Genetische Veränderungen des Protein-C-Systems

Zusammenfassung

Das Protein-C-System umfaßt neben dem Protein C (PC) das Protein S (PS) sowie Thrombomodulin (TM). Obwohl das PC bereits im Jahr 1976 isoliert und charakterisiert wurde, wurde familiärer PC-Mangel erst im Jahr 1981 mit familiärer Thrombophilie in Zusammenhang gebracht. Heute wissen wir, daß PC einen der wichtigsten Inhibitoren der Gerinnung repräsentiert. Zur Umwandlung des Zymogens PC durch Thrombin in aktiviertes PC (APC) ist das TM von essentieller Bedeutung. Dieses Protein wurde 1981 entdeckt und danach intensiv in seiner biochemischen Funktion studiert. Die klinische Relevanz von TM-Defekten ist allerdings bis heute unklar. APC inaktiviert proteolytisch die aktivierten Gerinnungsfaktoren Faktor V (FVa) und Faktor VIII (FVIIIa). Zur Entfaltung der vollen Aktivität benötigt PC einen Kofaktor, das PS. Ein Mangel von PS führt zu erhöhter Thromboseneigung. Eine häufig vorkommende Mutante des Faktor V (FV), der FV-Leiden, kann durch APC nur unzureichend inaktiviert werden und ist ebenfalls mit erhöhter Thromboseneigung assoziiert. Der genaue Mechanismus über den FV-Leiden zu einem erhöhten Thromboserisiko beiträgt wird derzeit noch kontrovers diskutiert. Heute sind die biochemischen Interaktionen der Komponenten des PC-Systems recht genau untersucht und viele zugrundeliegende Mutationen aufgeklärt. Darüber hinaus gibt es recht umfangreiche Studien an großen Patientenkollektiven, in denen die Auswirkungen der Mutationen in den einzelnen Komponenten des PC-Systems auf das Thromboserisiko analysiert wurden. Die Ergebnisse mehrerer Evaluierungen werden in diesem Artikel zusammengefaßt.

Schlüsselwörter

Thrombomodulin - Protein C - Protein S - APC-Resistenz - Faktor-V-Leiden - Thrombosegenetik - Thromboserisiko

• LITERATUR

• 1 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: 134-8.
• 2 Bernardi F, Faioni EM, Castoldi E, Lunghi B, Castaman G, Sacchi E, Mannucci PM. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90: 1552-7.
• 3 Bertina RM. Factor V Leiden and other coagulation factor mutations affecting thrombotic risk. Clin Chem 1997; 43: 1678-83.
• 4 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 5 Bertina RM, Ploos van Amstel HK, van Wijngaarden, Coenen J, Leemhuis MP, Deutz-Terlouw PP, van der Linden IK, Reitsma PH. Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460. Blood 1990; 76: 538-48.
• 6 Bertina RM, Reitsma PH, Rosendaal FR, Vandenbroucke JP. Resistance to activated protein C and factor V Leiden as risk factors for venous thrombosis. Thromb Haemost 1995; 74: 449-53.
• 7 Broze GJ. Thrombin-dependent inhibition of fibrinolysis. Current opinion in Hematology 1996; 03: 390-4.
• 8 Cadroy Y, Diquélou A, Dupouy D, Bossavy JP, Sakariassen KS, Sié P, Boneu B. The thrombomodulin/protein C/protein S anticoagulant pathway modulates the thrombogenic properties of the normal resting and stimulated endothelium. Artherioscler Thromb Vase Biol 1997; 17: 520-7.
• 9 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: 1135-9.
• 10 Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V. Biochemistry 1992; 31: 3777-85.
• 11 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8.
• 12 Conway EM, Pollefeyt S, Collen D, Steiner-Mosonyi M. The amino terminal lectinlike domain of thrombomodulin is required for constitutive endocytosis. Blood 1997; 89: 652-61.
• 13 Cooper PC, Hampton KK, Makris M, Abuzenadah A, Paul B, Preston PE. Further evidence that activated protein C resistance can be misdiagnosed as inherited functional protein S deficiency. Br J Haematol 1994; 88: 201-3.
• 14 Cumming AM, Tait RC, Fildes I, Yoong A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90: 725-7.
• 15 Dahlbäck B, Carlsson M, Svensson PJ. 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 Sei USA 1993; 90: 1004-8.
• 16 Dahlbäck B, Hildebrand B, Malm J. Characterization of functional important domains in human vitamin K-dependent protein S using monoclonal antibodies. J Biol Chem 1990; 265: 8127-35.
• 17 Dittmann WA, Majerus PW. Structure and function of thrombomodulin: a natural anticoagulant. Blood 1990; 75: 329-36.
• 18 Duchemin J, Gandrille S, Borgel D, Feurgard P, Alhenc-Gelas M, Matheron C, Dreyfus M, Dupuy E, Juhan-Vague I, Aiach M. The Ser 460 to Pro substitution of the protein S á (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency. Blood 1995; 86: 3436-43.
• 19 Dzimiri N, Meyer B. World distribution of factor V Leiden. Lancet 1996; 347: 481-2.
• 20 Edenbrandt CM, Lundwall A, Wydro R, Stenflo J. Molecular analysis of the gene for vitamin K dependent protein S and its pseudogene. Cloning and partial gene organization. Biochemistry 1990; 29: 7861-8.
• 21 Ehrenforth S, Radtke K, Scharrer I. Acquired activated protein C-resistance in patients with lupus anticoagulant. Thromb Haemost 1995; 74: 797-8.
• 22 Eichinger S, Pabinger I, Stümpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Minar E, Lechner K, Kyrle PA. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 1997; 77: 624-8.
• 23 Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J 1995; 09: 946-55.
• 24 Esmon CT. Defects in natural anticoagulant pathways as potential risk factors for myocardial infarktion. Circulation 1997; 96: 9-11.
• 25 Esmon CT, Owen WG. Identification of an endothelial cell cofactor for the thrombincatalyzed activation of Protein C. Proc Natl Acad Sci USA 1981; 78: 2249-52.
• 26 Espinosa-Parrilla Y, Morelli M, Souto JC, Borell M, Heine-Suner D, Tirado I, Volpini V, Estivill X, Sala N. Absence of linkage between type III protein S deficiency and the PROS1 and C4BP genes in families carrying the protein S Heerlen allele. Blood 1997; 89: 2799-806.
• 27 Faioni EM, Merati G, Peyvandi F, Bettini PM, Mannucci PM. The G1456 to T Mutation in the thrombomodulin gene is not frequent with venous thrombosis. Blood 1997; 89: 1467.
• 28 Faioni EM, Valsecchi C, Palla A, Taioli E, Razzari C, Mannucci PM. Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost 1997; 78: 1343-6.
• 29 Fernandez JA, Heeb MJ, Griffin JH. Identification of residues 413-433 of plasma protein S as essential for binding to C4bbinding protein. J Biol Chem 1993; 268: 16788-94.
• 30 Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. PNAS USA 1985; 82: 4673-7.
• 31 Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, Mizokami H, Kimoto M. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med 1998; 187: 1029-35.
• 32 Gandrille S, Borgel D, Ireland H, Lane DA, Simmonds R, Reitsma PH, Mannhalter C, Pabinger I, Saito H, Suzuki K, Formstone C, Cooper DN, Espinosa Y, Sala N, Bernardi F, Aiach M. Protein S deficiency: A database of mutations. For the plasma coagulation inhibitors subcommittee of the scientific and standardization committee of the International Society on Thrombosis and Haemost. Thromb Haemost 1997; 77: 1201-14.
• 33 Gandrille S, Greengard JS, Alhence-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, Griffin JH. and the French Network on the behalf of INSERM. Incidence of activated protein C resistance caused by the ARG 506 GLN Mutation in factor V in 113 unrelated symptomatic protein C deficient patients. Blood 1995; 86: 219-24.
• 34 Gewirtz AM, Shapiro C, Shen YM, Boyd R, Colman RW. Cellular and molecular regulation of factor V expression in human megakaryocytes. J Cell Physiol 1992; 153: 277-87.
• 35 Gouault-Heilmann M, Leroy-Matheron C, Levent M. Inherited protein S deficiency: clinical manifestations and laboratory findings in 63 patients. Thromb Res 1994; 76: 269-79.
• 36 Greengard JS, Sun X, Xu X, Fernandez JA, Griffin JH, Evatt B. Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 1994; 343: 1361-2.
• 37 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Widerman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-3.
• 38 Harpel PC, Zhang X, Borth W. Homocystein and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr 1996; 126: 1285S-9S.
• 39 Heeb MJ, Mesters RM, Tans G, Rosing J, Griffin JH. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem 1993; 268: 2872-7.
• 40 Henkens CMA, Bom VJJ, van der Meer J. Lowered APC-sensitivity ratio related to increased factor-VIII clotting activity. (Letter) Thromb Haemost 1995; 74: 1198-9.
• 41 Herrmann FH, Koesling M, Schröder W, Altman R, Jiménez RBonilla, Lopaciuk S, Perez-Requejo JL, Singh JR. Prevalence of factor V Leiden mutation in various populations. Genetic Epidemiology 1997; 14: 403-11.
• 42 Holm J, Zöller B, Berntorp E, Erhardt L, Dahlbäck B. Prevalence of Factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Int Med 1996; 239: 221-6.
• 43 Holvoet P, Collen D. Thrombosis and atherosclerosis. Curr Opin Lipidol 1997; 08: 320-8.
• 44 Hooper WC, Dilley A, Austin H, Wenger NK, Benson J, Evatt BL, Silva V, Rawlins P. Absence of mutations at APC cleavage sites Arg306 in Factor V and Arg336, Arg562 in Factor VIII in African-Americans. Thromb Haemost 1998; 79: 236.
• 45 Ireland H, Kunz G, Kyriakoulis K, Stubbs PJ, Lane DA. Thrombomodulin gene mutations associated with myocardial infarction. Circulation 1997; 96: 15-8.
• 46 Ishii H, Majerus PW. Thrombomodulin is present in human plasma and urine. J Clin Invest 1985; 76: 2178-81.
• 47 Jordan FJL, Nandorff A. The familial tendency in thromboembolic disease. Acta Med Scand 1956; 156: 267.
• 48 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
• 49 Koeleman BPC, van Rumpt D, Hamulyâk K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk for thrombosis in protein S deficient families?. Thromb Haemost 1995; 74: 580-3.
• 50 Koppelman SJ, Hackeng TM, Sixma JJ, Bouma BN. Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII. Blood 1995; 86: 1062-71.
• 51 Koster T, Rosendaal FR, Briët E, van der Meer FJM, Colly LP, Trienekens PH, Poort SR, Reitsma PH, Vandenbroucke JP. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995; 85: 2756-61.
• 52 Lindqvist PG, Svensson PJ, Dahlbäck B, Marsal K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss a possible evolutionary selection mechanism. Thromb Haemost 1998; 79: 69-73.
• 53 Luddington R, Brown K, Baglin T. Effect of platelet-phospholipid exposure on activated protein C resistance: Implications for thrombophilia screening. Br J Haematol 1996; 92: 744-6.
• 54 Maglott DR, Feldblyum TV, Durkin AS, Nierman WC. Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p). Mamm Genome 1996; 07: 400-1.
• 55 Martinelli I, Cattaneo M, Panzeri D, Mannucci PM. Low prevalence of Factor V:Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997; 77: 440-3.
• 56 Middeldorp S, Henkens CMA, Koopman MMW, van Pampus ECM, Hamulyâk K, van der Meer J, Prins MH, Biiller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden and venous thrombosis. Ann Intern Med 1998; 128: 15-20.
• 57 Miletich J, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-6.
• 58 Miletich JP, Prescott SM, White R, Majerus PW, Boville EG. Inherited predisposition to thrombosis. Cell 1993; 72: 477-80.
• 59 Molinari A, Giorgetti C, Lansen J, Vaghi F, Orsini G, Faioni EM, Mannucci PM. Thrombomodulin is a cofactor for thrombin degradation of recombinant singlechain urokinase-type plasminogen activator »in vitro« and in a perfused rabbit heart model. Thromb Haemost 1992; 67: 226-32.
• 60 Müller FM, Ehrenthal W, Hafner G, Schranz D. Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate. Eur J Pediatr 1996; 155: 20-5.
• 61 Mustafa S, Mannhalter C, Rintelen C, Kyrie PA, Knöbl P, Lechner K, Pabinger I. Clinical feature of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden. Blood Coagul Fibrinol 1998; 09: 85-9.
• 62 Mustafa S, Pabinger I, Mannhalter C. Two new frequent dimorphisms in the protein S (PROS1) gene. Thromb Haemost 1996; 76: 393-6.
• 63 Nesheim M, Wang W, Boffa M, Nagashima M, Mörser J, Bajzar L. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997; 78: 386-91.
• 64 Norlund L, Holm J, Zöller B, Öhlin A-K. A common thrombomodulin amino acid dimorphism is associated with myocardial infarction. Thromb Haemost 1997; 77: 248-51.
• 65 Öhlin A-K, Norlund L, Marlar RA. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost 1997; 78: 396-400.
• 66 Öhlin AK, Marlar RA. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood 1995; 85: 330-6.
• 67 Pabinger I, Kyrie PA, Heistinger M, Eichinger S, Wittmann E, Lechner K. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: A prospective cohort study. Thromb Haemost 1994; 71: 441-5.
• 68 Patracchini P, Aillo V, Palazzi P, Calzolari E, Bernardi F. Sublocalization of the human protein C gene on chromosome 2ql3-ql4. Hum Genet 1989; 81: 191-2.
• 69 Petäjä JM, Griffin JH. Activated protein C resistance: what have we learned now that the dust has settled?. Ann Med 1997; 29: 469-2.
• 70 Ploos van Amstel HK, Diepstraten CM, Reitsma PH, Bertina RM. Analysis of platelet protein S mRNA suggests silent alleles as frequent cause of hereditary protein S deficiency type I. Thromb Haemost 1991; 65: 808.
• 71 Ploos van Amstel HK, Huisman MV, Reitsma PH, Wouter ten Cate J, Bertina RM. Partial protein S gene deletion in a family with hereditary thrombophilia. Blood 1989; 73: 479-83.
• 72 Ploos van Amstel HK, Reitsma PH, van der Logt CP, Bertina RM. Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution. Biochemistry 1990; 29: 7853-61.
• 73 Ploos van Amstel JK, van der Zanden AL, Reitsma PH, Bertina RM. Two genes homologous with human protein S cDNA are located on chromosome 3. Thromb Haemost 1987; 58: 982-7.
• 74 Preston FE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJM. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
• 75 Reitsma PH. Protein C deficiency: from gene defect to disease. Thromb Haemost 1997; 78: 344-50.
• 76 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR, Saito H, Sala N, Witt I, Cooper DN. Protein C deficiency: a database of mutations, 1995 Update. Thromb Haemost 1995; 73: 876-89.
• 77 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-7.
• 78 Rodgers GM. Vascular smooth muscle cells synthesize, secrete and express coagulation factor V. Biochim Biophys Acta 1988; 968: 17-23.
• 79 Roelse JC, Koopman MMW, Büller HR, tenCate JW, Montaruli B, van Mourik JA, Voorberg J. Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis. Br J Haematol 1996; 92: 740-3.
• 80 Rosenberg D. Thrombomodulin gene disruption and mutation in mice. Thromb Haemost 1997; 78: 705-9.
• 81 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-8.
• 82 Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth Jr WT, Raghunathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young woman. Blood 1997; 89: 2817-21.
• 83 Sacchi E, Pinotti M, Marchetti G, Merati G, Tagliabue L, Mannucci PM, Bernardi F. Protein S mRNA in patients with protein S deficiency. Thromb Haemost 1995; 73: 746-9.
• 84 Saite R, Norberg K, Ødegaard OR. Evidence of a protein C-like anticoagulant system in bony fish. Thromb Res 1996; 83: 389-97.
• 85 Schmidel DK, Nelson RM, Broxson Jr EH, Comp PC, Marlar RA, Long GL. A 5.3-kb deletion including exon XIII of the protein S alpha gene occurs in two protein S-deficient families. Blood 1991; 77: 551-9.
• 86 Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL. Organization of the human protein S genes. Biochemistry 1990; 29: 7845-52.
• 87 Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated PC in degradation of factor VIIIa. J Biol Chem 1994; 269: 18735-8.
• 88 Shen NL, Fan ST, Pyati J, Graff R, LaPolla RJ, Edgington TS. The serine protease cofactor factor V is synthesized by lymphocytes. J Immunol 1993; 150: 2992-3001.
• 89 Simmonds RE, Ireland H, Lane DA, Zöller 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 characterized gene defect. Ann Intern Med 1998; 128: 8-14.
• 90 Simmonds RE, Zöller B, Ireland H, Thompson E, Garcia de Frutos P, Dahlbäck B, Lane DA. Genetic and phenotypic analysis of a large (122-member) protein Sdeficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood 1997; 89: 4364-70.
• 91 Soria JM, Berg L-P, Fontcuberta J, Kakkar VV, Estivill X, Cooper DN, Sala N. Ectopic transcript analysis indicates that allelic exclusion is an important cause of type I protein C deficiency in patients with nonsense and frameshift mutations in the PROC gene. Thromb Haemost 1996; 75: 870-6.
• 92 Tait RC, Walker ID, Reitsma PH, Islam SIAM, McCall F, Poort SR, Conkie JA, Bertina RM. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87-93.
• 93 Tans G, Nicolaes GAF, Rosing J. Regulation of thrombin formation by activated protein C: effect of the factor V Leiden mutation. Sem Haematol 1997; 34: 244-55.
• 94 Tripodi A, Franchi F, Krachmalnicoff A, Mannucci PM. Asymptomatic homozygous protein C deficiency. Acta Haematol 1990; 83: 152-5.
• 95 van der Velden PA, Krommenhoek-Van Es T, Allaart CF, Bertina RM, Reitsma PH. A frequent thrombomodulin amino acid dimorphism is not associated with thrombophilia. Thromb Haemost 1991; 65: 511-3.
• 96 van Wijnen M, Stam JG, van’t Veer C, Meijers JC, Reitsma PH, Bertina RM, Bouma BN. The interaction of protein S with the phospholipid surfaces is essential for the activated protein C-independent activity of protein S. Thromb Haemost 1996; 76: 397-403.
• 97 Vâradik, Rosing J, Tans G, Pabinger I, Keil B, Schwarz HP. Factor V enhances the cofactor function of protein S in the APC mediated inactivation of factor VIII: influence of the factor V^R506Q mutation. Thromb Haemost 1996; 76: 208-14.
• 98 Voorberg J, Roelse J, Koopman R, Biiller H, Berends F, tenCate JW, Mertens K, van Mourik JA. Association of idiopatic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-6.
• 99 Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306 →Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-4.
• 100 Yu K, Morioka H, Fritze LM, Beeler DL, Jackmann RW, Rosenberg RD. Transcriptional regulation of the thrombomodulin gene. J Biol Chem 1992; 267: 23237-47.
• 101 Zivelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conard J, Brenner B, Eldor A, Seligson U. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997; 89: 397-402.
• 102 Zöller B, Berntsdotter A, Garcia de Frutos P, Dahlbäck B. Resistence to activated protein C as an additional risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-23.
• 103 Zöller B, Garcia 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 deficiency to be phenotypic variants of the same genetic disease. Blood 1995; 85: 3524-31.
• 104 Zöller B, Svensson P, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-4.