-Sáez A, Echenagucia M, Rodriguez-Lemoin A. Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). Thromb Hae-most 2002; 88: 253-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Kumar R, Béguin S, Hemker C. The influence of fibrinogen and fibrin on thrombin generation-evidence for feedback activation of the clotting system by clot bound thrombin. Thromb Haemost 1994; 72: 713-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Nossel HL, Ti M, Kaplan KL, Spanondis K, Soland T, Butler Jr VP. The generation of fibrinopeptide A in clinical blood samples. Evidence for thrombin activity. J Clin Invest 1976; 58: 1136-44.
    CrossrefPubMedGoogle Scholar
  • 26 Francis CW, Markham RE, Barlow GH, Florack TM, Dobrzynski DM, Marder VJ. Thrombin activity of fibrin thrombi and soluble plasmic derivatives. J Lab Clin Med 1983; 102: 220-30.
    PubMedGoogle Scholar
  • 27 Owen J, Friedman KD, Grossman BA, Wil-kins C, Berke AD, Powers ER. Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity. Blood 1988; 72: 616-20.
    PubMedGoogle Scholar
  • 28 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
    CrossrefPubMedGoogle Scholar
  • 29 Mutch NJ, Robbie LA, Booth NA. Human thrombi contain an abundance of active thrombin. Thromb Haemost 2001; 86: 1028-34.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Di Minno G, Martinez J, Cirillo F, Cerbone AM, Silver MJ, Colucci M, Margaglione M, Tauro R, Semeraro N, Quattrone A, Mancini M. A role for platelets and thrombin in the juvenile stroke of two siblings with defective thrombin-absorbing capacity of fibrin(ogen). Arterioscl Thromb 1991; 11: 785-96.
    CrossrefPubMedGoogle Scholar
  • 31 Caen J, Faur Y, Inceman S, Chassigneux J, Seligmann M, Anagnostopoulos T, Bernard J. Nécrose ischémique bilatérale dans un cas de grande hypofibrinogénémie congénitale. Nouv Rev Fr Hématol 1964; 4: 321-6.
    PubMedGoogle Scholar
  • 32 Marchal G, Duhamel G, Samama M, Flandrin G. Thrombose massive des vaisseaux d’un membre au cours d’une hypofibrinémie con-génitale. Hémostase 1964; 4: 81-9.
    PubMedGoogle Scholar
  • 33 Nilsson IM, Niléhn J-E, Cronberg S, Nordén G. Hypofibrinogenemia and massive thrombosis. Acta Medica Scandinavica 1966; 180: 65-76.
    PubMedGoogle Scholar
  • 34 Ingram GI, McBrien DJ, Spencer H. Fatal pulmonary embolism in congenital fibrinopenia. Acta Haematol 1966; 35: 56-62.
    CrossrefPubMedGoogle Scholar
  • 35 Mackinnon HH, Fekete JF. Congenital afibrinogenemia: vascular changes and multiple thrombosis induced by fibrinogen infusions and contraceptive medication. Can Med Assoc J 1971; 140: 597-9.
    PubMedGoogle Scholar
  • 36 Cronin C, Fitzpatrick D, Temperly I. Multiple pulmonary emboli in a patient with afibrinogenaemia. Acta Haematol 1988; 7: 53-4.
    PubMedGoogle Scholar
  • 37 Drai E, Taillan B, Schneider S, Ferrari E, Bayle J, Dujardin P. Thrombose portale révélatrice d’une afibrinogénémie congénitale. La Presse Médicale 1992; 21: 1820-1.
    PubMedGoogle Scholar
  • 38 Chafa O, Chellali T, Sternberg C, Reghis A, Hamladji RM, Fischer AM. Severe hypofibrinogenemia associated with bilateral ischemic necrosis of toes and fingers. Blood Coagul Fibrinolysis 1995; 6: 549-52.
    CrossrefPubMedGoogle Scholar
  • 39 Dupuy E, Soria C, Molho P, Zini J-M, Rosenstingl S, Laurian C, Bruneval P, Tobelem G. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. Thromb Res 2001; 102: 211-9.
    CrossrefPubMedGoogle Scholar
  • 40 de Bosch N, Sáez A, Soria C, Soria J, Echenagucia M. Coagulation profile in afibrinogenemia. Thromb Haemost 1997. Suppl: 625 (abs).
    Google Scholar
  • 41 Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution. Clin Invest 1994; 72: 396-8.
    PubMedGoogle Scholar
  • 42 Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 2000; 106: 385-92.
    CrossrefPubMedGoogle Scholar
  • 43 Yang Z, Mochalkin I, Doolittle RF. A model of fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with synthetic peptides. Proc Natl Acad Sci USA 2000; 97: 14156-61.
    CrossrefPubMedGoogle Scholar