A Review of the Clinical and Diagnostic Utility of Laboratory Tests for the Detection of Congenital Thrombophilia

 

 Buy Article Permissions and Reprints

ABSTRACT

Laboratory tests to detect congenital thrombophilia are frequently requested by clinicians. This review attempts to define (1) whether and to what extent laboratory testing may help clinicians make decisions on patient management, (2) the types of conditions to be investigated, and (3) the types of testing to be performed for each condition.

REFERENCES

• 1 Greaves M, Baglin T. Laboratory testing for heritable thrombophilia: impact on clinical management of thrombotic disease.  Br J Haematol. 2000;  109 699-703
  CrossrefPubMedGoogle Scholar
• 2 Mannucci P M. Genetic hypercoagulability: prevention suggests testing family members.  Blood. 2001;  98 21-22
  CrossrefPubMedGoogle Scholar
• 3 De Stefano V, Finazzi G, Mannucci P M. Inherited thrombophilia: pathogenesis, clinical syndromes and management.  Blood. 1996;  87 3531-3544
  PubMedGoogle Scholar
• 4 Eichinger S, Pabinger I, Stumpflen A et al.. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden.  Thromb Haemost. 1997;  77 624-628
  PubMedGoogle Scholar
• 5 Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of anticoagulation.  Thromb Haemost. 1999;  81 684-689
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Kearon C, Gent M, Hirsh J et al.. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med. 1999;  340 901-907
  PubMedGoogle Scholar
• 7 Eichinger S, Weltermann A, Mannhalter C et al.. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism.  Arch Intern Med. 2002;  162 2357-2360
  CrossrefPubMedGoogle Scholar
• 8 Ridker P M, Miletich J P, Stampfer M J, Goldhaber S Z, Lindpaintner K, Hennekens C H. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism.  Circulation. 1995;  92 2800-2802
  CrossrefPubMedGoogle Scholar
• 9 Simioni P, Prandoni P, Lensing A W et al.. The risk of recurrent venous thromboembolism in patients with an Arg506→Gln mutation in the gene for factor V (factor V Leiden).  N Engl J Med. 1997;  336 399-403
  CrossrefPubMedGoogle Scholar
• 10 Simioni P, Prandoni P, Lensing A W et al.. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis.  Blood. 2000;  96 3329-3333
  PubMedGoogle Scholar
• 11 Eichinger S, Minar E, Hirschl M et al.. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene.  Thromb Haemost. 1999;  81 14-17
  PubMedGoogle Scholar
• 12 Miles J S, Miletich J P, Goldhaber S Z, Hennekens C H, Ridker P M. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism.  J Am Coll Cardiol. 2001;  37 215-218
  CrossrefPubMedGoogle Scholar
• 13 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood. 1995;  85 1504-1508
  PubMedGoogle Scholar
• 14 Koeleman B PC, Reitsma P H, Allaart C F, Bertina R M. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families.  Blood. 1994;  84 1031-1035
  PubMedGoogle Scholar
• 15 Zoller B, Berntsdotter A, Garcia 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
• 16 Van Boven H H, Reitsma P H, Rosendaal F R et al.. Factor V Leiden (FVR506Q) in families with inherited antithrombin deficiency.  Thromb Haemost. 1996;  75 417-421
  PubMedGoogle Scholar
• 17 Ridker P M, Hennekens C H, Selhub J, Miletich J P, Malinow M R, Stampfer M J. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and the risk of future venous thromboembolism.  Circulation. 1997;  95 1777-1782
  CrossrefPubMedGoogle Scholar
• 18 Lane D A, Bayston T, Olds R J et al.. Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.  Thromb Haemost. 1997;  77 197-211
  PubMedGoogle Scholar
• 19 Demers C, Henderson P, Blajchman M A et al.. An antithrombin III assay based on factor Xa inhibition provides a more reliable test to identify congenital antithrombin III deficiency than an assay based on thrombin inhibition.  Thromb Haemost. 1993;  69 231-235
  PubMedGoogle Scholar
• 20 Ungerstedt J S, Schulman S, Egberg N, Antovic J, Blombäck M. Discrepancy between antithrombin activity methods revealed in Antithrombin Stockholm: do factor Xa-based methods overestimate antithrombin activity in some patients?.  Blood. 2002;  99 2271-2272
  CrossrefPubMedGoogle Scholar
• 21 Perry D J, Daly M E, Tait R C et al.. Antithrombin Cambridge II (Ala384Ser): clinical, functional and haplotype analysis of 18 families.  Thromb Haemost. 1998;  79 249-253
  PubMedGoogle Scholar
• 22 Sas G, Pepper D S. Detection of thrombin-antithrombin III complex by crossed immunoelectrophoresis.  Thromb Res. 1976;  9 95-97
  CrossrefPubMedGoogle Scholar
• 23 Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in the subtypes of congenital antithrombin III deficiency: review of 404 cases.  Thromb Haemost. 1987;  58 1094
  PubMedGoogle Scholar
• 24 Reitsma P H, Bernardi F, Doig R G et al.. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH.  Thromb Haemost. 1995;  73 876-889
  PubMedGoogle Scholar
• 25 De Moerloose P, Reber G, Bouviar C A. Spuriously low levels of protein C with Protac activation clotting assay.  Thromb Haemost. 1988;  59 543
  PubMedGoogle Scholar
• 26 Simioni P, Lazzaro A, Zanardi S, Girolami A. Spurious protein C deficiency due to antiphospholipid antibodies.  Am J Hematol. 1991;  36 299-301
  PubMedGoogle Scholar
• 27 Faioni E M, Franchi F, Asti A, Mannucci P M. Resistance to activated protein C mimicking dysfunctional protein C: diagnostic approach.  Blood Coagul Fibrinolysis. 1996;  7 349-352
  PubMedGoogle Scholar
• 28 Faioni E M, Hermida J, Rovida E et al.. Type II protein C deficiency: identification and molecular modeling of two natural mutants with low anticoagulant and normal amydolitic activity.  Br J Haematol. 2000;  108 265-271
  CrossrefPubMedGoogle Scholar
• 29 Bovill E G, Tomczak J A, Grant B et al.. Protein C_Vermont: symptomatic type II protein C deficiency associated with two GLA domain mutations.  Blood. 1992;  79 1456-1465
  PubMedGoogle Scholar
• 30 Gandrille S, Borgel D, Sala N et al.. Plasma Coagulation Inhibitors. Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Protein S deficiency: a database of mutations-summary of the first update.  Thromb Haemost. 2000;  84 918
  PubMedGoogle Scholar
• 31 Preda L, Tripodi A, Valsecchi C, Lombardi A, Finotto E, Mannucci P M. A prothrombin time-based functional assay of protein S.  Thromb Res. 1990;  60 19-32
  CrossrefPubMedGoogle Scholar
• 32 Wolf M, Boyer-Neumann C, Martinoli J L et al.. A new functional assay for human protein S activity using activated factor V as substrate.  Thromb Haemost. 1989;  62 1144-1145
  PubMedGoogle Scholar
• 33 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
  PubMedGoogle Scholar
• 34 Faioni E M, Boyer-Neumann C, Franchi F, Wolf M, Meyer D, Mannucci P M. Another protein S functional assay is sensitive to resistance to activated protein C.  Thromb Haemost. 1994;  72 648
  PubMedGoogle Scholar
• 35 Malm J, Laurell M, Dahlbäck B. Changes in the plasma levels of vitamin-K dependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception.  Br J Haematol. 1988;  68 437-443
  PubMedGoogle Scholar
• 36 Amiral J, Grosley B, Boyer-Neuman C et al.. New direct assay of free protein S antigen using two distinct monoclonal antibodies specific for the free form.  Blood Coagul Fibrinolysis. 1994;  5 179-186
  PubMedGoogle Scholar
• 37 Giri T K, Hillarp A, Hardig Y, Zoller B, Dahlbäck B. A new direct, fast and quantitative enzyme-linked ligandsorbent assay for measurement of free protein S antigen.  Thromb Haemost. 1998;  79 767-772
  PubMedGoogle Scholar
• 38 Simmonds R E, Ireland H, Lane D A, Zoller B, Garcia de Frutos P, Dahlbäck B. Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect.  Ann Intern Med. 1998;  128 8-14
  PubMedGoogle Scholar
• 39 Makris M, Leach M, Beauchamp N J et al.. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S.  Blood. 2000;  95 1935-1941
  PubMedGoogle Scholar
• 40 Dahlbäck B, Carlsson M, Svensson P J. 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
• 41 Exner T, Murray B, Chong B H, Chesterman C N. Improved APC resistance method based on a Russell's Viper Venom clotting test.  Thromb Haemost. 1995;  73 1119
  PubMedGoogle Scholar
• 42 Le D T, Greegard J S, Mujumdar V, Rapaport S I. Use of a generally applicable tissue factor-dependent factor V assay to detect activated protein C-resistant factor Va in patients receiving warfarin and in patients with a lupus anticoagulant.  Blood. 1995;  85 1704-1711
  PubMedGoogle Scholar
• 43 Alhenc-Gelas M, Aillaud M F, Bonvarlet M N, Dupuy G, Juhan-Vague I, Aiach M. Specificity of an assay based on a factor V-depleted plasma in patients carrying the Arg 506 Gln mutation.  Thromb Haemost. 1996;  75 971-977
  PubMedGoogle Scholar
• 44 Hoagland L E, Triplett D A, Peng F, Barna L. APC-resistance as measured by a textarin time assay: comparison to the APTT-based method.  Thromb Res. 1996;  83 363-373
  CrossrefPubMedGoogle Scholar
• 45 Bertina R M, Koeleman B P, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 64-67
  CrossrefPubMedGoogle Scholar
• 46 Bernardi F, Faioni E M, Castoldi E et al.. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype.  Blood. 1997;  90 1552-1557
  PubMedGoogle Scholar
• 47 Williamsson D, Brown K, Luddington R, Baglin C, Baglin T. A new mutation (Arg306Thr) associated with resistance to activated protein C.  Blood. 1998;  91 1140-1144
  PubMedGoogle Scholar
• 48 Varadi K, Moritz B, Lang H et al.. A chromogenic assay for activated protein C resistance.  Br J Haematol. 1995;  90 884-889
  PubMedGoogle Scholar
• 49 Rosing J, Tans G, Nicolaes G A et al.. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives.  Br J Haematol. 1997;  97 233-238
  CrossrefPubMedGoogle Scholar
• 50 de Ronde H, Bertina R M. Laboratory diagnosis of APC resistance: a critical evaluation of the test and the development of diagnostic criteria.  Thromb Haemost. 1994;  72 880-886
  PubMedGoogle Scholar
• 51 Halbmayer D M, Hanshofer A, Schon R, Fisher M. Influence of lupus anticoagulant on a commercially available kit for APC-resistance.  Thromb Haemost. 1994;  72 645-646
  PubMedGoogle Scholar
• 52 Tripodi A, Negri B, Bertina R M, Mannucci P M. Screening of the FV:Q506 mutation. Evaluation of thirteen plasma-based methods for their diagnostic efficacy in comparison with DNA analysis.  Thromb Haemost. 1997;  77 436-439
  PubMedGoogle Scholar
• 53 Simioni P, Scudeller A, Radossi P et al.. “Pseudo homozygous” activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds.  Thromb Haemost. 1996;  75 422-426
  PubMedGoogle Scholar
• 54 Jorquera J I, Montoro J M, Angeles Fernandez M, Aznar J A, Aznar J. Modified test for activated protein C resistance.  Lancet. 1994;  344 1162-1163
  PubMedGoogle Scholar
• 55 Kraus M, Noah M, Fickensher K. The PCAT. A simple screening assay for assessing the functionality of the protein C anticoagulant pathway.  Thromb Res. 1995;  79 217-222
  CrossrefPubMedGoogle Scholar
• 56 Preda L, Simioni P, Legnani C et al.. A new global test for the evaluation of the protein C-protein S system.  Blood Coagul Fibrinolysis. 1996;  7 465-469
  PubMedGoogle Scholar
• 57 Robert A, Eschwege V, Hameg H, Drouet L, Aillaud M F. Anticoagulant response to Agkistrodon contortrix venom (ACV test): a new global test to screen for defects in the anticoagulant protein C pathway.  Thromb Haemost. 1996;  75 562-566
  PubMedGoogle Scholar
• 58 Gable P S, Le D T, McGehe W, Rapaport S I. A Protac-based screening test for activated protein-resistance factor Va and other defects of the protein C anticoagulant pathway.  Blood Coagul Fibrinolysis. 1997;  8 327-335
  PubMedGoogle Scholar
• 59 Rylatt D B, Hohnen-Behrens C, Pilgrim R L, Dickeson L E, Neal M, Exner T. Detecting APC resistant factor V: a functional method without plasma dilutions.  Blood Coagul Fibrinolysis. 1999;  10 359-366
  PubMedGoogle Scholar
• 60 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
  PubMedGoogle Scholar
• 61 Denson K WE, Haddon M E, Reed S V, Davidson S, Littlewood T J. A more discriminating test for APC resistance and possible screening test to include protein C and protein S.  Thromb Res. 1996;  81 151-156
  CrossrefPubMedGoogle Scholar
• 62 Sidelmann J, Gram J, Dyg Pedersen O, Jespersen J. Influence of plasma platelets on activated protein C resistance assay.  Thromb Haemost. 1995;  74 993-994
  PubMedGoogle Scholar
• 63 Tripodi A, Valsecchi C, Chantarangkul V, Battaglioli T, Mannucci P M. Standardisation of activated protein C resistance testing. Effect of residual platelets in frozen plasmas assessed with commercial and home made methods.  Br J Haematol. 2003;  120 825-828
  CrossrefPubMedGoogle Scholar
• 64 Tripodi A, Chantarangkul V, Negri B, Mannucci P M. Standardization of the APC-resistance test. Effects of normalization of results by means of pooled normal plasma.  Thromb Haemost. 1998;  79 564-566
  PubMedGoogle Scholar
• 65 Rosen S, Johansson K, Lindberg K, Dahlbäck B. Multicenter evaluation of a kit for activated protein C resistance on various coagulation instruments using plasma from healthy individuals.  Thromb Haemost. 1994;  72 255-260
  PubMedGoogle Scholar
• 66 Tripodi A, Peyvandi F, Chantarangkul V, Menegatti M, Mannucci P M. Relatively poor performance of clinical laboratories for DNA analyses in the detection of two thrombophilic mutations. A cause for concern.  Thromb Haemost. 2002;  88 690-691
  PubMedGoogle Scholar
• 67 de Visser M CH, Rosendaal F R, Bertina R M. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis.  Blood. 1999;  93 1271-1276
  PubMedGoogle Scholar
• 68 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism.  Ann Intern Med. 1999;  130 643-650
  PubMedGoogle Scholar
• 69 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thrombosis.  Blood. 1996;  88 3698-3703
  CrossrefPubMedGoogle Scholar
• 70 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen.  Thromb Haemost. 1995;  73 151-161
  PubMedGoogle Scholar
• 71 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis.  Thromb Haemost. 1999;  81 165-176
  PubMedGoogle Scholar
• 72 Tripodi A, Chantarangkul V, Lombardi R, Lecchi A, Mannucci P M, Cattaneo M. Multicenter study of homocysteine measurement. Performance characteristics of different methods, influence of standards on interlaboratory agreement of results.  Thromb Haemost. 2001;  85 291-295
  PubMedGoogle Scholar
• 73 Bauer K A. Conventional fibrinolytic assays for the evaluation of patients with venous thrombosis: don't bother.  Thromb Haemost. 2001;  85 377-378
  PubMedGoogle Scholar
• 74 Ariens R A, Alberio G, Moia M, Mannucci P M. Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis.  Thromb Haemost. 1999;  81 203-207
  PubMedGoogle Scholar

 Dr.
A. Tripodi

Via Pace 9, 20122 Milano, Italy

Email: armando.tripodi@unimi.it