Milestones and Perspectives in Coagulation and Hemostasis

 

 Buy Article Permissions and Reprints

ABSTRACT

Hemostasis is traditionally defined as the physiologic process whereby bleeding is antagonized and possibly stopped to minimize blood loss. The first medical description of the clinical and inherited features of hemostasis can be dated back more than 1000 years, when Abu al-Qasim Khalaf ibn ‘Abbas al-Andalusi al-Zahrawi’ medical treatise provided some initial insights into this puzzling process. Since then, continuous and revolutionary scientific developments have contributed to decoding several aspects of this intricate but essential physiologic phenomenon, providing a reliable model to explain the leading mechanisms involved. Although the point at which bleeding stops is commonly referred to as “coagulation,” blood coagulation is actually only one part of a two-part hemostatic process that develops through sequential steps referred to as primary and secondary hemostasis. Throughout its activation and development, the coagulation cascade is strictly regulated by a series of natural inhibitors, which prevent unnecessary and excessive clotting. The aim of this article is to provide a concise overview of the major discoveries and past and current perspectives in coagulation and hemostasis.

REFERENCES

• 1 al-Qasim Khalaf A, al-Andalusi al-Zahraw A. Medical treatise Kitab al-tasrîf liman ajaza an al-talîf fi al-tibb . Available at: http://www.museumwnf.net/database_item.php?id=object;ISL;ma;Mus01_F;16;en Accessed February 27, 2009
  Google Scholar
• 2 Schultze M. Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes.  Arch Mikrosc Anat. 1865;  1 1-42
  CrossrefPubMedGoogle Scholar
• 3 Bizzozero J. Über einen neuen Forrnbestandteil des Blutes und dessen Rolle bei der Thrombose und Blutgerinnung.  Arch Pathol Anat Physiol Klin Med. 1882;  90 261-332
  PubMedGoogle Scholar
• 4 Brewer D B. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet.  Br J Haematol. 2006;  133 251-258
  CrossrefPubMedGoogle Scholar
• 5 Hayward C P, Eikelboom J. Platelet function testing: quality assurance.  Semin Thromb Hemost. 2007;  33 273-282
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Briggs C, Harrison P, Machin S J. Continuing developments with the automated platelet count.  Int J Lab Hematol. 2007;  29 77-91
  CrossrefPubMedGoogle Scholar
• 7 Singh H, Chaudhary R, Ray V. Platelet indices as quality markers of platelet concentrates during storage.  Clin Lab Haematol. 2003;  25 307-310
  CrossrefPubMedGoogle Scholar
• 8 Abe Y, Wada H, Sakakura M et al.. Usefulness of fully automated measurement of reticulated platelets using whole blood.  Clin Appl Thromb Hemost. 2005;  11 263-270
  CrossrefPubMedGoogle Scholar
• 9 Althaus K, Greinacher A. MYH9-related platelet disorders.  Semin Thromb Hemost. 2009;  , in press
  PubMedGoogle Scholar
• 10 The British Society for Haematology BCSH Haemostasis and Thrombosis Task Force . Guidelines on platelet function testing.  J Clin Pathol. 1988;  41 1322-1330
  CrossrefPubMedGoogle Scholar
• 11 Ivy A C, Nelson D, Buchet C. The standardization of certain factors in the cutaneous “venostasis” bleeding time technique.  J Lab Clin Med. 1941;  26 1812-1941
  PubMedGoogle Scholar
• 12 Favaloro E J, Smith J, Petinos P, Collecutt M, Street A, Hertzberg M. on behalf of the RCPA Quality Assurance Program (QAP) in Haematology Scientific Haemostasis Advisory Panel . Laboratory testing, diagnosis and management of von Willebrand's disease: current practice in Australasia.  Am J Clin Pathol. 1999;  112 712-719
  PubMedGoogle Scholar
• 13 Fressinaud E, Veyradier A, Truchaud F et al.. Screening for von Willebrand disease with a new analyser using high shear stress: a study of 60 cases.  Blood. 1998;  91 1325-1331
  CrossrefPubMedGoogle Scholar
• 14 Lind S E. The bleeding time does not predict surgical bleeding.  Blood. 1991;  77 2547-2552
  CrossrefPubMedGoogle Scholar
• 15 De Caterina R, Lanza M, Manca G, Strata G B, Maffei S, Salvatore L. Bleeding time and bleeding: an analysis of the relationship of the bleeding time test with parameters of surgical bleeding.  Blood. 1994;  84 3363-3370
  PubMedGoogle Scholar
• 16 Born G V. Aggregation of blood platelets by adenosine diphosphate and its reversal.  Nature. 1962;  194 927-929
  PubMedGoogle Scholar
• 17 McGlasson D, Fritsma G A. Whole blood aggregometry.  Semin Thromb Hemost. 2009;  , in press
  PubMedGoogle Scholar
• 18 Cattaneo M. Light transmission aggregometry and ATP release for the diagnostic assessment of platelet function.  Semin Thromb Hemost. 2009;  , in press
  PubMedGoogle Scholar
• 19 Cardigan R, Turner C, Harrison P. Current methods of assessing platelet function: relevance to transfusion medicine.  Vox Sang. 2005;  88 153-163
  CrossrefPubMedGoogle Scholar
• 20 Favaloro E J. Internal quality control and external quality assesment of platelet function tests.  Semin Thromb Hemost. 2009;  , in press
  PubMedGoogle Scholar
• 21 Hartert H. Blutgerinnungsstudien mit der Thrombeastographie, einem neuen Untersuchungsverfahren.  Klin Wochenschr. 1948;  26 577-583
  CrossrefPubMedGoogle Scholar
• 22 Luddington R J. Thrombelastography/thromboelastometry.  Clin Lab Haematol. 2005;  27 81-90
  CrossrefPubMedGoogle Scholar
• 23 Adams M, Ward C, Thom J et al.. Emerging technologies in hemostasis diagnostics: a report from the Australasian Society of Thrombosis and Haemostasis Emerging Technologies Group.  Semin Thromb Hemost. 2007;  33 226-234
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Watson H G, Greaves M. Can we predict bleeding?.  Semin Thromb Hemost. 2008;  34 97-103
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Dempfle C E, Borggrefe M. Point of care coagulation tests in critically ill patients.  Semin Thromb Hemost. 2008;  34 445-450
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Baumgartner H R. The role of blood flow in platelet adhesion, fibrin deposition, and formation of mural thrombi.  Microvasc Res. 1973;  5 167-179
  CrossrefPubMedGoogle Scholar
• 27 Kratzer M A, Born G V. Simulation of primary haemostasis in vitro.  Haemostasis. 1985;  15 357-362
  PubMedGoogle Scholar
• 28 Favaloro E J. Clinical utility of the PFA-100.  Semin Thromb Hemost. 2008;  34 709-733
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Smith J W, Steinhubl S R, Lincoff A M et al.. Rapid platelet-function assay. An automated and quantitative cartridge-based method.  Circulation. 1999;  99 620-625
  PubMedGoogle Scholar
• 30 Varon D, Savion N. Cone and platelet analyzer. In Michelson AD Platelets. London, UK; Academic Press 2002: 337-345
  Google Scholar
• 31 Harrison P, Mumford A. Screening tests of platelet function – update on their appropriate uses for diagnostic testing.  Semin Thromb Hemost. 2009;  , in press
  PubMedGoogle Scholar
• 32 Rinder H M. Platelet function testing by flow cytometry.  Clin Lab Sci. 1998;  11 365-372
  PubMedGoogle Scholar
• 33 Enjeti A K, Lincz L F, Seldon M. Detection and measurement of microparticles: an evolving research tool for vascular biology.  Semin Thromb Hemost. 2007;  33 771-779
  Article in Thieme ConnectPubMedGoogle Scholar
• 34 Liu J, DeNofrio J, Yuan W, Wang Z, McFadden A W, Parise L V. Genetic manipulation of megakaryocytes to study platelet function.  Curr Top Dev Biol. 2008;  80 311-335
  PubMedGoogle Scholar
• 35 Senzel L, Gnatenko D V, Bahou W F. Genomic and proteomic applications in diagnosis of platelet disorders and classification.  Semin Thromb Hemost. 2008;  34 532-538
  Article in Thieme ConnectPubMedGoogle Scholar
• 36 Franchini M, Lippi G. The role of von Willebrand factor in hemorrhagic and thrombotic disorders.  Crit Rev Clin Lab Sci. 2007;  44 115-149
  CrossrefPubMedGoogle Scholar
• 37 von Willebrand E A. Hereditar pseudohemofili.  Finska Lak-Sallsk Handl. 1926;  67 87-112
  PubMedGoogle Scholar
• 38 Nilsson I M, Blomback M, Jorpes E. Von Villebrand's disease and its correction with human plasma fraction 1–0.  Acta Med Scand. 1957;  159 179-188
  PubMedGoogle Scholar
• 39 Zimmerman T S, Ruggeri Z M. Coagulation and Bleeding Disorders: The Role of Factor VIII and von Willebrand Factor. New York, NY; Marcel Dekker 1989
  Google Scholar
• 40 Owen W G, Wagner R H. Antihemophilic factor: separation of an active fragment following dissociation by salts or detergents.  Thromb Diath Haemorrh. 1972;  27 502-515
  PubMedGoogle Scholar
• 41 Ginsburg D, Handin R I, Bonthron D T et al.. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization.  Science. 1985;  228 1401-1406
  CrossrefPubMedGoogle Scholar
• 42 Lynch D C, Zimmerman T S, Collins C J et al.. Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method.  Cell. 1985;  41 49-56
  CrossrefPubMedGoogle Scholar
• 43 Sadler J E, Shelton-Inloes B B, Sorace J M, Harlan J M, Titani K, Davie E W. Cloning and characterization of two cDNAs coding for human von Willebrand factor.  Proc Natl Acad Sci U S A. 1985;  82 6394-6398
  CrossrefPubMedGoogle Scholar
• 44 Federici A B, Castaman G, Mannucci P M. Italian Association of Hemophilia Centers (AICE) . Guidelines for the diagnosis and management of von Willebrand disease in Italy.  Haemophilia. 2002;  8 607-621
  CrossrefPubMedGoogle Scholar
• 45 Favaloro E J. Laboratory identification of von Willebrand disease: technical and scientific perspectives.  Semin Thromb Hemost. 2006;  32 456-471
  Article in Thieme ConnectPubMedGoogle Scholar
• 46 Favaloro E J. An update on the von Willebrand factor collagen binding (VWF:CB) assay: 21 years of age and beyond adolescence, but not yet a mature adult.  Semin Thromb Hemost. 2007;  33 727-744
  Article in Thieme ConnectPubMedGoogle Scholar
• 47 Howard M A, Firkin B G. Ristocetin - a new tool in the investigation of platelet aggregation.  Thromb Diath Haemorrh. 1971;  26 362-369
  PubMedGoogle Scholar
• 48 Weiss H J, Hoyer L W, Rickles F R, Varma A, Rogers J. Quantitative assay of a plasma factor deficient in von Willebrand's disease that is necessary for platelet aggregation. Relationship to factor VIII procoagulant activity and antigen content.  J Clin Invest. 1973;  52 2708-2716
  CrossrefPubMedGoogle Scholar
• 49 Favaloro E J, Bonar R, Marsden K. (on behalf of the RCPA QAP Haemostasis Committee). Lower limit of assay sensitivity: an under-recognised and significant problem in von Willebrand disease identification and classification.  Clin Lab Sci. 2008;  21 178-185
  PubMedGoogle Scholar
• 50 Favaloro E J, Bonar R, Meiring M, Street A, Marsden K. (on behalf of the RCPA QAP in Haematology). 2B or not 2B? Disparate discrimination of functional VWF discordance using different assay panels or methodologies may lead to success or failure in the early identification of type 2B VWD.  Thromb Haemost. 2007;  98 346-358
  PubMedGoogle Scholar
• 51 Kempfer A C, Silaf M R, Farias C E et al.. Binding of von Willebrand factor to collagen by flow cytometry.  Am J Clin Pathol. 1999;  111 418-423
  CrossrefPubMedGoogle Scholar
• 52 Chen D, Daigh C A, Hendricksen J I et al.. A highly sensitive plasma von Willebrand factor ristocetin cofactor (VWF:RCo) activity assay by flow cytometry.  J Thromb Haemost. 2008;  6 323-330
  CrossrefPubMedGoogle Scholar
• 53 Giannini S, Mezzasoma A M, Leone M, Gresele P. Laboratory diagnosis and monitoring of desmopressin treatment of von Willebrand's disease by flow cytometry.  Haematologica. 2007;  92 1647-1654
  CrossrefPubMedGoogle Scholar
• 54 Blombäck B. Fibrinogen: evolution of the structure-function concept. Keynote address at Fibrinogen 2000 Congress.  Ann N Y Acad Sci. 2001;  936 1-10
  PubMedGoogle Scholar
• 55 Schmidt A. Neue Untersuchungen ueber die Fasserstoffesgerinnung.  Pflueger's Arch F Ges Physiol. 1872;  6 413-538
  PubMedGoogle Scholar
• 56 Monroe D M, Hoffman M, Roberts H R. Fathers of modern coagulation.  Thromb Haemost. 2007;  98 3-5
  PubMedGoogle Scholar
• 57 MacFarlane R G. An enzyme cascade in the blood clotting mechanism and its function as a biochemical amplifier.  Nature. 1964;  202 498-499
  CrossrefPubMedGoogle Scholar
• 58 Davie E W, Ratnoff O D. Waterfall sequence for intrinsic blood clotting.  Science. 1964;  145 1310-1312
  CrossrefPubMedGoogle Scholar
• 59 Mann K G. Biochemistry and physiology of blood coagulation.  Thromb Haemost. 1999;  82 165-174
  PubMedGoogle Scholar
• 60 Hemker H C. The initiation phase - a review of old (clotting-) times.  Thromb Haemost. 2007;  98 20-23
  PubMedGoogle Scholar
• 61 Lippi G, Franchini M, Guidi G C. Diagnostic approach to inherited bleeding disorders.  Clin Chem Lab Med. 2007;  45 2-12
  CrossrefPubMedGoogle Scholar
• 62 McVey J H. Tissue factor pathway.  Baillieres Best Pract Res Clin Haematol. 1999;  12 361-372
  CrossrefPubMedGoogle Scholar
• 63 Mackman N, Tilley R E, Key N S. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis.  Arterioscler Thromb Vasc Biol. 2007;  27 1687-1693
  CrossrefPubMedGoogle Scholar
• 64 Koller F, Loeliger A, Duckert F. Experiments on a new clotting factor (factor VII).  Acta Haematol. 1951;  6 1-18
  CrossrefPubMedGoogle Scholar
• 65 Eigenbrot C. Structure, function, and activation of coagulation factor VII.  Curr Protein Pept Sci. 2002;  3 287-299
  CrossrefPubMedGoogle Scholar
• 66 Franchini M, Veneri D, Lippi G. The potential role of recombinant activated FVII in the management of critical hemato-oncological bleeding: a systematic review.  Bone Marrow Transplant. 2007;  39 729-735
  CrossrefPubMedGoogle Scholar
• 67 Kato H. Regulation of functions of vascular wall cells by tissue factor pathway inhibitor: basic and clinical aspects.  Arterioscler Thromb Vasc Biol. 2002;  22 539-548
  CrossrefPubMedGoogle Scholar
• 68 Römisch J. Factor VII activating protease (FSAP): a novel protease in hemostasis.  Biol Chem. 2002;  383 1119-1124
  CrossrefPubMedGoogle Scholar
• 69 Lisman T, De Groot P G. Mechanism of action of recombinant factor VIIa.  J Thromb Haemost. 2003;  1 1138-1139
  CrossrefPubMedGoogle Scholar
• 70 Middeldorp S, Levi M. Thrombophilia: an update.  Semin Thromb Hemost. 2007;  33 563-572
  Article in Thieme ConnectPubMedGoogle Scholar
• 71 Mahmoodi B K, Brouwer J L, Veeger N J, van der Meer J. Hereditary deficiency of protein C or protein S confers increased risk of arterial thromboembolic events at a young age. Results from a large family cohort study.  Circulation. 2008;  118 1659-1667
  CrossrefPubMedGoogle Scholar
• 72 Prandoni P, Bilora F, Marchiori A et al.. An association between atherosclerosis and venous thrombosis.  N Engl J Med. 2003;  348 1435-1441
  CrossrefPubMedGoogle Scholar
• 73 Boekholdt S M, Kramer M H. Arterial thrombosis and the role of thrombophilia.  Semin Thromb Hemost. 2007;  33 588-596
  Article in Thieme ConnectPubMedGoogle Scholar
• 74 Sorensen H T, Horvath-Puho E, Pedersen L, Baron J A, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study.  Lancet. 2007;  370 1773-1779
  CrossrefPubMedGoogle Scholar
• 75 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen P W. Cardiovascular risk factors and venous thromboembolism: a meta-analysis.  Circulation. 2008;  117 93-102
  CrossrefPubMedGoogle Scholar
• 76 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-530
  PubMedGoogle Scholar
• 77 Nicolaides A N, Breddin H K, Carpenter P The European Genetics Foundation et al.. Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence.  Int Angiol. 2005;  24 1-26
  PubMedGoogle Scholar
• 78 van Boven H H, Vandenbroucke J P, Briët E, Rosendaal F R. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency.  Blood. 1999;  94 2590-2594
  PubMedGoogle Scholar
• 79 Cohn D M, Roshani S, Middeldorp S. Thrombophilia and venous thromboembolism: implications for testing.  Semin Thromb Hemost. 2007;  33 573-581
  Article in Thieme ConnectPubMedGoogle Scholar
• 80 Marcum J A. The origin of the dispute over the discovery of heparin.  J Hist Med Allied Sci. 2000;  55 37-66
  CrossrefPubMedGoogle Scholar
• 81 Fareed J, Hoppensteadt D A, Fareed D et al.. Survival of heparins, oral anticoagulants, and aspirin after the year 2010.  Semin Thromb Hemost. 2008;  34 58-73
  Article in Thieme ConnectPubMedGoogle Scholar
• 82 Howell W H, Holt E. Two new factors in blood coagulation – heparin and pro-antithrombin.  Am J Physiol. 1918;  47 328-341
  PubMedGoogle Scholar
• 83 Wardrop D, Keeling D. The story of the discovery of heparin and warfarin.  Br J Haematol. 2008;  141 757-763
  CrossrefPubMedGoogle Scholar
• 84 Fareed J, Leong W L, Hoppensteadt D A et al.. Generic low-molecular-weight heparins: some practical considerations.  Semin Thromb Hemost. 2004;  30 703-713
  Article in Thieme ConnectPubMedGoogle Scholar
• 85 Spinler S A, Wittkowsky A K, Nutescu E A, Smythe M A. Anticoagulation monitoring part 2: unfractionated heparin and low-molecular-weight heparin.  Ann Pharmacother. 2005;  39 1275-1285
  CrossrefPubMedGoogle Scholar
• 86 Bianchini P, Liverani L, Spelta F, Mascellani G, Parma B. Variability of heparins and heterogeneity of low molecular weight heparins.  Semin Thromb Hemost. 2007;  33 496-502
  Article in Thieme ConnectPubMedGoogle Scholar
• 87 Esmon C T. The protein C pathway.  Chest. 2003;  124(3, Suppl) 26S-32S
  CrossrefPubMedGoogle Scholar
• 88 Griffin J H, Evatt B, Zimmerman T S, Kleiss A J, Wideman C. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest. 1981;  68 1370-1373
  CrossrefPubMedGoogle Scholar
• 89 Nizzi Jr F A, Kaplan H S. Protein C and S deficiency.  Semin Thromb Hemost. 1999;  25 265-272
  Article in Thieme ConnectPubMedGoogle Scholar
• 90 Martí-Carvajal A, Salanti G, Cardona A F. Human recombinant activated protein C for severe sepsis.  Cochrane Database Syst Rev. 2008;  (1) CD004388
  PubMedGoogle Scholar
• 91 Di Scipio R G, Hermodson M A, Yates S G, Davie E W. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S.  Biochemistry. 1977;  16 698-706
  CrossrefPubMedGoogle Scholar
• 92 Walker F J. Regulation of activated protein C by a new protein. A possible function for bovine protein S.  J Biol Chem. 1980;  255 5521-5524
  PubMedGoogle Scholar
• 93 García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N. Molecular basis of protein S deficiency.  Thromb Haemost. 2007;  98 543-556
  PubMedGoogle Scholar
• 94 Comp P C, Esmon C. Recurrent venous thromboembolism in patients with a partial deficiency of protein S.  N Engl J Med. 1984;  311 1525-1528
  CrossrefPubMedGoogle Scholar
• 95 Goodwin A J, Rosendaal F R, Kottke-Marchant K, Bovill E G. A review of the technical, diagnostic, and epidemiologic considerations for protein S assays.  Arch Pathol Lab Med. 2002;  126 1349-1366
  PubMedGoogle Scholar
• 96 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
• 97 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 U S A. 1993;  90 1004-1008
  PubMedGoogle Scholar
• 98 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
  CrossrefPubMedGoogle Scholar
• 99 Svensson P J, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis.  N Engl J Med. 1994;  330 517-522
  CrossrefPubMedGoogle Scholar
• 100 Bauduer F, Lacombe D, Factor V. Leiden, prothrombin 20210A, methylenetetrahydrofolate reductase 677T, and population genetics.  Mol Genet Metab. 2005;  86 91-99
  PubMedGoogle Scholar
• 101 Rosendorff A, Dorfman D M. Activated protein C resistance and factor V Leiden: a review.  Arch Pathol Lab Med. 2007;  131 866-871
  PubMedGoogle Scholar
• 102 Norstrøm E, Thorelli E, Dahlbäck B. Functional characterization of recombinant FV Hong Kong and FV Cambridge.  Blood. 2002;  100 524-530
  CrossrefPubMedGoogle Scholar
• 103 Steen M, Norstrom E A, Tholander A L et al.. Functional characterization of factor V–Ile359Thr: a novel mutation associated with thrombosis.  Blood. 2004;  103 3381-3387
  CrossrefPubMedGoogle Scholar
• 104 Lunghi B, Iacoviello L, Gemmati D et al.. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma.  Thromb Haemost. 1996;  75 45-48
  PubMedGoogle Scholar
• 105 Castaman G, Faioni E M, Tosetto A, Bernardi F. The factor V HR2 haplotype and the risk of venous thrombosis: a meta-analysis.  Haematologica. 2003;  88 1182-1189
  PubMedGoogle Scholar
• 106 Tormene D, Fortuna S, Tognin G et al.. The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study.  J Thromb Haemost. 2005;  3 1414-1420
  CrossrefPubMedGoogle Scholar
• 107 Varga E A, Kerlin B A, Wurster M W. Social and ethical controversies in thrombophilia testing and update on genetic risk factors for venous thromboembolism.  Semin Thromb Hemost. 2008;  34 549-561
  Article in Thieme ConnectPubMedGoogle Scholar
• 108 Hertzberg M, Neville S, Favaloro E J, MacDonald D. External quality assurance of DNA testing for thrombophilia mutations.  Am J Clin Pathol. 2005;  123 189-193
  CrossrefPubMedGoogle Scholar
• 109 Favaloro E J. Diagnostic issues in thrombophilia: a laboratory scientist's view.  Semin Thromb Hemost. 2005;  31 11-16
  Article in Thieme ConnectPubMedGoogle Scholar
• 110 Favaloro E J, Bonar R, Sioufi J on behalf of the RCPA QAP in Haematology et al. Multi-laboratory testing of thrombophilia: current and past practice in Australasia as assessed through the Royal College of Pathologists of Australasia Quality Assurance Program in Haematology.  Semin Thromb Hemost. 2005;  31 49-58
  Article in Thieme ConnectPubMedGoogle Scholar
• 111 Reitsma P H, Rosendaal F R. Past and future of genetic research in thrombosis.  J Thromb Haemost. 2007;  5(Suppl 1) 264-269
  CrossrefPubMedGoogle Scholar
• 112 Bernardi E, Pesavento R, Prandoni P. Upper extremity deep venous thrombosis.  Semin Thromb Hemost. 2006;  32 729-736
  Article in Thieme ConnectPubMedGoogle Scholar

Prof. Giuseppe LippiM.D. 

Sezione di Chimica Clinica, Dipartimento di Scienze Morfologico-Biomediche, Università degli Studi di Verona

Ospedale Policlinico G.B. Rossi, Piazzale Scuro, 10 37134 Verona, Italy

Email: giuseppe.lippi@univr.it