Download PDF
Semin Thromb Hemost 2024; 50(08): 1131-1152
DOI: 10.1055/s-0044-1786807
Review Article

Thrombophilia Screening: Not So Straightforward

Gary W. Moore
1   Specialist Haemostasis Laboratory, Cambridge Haemophilia and Thrombophilia Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
2   Department of Natural Sciences, Middlesex University, London, United Kingdom
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

Although inherited thrombophilias are lifelong risk factors for a first thrombotic episode, progression to thrombosis is multifactorial and not all individuals with inherited thrombophilia develop thrombosis in their lifetimes. Consequently, indiscriminate screening in patients with idiopathic thrombosis is not recommended, since presence of a thrombophilia does not necessarily predict recurrence or influence management, and testing should be selective. It follows that a decision to undertake laboratory detection of thrombophilia should be aligned with a concerted effort to identify any significant abnormalities, because it will inform patient management. Deficiencies of antithrombin and protein C are rare and usually determined using phenotypic assays assessing biological activities, whereas protein S deficiency (also rare) is commonly detected with antigenic assays for the free form of protein S since available activity assays are considered to lack specificity. In each case, no single phenotypic assay is capable of detecting every deficiency, because the various mutations express different molecular characteristics, rendering thrombophilia screening repertoires employing one assay per potential deficiency, of limited effectiveness. Activated protein C resistance (APCR) is more common than discrete deficiencies of antithrombin, protein C, and protein S and also often detected initially with phenotypic assays; however, some centres perform only genetic analysis for factor V Leiden, as this is responsible for most cases of hereditary APCR, accepting that acquired APCR and rare F5 mutations conferring APCR will go undetected if only factor V Leiden is evaluated. All phenotypic assays have interferences and limitations, which must be factored into decisions about if, and when, to test, and be given consideration in the laboratory during assay performance and interpretation. This review looks in detail at performance and limitations of routine phenotypic thrombophilia assays.

Keywords

activated protein C resistance - antithrombin - protein C - protein S - thrombophilia


Publication History

Article published online:
11 May 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Colucci G, Tsakiris DA. Thrombophilia screening revisited: an issue of personalized medicine. J Thromb Thrombolysis 2020; 49 (04) 618-629
    CrossrefPubMedGoogle Scholar
  • 2 Colucci G, Tsakiris DA. Thrombophilia screening: universal, selected, or neither?. Clin Appl Thromb Hemost 2017; 23 (08) 893-899
    CrossrefPubMedGoogle Scholar
  • 3 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (01) e1-e47
    CrossrefPubMedGoogle Scholar
  • 4 Heit JA. Thrombophilia: common questions on laboratory assessment and management. Hematology (Am Soc Hematol Educ Program) 2007; 2007: 127-135
    CrossrefPubMedGoogle Scholar
  • 5 Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008; 112 (01) 19-27
    CrossrefPubMedGoogle Scholar
  • 6 Zöller B, Svensson PJ, Dahlbäck B, Lind-Hallden C, Hallden C, Elf J. Genetic risk factors for venous thromboembolism. Expert Rev Hematol 2020; 13 (09) 971-981
    CrossrefPubMedGoogle Scholar
  • 7 Arachchillage DJ, Mackillop L, Chandratheva A, Motawani J, MacCallum P, Laffan M. Thrombophilia testing: a British Society for Haematology guideline. Br J Haematol 2022; 198 (03) 443-458
    CrossrefPubMedGoogle Scholar
  • 8 Mannucci PM, Franchini M. Classic thrombophilic gene variants. Thromb Haemost 2015; 114 (05) 885-889
    PubMedGoogle Scholar
  • 9 Van Cott EM, Khor B, Zehnder JL, Factor V. Factor V Leiden. Am J Hematol 2016; 91 (01) 46-49
    CrossrefPubMedGoogle Scholar
  • 10 Rolla R, Pergolini P, Vidali M. et al. Routine coagulation tests are not useful as a screening tool for the FII G20210A polymorphism. Clin Lab 2014; 60 (10) 1725-1733
    PubMedGoogle Scholar
  • 11 Nicolaes GA, Dahlbäck B. Activated protein C resistance (FV(Leiden)) and thrombosis: factor V mutations causing hypercoagulable states. Hematol Oncol Clin North Am 2003; 17 (01) 37-61 , vi
    CrossrefPubMedGoogle Scholar
  • 12 Kujovich JL, Factor V. Factor V Leiden thrombophilia. Genet Med 2011; 13 (01) 1-16
    CrossrefPubMedGoogle Scholar
  • 13 Middeldorp S, Nieuwlaat R, Baumann Kreuziger L. et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv 2023; 7 (22) 7101-7138
    CrossrefPubMedGoogle Scholar
  • 14 Kudo M, Lee HL, Yang IA, Masel PJ. Utility of thrombophilia testing in patients with venous thrombo-embolism. J Thorac Dis 2016; 8 (12) 3697-3703
    CrossrefPubMedGoogle Scholar
  • 15 Connors JM. Thrombophilia testing and venous thrombosis. N Engl J Med 2017; 377 (12) 1177-1187
    CrossrefPubMedGoogle Scholar
  • 16 De Stefano V, Rossi E. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost 2013; 110 (04) 697-705
    PubMedGoogle Scholar
  • 17 Stevens SM, Woller SC, Bauer KA. et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis 2016; 41 (01) 154-164
    CrossrefPubMedGoogle Scholar
  • 18 MacCallum P, Bowles L, Keeling D. Diagnosis and management of heritable thrombophilias. BMJ 2014; 349: g4387
    CrossrefPubMedGoogle Scholar
  • 19 Middeldorp S. Inherited thrombophilia: a double-edged sword. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 20 Franchini M. The utility of thrombophilia testing. Clin Chem Lab Med 2014; 52 (04) 495-497
    CrossrefPubMedGoogle Scholar
  • 21 Fell C, Ivanovic N, Johnson SA, Seegers WH. Differentiation of plasma antithrombin activities. Proc Soc Exp Biol Med 1954; 85 (02) 199-202
    CrossrefPubMedGoogle Scholar
  • 22 Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med 2002; 126 (11) 1326-1336
    CrossrefPubMedGoogle Scholar
  • 23 Rezaie AR, Giri H. Anticoagulant and signaling functions of antithrombin. J Thromb Haemost 2020; 18 (12) 3142-3153
    CrossrefPubMedGoogle Scholar
  • 24 Muszbek L, Bereczky Z, Kovács B, Komáromi I. Antithrombin deficiency and its laboratory diagnosis. Clin Chem Lab Med 2010; 48 (Suppl. 01) S67-S78
    PubMedGoogle Scholar
  • 25 Pabinger I, Thaler J. How I treat patients with hereditary antithrombin deficiency. Blood 2019; 134 (26) 2346-2353
    CrossrefPubMedGoogle Scholar
  • 26 Law RH, Zhang Q, McGowan S. et al. An overview of the serpin superfamily. Genome Biol 2006; 7 (05) 216
    CrossrefPubMedGoogle Scholar
  • 27 Opal SM, Kessler CM, Roemisch J, Knaub S. Antithrombin, heparin, and heparan sulfate. Crit Care Med 2002; 30 (5, Suppl): S325-S331
    CrossrefPubMedGoogle Scholar
  • 28 Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW. The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci U S A 1997; 94 (26) 14683-14688
    CrossrefPubMedGoogle Scholar
  • 29 Liu J, Pedersen LC. Anticoagulant heparan sulfate: structural specificity and biosynthesis. Appl Microbiol Biotechnol 2007; 74 (02) 263-272
    CrossrefPubMedGoogle Scholar
  • 30 Swedenborg J. The mechanisms of action of alpha- and beta-isoforms of antithrombin. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 03) S7-S10
    PubMedGoogle Scholar
  • 31 Teitel JM, Rosenberg RD. Protection of factor Xa from neutralization by the heparin-antithrombin complex. J Clin Invest 1983; 71 (05) 1383-1391
    CrossrefPubMedGoogle Scholar
  • 32 Weitz JI. Heparan sulfate: antithrombotic or not?. J Clin Invest 2003; 111 (07) 952-954
    CrossrefPubMedGoogle Scholar
  • 33 Egeberg O. Thrombophilia caused by inheritable deficiency of blood antithrombin. Scand J Clin Lab Invest 1965; 17: 92
    CrossrefPubMedGoogle Scholar
  • 34 Bravo-Pérez C, de la Morena-Barrio ME, Vicente V, Corral J. Antithrombin deficiency as a still underdiagnosed thrombophilia: a primer for internists. Pol Arch Intern Med 2020; 130 (10) 868-877
    PubMedGoogle Scholar
  • 35 Alhenc-Gelas M, Plu-Bureau G, Hugon-Rodin J, Picard V, Horellou MH. GFHT study group on Genetic Thrombophilia. Thrombotic risk according to SERPINC1 genotype in a large cohort of subjects with antithrombin inherited deficiency. Thromb Haemost 2017; 117 (06) 1040-1051
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008; 14 (06) 1229-1239
    CrossrefPubMedGoogle Scholar
  • 37 Corral J, de la Morena-Barrio ME, Vicente V. The genetics of antithrombin. Thromb Res 2018; 169: 23-29
    CrossrefPubMedGoogle Scholar
  • 38 Brown SA, Mitchell M, Cutler JA, Moore G, Smith MP, Savidge GF. Rapid genetic diagnosis in neonatal pulmonary artery thrombosis caused by homozygous antithrombin Budapest 3. Clin Appl Thromb Hemost 2000; 6 (03) 181-183
    CrossrefPubMedGoogle Scholar
  • 39 Van Cott EM, Orlando C, Moore GW, Cooper PC, Meijer P, Marlar R. Subcommittee on Plasma Coagulation Inhibitors. Recommendations for clinical laboratory testing for antithrombin deficiency; communication from the SSC of the ISTH. J Thromb Haemost 2020; 18 (01) 17-22
    CrossrefPubMedGoogle Scholar
  • 40 Cooper PC, Coath F, Daly ME, Makris M. The phenotypic and genetic assessment of antithrombin deficiency. Int J Lab Hematol 2011; 33 (03) 227-237
    CrossrefPubMedGoogle Scholar
  • 41 Kovács B, Bereczky Z, Oláh Z. et al. The superiority of anti-FXa assay over anti-FIIa assay in detecting heparin-binding site antithrombin deficiency. Am J Clin Pathol 2013; 140 (05) 675-679
    CrossrefPubMedGoogle Scholar
  • 42 Moser KA, Smock KJ. Direct oral anticoagulant (DOAC) interference in hemostasis assays. Hematology (Am Soc Hematol Educ Program) 2021; 2021 (01) 129-133
    CrossrefPubMedGoogle Scholar
  • 43 Smogorzewska A, Brandt JT, Chandler WL. et al. Effect of fondaparinux on coagulation assays: results of College of American Pathologists proficiency testing. Arch Pathol Lab Med 2006; 130 (11) 1605-1611
    CrossrefPubMedGoogle Scholar
  • 44 Van Blerk M, Bailleul E, Chatelain B. et al. Influence of dabigatran and rivaroxaban on routine coagulation assays. A nationwide Belgian survey. Thromb Haemost 2015; 113 (01) 154-164
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Favresse J, Lardinois B, Sabor L. et al. Evaluation of the DOAC-Stop® procedure to overcome the effect of DOACs on several thrombophilia screening tests. TH Open 2018; 2 (02) e202-e209
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Antovic J, Söderström J, Karlman B, Blombäck M. Evaluation of a new immunoturbidimetric test (Liatest antithrombin III) for determination of antithrombin antigen. Clin Lab Haematol 2001; 23 (05) 313-316
    CrossrefPubMedGoogle Scholar
  • 47 Heit JA. Thrombophilia: clinical and laboratory assessment and management. In: Kitchens CS, Alving BM, Kessler CM. eds. Consultative Hemostasis and Thrombosis. 2nd ed.. Philadelphia: Saunders; 2007: 213-244
    Google Scholar
  • 48 Kovács B, Bereczky Z, Selmeczi A. et al. Progressive chromogenic anti-factor Xa assay and its use in the classification of antithrombin deficiencies. Clin Chem Lab Med 2014; 52 (12) 1797-1806
    CrossrefPubMedGoogle Scholar
  • 49 Chowdhury V, Mille B, Olds RJ. et al. Antithrombins Southport (Leu 99 to Val) and Vienna (Gln 118 to Pro): two novel antithrombin variants with abnormal heparin binding. Br J Haematol 1995; 89 (03) 602-609
    CrossrefPubMedGoogle Scholar
  • 50 Moore GW, de Jager N, Cutler JA. Development of a novel, rapid assay for detection of heparin-binding defect antithrombin deficiencies: the heparin-antithrombin binding (HAB) ratio. Thromb Res 2015; 135 (01) 161-166
    CrossrefPubMedGoogle Scholar
  • 51 Corral J, Hernandez-Espinosa D, Soria JM. et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood 2007; 109 (10) 4258-4263
    CrossrefPubMedGoogle Scholar
  • 52 Perry DJ, Daly ME, Tait RC. et al. Antithrombin Cambridge II (Ala384Ser): clinical, functional and haplotype analysis of 18 families. Thromb Haemost 1998; 79 (02) 249-253
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Olson ST, Stephens AW, Hirs CH, Bock PE, Björk I. Kinetic characterization of the proteinase binding defect in a reactive site variant of the serpin, antithrombin. Role of the P1′ residue in transition-state stabilization of antithrombin-proteinase complex formation. J Biol Chem 1995; 270 (17) 9717-9724
    CrossrefPubMedGoogle Scholar
  • 54 Ungerstedt JS, Schulman S, Egberg N, Antovic J, Blombäck N. Discrepancy between antithrombin activity methods revealed in antithrombin Stockholm: do factor Xa-based methods overestimate antithrombin activity in some patients?. Blood 2002; 99 (06) 2271-2272
    CrossrefPubMedGoogle Scholar
  • 55 Lane DA, Lowe GD, Flynn A, Thompson E, Ireland H, Erdjument H. Antithrombin III Glasgow: a variant with increased heparin affinity and reduced ability to inactivate thrombin, associated with familial thrombosis. Br J Haematol 1987; 66 (04) 523-527
    CrossrefPubMedGoogle Scholar
  • 56 Beauchamp NJ, Pike RN, Daly M. et al. Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation. Blood 1998; 92 (08) 2696-2706
    CrossrefPubMedGoogle Scholar
  • 57 Bravo-Pérez C, de la Morena-Barrio ME, de la Morena-Barrio B. et al. Molecular and clinical characterization of transient antithrombin deficiency: a new concept in congenital thrombophilia. Am J Hematol 2022; 97 (02) 216-225
    CrossrefPubMedGoogle Scholar
  • 58 Bruce D, Perry DJ, Borg JY, Carrell RW, Wardell MR. Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn–>Asp). J Clin Invest 1994; 94 (06) 2265-2274
    CrossrefPubMedGoogle Scholar
  • 59 Picard V, Bauters A, Khairy M. et al. Conformational Asn187Asp/Lys antithrombin variants and thrombosis. Clinical and biological features in 13 new heterozygotes. Thromb Haemost 2005; 93 (01) 57-62
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Navarro-Fernández J, de la Morena-Barrio ME, Padilla J. et al. Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency. Thromb Haemost 2016; 116 (01) 146-154
    PubMedGoogle Scholar
  • 61 Weronska A, De la Morena-Barrio B, Goldman-Mazur S. et al. Functional, biochemical, molecular and clinical characterization of antithrombin c.1157T>C (p.Ile386Thr), a recurrent Polish variant with a founder effect. Haematologica 2023; 108 (10) 2803-2807
    CrossrefPubMedGoogle Scholar
  • 62 de la Morena-Barrio ME, Suchon P, Jacobsen EM. et al. Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays. Blood 2022; 140 (02) 140-151
    CrossrefPubMedGoogle Scholar
  • 63 Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia 2008; 14 (06) 1214-1221
    CrossrefPubMedGoogle Scholar
  • 64 Stenflo J. A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization. J Biol Chem 1976; 251 (02) 355-363
    CrossrefPubMedGoogle Scholar
  • 65 Dahlbäck B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005; 25 (07) 1311-1320
    CrossrefPubMedGoogle Scholar
  • 66 Thiyagarajan M, Cheng T, Zlokovic BV. Endothelial cell protein C receptor: role beyond endothelium?. Circ Res 2007; 100 (02) 155-157
    CrossrefPubMedGoogle Scholar
  • 67 Loghmani H, Conway EM. Exploring traditional and nontraditional roles for thrombomodulin. Blood 2018; 132 (02) 148-158
    CrossrefPubMedGoogle Scholar
  • 68 Kottke-Marchant K, Comp P. Laboratory issues in diagnosing abnormalities of protein C, thrombomodulin, and endothelial cell protein C receptor. Arch Pathol Lab Med 2002; 126 (11) 1337-1348
    CrossrefPubMedGoogle Scholar
  • 69 Nicolaes GA, Dahlbäck B. Factor V and thrombotic disease: description of a Janus-faced protein. Arterioscler Thromb Vasc Biol 2002; 22 (04) 530-538
    CrossrefPubMedGoogle Scholar
  • 70 Dinarvand P, Moser KA, Protein C. Deficiency. Arch Pathol Lab Med 2019; 143 (10) 1281-1285
    CrossrefPubMedGoogle Scholar
  • 71 Bahou WF. Thrombin's faces revealed: cellular effects include induction of neoangiogenesis. J Thromb Haemost 2003; 1 (10) 2078-2080
    CrossrefPubMedGoogle Scholar
  • 72 MacMahon A. The realm of Janus: Doorways in the Roman World. In: Carr G, Swift E, Weekes J. eds. TRAC 2002: Proceedings of the Twelfth Annual Theoretical Roman Archaeology Conference, Canterbury 2002. Oxford: Oxbow Books; 2003: 58-73
    Google Scholar
  • 73 Suzuki K. The multi-functional serpin, protein C inhibitor: beyond thrombosis and hemostasis. J Thromb Haemost 2008; 6 (12) 2017-2026
    CrossrefPubMedGoogle Scholar
  • 74 Marlar RA, Gausman JN. Laboratory testing issues for protein C, protein S, and antithrombin. Int J Lab Hematol 2014; 36 (03) 289-295
    CrossrefPubMedGoogle Scholar
  • 75 Minford A, Brandão LR, Othman M. et al. Diagnosis and management of severe congenital protein C deficiency (SCPCD): communication from the SSC of the ISTH. J Thromb Haemost 2022; 20 (07) 1735-1743
    CrossrefPubMedGoogle Scholar
  • 76 Tripodi A, Franchi F, Krachmalnicoff A, Mannucci PM. Asymptomatic homozygous protein C deficiency. Acta Haematol 1990; 83 (03) 152-155
    CrossrefPubMedGoogle Scholar
  • 77 Shakoor MT, Ayub S, Ayub Z. Warfarin induced skin necrosis: a diagnostic challenge. MOJ Clin Med Case Rep 2017; 6: 21-22
    PubMedGoogle Scholar
  • 78 Khor B, Van Cott EM. Laboratory tests for protein C deficiency. Am J Hematol 2010; 85 (06) 440-442
    CrossrefPubMedGoogle Scholar
  • 79 Cooper PC, Pavlova A, Moore GW, Hickey KP, Marlar RA. Recommendations for clinical laboratory testing for protein C deficiency, for the subcommittee on plasma coagulation inhibitors of the ISTH. J Thromb Haemost 2020; 18 (02) 271-277
    CrossrefPubMedGoogle Scholar
  • 80 Moore GW. Snake venoms in diagnostic hemostasis and thrombosis. Semin Thromb Hemost 2022; 48 (02) 145-160
    Article in Thieme ConnectPubMedGoogle Scholar
  • 81 Cooper PC, Hill M, Maclean RM. The phenotypic and genetic assessment of protein C deficiency. Int J Lab Hematol 2012; 34 (04) 336-346
    CrossrefPubMedGoogle Scholar
  • 82 Simioni P, Lazzaro A, Zanardi S, Girolami A. Spurious protein C deficiency due to antiphospholipid antibodies. Am J Hematol 1991; 36 (04) 299-301
    CrossrefPubMedGoogle Scholar
  • 83 Favre R, Zia-Chahabi S, Talb Y, de Gunzburg N, Flaujac C. Direct oral anticoagulant neutralization by activated charcoal DOAC-remove for thrombophilia screening. Blood Coagul Fibrinolysis 2021; 32 (05) 356-358
    CrossrefPubMedGoogle Scholar
  • 84 Ruinemans-Koerts J, Peterse-Stienissen I, Verbruggen B. Non-parallelism in the one-stage coagulation factor assay is a phenomenon of lupus anticoagulants and not of individual factor inhibitors. Thromb Haemost 2010; 104 (05) 1080-1082
    PubMedGoogle Scholar
  • 85 Mackie IJ, Gallimore M, Machin SJ. Contact factor proteases and the complexes formed with alpha 2-macroglobulin can interfere in protein C assays by cleaving amidolytic substrates. Blood Coagul Fibrinolysis 1992; 3 (05) 589-595
    CrossrefPubMedGoogle Scholar
  • 86 Han P, Fung KP, Rahdakrishnan U. Lack of agreement of chromogenic and clotting assays for factor X and protein C in warfarinised plasma. Thromb Haemost 1991; 65 (04) 360-363
    Article in Thieme ConnectPubMedGoogle Scholar
  • 87 Bovill EG, Tomczak JA, Grant B. et al. Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations. Blood 1992; 79 (06) 1456-1465
    CrossrefPubMedGoogle Scholar
  • 88 Gaussem P, Gandrille S, Duchemin J. et al. Influence of six mutations of the protein C gene on the Gla domain conformation and calcium affinity. Thromb Haemost 1994; 71 (06) 748-754
    Article in Thieme ConnectPubMedGoogle Scholar
  • 89 Seidel H, Haracska B, Naumann J, Westhofen P, Hass MS, Kruppenbacher JP. Laboratory limitations of excluding hereditary protein C deficiency by chromogenic assay: discrepancies of phenotype and genotype. Clin Appl Thromb Hemost 2020; 26: 1076029620912028
    CrossrefPubMedGoogle Scholar
  • 90 Cooper PC, Siddiq S, Morse C, Nightingale J, Mumford AD. Marked discrepancy between coagulometric protein C activity assays with the pro-thrombotic protein C Asn2Ile substitution. Int J Lab Hematol 2011; 33 (05) 451-456
    CrossrefPubMedGoogle Scholar
  • 91 Noguchi K, Nakazono E, Tsuda T. et al. Plasma phenotypes of protein S Lys196Glu and protein C Lys193del variants prevalent among young Japanese women. Blood Coagul Fibrinolysis 2019; 30 (08) 393-400
    CrossrefPubMedGoogle Scholar
  • 92 Efthymiou M, Arachchillage DRJ, Lane PJ. et al. Antibodies against TFPI and protein C are associated with a severe thrombotic phenotype in patients with and without antiphospholipid syndrome. Thromb Res 2018; 170: 60-68
    CrossrefPubMedGoogle Scholar
  • 93 MacCallum PK, Cooper JA, Martin J, Howarth DJ, Meade TW, Miller GJ. Associations of protein C and protein S with serum lipid concentrations. Br J Haematol 1998; 102 (02) 609-615
    CrossrefPubMedGoogle Scholar
  • 94 Cushman M, Psaty BM, Meilahn EN, Dobs AS, Kuller LH. Post-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women. Br J Haematol 2001; 114 (01) 162-168
    CrossrefPubMedGoogle Scholar
  • 95 Said JM, Ignjatovic V, Monagle PT, Walker SP, Higgins JR, Brennecke SP. Altered reference ranges for protein C and protein S during early pregnancy: implications for the diagnosis of protein C and protein S deficiency during pregnancy. Thromb Haemost 2010; 103 (05) 984-988
    Article in Thieme ConnectPubMedGoogle Scholar
  • 96 Monagle P, Barnes C, Ignjatovic V. et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95 (02) 362-372
    Article in Thieme ConnectPubMedGoogle Scholar
  • 97 Toulon P. Developmental hemostasis: laboratory and clinical implications. Int J Lab Hematol 2016; 38 (Suppl. 01) 66-77
    CrossrefPubMedGoogle Scholar
  • 98 Appel IM, Grimminck B, Geerts J, Stigter R, Cnossen MH, Beishuizen A. Age dependency of coagulation parameters during childhood and puberty. J Thromb Haemost 2012; 10 (11) 2254-2263
    CrossrefPubMedGoogle Scholar
  • 99 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70 (01) 165-172
    CrossrefPubMedGoogle Scholar
  • 100 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80 (08) 1998-2005
    CrossrefPubMedGoogle Scholar
  • 101 Toulon P, Berruyer M, Brionne-François M. et al. Age dependency for coagulation parameters in paediatric populations. Results of a multicentre study aimed at defining the age-specific reference ranges. Thromb Haemost 2016; 116 (01) 9-16
    PubMedGoogle Scholar
  • 102 Attard C, van der Straaten T, Karlaftis V, Monagle P, Ignjatovic V. Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 2013; 11 (10) 1850-1854
    CrossrefPubMedGoogle Scholar
  • 103 Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Wu KK. Correlation of plasma protein C levels with cardiovascular risk factors in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) study. Thromb Haemost 1993; 70 (05) 762-767
    Article in Thieme ConnectPubMedGoogle Scholar
  • 104 Tait RC, Walker ID, Islam SI. et al. Protein C activity in healthy volunteers–influence of age, sex, smoking and oral contraceptives. Thromb Haemost 1993; 70 (02) 281-285
    Article in Thieme ConnectPubMedGoogle Scholar
  • 105 Lowe GD, Rumley A, Woodward M. et al. Epidemiology of coagulation factors, inhibitors and activation markers: the Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997; 97 (04) 775-784
    CrossrefPubMedGoogle Scholar
  • 106 Franchi F, Biguzzi E, Martinelli I. et al. Normal reference ranges of antithrombin, protein C and protein S: effect of sex, age and hormonal status. Thromb Res 2013; 132 (02) e152-e157
    CrossrefPubMedGoogle Scholar
  • 107 Rodeghiero F, Tosetto A. The VITA Project: population-based distributions of protein C, antithrombin III, heparin-cofactor II and plasminogen–relationship with physiological variables and establishment of reference ranges. Thromb Haemost 1996; 76 (02) 226-233
    Article in Thieme ConnectPubMedGoogle Scholar
  • 108 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341 (8838): 134-138
    CrossrefPubMedGoogle Scholar
  • 109 Di Scipio RG, Hermodson MA, Yates SG, Davie EW. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry 1977; 16 (04) 698-706
    CrossrefPubMedGoogle Scholar
  • 110 Ahnström J, Andersson HM, Canis K. et al. Activated protein C cofactor function of protein S: a novel role for a γ-carboxyglutamic acid residue. Blood 2011; 117 (24) 6685-6693
    CrossrefPubMedGoogle Scholar
  • 111 Hackeng TM, Maurissen LF, Castoldi E, Rosing J. Regulation of TFPI function by protein S. J Thromb Haemost 2009; 7 (Suppl. 01) 165-168
    CrossrefPubMedGoogle Scholar
  • 112 Gierula M, Ahnström J. Anticoagulant protein S-New insights on interactions and functions. J Thromb Haemost 2020; 18 (11) 2801-2811
    CrossrefPubMedGoogle Scholar
  • 113 Dahlbäck B, Guo LJ, Livaja-Koshiar R, Tran S. Factor V-short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors. Res Pract Thromb Haemost 2017; 2 (01) 114-124
    CrossrefPubMedGoogle Scholar
  • 114 Gierula M, Noakes VM, Salles-Crawley II, Crawley JTB, Ahnström J. The TFPIα C-terminal tail is essential for TFPIα-FV-short-protein S complex formation and synergistic enhancement of TFPIα. J Thromb Haemost 2023; 21 (12) 3568-3580
    CrossrefPubMedGoogle Scholar
  • 115 Dahlbäck B. The tale of protein S and C4b-binding protein, a story of affection. Thromb Haemost 2007; 98 (01) 90-96
    PubMedGoogle Scholar
  • 116 Maurissen LF, Thomassen MC, Nicolaes GA. et al. Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation. Blood 2008; 111 (06) 3034-3041
    CrossrefPubMedGoogle Scholar
  • 117 ten Kate MK, van der Meer J. Protein S deficiency: a clinical perspective. Haemophilia 2008; 14 (06) 1222-1228
    CrossrefPubMedGoogle Scholar
  • 118 Marlar RA, Gausman JN, Tsuda H, Rollins-Raval MA, Brinkman HJM. Recommendations for clinical laboratory testing for protein S deficiency: communication from the SSC committee plasma coagulation inhibitors of the ISTH. J Thromb Haemost 2021; 19 (01) 68-74
    CrossrefPubMedGoogle Scholar
  • 119 Zöller B, García 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 (12) 3524-3531
    CrossrefPubMedGoogle Scholar
  • 120 Marlar RA, Gausman JN. Protein S abnormalities: a diagnostic nightmare. Am J Hematol 2011; 86 (05) 418-421
    CrossrefPubMedGoogle Scholar
  • 121 Pintao MC, Ribeiro DD, Bezemer ID. et al. Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. Blood 2013; 122 (18) 3210-3219
    CrossrefPubMedGoogle Scholar
  • 122 Anderson DR, Brill-Edwards P, Walker I. Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy. Haemostasis 1992; 22 (03) 124-128
    PubMedGoogle Scholar
  • 123 Tai CY, Ierardi R, Alexander JB. A case of warfarin skin necrosis despite enoxaparin anticoagulation in a patient with protein S deficiency. Ann Vasc Surg 2004; 18 (02) 237-242
    CrossrefPubMedGoogle Scholar
  • 124 Fraga R, Diniz LM, Lucas EA, Emerich PS. Warfarin-induced skin necrosis in a patient with protein S deficiency. An Bras Dermatol 2018; 93 (04) 612-613
    CrossrefPubMedGoogle Scholar
  • 125 Tsuda T, Jin X, Tsuda H. et al. New quantitative total protein S-assay system for diagnosing protein S type II deficiency: clinical application of the screening system for protein S type II deficiency. Blood Coagul Fibrinolysis 2012; 23 (01) 56-63
    CrossrefPubMedGoogle Scholar
  • 126 Goodwin AJ, Rosendaal FR, Kottke-Marchant K, Bovill EG. A review of the technical, diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med 2002; 126 (11) 1349-1366
    CrossrefPubMedGoogle Scholar
  • 127 Smock KJ, Plumhoff EA, Meijer P. et al. Protein S testing in patients with protein S deficiency, factor V Leiden, and rivaroxaban by North American Specialized Coagulation Laboratories. Thromb Haemost 2016; 116 (01) 50-57
    PubMedGoogle Scholar
  • 128 Lawrie AS, Lloyd ME, Mohamed F, Irons S, Hughes GR, Savidge GF. Assay of protein S in systemic lupus erythematosus. Blood Coagul Fibrinolysis 1995; 6 (04) 322-324
    CrossrefPubMedGoogle Scholar
  • 129 Rossi E, Gatti L, Guarneri D, Finotto E, Lombardi A, Preda L. Functional protein S in women with lupus anticoagulant inhibitor. Thromb Res 1992; 65 (02) 253-262
    CrossrefPubMedGoogle Scholar
  • 130 Tomás JF, Alberca I, Tabernero MD, Cordero M, Del Pino-Montes J, Vicente V. Natural anticoagulant proteins and antiphospholipid antibodies in systemic lupus erythematosus. J Rheumatol 1998; 25 (01) 57-62
    PubMedGoogle Scholar
  • 131 Seriolo B, Cutolo M, Accardo S. Association between acquired free protein S deficiency, anticardiolipin antibodies, and thrombotic events in rheumatoid arthritis. J Rheumatol 1998; 25 (11) 2281-2282
    PubMedGoogle Scholar
  • 132 Parke AL, Weinstein RE, Bona RD, Maier DB, Walker FJ. The thrombotic diathesis associated with the presence of phospholipid antibodies may be due to low levels of free protein S. Am J Med 1992; 93 (01) 49-56
    CrossrefPubMedGoogle Scholar
  • 133 Van Cott EM, Ledford-Kraemer M, Meijer P, Nichols WL, Johnson SM, Peerschke EI. NASCOLA Proficiency Testing Committee. Protein S assays: an analysis of North American Specialized Coagulation Laboratory Association proficiency testing. Am J Clin Pathol 2005; 123 (05) 778-785
    CrossrefPubMedGoogle Scholar
  • 134 Jennings I, Kitchen S, Woods TA, Preston FE. Multilaboratory testing in thrombophilia through the United Kingdom National External Quality Assessment Scheme (Blood Coagulation) Quality Assurance Program. Semin Thromb Hemost 2005; 31 (01) 66-72
    Article in Thieme ConnectPubMedGoogle Scholar
  • 135 Jennings I, Kitchen S, Cooper P, Makris M, Preston FE. Sensitivity of functional protein S assays to protein S deficiency: a comparative study of three commercial kits. J Thromb Haemost 2003; 1 (05) 1112-1114
    CrossrefPubMedGoogle Scholar
  • 136 Marlar RA, Potts RM, Welsh CW. Accuracy of diagnosis of protein S deficiency by protein S activity and antigen assays. J Clin Ligand 2005; 28: 130-135
    PubMedGoogle Scholar
  • 137 Rodger MA, Carrier M, Gervais M, Rock G. Normal functional protein S activity does not exclude protein S deficiency. Pathophysiol Haemost Thromb 2003; 33 (04) 202-205
    CrossrefPubMedGoogle Scholar
  • 138 Siriez R, Dogné JM, Gosselin R, Laloy J, Mullier F, Douxfils J. Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: practical recommendations for the laboratory. Int J Lab Hematol 2021; 43 (01) 7-20
    CrossrefPubMedGoogle Scholar
  • 139 Bovill EG, Landesman MM, Busch SA, Fregeau GR, Mann KG, Tracy RP. Studies on the measurement of protein S in plasma. Clin Chem 1991; 37 (10 Pt 1): 1708-1714
    CrossrefPubMedGoogle Scholar
  • 140 Hubbard AR, Wong MY. A collaborative study on the measurement of protein S antigen in plasma. Thromb Haemost 1992; 68 (02) 115-118
    Article in Thieme ConnectPubMedGoogle Scholar
  • 141 Persson KE, Hillarp A, Dahlbäck B. Analytical considerations for free protein S assays in protein S deficiency. Thromb Haemost 2001; 86 (05) 1144-1147
    PubMedGoogle Scholar
  • 142 Duebgen S, Kauke T, Marschall C. et al. Genotype and laboratory and clinical phenotypes of protein s deficiency. Am J Clin Pathol 2012; 137 (02) 178-184
    CrossrefPubMedGoogle Scholar
  • 143 Brinkman HJM, Ahnström J, Castoldi E, Dahlbäck B, Marlar RA. Pleiotropic anticoagulant functions of protein S, consequences for the clinical laboratory. Communication from the SSC of the ISTH. J Thromb Haemost 2021; 19 (01) 281-286
    CrossrefPubMedGoogle Scholar
  • 144 Bertina RM, Ploos van Amstel HK, van Wijngaarden A. et al. Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460. Blood 1990; 76 (03) 538-548
    CrossrefPubMedGoogle Scholar
  • 145 Duchemin J, Gandrille S, Borgel D. et al. The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency. Blood 1995; 86 (09) 3436-3443
    CrossrefPubMedGoogle Scholar
  • 146 Varvenne M, Kochhan L, Trummer A, Eisert R, Birschmann I. Clinical consequences of compound heterozygosity for protein S mutation Heerlen and p.Cys252Gly protein S mutation. Thromb Res 2011; 128 (05) 498-500
    CrossrefPubMedGoogle Scholar
  • 147 Wypasek E, Potaczek DP, Alhenc-Gelas M, Undas A. Heerlen polymorphism associated with type III protein S deficiency and factor V Leiden mutation in a Polish patient with deep vein thrombosis. Blood Coagul Fibrinolysis 2014; 25 (01) 84-85
    CrossrefPubMedGoogle Scholar
  • 148 Suchon P, Germain M, Delluc A. et al. Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk. Sci Rep 2017; 7: 45507
    CrossrefPubMedGoogle Scholar
  • 149 Espinosa-Parrilla Y, Navarro G, Morell M, Abella E, Estivill X, Sala N. Homozygosity for the protein S Heerlen allele is associated with type I PS deficiency in a thrombophilic pedigree with multiple risk factors. Thromb Haemost 2000; 83 (01) 102-106
    Article in Thieme ConnectPubMedGoogle Scholar
  • 150 Alhenc-Gelas M, Canonico M, Morange PE, Emmerich J. Geht Genetic Thrombophilia Group. Protein S inherited qualitative deficiency: novel mutations and phenotypic influence. J Thromb Haemost 2010; 8 (12) 2718-2726
    CrossrefPubMedGoogle Scholar
  • 151 Denis CV, Roberts SJ, Hackeng TM, Lenting PJ. In vivo clearance of human protein S in a mouse model: influence of C4b-binding protein and the Heerlen polymorphism. Arterioscler Thromb Vasc Biol 2005; 25 (10) 2209-2215
    CrossrefPubMedGoogle Scholar
  • 152 Heeb MJ, Koenen RR, Fernández JA, Hackeng TM. Direct anticoagulant activity of protein S-C4b binding protein complex in Heerlen heterozygotes and normals. J Thromb Haemost 2004; 2 (10) 1766-1773
    CrossrefPubMedGoogle Scholar
  • 153 Hayashi T, Nishioka J, Suzuki K. Molecular mechanism of the dysfunction of protein S(Tokushima) (Lys155–>Glu) for the regulation of the blood coagulation system. Biochim Biophys Acta 1995; 1272 (03) 159-167
    CrossrefPubMedGoogle Scholar
  • 154 D'Angelo A, Viganò D'Angelo S. Protein S deficiency. Haematologica 2008; 93 (04) 498-501
    CrossrefPubMedGoogle Scholar
  • 155 Vigano-D'Angelo S, D'Angelo A, Kaufman Jr CE, Sholer C, Esmon CT, Comp PC. Protein S deficiency occurs in the nephrotic syndrome. Ann Intern Med 1987; 107 (01) 42-47
    CrossrefPubMedGoogle Scholar
  • 156 Ceriello A, Giugliano D, Quatraro A, Marchi E, Barbanti M, Lefebvre P. Possible role for increased C4b-binding-protein level in acquired protein S deficiency in type I diabetes. Diabetes 1990; 39 (04) 447-449
    CrossrefPubMedGoogle Scholar
  • 157 Addai-Mensah O, Annani-Akollor ME, Nsafoah FO. et al. Effect of poor glycaemic control on plasma levels and activity of protein C, protein S, and antithrombin III in type 2 diabetes mellitus. PLoS One 2019; 14 (09) e0223171
    CrossrefPubMedGoogle Scholar
  • 158 Fernández JA, Estellés A, Gilabert J, España F, Aznar J. Functional and immunologic protein S in normal pregnant women and in full-term newborns. Thromb Haemost 1989; 61 (03) 474-478
    Article in Thieme ConnectPubMedGoogle Scholar
  • 159 Fu M, Liu J, Xing J. et al. Reference intervals for coagulation parameters in non-pregnant and pregnant women. Sci Rep 2022; 12 (01) 1519
    CrossrefPubMedGoogle Scholar
  • 160 Szecsi PB, Jørgensen M, Klajnbard A, Andersen MR, Colov NP, Stender S. Haemostatic reference intervals in pregnancy. Thromb Haemost 2010; 103 (04) 718-727
    Article in Thieme ConnectPubMedGoogle Scholar
  • 161 Oruç S, Saruç M, Koyuncu FM, Ozdemir E. Changes in the plasma activities of protein C and protein S during pregnancy. Aust N Z J Obstet Gynaecol 2000; 40 (04) 448-450
    CrossrefPubMedGoogle Scholar
  • 162 Stahl CP, Wideman CS, Spira TJ, Haff EC, Hixon GJ, Evatt BL. Protein S deficiency in men with long-term human immunodeficiency virus infection. Blood 1993; 81 (07) 1801-1807
    CrossrefPubMedGoogle Scholar
  • 163 Lafeuillade A, Sorice M, Griggi T, Pellegrino P, Geoffroy M, Profizi N. Role of autoimmunity in protein S deficiency during HIV-1 infection. Infection 1994; 22 (03) 201-203
    CrossrefPubMedGoogle Scholar
  • 164 D'Angelo A, Della Valle P, Crippa L, Pattarini E, Grimaldi LM, Viganò D'Angelo S. Brief report: autoimmune protein S deficiency in a boy with severe thromboembolic disease. N Engl J Med 1993; 328 (24) 1753-1757
    CrossrefPubMedGoogle Scholar
  • 165 Regnault V, Boehlen F, Ozsahin H. et al. Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generation. J Thromb Haemost 2005; 3 (06) 1243-1249
    CrossrefPubMedGoogle Scholar
  • 166 Deitcher SR, Erban JK, Limentani SA. Acquired free protein S deficiency associated with multiple myeloma: a case report. Am J Hematol 1996; 51 (04) 319-323
    CrossrefPubMedGoogle Scholar
  • 167 Guermazi S, Hamza M, Dellagi K. Protein S deficiency and antibodies to protein S in patients with Behçet's disease. Thromb Res 1997; 86 (03) 197-204
    CrossrefPubMedGoogle Scholar
  • 168 Crowther MA, Johnston M, Weitz J, Ginsberg JS. Free protein S deficiency may be found in patients with antiphospholipid antibodies who do not have systemic lupus erythematosus. Thromb Haemost 1996; 76 (05) 689-691
    Article in Thieme ConnectPubMedGoogle Scholar
  • 169 Erkan D, Zhang HW, Shriky RC, Merrill JT. Dual antibody reactivity to beta2-glycoprotein I and protein S: increased association with thrombotic events in the antiphospholipid syndrome. Lupus 2002; 11 (04) 215-220
    CrossrefPubMedGoogle Scholar
  • 170 Ginsberg JS, Demers C, Brill-Edwards P. et al. Acquired free protein S deficiency is associated with antiphospholipid antibodies and increased thrombin generation in patients with systemic lupus erythematosus. Am J Med 1995; 98 (04) 379-383
    CrossrefPubMedGoogle Scholar
  • 171 Guermazi S, Regnault V, Gorgi Y, Ayed K, Lecompte T, Dellagi K. Further evidence for the presence of anti-protein S autoantibodies in patients with systemic lupus erythematosus. Blood Coagul Fibrinolysis 2000; 11 (05) 491-498
    CrossrefPubMedGoogle Scholar
  • 172 Song KS, Park YS, Kim HK. Prevalence of anti-protein S antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 2000; 43 (03) 557-560
    CrossrefPubMedGoogle Scholar
  • 173 Wun T, Brunson A. Sickle cell disease: an inherited thrombophilia. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 640-647
    CrossrefPubMedGoogle Scholar
  • 174 Noubouossie D, Key NS, Ataga KI. Coagulation abnormalities of sickle cell disease: relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev 2016; 30 (04) 245-256
    CrossrefPubMedGoogle Scholar
  • 175 Henkens CM, Bom VJ, Van der Schaaf W. et al. Plasma levels of protein S, protein C, and factor X: effects of sex, hormonal state and age. Thromb Haemost 1995; 74 (05) 1271-1275
    Article in Thieme ConnectPubMedGoogle Scholar
  • 176 Ignjatovic V, Kenet G, Monagle P. Perinatal and Paediatric Haemostasis Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Developmental hemostasis: recommendations for laboratories reporting pediatric samples. J Thromb Haemost 2012; 10 (02) 298-300
    CrossrefPubMedGoogle Scholar
  • 177 Mulder R, Ten Kate MK, Kluin-Nelemans HC, Mulder AB. Low cut-off values increase diagnostic performance of protein S assays. Thromb Haemost 2010; 104 (03) 618-625
    PubMedGoogle Scholar
  • 178 Nicolaes GA, Dahlbäck B. Congenital and acquired activated protein C resistance. Semin Vasc Med 2003; 3 (01) 33-46
    Article in Thieme ConnectPubMedGoogle Scholar
  • 179 Moore GW, Van Cott EM, Cutler JA, Mitchell MJ, Adcock DM. subcommittee on plasma coagulation inhibitors. Recommendations for clinical laboratory testing of activated protein C resistance; communication from the SSC of the ISTH. J Thromb Haemost 2019; 17 (09) 1555-1561
    CrossrefPubMedGoogle Scholar
  • 180 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369 (6475): 64-67
    CrossrefPubMedGoogle Scholar
  • 181 Moore GW, Castoldi E, Teruya J, Morishita E, Adcock DM, Factor V. Factor V Leiden-independent activated protein C resistance: communication from the plasma coagulation inhibitors subcommittee of the International Society on Thrombosis and Haemostasis Scientific and Standardisation Committee. J Thromb Haemost 2023; 21 (01) 164-174
    CrossrefPubMedGoogle Scholar
  • 182 Sheppard DR. Activated protein C resistance: the most common risk factor for venous thromboembolism. J Am Board Fam Pract 2000; 13 (02) 111-115
    CrossrefPubMedGoogle Scholar
  • 183 Williamson D, Brown K, Luddington R, Baglin C, Baglin T, Factor V. Factor V Cambridge: a new mutation (Arg306–>Thr) associated with resistance to activated protein C. Blood 1998; 91 (04) 1140-1144
    CrossrefPubMedGoogle Scholar
  • 184 Chan WP, Lee CK, Kwong YL, Lam CK, Liang R. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91 (04) 1135-1139
    CrossrefPubMedGoogle Scholar
  • 185 Cai H, Hua B, Fan L, Wang Q, Wang S, Zhao Y. A novel mutation (g2172–>c) in the factor V gene in a Chinese family with hereditary activated protein C resistance. Thromb Res 2010; 125 (06) 545-548
    CrossrefPubMedGoogle Scholar
  • 186 Gandrille S, Greengard JS, Alhenc-Gelas M. et al. Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM. Blood 1995; 86 (01) 219-224
    CrossrefPubMedGoogle Scholar
  • 187 Mumford AD, McVey JH, Morse CV. et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003; 123 (03) 496-501
    CrossrefPubMedGoogle Scholar
  • 188 Pezeshkpoor B, Castoldi E, Mahler A. et al. Identification and functional characterization of a novel F5 mutation (Ala512Val, FVB onn) associated with activated protein C resistance. J Thromb Haemost 2016; 14 (07) 1353-1363
    CrossrefPubMedGoogle Scholar
  • 189 Nogami K, Shinozawa K, Ogiwara K. et al. Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC resistance relative to FVLeiden. Blood 2014; 123 (15) 2420-2428
    CrossrefPubMedGoogle Scholar
  • 190 Castoldi E, Hézard N, Mourey G. et al. Severe thrombophilia in a factor V-deficient patient homozygous for the Ala2086Asp mutation (FV Besançon). J Thromb Haemost 2021; 19 (05) 1186-1199
    CrossrefPubMedGoogle Scholar
  • 191 Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost 2010; 8 (03) 445-453
    CrossrefPubMedGoogle Scholar
  • 192 Castaman G, Tosetto A, Simioni M, Ruggeri M, Madeo D, Rodeghiero F. Phenotypic APC resistance in carriers of the A20210 prothrombin mutation is associated with an increased risk of venous thrombosis. Thromb Haemost 2001; 86 (03) 804-808
    PubMedGoogle Scholar
  • 193 Graf LL, Welsh CH, Qamar Z, Marlar RA. Activated protein C resistance assay detects thrombotic risk factors other than factor V Leiden. Am J Clin Pathol 2003; 119 (01) 52-60
    CrossrefPubMedGoogle Scholar
  • 194 Simioni P, Cagnin S, Sartorello F. et al. Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood 2021; 137 (17) 2383-2393
    CrossrefPubMedGoogle Scholar
  • 195 Tripodi A, Chantarangkul V, Mannucci PM. Hyperprothrombinemia may result in scquired activated protein C resistance. Blood 2000; 96 (09) 3295-3296
    CrossrefPubMedGoogle Scholar
  • 196 de Visser MC, van Hylckama Vlieg A, Tans G. et al. Determinants of the APTT- and ETP-based APC sensitivity tests. J Thromb Haemost 2005; 3 (07) 1488-1494
    CrossrefPubMedGoogle Scholar
  • 197 Sarig G, Michaeli Y, Lanir N, Brenner B, Haim N. Mechanisms for acquired activated protein C resistance in cancer patients. J Thromb Haemost 2005; 3 (03) 589-590
    CrossrefPubMedGoogle Scholar
  • 198 Negaard HF, Iversen PO, Ostenstad B, Mowinckel MC, Sandset PM. Increased acquired activated protein C resistance in unselected patients with hematological malignancies. J Thromb Haemost 2008; 6 (09) 1482-1487
    CrossrefPubMedGoogle Scholar
  • 199 Wahl D, Membre A, Perret-Guillaume C, Regnault V, Lecompte T. Mechanisms of antiphospholipid-induced thrombosis: effects on the protein C system. Curr Rheumatol Rep 2009; 11 (01) 77-81
    CrossrefPubMedGoogle Scholar
  • 200 Kadauke S, Khor B, Van Cott EM. Activated protein C resistance testing for factor V Leiden. Am J Hematol 2014; 89 (12) 1147-1150
    CrossrefPubMedGoogle Scholar
  • 201 Moore GW, Chege E, Culhane AP, Hunt BJ. Maximising the diagnostic potential of APTT-based screening assays for activated protein C resistance. Int J Lab Hematol 2015; 37 (06) 844-852
    CrossrefPubMedGoogle Scholar
  • 202 Saenz AJ, Johnson NV, Van Cott EM. Acquired activated protein C resistance caused by lupus anticoagulants. Am J Clin Pathol 2011; 136 (03) 344-349
    CrossrefPubMedGoogle Scholar
  • 203 Ragland BD, Reed CE, Eiland BM. et al. The effect of lupus anticoagulant in the second-generation assay for activated protein C resistance. Am J Clin Pathol 2003; 119 (01) 66-71
    CrossrefPubMedGoogle Scholar
  • 204 Valverde S, Trabuio E, Antico F, Manoni F, Gessoni G. Evaluation of two functional assays in detection of factor V Leiden carriers. I J La M 2009; 5: 212-216
    PubMedGoogle Scholar
  • 205 Quehenberger P, Handler S, Mannhalter C, Kyrle PA, Speiser W. The Factor V (Leiden) test: evaluation of an assay based on dilute Russell Viper Venom Time for the detection of the Factor V Leiden mutation. Thromb Res 1999; 96 (02) 125-133
    CrossrefPubMedGoogle Scholar
  • 206 Quenhenberger P, Handler S, Mannhalter C, Pabinger-Fasching I, Speiser W. Evaluation of a highly specific functional test for the detection of factor V Leiden. Int J Clin Lab Res 2000; 30 (03) 113-117
    CrossrefPubMedGoogle Scholar
  • 207 Coen Herak D, Milos M, Zadro R. Improvement of STA:STACLOT APC-R Test for the detection of factor V Leiden by using APCR ratio. J Thromb Haemost 2005; 3 (Suppl. 01) abstract P1292
    PubMedGoogle Scholar
  • 208 Schöni R, Quehenberger P, Wu JR, Wilmer M. Clinical evaluation of a new functional test for detection of activated protein C resistance (Pefakit APC-R Factor V Leiden) at two centers in Europe and the USA. Thromb Res 2007; 119 (01) 17-26
    CrossrefPubMedGoogle Scholar
  • 209 Amiral J, Vissac AM, Seghatchian J. Laboratory assessment of activated protein C resistance/factor V-Leiden and performance characteristics of a new quantitative assay. Transfus Apheresis Sci 2017; 56 (06) 906-913
    CrossrefPubMedGoogle Scholar
  • 210 Tripodi A, Chantarangkul V, Negri B, Mannucci PM. Standardization of the APC resistance test. Effects of normalization of results by means of pooled normal plasma. Thromb Haemost 1998; 79 (03) 564-566
    Article in Thieme ConnectPubMedGoogle Scholar
  • 211 Wilmer M, Stocker C, Bühler B, Conell B, Calatzis A. Improved distinction of factor V wild-type and factor V Leiden using a novel prothrombin-based activated protein C resistance assay. Am J Clin Pathol 2004; 122 (06) 836-842
    CrossrefPubMedGoogle Scholar
  • 212 Foster PA, Varma RR. Phenotypic correction of activated protein C resistance following orthotopic liver transplantation. Blood Coagul Fibrinolysis 1996; 7 (01) 65-68
    CrossrefPubMedGoogle Scholar
  • 213 Leroy-Matheron C, Duvoux C, Van Nhieu JT, Leroy K, Cherqui D, Gouault-Heilmann M. Activated protein C resistance acquired through liver transplantation and associated with recurrent venous thrombosis. J Hepatol 2003; 38 (06) 866-869
    CrossrefPubMedGoogle Scholar
  • 214 Willems M, Sterneck M, Langer F. et al. Recurrent deep-vein thrombosis based on homozygous factor V Leiden mutation acquired after liver transplantation. Liver Transpl 2003; 9 (08) 870-873
    CrossrefPubMedGoogle Scholar
  • 215 Ayala R, Martínez-López J, Cedena T. et al. Recipient and donor thrombophilia and the risk of portal venous thrombosis and hepatic artery thrombosis in liver recipients. BMC Gastroenterol 2011; 11: 130
    CrossrefPubMedGoogle Scholar
  • 216 Chiusolo P, Sica S, Salutari P. et al. Factor V Leiden and allogeneic bone marrow transplantation: chimerism as a confounding factor in genetic test interpretation. Clin Lab Haematol 1999; 21 (06) 401-402
    CrossrefPubMedGoogle Scholar
  • 217 Cunningham MT, Brandt JT, Laposata M, Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med 2002; 126 (04) 499-505
    CrossrefPubMedGoogle Scholar
  • 218 Thorsen LI, Brosstad F, Solum NO, Stormorken H. Increased binding to ADP-stimulated platelets and aggregation effect of the dysfibrinogen Oslo I as compared with normal fibrinogen. Scand J Haematol 1986; 36 (02) 203-210
    CrossrefPubMedGoogle Scholar
  • 219 Shapiro SE. Diagnosis and management of dysfibrinogenemia. Clin Adv Hematol Oncol 2018; 16 (09) 602-605
    PubMedGoogle Scholar
  • 220 Franchini M, Martinelli I, Mannucci PM. Uncertain thrombophilia markers. Thromb Haemost 2016; 115 (01) 25-30
    Article in Thieme ConnectPubMedGoogle Scholar
  • 221 Sachs UJ, Kirsch-Altena A, Müller J. Markers of hereditary thrombophilia with unclear significance. Hamostaseologie 2022; 42 (06) 370-380
    Article in Thieme ConnectPubMedGoogle Scholar
  • 222 Simioni P, Tormene D, Tognin G. et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009; 361 (17) 1671-1675
    CrossrefPubMedGoogle Scholar
  • 223 Miyawaki Y, Suzuki A, Fujita J. et al. Thrombosis from a prothrombin mutation conveying antithrombin resistance. N Engl J Med 2012; 366 (25) 2390-2396
    CrossrefPubMedGoogle Scholar
  • 224 Djordjevic V, Kovac M, Miljic P. et al. A novel prothrombin mutation in two families with prominent thrombophilia–the first cases of antithrombin resistance in a Caucasian population. J Thromb Haemost 2013; 11 (10) 1936-1939
    CrossrefPubMedGoogle Scholar
  • 225 Bulato C, Radu CM, Campello E. et al. New prothrombin mutation (Arg596Trp, Prothrombin Padua 2) associated with venous thromboembolism. Arterioscler Thromb Vasc Biol 2016; 36 (05) 1022-1029
    CrossrefPubMedGoogle Scholar
  • 226 Sivasundar S, Oommen AT, Prakash O. et al. Molecular defect of 'Prothrombin Amrita': substitution of arginine by glutamine (Arg553 to Gln) near the Na(+) binding loop of prothrombin. Blood Cells Mol Dis 2013; 50 (03) 182-183
    CrossrefPubMedGoogle Scholar
  • 227 Tamura S, Suga Y, Tanamura M. et al. Optimisation of antithrombin resistance assay as a practical clinical laboratory test: development of prothrombin activator using factors Xa/Va and automation of assay. Int J Lab Hematol 2018; 40 (03) 312-319
    CrossrefPubMedGoogle Scholar
  • 228 Gosselin RC, Marlar RA. Preanalytical variables in coagulation testing: setting the stage for accurate results. Semin Thromb Hemost 2019; 45 (05) 433-448
    Article in Thieme ConnectPubMedGoogle Scholar
  • 229 Favaloro EJ, Gosselin RC, Pasalic L, Lippi G. Post-analytical Issues in hemostasis and thrombosis testing: an update. Methods Mol Biol 2023; 2663: 787-811
    CrossrefPubMedGoogle Scholar
  • 230 Hubbard AR. International biological standards for coagulation factors and inhibitors. Semin Thromb Hemost 2007; 33 (03) 283-289
    Article in Thieme ConnectPubMedGoogle Scholar
  • 231 Mackie I, Cooper P, Kitchen S. Quality assurance issues and interpretation of assays. Semin Hematol 2007; 44 (02) 114-125
    CrossrefPubMedGoogle Scholar
  • 232 Jerrard-Dunne P, Evans A, McGovern R. et al. Ethnic differences in markers of thrombophilia: implications for the investigation of ischemic stroke in multiethnic populations: the South London Ethnicity and Stroke Study. Stroke 2003; 34 (08) 1821-1826
    CrossrefPubMedGoogle Scholar
  • 233 Chen TY, Su WC, Tsao CJ. Incidence of thrombophilia detected in southern Taiwanese patients with venous thrombosis. Ann Hematol 2003; 82 (02) 114-117
    CrossrefPubMedGoogle Scholar
  • 234 Kinoshita S, Iida H, Inoue S. et al. Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. Clin Biochem 2005; 38 (10) 908-915
    CrossrefPubMedGoogle Scholar
  • 235 Zhu T, Ding Q, Bai X. et al. Normal ranges and genetic variants of antithrombin, protein C and protein S in the general Chinese population. Results of the Chinese Hemostasis Investigation on Natural Anticoagulants Study I Group. Haematologica 2011; 96 (07) 1033-1040
    CrossrefPubMedGoogle Scholar
  • 236 Tang L, Lu X, Yu JM. et al. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. J Thromb Haemost 2012; 10 (10) 2019-2026
    CrossrefPubMedGoogle Scholar
  • 237 Ormesher L, Simcox LE, Tower C, Greer IA. 'To test or not to test', the arguments for and against thrombophilia testing in obstetrics. Obstet Med 2017; 10 (02) 61-66
    CrossrefPubMedGoogle Scholar