Download PDF
Thromb Haemost 2001; 86(04): 1007-1011
DOI: 10.1055/s-0037-1616525
Special Article
Schattauer GmbH

Homozygous Antithrombin Deficiency Type II (99 Leu to Phe Mutation) and Childhood Thromboembolism

Stefan Kuhle
1   Dept. of Paediatrics, Division of Neonatology and Paediatric Intensive Care, Vienna University Hospital, Austria
2   Dept. of Internal Medicine, Division of Haematology, Vienna University Hospital, Austria
,
David A. Lane
3   Dept. of Haematology, Imperial College School of Medicine, London, U.K.
,
Kristin Jochmanns
4   Dept. of Haematology, Academic Hospital, Free University of Brussels, Belgium
,
Christoph Male
5   Dept. of Paediatrics, Division of General Paediatrics, Vienna University Hospital, Austria
,
Peter Quehenberger
6   Dept. of Laboratory Medicine, Vienna University Hospital, Austria
,
Klaus Lechner
2   Dept. of Internal Medicine, Division of Haematology, Vienna University Hospital, Austria
,
Ingrid Pabinger
2   Dept. of Internal Medicine, Division of Haematology, Vienna University Hospital, Austria
› Author Affiliations
Further Information

Publication History

Received 19 October 2000

Accepted after resubmission 14 May 2001

Publication Date:
09 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

We report 5 children from 3 families with homozygous antithrombin deficiency type II affecting the heparin binding site (99 Leu to Phe mutation). Four children had severe spontaneous thromboembolic events (deep leg or caval vein thrombosis, ischaemic stroke) at one week, 3 months, 13 and 14 years of age. The fifth patient, a 17 year-old boy was asymptomatic. Early manifestation of homozygous deficiency calls for prompt and accurate diagnosis. In doubtful cases genetic analysis is required. Long-term oral anticoagulation should be considered in affected individuals.

Keywords

Antithrombin-deficiency - thromboembolism - children
 

  • References

  • 1 Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol 1981; 10: 369-90.
    PubMedGoogle Scholar
  • 2 Lane DA, Bayston T, Olds RJ, Fitches AC, Cooper DN, Millar DS, Jochmans K, Perry DJ, Okajima K, Thein SL, Emmerich J. Antithrombin Mutation Database: 2nd (1997) Update. Thromb Haemost 1997; 77: 197-211.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Andrew M, Monagle PT, Brooker LA. Congenital prothrombotic disorders. In: Thromboembolic complications during infancy and childhood. Hamilton: BC Decker; 2000: 47-110.
    Google Scholar
  • 4 Tait RC, Walker ID, Perry DJ, Islam SIAM, Daly ME, McCall F, Conkie JA, Carrell RW. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-12.
    CrossrefPubMedGoogle Scholar
  • 5 Sakuragawa N, Takahashi K, Kondo S, Koide T. Antithrombin III Toyama: a hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis. Thromb Res 1983; 31: 305-17.
    CrossrefPubMedGoogle Scholar
  • 6 Fischer AM, Cornu P, Sternberg C, Meriane F, Dautzenberg MD, Chafa O, Beguin S, Desnos M. Antithrombin III Alger: a new homozygous variant. Thromb Haemost 1986; 55: 218-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Okajima K, Ueyama H, Hashimoto Y, Sasaki Y, Matsumoto K, Okabe H, Inoue M, Araki S, Takatsuki K. Homozgyous variant of antithrombin III that lacks affinity for heparin, AT III Kumamoto. Thromb Haemost 1989; 61: 20-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Bauters A, Zawadzki C, Bura A, Thery C, Watel A, Subtil D, Aiach M, Emmerich J, Jude B. Homozygous variant of antithrombin with lack of affinity for heparin: management of severe thrombotic complications associated with intrauterine fetal demise. Blood Coagulation Fibrinolysis 1996; 705-10.
    PubMedGoogle Scholar
  • 9 Olds RJ, Lane DA, Boisclair M, Sas G, Bock SC, Thein SL. Antithrombin Budapest 3: an antithrombin variant with reduced heparin affinity resulting from the substitution L99F. FEBS Letters 1992; 300: 241-6.
    CrossrefPubMedGoogle Scholar
  • 10 Chowdhury V, Lane DA, Mille B, Auberger K, Gandenberger-Bachem S, Pabinger I, Olds RJ, Thein SL. Homozygous Antithrombin Deficiency: Report of two new cases (99 Leu to Phe) associated with arterial and venous thrombosis. Thromb Haemost 1994; 72: 198-202.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Brown SA, Mitchell M, Cutler JA, Moore G, Smith MP, Savidge GF. Rapid genetic diagnosis in neonatal pulmonary artery thrombosis caused by homozygous antithrombin Budapest 3. Clin Appl Thromb Hemost 2000; 6: 181-3.
    CrossrefPubMedGoogle Scholar
  • 12 Olds RJ, Lane DA, Caso R, Panico M, Morris HR, Sas G, Dawes J, Thein SL. Antithrombin III Budapest: A single amino acid substitution (429 Pro to Leu) in a region highly conserved in the serpin family. Blood 1992; 79: 1206-12.
    PubMedGoogle Scholar
  • 13 Chowdhury V, Olds RJ, Lane DA, Conard J, Pabinger I, Ryan K, Bauer KA, Bhavnani M, Abildgaard U, Finazzi G, Castaman G, Mannucci PM, Thein SL. Identification of nine novel mutations in type I antithrombin deficiency by heteroduplex screening. Br J Haematol 1993; 84: 656-61.
    CrossrefPubMedGoogle Scholar
  • 14 Jochmans K, Lissens W, Vervoort R, Peeters S, De Waele M, Libaers I. Antithrombin-Gly 424 Arg: A novel point mutation responsible for type I antithrombin deficiency and neonatal thrombosis. Blood 1994; 83: 146-51.
    PubMedGoogle Scholar
  • 15 Manco-Johnson MJ, Marlar RA, Jacobson LJ, Hays T, Warady BA. Severe protein C deficiency in newborn infants. J Pediatr 1988; 113: 359-63.
    CrossrefPubMedGoogle Scholar
  • 16 Hakten M, Deniz U, Ozbay G, Ulutin ON. Two cases of homozygous anti-thrombin III deficiency in a family with congenital deficiency of AT III. In: Thrombosis and haemorrhagic disorders. Proceedings of the 5th International Meeting of the Danubian League against Thrombosis and Haemorrhagic Disorders. Sinzinger H, Vinazzer H. eds. Würzburg, Germany: Schmitt and Meyer; 1989: 177-81.
    Google Scholar
  • 17 Boyer C, Wolf M, Vedrenne J, Meyer D, Larrieu MJ. Homozygous variant of antithrombin III: AT III Fontainebleau. Thromb Haemost 1986; 56: 18-22.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Cucuianu M, Blaga S, Pop S, Olinic D, Olinic N, Colhon D, Cristea A. Homozygous or compund heterozygous qualitative antithrombin III deficiency. Nouv Rev Fr Hematol 1994; 36: 335-7.
    PubMedGoogle Scholar
  • 19 Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in th subtypes of congenital antithrombin III deficiency: Review of 404 cases. Thromb Haemost 1987; 58: 1094.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Sas G, Petö I, Bánhegyi D, Blaskó G, Domján G. Heterogeneity of the “classical” Antithrombin III deficiency. Thromb Haemost 1980; 43: 133-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Olds RJ, Lane DA, Chowdhury V, Sas G, Pabinger I, Auberger K, Thein SL. (ATT) trinucleotide repeats in the antithrombin gene and their use in determining the origin of repeated mutations. Hum Mutation 1994; 4: 31-41.
    CrossrefPubMedGoogle Scholar
  • 22 Koide T, Odani S, Takahashi K, Ono T, Sakuragawa N. Antithrombin III Toyama: Replacement of arginine-47 by cysteine in hereditary abnormal antithrombin III lacks heparin binding ability. Proc Natl Acad Sci 1984; 81: 289-93.
    CrossrefPubMedGoogle Scholar
  • 23 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-72.
    PubMedGoogle Scholar
  • 24 Harper PL, Daly M, Price J, Edgar PF, Carrell RW. Screening for heparin binding variants of antithrombin. J Clin Pathol 1991; 44: 477-9.
    CrossrefPubMedGoogle Scholar
  • 25 Lane DA, Auberger K, Ireland H, Roscher AA, Thein SL. Prenatal diagnosis in combined antithrombin and factor V gene mutation. Br J Haematol 1996; 94: 753-5.
    CrossrefPubMedGoogle Scholar
  • 26 Mitchell L, Piovella F, Ofosu F, Andrew M. α2-Macroglobulin may provide protection from thromboembolic events in Antithrombin III-deficient children. Blood 1991; 78: 2299-304.
    PubMedGoogle Scholar
  • 27 Olds RJ, Lane DA, Mille B, Chowdhury V, Thein SL. Antithrombin: The principal inhibitor of thrombin. Sem Thromb Hemost 1994; 20: 353-72.
    Article in Thieme ConnectPubMedGoogle Scholar