Laboratory Screening of Inherited Thrombotic Syndromes

Summary

The prevalence of inherited thrombotic syndromes in the general population (1 in 2,500/5,000) appears to be higher than that of inherited bleeding disorders. The problems of their laboratory diagnosis are reviewed and a screening procedure is proposed. The most important candidates for screening are patients with unexplained venous thromboembolism at ages of less than 40-45 years, particularly when thrombotic episodes are recurrent. Screening must start from the exclusion of common acquired causes of thrombophilia. A negative family history does not exclude inherited thrombophilia, because the defects have a low penetrance and fresh mutations may have occurred in the propositi. Laboratory screening is based on a two-step procedure. The first step is aimed at detecting, preferably with specific functional assays. the most frequent and well established causes of inherited thrombophilia, i.e. deficiencies or dysfunctions of antithrombin III, protein C, protein S, plasminogen and fibrinogen. The tests included in the second step of the screening are aimed at detecting the less common or less well established causes of inherited thrombophitia (low heparin cofactor II, defective release of tissue plasminogen activator, and high plasminogen activator inhibitor). The simplest, more reliable and specific assay methods to be used in laboratory practice are recommended.

Keywords

Inherited thrombophilia - Antithrombin III - Protein C - Protein S - Heparin cofactor II - Plasminogen - Dysfibrinogenemia - Tissue plasminogen activator

• References

• 1 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thrombos Diath Haemorrh 1965; 13: 516-530
• 2 Gladson CL, Griffin JH, Hach V, Beck KH, Scharrer I. The incidence of protein C and protein S deficiency in young thrombotic patients. Blood 1985; 66 (Suppl. 01) 350a
• 3 Vikydal R, Korninger C, Kyrle PA, Niessner H, Pabinger I, Thaler E, Lechner K. The prevalence of hereditary antithrombin III deficiency in patients with a history of venous thromboembolism. Thromb Haemostas 1985; 54: 744-745
• 4 Fagerhol MK, Abildgaard U. Immunological studies on human antithrombin III. Influence of age, sex and use of oral contraceptives on serum concentration. Scand J Haematol 1970; 7: 10-17
• 5 Parvez Z, Fareed J, Messmore HL, Moncada R. Laser nephelometric quantitation of antithrombin III (AT III): development of a new assay. Thrombos Res 1981; 24: 367-377
• 6 Odegard OR, Lie M, Abildgaard U. Heparin cofactor activity measured with an amidolytic method. Thrombos Res 1975; 6: 287-294
• 7 Odegard OR, Lie M, Abildgaard U. Antifactor Xa activity measured with an amidolytic method. Haemostasis 1976; 5: 265-275
• 8 Sas G, Pepper DS, Cash JD. Plasma and serum antithrombin III: differentiation by crossed immunoelectrophoresis. Thrombos Res 1975; 6: 87-91
• 9 Sas G, Bánhegyi D, Peto I. Heparin affinity of antithrombin III in a family with congenital antithrombin III deficiency. Thromb Haemostas 1979; 42: 187 (Abstr)
• 10 Sas G. Congenital and acquired defects of antithrombin III. La Ricerca Clin Lab 1984; 14: 491-497
• 11 van Voorthuizen H, Kluft C. Improved assay conditions for automated antithrombin III determination with the chromogenic substrate S-2238. Thromb Haemostas 1984; 52: 350-353
• 12 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Inv 1981; 68: 1370-1373
• 13 Branson HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; 2: 1165-1168
• 14 Broekmans AW, van der Linden IK, Jansen-Koeter Y, Bertina RM. Prevalence of protein C (PC) and protein S (PS) deficiency in patients with thrombotic disease. Thrombos Res 1986; suppl. VI 135
• 15 Bertina RM, Broekmans AW, Krommenhoek-van EsC, van Wijngaarden A. The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency. Thromb Haemostas 1984; 51: 1-5
• 16 Sala N, Owen WG, Collen D. A functional assay of protein C in human plasma. Blood 1984; 63: 671-675
• 17 Francis RB, Patch MJ. A functional assay for protein C in human plasma. Thrombos Res 1983; 32: 605-613
• 18 Francis RB. A simplified PTT-based protein C activity assay using the thrombon-thrombomodulin complex. Thrombos Res 1986; 37: 337-344
• 19 Viganò-D’Angelo S, Comp PC, Esmon CT, D’Angelo A. Relationship between protein C antigen and anticoagulant activity during oral anticoagulants and in selected disease states. J Clin Inv 1986; 77: 416-425
• 20 Mannucci PM, Boyer C, Tripodi A, Viganò-D’Angelo S, Wolf M, Valsecchi C, D’Angelo A, Meyer D, Larrieu MJ. Multicenter comparison of five functional and two immunological assays for protein C. Thromb Haemostas 1987; 57: 44-48
• 21 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Inv 1984; 74: 2082-2099
• 22 Dahlback B. Interaction between vitamin-K dependent protein S and the complement protein. C4b-binding protein. A link between coagulation and the complement system. Semin Thrombos Haemostas 1984; 10: 139-148
• 23 Kamiya T, Sugihara T, Ogata K, Saito H, Suzuki K, Nishioka J, Hashimoto S, Yamagata K. Inherited deficiency of protein S in a Japanese family with recurrent venous thrombosis: a study of three generations. Blood 1986; 67: 406-410
• 24 Schwartz HP, Fisher M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300
• 25 Bertina RM, van Wijngaarden A, Reinalda-Poot J, Poort SR, Bom V JJ. Determination of plasma protein S. The protein cofactor of activated protein C. Thromb Haemostas 1985; 53: 268-272
• 26 Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504-508
• 27 Tran TH, Marbet GA, Duckert F. Association of hereditary heparin cofactor II deficiency with thrombosis. Lancet 1985; 2: 413-414
• 28 Sie P, Pichon J, Dupouy D, Boneu B. Constitutional heparin cofactor II deficiency associated with recurrent thrombosis. Lancet 1985; 2: 414-416
• 29 Bertina RM, van der Linden IK, Muller H PM, Engesser L, Brommer E JP. Hereditary heparin cofactor II deficiency and the risk of development of thrombosis. Thromb Haemostas 1987; 57: 196-200
• 30 Tran TH, Duckert F. Heparin cofactor II determination. Levels in normals and patients with hereditary antithrombin III deficiency and disseminated intravascular coagulation. Thromb Haemostas 1984; 52: 112-116
• 31 Tollefsen DM, Pestka CA. Heparin cofactor II activity in patients with disseminated intravascular coagulation and hepatic failure. Blood 1985; 66: 769-774
• 32 Abildgaard U, Larsen ML. Assay of dermatan sulfate cofactor (heparin cofactor II) activity in human plasma. Thrombos Res 1984; 35: 257-266
• 33 Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M. Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Inv 1978; 61: 1186-1195
• 34 Kazama M, Tahara C, Suzuki Z, Gohchi K, Abe T. Abnormal plasminogen, a case of recurrent thrombosis. Thrombos Res 1981; 21: 517-522
• 35 Soria J, Soria C, Bertrand O, Dunn F, Drouet L, Caen JP. Plasminogen Paris I: congenital abnormal plasminogen and its incidence in thrombosis. Thrombos Res 1983; 32: 229-238
• 36 Mannucci PM, Kluft C, Traas DW, Seveso P, D’Angelo A. Congenital plasminogen deficiency associated with venous thromboembolism: therapeutic trial with stanazolol. Brit J Haematol 1986; 63: 753-759
• 37 Friberger P, Knos M, Gustawson S, Aurell L, Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-145
• 38 Gram J, Jespersen J. A functional plasminogen assay utilizing the potentiating effect of fibrinogen to correct for the overestimation of plasminogen in pathological plasma samples. Thromb Haemostas 1985; 53: 255-259
• 39 Johansson L, Hedner U, Nilsson IM. A family with thromboembolic disease associated with deficient fibrinolytic activity in vessel wall. Acat Med Scand 1978; 203: 477-480
• 40 Jorgensen M, Mortensen JZ, Madsen AG, Thorsen S, Jacobsen B. A family with reduced plasminogen activator activity in blood associated with recurrent venous thrombosis. Scand J Haematol 1982; 29: 217-223
• 41 Stead NW, Bauer KA, Kinney TR, Lewis JG, Campbell EE, Shifman MA, Rosemberg RD, Pizzo SV. Venous thrombosis in a family with defective release of vascular plasminogen activator and elevated plasma factor VIII/von Willebrand’s factor. Am J Med 1983; 74: 33-39
• 42 Haverkate F, Brakman P. Fibrin plate assay. In: Davidson, Samama, and Desnoyers Progress in chemical fibrinolysis and thrombolysis. pp. 151-159 Raven Press; New York: 1975
• 43 Verheijen JH, Mullaart E, Chang G TG, Kluft C, Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemostas 1982; 48: 266-269
• 44 Nilsson IM, Tengborn L. Impaired fibrinolysis. New evidence in relation to thrombosis. In: Jesperson, Kluft and Korsgaard Clinical aspects of fibrinolysis and thrombolysis. pp. 273-291 South Jutland University Press; Esbjerg: 1983
• 45 Henschen A, Kehl M, Southan C, Lottspeich F, Georgopoulos D. Genetically abnormal fibrinogens - some current characterization strategies. In: Haverkate, Henschen, Nieuwenhuizen, and Straub Fibrinogen: structure, functional aspects, metabolism. pp. 125-144 Walter de Gruyter; Berlin: 1983
• 46 Rocha E, Paramo JA, Arauda A, Cuesta B, Fernandez J. Congenital dysfibrinogenemia. A review. La Ricerca Clin Lab 1985; 15: 205-229
• 47 Rodgers GM, Shuman MA. Congenital thrombotic disorders. Am J Haematol 1986; 21: 419-430