Download PDF
Thromb Haemost 1988; 59(01): 096-100
DOI: 10.1055/s-0038-1646773
Review Article
Schattauer GmbH Stuttgart

Mild Haemostatic Problems Associated with Congenital Heterozygous α2-Antiplasmin Deficiency

F W G Leebeek
*   The Department of Haematology of the University Hospital Dijkzigt, Rotterdam, The Netherlands
,
J Stibbe
*   The Department of Haematology of the University Hospital Dijkzigt, Rotterdam, The Netherlands
,
E A R Knot
**   The Department of Internal Medicine II of the University Hospital Dijkzigt, Rotterdam, The Netherlands
,
C Kluft
***   Gaubius Institute TNO, Leiden, The Netherlands.
,
M J Gomes
*   The Department of Haematology of the University Hospital Dijkzigt, Rotterdam, The Netherlands
,
M Beudeker
*   The Department of Haematology of the University Hospital Dijkzigt, Rotterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 01 April 1987

Accepted after revision 20 October 1987

Publication Date:
18 April 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

A Dutch family, of which 13 members are heterozygotes, deficient for α2-antiplasmin (α2-AP) is reported. Clinical studies showed that 2 heterozygotes had a mild bleeding tendency, which presented as bleeding episodes after tooth extraction and after surgery and, in one patient, also as excessive menstruation. Laboratory investigations revealed an α2-AP activity of 62% (51-71) (median and range) and an antigen level of 60% (60-66). The plasminogen binding as well as the fibrin binding properties of α2-AP were normal. Plasminogen concentrations were significantly higher in the heterozygotes compared to the other family members. However, free plasminogen not bound to histidine-rich glycoprotein was not significantly different between these two groups. We propose that in this family the deficiency of α2-AP is due to a decreased synthesis of a normal α2-AP molecule. This present study brings the frequency of heterozygous α2-AP deficient patients with a bleeding tendency to 13 out of 59 heterozygotes reported in the literature.

Key words

Fibrinolysis - α2-antiplasmin - Deficiency - Plasminogen - Haemorrhagic diathesis
 

  • References

  • 1 Collen D. Identification and some properties of a new fast reacting plasma inhibitor in human plasma. Eur J Biochem 1976; 69: 209-216
    CrossrefPubMedGoogle Scholar
  • 2 Moroi M, Aoki N. Isolation and characterization of α2-plasmin inhibitor from human plasma. J Biol Chem 1976; 251: 5956-5965
    PubMedGoogle Scholar
  • 3 Saito H, Goodnough LT, Knowles BB, Aden DP. Synthesis and secretion of ob-plasmin inhibitor by established human liver cell lines. Proc Natl Acad Sci 1982; 79: 5684-5687
    CrossrefPubMedGoogle Scholar
  • 4 Hogstrop H, Saldeen T. Synthesis of α2-antiplasmin by rat liver cells. Thromb Res 1982; 28: 19-25
    CrossrefPubMedGoogle Scholar
  • 5 Miillertz S, Clemmensen I. The primary inhibitor of plasmin in human plasma. Biochem J 1976; 159: 545-553
    CrossrefPubMedGoogle Scholar
  • 6 Wiman B, Collen D. Purification and characterization of human antiplasmin, the fast acting plasmin inhibitor in plasma. Eur J Biochem 1977; 78: 19-26
    CrossrefPubMedGoogle Scholar
  • 7 Collen D, Wiman B. Fast-acting plasma inhibitor in human plasma. Blood 1978; 51: 563-569
    PubMedGoogle Scholar
  • 8 Clemmensen I. Different molecular forms of α2-antiplasmin. In: The physiological inhibitors of coagulation and fibrinolysis Collen D, Wiman B, Verstraete M. eds. Elsevier North Holland, Paramedical Press; Amsterdam: 1979: 131-136
  • 9 Wiman B. Affinity-chromatographic purification of human α2-antiplasmin. Biochem J 1980; 191: 229-232
    CrossrefPubMedGoogle Scholar
  • 10 Mimuro J, Kimura S, Aoki N. Release of α2-plasmin inhibitor from plasma fibrin clots by activated coagulation factor XIII. It’s effect on fibrinolysis. J Clin Invest 1986; 77: 1006-1013
    CrossrefPubMedGoogle Scholar
  • 11 Moroi M, Aoki N. Inhibition of plasminogen binding to fibrin by α2-plasmin inhibitor. Thromb Res 1977; 10: 851-856
    CrossrefPubMedGoogle Scholar
  • 12 Sakata Y, Aoki N. Cross-linking of α2-plasmin inhibitor to fibrin stabilizing factor. J Clin Invest 1980; 65: 290-297
    CrossrefPubMedGoogle Scholar
  • 13 Kluft C, Los P. Demonstration of two forms of α2-antiplasmin in plasma by modified crossed immunoelectrophoresis. Thromb Res 1981; 21: 65-71
    CrossrefPubMedGoogle Scholar
  • 14 Kluft C, Los P, Jie AF H, van Hinsbergh VW M, Vellenga EM, Jespersen JM, Henny Ch PM. The mutual relation of the two molecular forms of the major fibrinolysis inhibitor, α2-antiplasmin in blood. Blood 1986; 67: 616-622
    PubMedGoogle Scholar
  • 15 Clemmensen I, Thorsen S, Miillertz S, Petersen LC. Properties of three different molecular forms of the α2-plasmin inhibitor. Eur J Biochem 1981; 120: 105-112
    CrossrefPubMedGoogle Scholar
  • 16 Kluft C, Los P, Jie AF H. The molecular form of α2-antiplasmin with affinity for plasminogen is selectively bound to fibrin by factor XIII. Thromb Res 1984; 33: 419-425
    CrossrefPubMedGoogle Scholar
  • 17 Koie K, Kamiya T, Ogata K, Takamatsu J, Kobakura M. α2-plasmin inhibitor deficiency (Miyasato disease). Lancet 1978; II: 1334-1336
    PubMedGoogle Scholar
  • 18 Aoki N, Saito H, Kamiya T, Koie K, Sakata Y, Kobakura M. Congenital deficiency of α2-plasmin inhibitor associated with severe hemorrhagic tendency. J Clin Invest 1979; 63: 877-884
    CrossrefPubMedGoogle Scholar
  • 19 Kluft C, Vellenga E, Rrommer EJ P. Homozygous α2-antiplasmin deficiency. Lancet 1979; II: 206
    PubMedGoogle Scholar
  • 20 Kluft C, Vellenga E, Brommer EJ P, Wijngaards G. A familial hemorrhagic diathesis in a Dutch family: An inherited deficiency of α2-antiplasmin. Blood 1982; 59: 1169-1180
    PubMedGoogle Scholar
  • 21 Miles LA, Plow EF, Donnelly KJ, Hougie C, Griffin JH. A bleeding disorder due to deficiency of α2-antiplasmin. Blood 1982; 59: 1246-1257
    PubMedGoogle Scholar
  • 22 Yoshioka A, Kamitsuji H, Takase T, Lida Y, Tsukada S, Mikami S, Fukui H. Congenital deficiency of α2-plasmin inhibitor in three sisters. Haemostasis 1982; 11: 176-184
    PubMedGoogle Scholar
  • 23 Stormorken H, Gogstad GO, Brosstad F. Hereditary α2-antiplasmin deficiency. Thromb Res 1983; 31: 647-651
    CrossrefPubMedGoogle Scholar
  • 24 Kettle P, Mayne RR. A bleeding disorder due to a deficiency of α2-antiplasmin. J Clin Pathol 1985; 38: 428-429
    CrossrefPubMedGoogle Scholar
  • 25 Kordich L, Feldman L, Porteie P, Lago O. Severe hemorrhagic tendency in heterozygous α2-antiplasmin deficiency. Thromb Res 1985; 40: 645-651
    CrossrefPubMedGoogle Scholar
  • 26 Knot EA R, Ten Cate JW, Lamping RJ, Gie LiemKian. α2-antiplasmin: Functional characterization and metabolism in a heterozygote deficient patient. Thromb Haemostas 1986; 55: 375-378
    PubMedGoogle Scholar
  • 27 Abildgaard U, Lie M, Odegard OR. Antithrombin (heparin cofactor) assay with “new” chromogenic substrates (S-2238 and Chromozym TH). Thromb Res 1977; 11: 549-553
    CrossrefPubMedGoogle Scholar
  • 28 Friberger P, Knos M, Gustavsson S, Aurell L, Cleason G. Methods for the determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-145
    PubMedGoogle Scholar
  • 29 Laurell CB. Quantitative estimations of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem 1966; 15: 57-65
    PubMedGoogle Scholar
  • 30 Kluft C, Preston FE, Malia RG, Bertina RM, Wijngaards G, Greaves M, Verheijen JH, Dooijewaard G. Stanozolol-induced changes in fibrinolysis and coagulation in healthy adults. Thromb Haemostas 1984; 51: 157-164
    PubMedGoogle Scholar
  • 31 Koopman J, Haverkate F, Koppert P, Nieuwenhuizen W, Brommer EJ P, van der Werf WG C. A new enzyme immunoassay of fibrin(ogen) degradation products in plasma using a monoclonal antibody. In: Fibrinogen-Fibrin Formation and Fibrinolysis Vol.4 Lane DA, Henschen A, Jasani MK. eds. De Gruyter&Co; Berlin: 1986: 261-270
  • 32 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol (Basel) 1957; 17: 237-246
    CrossrefPubMedGoogle Scholar
  • 33 Recent Developments on Protein C. Boehringer Mannheim GmbH. Catno 4308 October 1983
    Google Scholar
  • 34 Verheijen JH, Mullaart E, Chang GT G, Kluft C, Wijngaards G. A simple sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measuiement in plasma. Thromb Haemostas 1982; 48: 266-269
    PubMedGoogle Scholar
  • 35 Verheijen JH, Chang GT G, Kluft C. Evidence for the occurrence of a fast acting inhibitor of tissue type plasminogen activator in human plasma. Thromb Haemostas 1984; 51: 392-395
    PubMedGoogle Scholar
  • 36 Kluft C, Brakman P, Veldhuyzen-Stolk EC. Screening of fibrinolytic activity in plasma euglobulin fractions on the fibrin plate. In: Progress in chemical fibrinolysis and thrombolysis Davidson JF, Samama MM, Desnoyers PC. eds. Vol.2 57-65 Raven Press; New York: 1976
  • 37 Chohan IS, Vermylen J, Singh I, Balakrishnan K, Verstraete M. Sodium acetate buffer: A diluent of choice in the clot lysis time technique. Thrombos Diathes Haemorrh 1975; 33: 226-229
    PubMedGoogle Scholar
  • 38 Nieuwenhuis HK, Kluft C, Wijngaards Gv, Berkel W, Sixma JJ. α2-Antiplasmin Enschede: An autosomal recessive hemorrhagic disorder caused by a dysfunctional α2-antiplasmin molecule. Thromb Haemostas 1983; 50: 170 (Abstr)
    PubMedGoogle Scholar
  • 39 Kluft C, Nieuwenhuis HK, Rijken DC, Groeneveld E, Wijngaards Gv, Berkel W, Dooijewaard G, Sixma JJ. α2-Antiplasmin Enschede: A dysfunctional α2-antiplasmin molecule, associated with an autosomal recessive hemorrhagic disorder. J Clin Invest 1987 (in press)
    Google Scholar