BMSEHA15
Haematologica, Vol 94, Issue 6, 762-763 doi:10.3324/haematol.2009.006882
Copyright © 2009 by Ferrata Storti Foundation
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Editorials and Perspectives

{alpha}1-antitrypsin and the maintenance of hemostatic balance

Joseph Emmerich

University Paris Descartes, INSERM U765, Department of Vascular Medicine, Hôpital Européen Georges Pompidou, Paris, France, E-mail:joseph.emmerich{at}egp.aphp.fr

Serine protease inhibitors, known as serpins, belong to a superfamily of proteins that are the quintessential regulators of extracellular peptidase pathways.1 Serpins prevent the deleterious effects of excessive peptide bond hydrolysis. The principal determinant of serpin specificity appears to be the P1 residue localized within the substrate recognition sequence of the reactive center loop.2 A serine protease and its specific serpin form a tight inactive complex after cleavage of a scissile bond between P1 and P1’ residues. Antithrombin is the principal serpin involved in the regulation of blood clotting proteinases but it differs from other serpins in having several multiple target proteinases such as thrombin, factor Xa, factor IXa, factor XIa and factor XIIa. Its importance as a major regulator of thrombin generation is well demonstrated since the initial publication of antithrombin deficiency.3 Alpha1-antitrypsin has major homology with antithrombin, but its major substrate is the leucocyte elastase, with accessory inhibitory activity toward trypsin, chymotrypsin and activated protein C. P1-P1’ residues in antithrombin are constituted of the Arg 393-Ser 394 residues when this bound is Met 358-Ser 359 in {alpha}1-antitrypsin.

In 1978, Lewis et al. described the first report of {alpha}1-antitrypsin Pittsburgh (Met 358 to Arg mutation) as a variant causing severe hemorrhagic disease in a young boy born in 1966 who died at the age of 14 of a huge hematoma of his leg and abdomen in 1981, after more than 50 severe bleeding episodes during his short life.4,5 We described, in 1992, a second case of {alpha}1-antitrypsin Pittsburgh in a 15 year-old boy during a routine pre-operative laboratory investigation before an operation.6,7 We have been following this case since 1990 and he is now 35 years-old. He has had an uneventful life except for one bleeding episode of the right buttock after a minor trauma that required surgery due to compression of the sciatic nerve.7 Since then he has never experienced new bleeding episodes. In this issue of the journal, Hua et al.8 describe 2 new cases of {alpha}1-antitrypsin Pittsburgh and the first history of family transmission of the mutation from one father to his daughter.8 The father presented several bleeding episodes after mild triggering factors and his daughter had pelvic hematoma following surgery for ovarian hematoma due to rupture of an ovarian corpus luteum. Both patients presented with mild bleeding tendency in agreement with the clinical features depicted by the second patient we reported.

What could explain the discrepancy between the first case of {alpha}1-antitrypsin Pittsburgh who died of severe bleeding compared to now 3 other cases who have experienced only mild bleeding tendency after triggering events? We can speculate that the first case had maybe another bleeding disease associated with {alpha}1-antitrypsin Pittsburg mutation, as the initial description reported an abnormal bleeding time. On the other hand, and as reported in this issue, patients with {alpha}1-antit-rypsin had normal platelet aggregation except when thrombin was used as an agonist. That was probably due to inhibition of the low dose of thrombin used and it would have been of interest to demonstrate that higher doses of this platelet agonist overcome this inhibition. The second explanation is the inhibition of protein C associated with the variant form of {alpha}1-antitrypsin.9,10 In a detailed evaluation of the second case we analyzed the mechanism of protein C inhibition: in the presence of {alpha}1-antitrypsin Pittsburgh protein C can be activated but is abnormally rapidly cleared by this variant.7 The very low levels of protein C observed in the second reported case, as well as in these 2 new reports, could partially explain the discrepancy observed. In a plasma sample kept frozen for more than ten years from the original case, protein C level was only slightly decreased (62%), but {alpha}1-antitrypsin/protein C complexes were still detected.7 We can now reconsider the consequences of {alpha}1-antitrypsin Pittsburgh and affirm with more certainty that it is associated with a mild bleeding tendency, bleeding episodes occurring after triggering events such as mild trauma, surgery or follicle rupture. It also raises questions on prophylactic treatment in this young woman who experienced ovarian hematoma after ovulation, and on treatment procedure in case of pregnancy, a problem that is absent in classical forms of hemophilia. The autosomic transmission of the disease could also lead to ethical considerations concerning genetic screening of the variant in case of pregnancy in women expecting a daughter. In order to overcome these difficult issues we will have to update information among clinicians in charge of patients who are carriers of this orphan disease.

Footnotes

Joseph Emmerich, MD, PhD, board certified in Cardiology, is Professor of Vascular Medicine at the University Hospital Georges Pompidou, Paris, France (University Paris Descartes) and head of INSERM laboratory U765.

References

  1. Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, et al. An overview of the serpin superfamily. Genome Biol 2006;7:216-26.[CrossRef][Medline]
  2. Ardelt W, Lakowski M. Turkey ovomucoid third domain inhibits eight different serine proteinases of varied specificity on the same Leu 18-Glu 19 reactive site. Biochemistry 1985;24:5313-20.[CrossRef][Web of Science][Medline]
  3. Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrhag 1965;13:516-30.
  4. Lewis JH, Iammarino RM, Spero JA, Hasiba U. Anti-thrombin Pittsburgh: an {alpha}1-antitrypsin variant causing hemorrhagic disease. Blood 1978;51:129-37.[Abstract/Free Full Text]
  5. Owen MC, Brennan SO, Lewis JH, Carrel RW. Mutation of antitrypsin to antithrombin. A1-antitrypsin Pittsburg (358 Meth ->Arg), a fatal bleeding disorder. N Engl J Med 1983;309:694-8.[Abstract]
  6. Vidaud D, Emmerich J, Alhenc-Gelas M, Yvart J, Fiessinger JN, Aiach M. Met 358 to Arg mutation of alpha1-antit-rypsin associated with protein C deficiency in a patient with mild bleeding tendency. J Clin Invest 1992;89:1537-43.[Web of Science][Medline]
  7. Emmerich J, Alhenc-Gelas M, Gandrille S, Guichet C, Fiessinger JN, Aiach M. Mechanism of protein C deficiency in a patient with arginine 358 alpha1-antitrypsin(Pittsburg mutation): role in the maintenance of hemostatic balance. J Lab Clin Med 1995;125:531-9.[Web of Science][Medline]
  8. Hua B, Fan L, Liang Y, Zhao Y, Tuddenham EGD. Alpha1-antitrypsin Pittsburg in a family with bleeding tendency. Haematologica 2009;94:881-4.[Abstract/Free Full Text]
  9. Heeb MJ, Griffin JH. Physiologic inhibition of human activated protein C by {alpha}1 antitrypsin. J Biol Chem 1988;263:11613-6.[Abstract/Free Full Text]
  10. Heeb MJ, Bischoff R, Courtney M, Griffin JH. Inhibition of activated protein C by recombinant alpha1-antitrypsin variants with substitution of arginine or leucine for methionine 358. J Biol Chem 1990;265:2365-9.[Abstract/Free Full Text]

Related Article

{alpha}1-antitrypsin Pittsburgh in a family with bleeding tendency
Baolai Hua, Liankai Fan, Yan Liang, Yongqiang Zhao, Edward G.D. Tuddenham
Haematologica 2009 94: 881-884. [Abstract] [Full Text] [PDF]




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