Laboratory Detection of Inherited Thrombophilia: A Historical Perspective

ABSTRACT

Considerable progress has been made in determining the molecular bases of inherited thrombophilia in the last 25 years. There are several genetic abnormalities that can be detected in the laboratory and are currently recognized to be unequivocally associated with an increased tendency to develop venous thrombosis. Testing for inherited and acquired causes of thrombophilia may make counseling more focused in ostensibly healthy members of thrombophilic families (i.e., those in which a measurable abnormality was identified in one or more asymptomatic persons). In other situations, including women who start taking oral contraceptives, become pregnant, or consider hormone replacement therapy, screening is generally not useful. It is hoped that because we currently have such simple and clinically useful global tests of hypocoagulability as the prothrombin time and activated partial thromboplastin time, it may soon become possible to measure multifactorial thrombophilia without resorting to the multiplicity of tests now necessary.

Thrombophilia - factor V Leiden - prothrombin gene mutation - hypercoagulability - laboratory testing

REFERENCES

• 1 Rokitansky C. Pathological Anatomy, IV. London; Sydenham Society 1852
• 2 Virchow R. Cellular Pathology. London; Churchill 1860
• 3 Kamphuisen P W, Eikenboom J CJ, Bertina R M. Elevated factor VIII levels and the risk of thrombosis.  Arterioscler Thromb Vasc Biol. 2001;  21 731-738
• 4 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-520
• 5 Griffin J H, Evatt B, Zimmerman T, Kleiss A, Wideman C. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest. 1981;  68 1370-1373
• 6 Comp P C, Esmon C T. Recurrent venous thromboembolism in patients with a partial deficiency of protein S.  N Engl J Med. 1984;  311 1525-1528
• 7 Schwartz H P, Fischer M, Hopmeier P, Batard M, Griffin J. Plasma protein S deficiency in familial thrombotic disease.  Blood. 1984;  64 1297-1300
• 8 Kalafatis M, Rand M D, Mann K G. The mechanism of inactivation of human factor V and human factor Va by activated protein C.  J Biol Chem. 1994;  269 31869-31880
• 9 Branson H E, Katz J, Marble R, Griffin J H. Inherited protein C deficiency and coumarin‐responsive chronic relapsing purpura fulminans in a newborn infant.  Lancet. 1983;  2 1165-1168
• 10 Mahasandana C, Suvatte V, Marlar R A, Manco-Johnson M J, Jacobson L J, Hathaway W E. Neonatal purpura fulminans associated with homozygous protein S deficiency.  Lancet. 1990;  335 61-62
• 11 Dahlbäck B, Carlsson M, Svensson P J. Familial thrombophilia due to a previously unrecognised 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
• 12 Griffin J H, Evatt B, Wideman C, Fernandez J A. Anticoagulant protein C pathway defective in majority of thrombophilic patients.  Blood. 1993;  82 1989-1993
• 13 Koster T, Rosendaal F R, de Ronde H, Briët E, Vandenbroucke J P, Bertina R M. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.  Lancet. 1993;  342 1503-1506
• 14 Faioni E M, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci P M. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay.  Thromb Haemost. 1993;  70 1067-1071
• 15 Dahlbäck B. The discovery of activated protein C resistance.  J Thromb Haemost. 2003;  1 3-9
• 16 Bertina R M, Koeleman BP C, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 64-67
• 17 Kalafatis M, Bertina R M, Rand M D, Mann K G. Characterization of the molecular defect in factor V R506Q.  J Biol Chem. 1995;  270 4053-4057
• 18 Poort S R, Rosendaal F R, Reitsma P M, Bertina R M. A common genetic variation in the 3′‐untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood. 1996;  88 3698-3703
• 19 Lane D A, Mannucci P M, Bauer K A et al.. Inherited thrombophilia: Part 1.  Thromb Haemost. 1996;  76 651-662
• 20 Lane D A, Mannucci P M, Bauer K A et al.. Inherited thrombophilia: Part 2.  Thromb Haemost. 1996;  76 824-834
• 21 Chan W P, Lee C K, Kwong Y L, Lam C K, Liang R. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese.  Blood. 1998;  91 1135-1139
• 22 Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C.  Blood. 1998;  91 1140-1144
• 23 Roelse J C, Koopman M M, Büller H R et al.. Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis.  Br J Haematol. 1996;  92 740-743
• 24 Bokarewa M I, Falk G, Bremme K, Blombäck M, Wiman B. Search for mutations in the genes for coagulation factors V and VIII with a possible predisposition to activated protein C resistance.  Eur J Clin Invest. 1997;  27 340-345
• 25 Ceelie H, Bertina R M, van Hylckama Vlieg A, Rosendaal F R, Vos H L. Polymorphisms in the prothrombin gene and their association with plasma prothrombin levels.  Thromb Haemost. 2001;  85 1066-1070
• 26 Souto J C, Almasy L, Borrell M et al.. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia.  Am J Hum Genet. 2000;  67 1452-1459
• 27 Souto J C, Almasy L, Borrell M et al.. Genetic determinants of hemostasis phenotypes in Spanish families.  Circulation. 2000;  101 1546-1551
• 28 Soria JM, Almasy L, Souto J C et al.. A quantitative‐trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease.  Am J Hum Genet. 2002;  70 567-574
• 29 Soria J M, Almasy L, Souto J C et al.. A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility.  Blood. 2003;  101 163-167
• 30 Robert A, Eschwage V, Hameg H, Drouet L, Aillaud M F. Anticoagulant response to Agkistrodon contortrix venom (AVC test): a new global test to screen for defects in the anticoagulant protein C pathway.  Thromb Haemost. 1996;  75 562-566
• 31 Tripodi A, Akhavan S, Asti D, Faioni E M, Mannucci P M. Laboratory screening of thrombophilia. Evaluation of the diagnostic efficacy of a global test to detect congenital deficiencies of the protein C anticoagulant pathway.  Blood Coagul Fibrinolysis. 1998;  9 485-489
• 32 Rosendaal F R, van der Meer FJ, de Visser M C, Wagner C. ProcC global screening test and the risk of thrombosis.  Thromb Haemost. 1999;  82(suppl) 731
• 33 Curvers J, Christella M, Thomassen L G et al.. Effects of hereditary and acquired risk factors of venous thrombosis on a tissue‐factor based APC‐resistance test.  Thromb Haemost. 2002;  88 5-11
• 34 Rosing J, Middeldorp S, Curvers J et al.. Low dose oral contraceptives and acquired resistance to activated protein C: a randomized cross‐over study.  Lancet. 1999;  354 2036-2040
• 35 Hemker H C, Wielders S, Kessels H, Beguin S. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential.  Thromb Haemost. 1993;  70 617-624
• 36 Rottevell R C, Roozendaal K J, Eijsman L, Hemker H C. The influence of oral contraceptives on the time integral of thrombin generation (thrombin potential).  Thromb Haemost. 1993;  70 959-962
• 37 Kyrle P A, Mannhalter C, Beguin S et al.. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene.  Arterioscler Thromb Vasc Biol. 1998;  18 1287-1291
• 38 Wielders S, Mukherjee M, Michiels J et al.. The routine determination of the endogenous thrombin potential, first results in different forms of hyper‐ and hypocoagulability.  Thromb Haemost. 1997;  77 629-636
• 39 Tripodi A, Mannucci P M. Laboratory investigation of thrombophilia.  Clin Chem. 2001;  47 1597-1606