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Thromb Haemost 1999; 82(04): 1240-1246
DOI: 10.1055/s-0037-1614368
Review Article
Schattauer GmbH

Reevaluation of the Incidence of Thromboembolic Complications in Congenital Factor XII Deficiency

A Study on 73 Subjects from 14 Swiss Families[*]
S. Zeerleder
2   From the Central Hematology Laboratory, University Hospital of Bern, Bern, Switzerland
,
M. Schloesser
1   Institut für Humangenetik der Universität Göttingen, Göttingen, Germany
,
M. Redondo
2   From the Central Hematology Laboratory, University Hospital of Bern, Bern, Switzerland
,
W. A. Wuillemin
2   From the Central Hematology Laboratory, University Hospital of Bern, Bern, Switzerland
,
W. Engel
1   Institut für Humangenetik der Universität Göttingen, Göttingen, Germany
,
M. Furlan
2   From the Central Hematology Laboratory, University Hospital of Bern, Bern, Switzerland
,
B. Lämmle
2   From the Central Hematology Laboratory, University Hospital of Bern, Bern, Switzerland
› Author Affiliations
Further Information

Publication History

Received 01 April 1999

Accepted after revision 24 June 1999

Publication Date:
08 December 2017 (online)

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Summary

To further elucidate the debated role of hereditary FXII deficiency as a thrombophilic risk factor this follow-up study on 65 subjects out of 12 Swiss families was undertaken (follow-up: 6 yrs). Fifteen severely FXII deficient subjects (FXII:C < 1%), 35 partially FXII deficient subjects (FXII:C ≥ 1-59%), 10 with normal FXII values (FXII:C ≥ 70%), and 5 non-classifiable subjects (FXII:C ≥ 60-69%) were reevaluated. Eight subjects (4 severely and 3 partially FXII deficient, 1 non-classifiable) were newly enrolled. Four instances of deep vein thrombosis, one superficial vein thrombosis and one myocardial infarction were noted in 2 out of 19 severely FXII deficient subjects during a total life-time period of 866.6 patient-years. In 38 partially FXII deficient subjects (1862.8 patient-years) one ischemic cerebrovascular stroke and one superficial vein thrombosis were recorded in 2 individuals. The 10 subjects with normal FXII values (498.2 patient-years) remained thrombosis-free. One superficial vein thrombosis occurred in an unclassifiable woman. None of the 3 different FXII gene defects revealed in our patients was specifically associated with thromboembolic complications. Kaplan-Meier analysis of thrombosis-free survival suggests that hereditary partial (and probably severe) FXII deficiency does not constitute a thrombophilic condition.

Keywords

Factor XII deficiency - thromboembolic disease - factor XII gene mutations - thrombophilia

* Supported by grants from the Swiss National Foundation for Scientific Research (No. 32-36443.92 and No. 32-47016.96)


 

  • References

  • 1 Griffin JH, Cochrane CG. Human factor XII (Hageman Factor). Methods Enzymol 1976; 45: 56-65.
    PubMedGoogle Scholar
  • 2 Fujikawa K, Davie EW. Human factor XII (Hageman factor). Methods Enzymol 1981; 80: 198-211.
    PubMedGoogle Scholar
  • 3 Tans G, Rosing J. Structural and functional characterization of factor XII. Semin Thromb Haemost 1987; 13: 1-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Lämmle B, Wuillemin WA. Factor XII. In: Human Protein Data. Haeberli A. ed. Weinheim: Wiley-VCH Verlag GmbH; 1997
    Google Scholar
  • 5 Colman RW. Surface-mediated defense reactions. The plasma contact activation system. J Clin Invest 1984; 73: 1249-53.
    CrossrefPubMedGoogle Scholar
  • 6 Kaplan AP, Silverberg M. The coagulation-kinin pathway of human plasma. Blood 1987; 70: 1-15.
    PubMedGoogle Scholar
  • 7 Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. FXII. Blut 1990; 61: 258-66.
    CrossrefPubMedGoogle Scholar
  • 8 Wachtfogel YT, DeLa Cadena RA, Colman RW. Structural biology, cellular interactions and pathophysiology of the contact system. Thromb Res 1993; 72: 1-21.
    CrossrefPubMedGoogle Scholar
  • 9 Glueck HI, Roehll W. Myocardial infarction in a patient with a hageman (factor XII) defect. Ann Intern Med 1966; 64: 390-6.
    CrossrefPubMedGoogle Scholar
  • 10 Hoak JC, Swanson LW, Warner ED, Connor WE. Myocardial infarction associated with severe factor XII deficiency. Lancet 1966; 2: 884-6.
    PubMedGoogle Scholar
  • 11 Ratnoff OD, Busse RJ, Sheon RP. The demise of John Hageman. N Engl J Med 1968; 279: 760-1.
    CrossrefPubMedGoogle Scholar
  • 12 Baumann R, Straub PW. Congenital deficiency of Hageman factor (clotting factor XII). Report on the first two families found in Switzerland. Helv Med Acta 1968; 34: 313-26.
    PubMedGoogle Scholar
  • 13 Mc Pherson RA. Thromboembolism in Hageman trait. Am J Clin Pathol 1977; 68: 420-3.
    CrossrefPubMedGoogle Scholar
  • 14 Dyerberg J, Stoffersen E. Recurrent thrombosis in a patient with factor XII deficiency. Acta Haematol 1980; 63: 278-82.
    CrossrefPubMedGoogle Scholar
  • 15 Hellstern P, Köhler M, Schmengler K, Doenecke P, Wenzel E. Arterial and venous thrombosis and normal response to streptokinase treatment in a young patient with severe Hageman factor deficiency. Acta Haematol 1983; 69: 123-6.
    CrossrefPubMedGoogle Scholar
  • 16 Lodi S, Isa L, Pollini E, Bravo AF, Scalvini A. Defective intrinsic fibrinolytic activity in a patient with severe factor XII-deficiency and myocardial infarction. Scand J Haematol 1984; 33: 80-2.
    PubMedGoogle Scholar
  • 17 Londino AV, Luparello FJ. Factor XII deficiency in a man with gout and angioimmunoblastic lymphadenopathy. Arch Intern Med 1984; 144: 1497-8.
    CrossrefPubMedGoogle Scholar
  • 18 Penny WJ, Colvin BT, Brooks N. Myocardial infarction with normal coronary arteries and factor XII deficiency. Br Heart J 1985; 53: 230-4.
    CrossrefPubMedGoogle Scholar
  • 19 Vergnes C, Lorient-Roudaut MF, Haissaguerre M, Roudaut R, Wicker P, Boisseau MR, Dallocchio M. Thrombophlébites et embolies pulmonaires lors d’un déficit congénital en facteur XII. Arch Mal Coeur Vaiss 1985; 78: 440-3.
    PubMedGoogle Scholar
  • 20 Mannhalter C, Fischer M, Hopmeier P, Deutsch E. Factor XII activity and antigen concentrations in patients suffering from recurrent thrombosis. Fibrinolysis 1987; 1: 259-63.
    PubMedGoogle Scholar
  • 21 Halbmayer WA, Mannhalter C, Feichtinger C, Rubi K, Fischer M. The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thrombosis. Thromb Haemost 1992; 68: 285-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Halbmayer WA, Haushofer A, Radek J, Schön R, Deutsch M, Fischer M. Prevalence of factor XII (Hageman factor) deficiency among 426 patients with coronary heart disease awaiting cardiac surgery. Coron Artery Dis 1994; 5: 451-4.
    CrossrefPubMedGoogle Scholar
  • 23 Winter M, Gallimore M, Jones DW. Should factor XII assays be included in thrombophilia screening. Lancet 1995; 346: 52.
    CrossrefPubMedGoogle Scholar
  • 24 von Känel R, Wuillemin WA, Furlan M, Lämmle B. Factor XII clotting activity and antigen levels in patients with thromboembolic disease. Blood Coagul Fibrinolysis 1992; 3: 555-61.
    CrossrefPubMedGoogle Scholar
  • 25 Koster T, Rosendaal FR, Briët E, Vandenbroucke JP. John Hageman’s factor and deep vein thrombosis: Leiden Thrombophilia Study. Br J Haematol 1994; 87: 422-4.
    CrossrefPubMedGoogle Scholar
  • 26 Kelleher CC, Mitropoulos KA, Imeson J, Meade TW, Martin JC, Reeves BEA, Hughes LO. Hageman factor and risk of myocardial infarction in middle-aged men. Atherosclerosis 1992; 97: 67-73.
    CrossrefPubMedGoogle Scholar
  • 27 Merlo C, Furlan M, Sulzer I, Kremer Hovinga J, Binder BR, Lämmle B. Contact activation factors in 200 survivors of myocardial infarction. Thromb Haemost 1994; (abstr) 73: 1410a.
    PubMedGoogle Scholar
  • 28 Lämmle B, Wuillemin WA, Huber I, Krauskopf M, Zürcher C, Pflugshaupt R, Furlan M. Thromboembolism and bleeding tendency in congenital factor XII deficiency – A study on 74 subjects from 14 Swiss families. Thromb Haemost 1991; 65: 117-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Cool DE, Edgell CJS, Louie GV, Zoller MJ, Brayer GD, MacGillivray RTA. Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of factor XII and the tertiary structure of beta-factor XIIa. J Biol Chem 1985; 260: 13666-76.
    PubMedGoogle Scholar
  • 30 Tripodi M, Citarella F, Guida S, Galeffi P, Fantoni A, Cortese R. cDNA sequence coding for human coagulation factor XII (Hageman). Nucleic Acids Res 1986; 14: 3146.
    CrossrefPubMedGoogle Scholar
  • 31 Que BG, Davie EW. Characterization of a cDNA coding for human factor XII (Hageman factor). Biochemistry 1986; 25: 1525-8.
    CrossrefPubMedGoogle Scholar
  • 32 Cool DE, MacGillivray RTA. Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5’-flanking region. J Biol Chem 1987; 262: 13662-73.
    PubMedGoogle Scholar
  • 33 Royle NJ, Nigli M, Cool DE, MacGillivray RTA, Hamerton JL. Structural gene encoding human factor XII is located at 5q33-qter. Somat Cell Mol Genet 1988; 14: 217-21.
    CrossrefPubMedGoogle Scholar
  • 34 Bernardi F, Marchetti G, Patracchini P, del Senno L, Tripodi M, Fantoni A, Bartolai S, Vannini F, Felloni L, Rossi L, Panicucci F, Conconi F. Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme. Blood 1987; 69: 1421-4.
    PubMedGoogle Scholar
  • 35 Hofferbert S, Müller J, Köstering H, von Ohlen WD, Schloesser M. A novel 5’-upstream mutation in the factor XII gene is associated with a TaqI restriction site in an Alu repeat in factor XII-deficient patients. Hum Genet 1996; 97: 838-41.
    CrossrefPubMedGoogle Scholar
  • 36 Schloesser M, Zeerleder S, Lutze G, Halbmayer WM, Hofferbert S, Hinney B, Koestering H, Lämmle B, Pindur G, Thies K, Köhler M, Engel W. Mutations in the human factor XII gene. Blood 1997; 90: 3967-77.
    PubMedGoogle Scholar
  • 37 Schloesser M, Hofferbert S, Bartz U, Lutze G, Lämmle B, Engel W. The novel acceptor splice site mutation 11397 (G → A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients. Hum Mol Genet 1995; 4: 1235-7.
    CrossrefPubMedGoogle Scholar
  • 38 Miyata T, Kawabata SI, Iwanaga S, Takahashi I, Alving B, Saito H. Coagulation factor XII (Hageman factor) Washington D. C.: Inactive factor XIIa results from Cys-571 → Ser substitution. Proc Natl Acad Sci USA 1989; 86: 8319-22.
    CrossrefPubMedGoogle Scholar
  • 39 Kremer Hovinga J, Schaller J, Stricker H, Wuillemin WA, Furlan M, Lämmle B. Coagulation factor XII Locarno: The functional defect is caused by the amino acid substitution Arg 353 → Pro leading to loss of a kallikrein cleavage site. Blood 1994; 84: 1173-81.
    CrossrefPubMedGoogle Scholar
  • 40 Wuillemin WA, Furlan M, Lämmle B. A quantitative dot immunobinding assay for coagulation factor XII in plasma. J Immunol Methods 1990; 130: 133-40.
    CrossrefPubMedGoogle Scholar
  • 41 Wuillemin WA, Huber I, Furlan M, Lämmle B. Functional characterization of an abnormal factor XII molecule (FXII Bern). Blood 1991; 78: 997-1004.
    PubMedGoogle Scholar
  • 42 Ratnoff OD, Colopy JE. Familial hemorrhagic trait associated with deficiency of clot-promoting fraction of plasma. J Clin Invest 1955; 34: 602-13.
    CrossrefPubMedGoogle Scholar
  • 43 Ratnoff OD, Saito H. Surface-mediated reactions. Curr Top Hematol 1979; 2: 1-57.
    PubMedGoogle Scholar
  • 44 Saito H. Contact factors in health and disease. Semin Thromb Hemost 1987; 13: 36-49.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Haanen C, Hommes F, Benraad H, Morselt G. A case of Hageman-factor deficiency and a method to purify the factor. Thromb Diath Heamorrh 1960; 5: 201-7.
    PubMedGoogle Scholar
  • 46 Didisheim P. Hageman factor deficiency (Hageman trait). Arch Intern Med 1962; 110: 74-81.
    PubMedGoogle Scholar
  • 47 Ikkala E, Myllylä G, Nevanlinna HR. Rare congenital coagulation factor defects in Finland. Scand J Haematol 1971; 8: 210-5.
    PubMedGoogle Scholar
  • 48 Aznar J, Mayans J, Aznar JA, Fernandez-Pavon A, Calabuig R. Deficiencia de factor Hageman. A proposito de un caso. Sangre 1973; 18: 356-64.
    PubMedGoogle Scholar
  • 49 Burman JF, Chung HI, Lane DA, Philippou H, Adami A, Lincoln JCR. Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass. Lancet 1994; 344: 1192-3.
    CrossrefPubMedGoogle Scholar
  • 50 Goodnough LT, Saito H, Ratnoff OD. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine 1983; 62: 248-55.
    CrossrefPubMedGoogle Scholar
  • 51 Levi M, Hack CE, de Boer JP, Brandjes DPM, Büller HR, ten Cate JW. Reduction of contact activation related fibrinolytic activity in factor XII deficient patients. Further evidence for the role of the contact system in fibrinolysis in vivo. J Clin Invest 1991; 88: 1155-60.
    CrossrefPubMedGoogle Scholar
  • 52 La Follette L, Gordon EM, Mazur CA, Ratnoff OD, Yamashita TS. Hyperprolactinemia and reduction in plasma titers of Hageman factor, prekallikrein, and high molecular weight kininogen in patients with acute myocardial infarction. J Lab Clin Med 1987; 110: 318-21.
    PubMedGoogle Scholar
  • 53 Hoffmeister HM, Jur M, Wendel HP, Heller W, Seipel L. Alterations of coagulation and fibrinolytic and kallikrein-kinin systems in the acute and postacute phases in patients with unstable angina pectoris. Circulation 1995; 91: 2520-7.
    CrossrefPubMedGoogle Scholar
  • 54 Citarella F, Felici A, Brouwer M, Wagstaff J, Fantoni A, Hack CE. Interleukin-6 downregulates factor XII production by human hepatoma cell line (hepG2). Blood 1997; 90: 1501-7.
    PubMedGoogle Scholar
  • 55 Gordon EM, Donaldson VH, Saito H, Su E, Ratnoff OD. Reduced titers of Hageman factor (factor XII) in Orientals. Ann Intern Med 1981; 95: 697-700.
    CrossrefPubMedGoogle Scholar
  • 56 Kanaji T, Okamura T, Osaki K, Kuroiwa M, Shimoda K, Hamasaki N, Niho Y. A common genetic polymorphism (46 C to T substitution) in the 5’-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-4.
    PubMedGoogle Scholar
  • 57 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-7.
    PubMedGoogle Scholar
  • 58 Dahlbäck B, Hillarp A, Rosen S, Zöller B. Resistance to activated protein C, the FV:Q 506 allele, and venous thrombosis. Ann Hematol 1996; 72: 166-76.
    CrossrefPubMedGoogle Scholar