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Thromb Haemost 1997; 77(03): 444-451
DOI: 10.1055/s-0038-1655986
Clinical Studies
Schattauer GmbH Stuttgart

Laboratory Evaluation and Clinical Characteristics of 2,132 Consecutive Unselected Patients with Venous Thromboembolism – Results of the Spanish Multicentric Study on Thrombophilia (EMET*-Study)

José Mateo
The Spanish Multicentric Study on Thrombophilia (EMET), Barcelona, Spain
,
Artur Oliver
The Spanish Multicentric Study on Thrombophilia (EMET), Barcelona, Spain
,
Montserrat Borrell
The Spanish Multicentric Study on Thrombophilia (EMET), Barcelona, Spain
,
Núria Sala
The Spanish Multicentric Study on Thrombophilia (EMET), Barcelona, Spain
,
EMET Group,
Jordi Fontcuberta
The Spanish Multicentric Study on Thrombophilia (EMET), Barcelona, Spain
› Author Affiliations
Further Information

Publication History

Received 16 July 1996

Accepted after resubmission 21 November 1996

Publication Date:
11 July 2018 (online)

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Summary

Previous studies on the prevalence of biological abnormalities causing venous thrombosis and the clinical characteristics of thrombotic patients are conflicting. We conducted a prospective study on 2,132 consecutive evaluable patients with venous thromboembolism to determine the prevalence of biological causes. Antithrombin, protein C, protein S, plasminogen and heparin cofactor-II deficiencies, dysfibrinoge-nemia, lupus anticoagulant and antiphospholipid antibodies were investigated. The risk of any of these alterations in patients with familial, recurrent, spontaneous or juvenile venous thrombosis was assessed. The overall prevalence of protein deficiencies was 12.85% (274/2,132) and antiphospholipid antibodies were found in 4.08% (87/2,132). Ten patients (0.47%) had antithrombin deficiency, 68 (3.19%) protein C deficiency, 155 (7.27%) protein S deficiency, 16 (0.75%) plasminogen deficiency, 8 (0.38%) heparin cofactor-II deficiency and 1 had dysfib-rinogenemia. Combined deficiencies were found in 16 cases (0.75%). A protein deficiency was found in 69 of 303 (22.8%) patients with a family history of thrombosis and in 205/1,829 (11.2%) without a history (crude odds ratio 2.34, 95% Cl 1.72-3.17); in 119/665 (17.9%) patients with thrombosis before the age of 45 and in 153/1,425 (10.7%) after the age of 45 (crude odds ratio 1.81, 95% Cl 1.40-2.35); in 103/616 (16.7%) with spontaneous thrombosis and in 171/1,516 (11.3%) with secondary thrombosis (crude odds ratio 1.58, 95% Cl 1.21-2.06); in 68/358 (19.0%) with recurrent thrombosis and in 206/1,774 (11.6%) with a single episode (crude odds ratio 1.78,95% Cl 1.32-2.41). Patients with combined clinical factors had a higher risk of carrying some deficiency. Biological causes of venous thrombosis can be identified in 16.93% of unselected patients. Family history of thrombosis, juvenile, spontaneous and recurrent thrombosis are the main clinical factors which enhance the risk of a deficiency. Laboratory evaluation of thrombotic patients is advisable, especially if some of these clinical factors are present.

 

  • References

  • 1 Kierkegaard A. Incidence of acute deep vein thrombosis in two districts: a phlebographic study. Acta Chir Scand 1980; 146: 0267-0269
    PubMedGoogle Scholar
  • 2 Lane DA, Olds RR, Thein SL. Antithrombin and its deficiency states. Blood Coagul Fibrinol 1992; 3: 0315-0341
    CrossrefPubMedGoogle Scholar
  • 3 Demers C, Ginsberg JS, Hirsh J, Henderson P, Blajchman MA. Thrombosis in antithrombin-III-deficient persons. Report of a large kindred and literature review. Ann Intern Med 1992; 116: 0754-0761
    CrossrefPubMedGoogle Scholar
  • 4 Pabinger I, Kyrle PA, Heistinger M, Eichinger S, Wittmann E, Lechner K. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency:A prospective cohort study. Thromb Haemost 1994; 71: 0441-0445
    PubMedGoogle Scholar
  • 5 Griffin JH, Evatt B, Zimmerman T, Kleiss A, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373
    CrossrefPubMedGoogle Scholar
  • 6 Allart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Brёt E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 0134-0138
    CrossrefPubMedGoogle Scholar
  • 7 Koster T, Rosendaal FR, Briët E, van der Meer FJM, Colly LP, Trienekens PH, Poort SR, Reitsma PH, Vandenbroucke JP. Protein C deficiency in a controlled series of unselected outpatients:and infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995; 2756-2761
    PubMedGoogle Scholar
  • 8 Schwartz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300
    PubMedGoogle Scholar
  • 9 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-2088
    CrossrefPubMedGoogle Scholar
  • 10 Engesser L, Broekmans AW, Briët E, Brommer EJP, Bertina RM. Hereditary protein S deficiency:clinical manifestations. Ann Intern Med 1987; 106: 0677-0682
    CrossrefPubMedGoogle Scholar
  • 11 Zöller B, Bemtsdotter A, GarcÍa de Frutos P, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-3523
    PubMedGoogle Scholar
  • 12 Dahlbäck B. Protein S and C4b-binding protein:proteins involved in the regulation of the protein C anticoagulant system. Thromb Haemost 1991; 66: 0049-0061
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Zӧller B, Garcia de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85: 3524-3531
    CrossrefPubMedGoogle Scholar
  • 14 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C:prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
    CrossrefPubMedGoogle Scholar
  • 15 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 0064-0067
    CrossrefPubMedGoogle Scholar
  • 16 Dahlbäck B. Inherited thrombophilia:Resistance to activated protein C as a pathogenic factor of venous thrombosis. Blood 1995; 85: 0607-0614
    PubMedGoogle Scholar
  • 17 Tran TH, Marbet GH, Duckert F. Association of hereditary heparin cofactor-II deficiency with thrombosis. Lancet 1985; 2: 0413-0414
    PubMedGoogle Scholar
  • 18 Sié P, Dupouy D, Pichon J, Boneu B. Constitutional heparin cofactor-II deficiency associated with recurrent thrombosis. Lancet 1985; 2: 0414-0416
    PubMedGoogle Scholar
  • 19 Aoki N, Moroi M, Sakata Y, Yoshida N. Abnormal plasminogen, a hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 1978; 61: 1186-1195
    CrossrefPubMedGoogle Scholar
  • 20 Scharrer IM, Wohl RC, Hach V, Sinio L, Boreisha I, Robbins KC. Investigation of a congenital abnormal plasminogen, Frankfurt I and its relationship with thrombosis. Thromb Haemost 1986; 55: 0396-0401
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Bithell TC. Hereditary dysfibrinogenemia. Clin Chem 1985; 31: 0509-0516
    PubMedGoogle Scholar
  • 22 Bertina RM, van der Linden IK, Engesser L, Muller HP, Brommer EJ. Hereditary heparin cofactor-II deficiency and the risk of development of thrombosis. Thromb Haemostas 1987; 57: 0196-0200
    PubMedGoogle Scholar
  • 23 Triplett DA. Protean clinical presentation of antiphospholipid-protein antibodies. Thromb Haemost 1995; 74: 0329-0337
    PubMedGoogle Scholar
  • 24 Brёt E, Engesser L, Brommer EJP, Broekmans AW, Bertina RM. Thrombophilia:its causes and a rough estimate of its prevalence [abstract]. Thromb Haemost 1987; 58: 0039
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988; 59: 0018-0022
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Ben-Tal O, Zivelin A, Seligsohn U. The relative frequency of hereditary thrombotic disorders among 107 patients with thrombophilia in Israel. Thromb Haemost 1990; 61: 0050-0054
    PubMedGoogle Scholar
  • 27 Engesser L, Brommer EJP, Kluft C, Brёt E. Elevated plasminogen activator inhibitor (PAI), a cause of thrombophilia?. A study in 203 patients with familial or sporadic thrombophilia. Thromb Haemost 1989; 62: 0673-0680
    PubMedGoogle Scholar
  • 28 Heijboer H, Brandjes DPM, Biiller HR, Sturk A, ten Cate LW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323: 1512-1516
    CrossrefPubMedGoogle Scholar
  • 29 Tabernero MD, Tomas JF, Alberca I, Orfao A, Lopez-Borrasca A, Vicente V. Incidence and clinical characteristics of hereditary disorders associated with venous thrombosis. Am J Hematol 1991; 36: 0249-0254
    CrossrefPubMedGoogle Scholar
  • 30 Bick RL, Jakway J, Baker WF. Deep vein thrombosis:prevalence of etiologic factors and results of management in consecutive patients. Sem Thromb Hemost 1992; 18: 0267-0274
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Melissari E, Monte G, Lindo VS, Pemberton KD, Wilson NV, Edmondson R, Das S, Kakkar VV. Congenital thrombophilia among patients with venous thromboembolism. Blood Coagul Fibrinol 1992; 3: 0749-0758
    CrossrefPubMedGoogle Scholar
  • 32 Malm J, Laurell M, Nilsson IM, Dahlbäck B. Thromboembolic disease. Critical evaluation of laboratory investigation. Thromb Haemost 1992; 68: 0007-0013
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Pabinger I, Briicker S, Kyrle PA, Schneider B, Kominger HC, Niessner H, Lechner K. Hereditary deficiency of antithrombin III protein C and protein S:prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinol 1992; 3: 0547-0553
    CrossrefPubMedGoogle Scholar
  • 34 Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 0504-0508
    PubMedGoogle Scholar
  • 35 GarÍ M, Falkon L, Urrutia T, Vallvé C, Borrell M, Fontcuberta J. The influence of low protein S plasma levels in young women, on the definition of normal range. Thromb Res 1994; 73: 0149-0152
    CrossrefPubMedGoogle Scholar
  • 36 Clauss A. Gerinnungsphysiologische Schenellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 0237-0246
    CrossrefPubMedGoogle Scholar
  • 37 Exner T, Rickard KA, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol 1978; 40: 0143-0151
    CrossrefPubMedGoogle Scholar
  • 38 Gharavi AE, Harris EN, Asherson RA, Hughes GRV. Anticardiolipin antibodies:isotype distribution and phospholipid specificity. Ann Rheum Dis 1987; 46: 0001-0006
    CrossrefPubMedGoogle Scholar
  • 39 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: 0106-0112
    CrossrefPubMedGoogle Scholar
  • 40 Miletich J, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 0991-0996
    CrossrefPubMedGoogle Scholar
  • 41 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. the Framingham Study. JAMA 1987; 258: 1183-1186
    CrossrefPubMedGoogle Scholar
  • 42 Koster T, Rosendaal FR, Reitsma PH, van der VeldenPA, Brёt E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms. The Leiden Thrombophilia Study. Thromb Haemost 1994; 71: 0719-0722
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Vila P, Hernandez MC, López-Fenández MF, Batlle J. Prevalence, follow-up and clinical significance of the anticardiolipin antibodies in normal subjects. Thromb Haemost 1994; 72: 0209-0213
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Forastiero RR, Kordich L, Basi lotta, Carreras LO. Differences in protein S and C4b-binding protein levels in different groups of patients with antiphospholipid antibodies. Blood Coagul Fibrinol 1994; 5: 0609-0616
    PubMedGoogle Scholar
  • 45 Parke AL, Wilson D, Maier D. The prevalence of antiphospholipid antibodies in women with recurrent spontaneous abortion, women with successful pregnancies, and women who have never been pregnant. Arthritis Rheum 1987; 30: 0601-0606
    CrossrefPubMedGoogle Scholar
  • 46 Brёt E, van der Meer FJM, Rosendaal FR, Houwing-Duistermaat JJ, van Houwelingen HC. The family history and inherited thrombophilia. Br J Haematol 1994; 87: 0348-0352
    CrossrefPubMedGoogle Scholar
  • 47 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993; 72: 0477-0480
    CrossrefPubMedGoogle Scholar
  • 48 Majerus PW. Bad blood by mutation. Nature 1994; 369: 0014-0015
    CrossrefPubMedGoogle Scholar