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Heritability of Plasma Concentrations of Clotting Factors and Measures of A Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-deficient family Vossen, C.Y.; Hasstedt, S.J.; Rosendaal, F.R.; Callas, P.W.; Bauer, K.A.; Broze, G.J.; ... ; Bovill, E.G. Citation Vossen, C. Y., Hasstedt, S. J., Rosendaal, F. R., Callas, P. W., Bauer, K. A., Broze, G. J., … Bovill, E. G. (2004). Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-deficient family. Journal Of Thrombosis And Haemostasis, 2(2), 242-247. Retrieved from https://hdl.handle.net/1887/5097 Version: Not Applicable (or Unknown) License: Downloaded from: https://hdl.handle.net/1887/5097 Note: To cite this publication please use the final published version (if applicable). Journal of Thrombosis and Haemostasis, 2: 242±247 ORIGINAL ARTICLE Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-de®cient family C. Y. VOSSEN,Ãy S. J. HASSTEDT,z F. R. ROSENDAAL,y§ P. W. CALLAS,ô K. A. BAUER,Ãà G. J. BROZE,yy H. HOOGENDOORN,zz G. L. LONG,§§ B. T. SCOTTà andE. G. BOVILLà ÃPathology, University of Vermont, Burlington, VT, USA; yClinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; zHuman Genetics, University of Utah, Salt Lake City, UT, USA; §Hematology, Leiden University Medical Center, Leiden, the Netherlands; ôBiostatistics, University of Vermont, Burlington, VT, USA; ÃÃMedicine, VA Medical Center, West Roxbury, MA, USA; yyHematology, Barnes-Jewish Hospital, St Louis, MO, USA; zzAf®nity Biologicals Inc., Hamilton, Ontario, Canada; and §§Biochemistry, University of Vermont, Burlington, VT, USA To cite this article: Vossen CY, Hasstedt SJ, Rosendaal FR, Callas PW, Bauer KA, Broze GJ, Hoogendoorn H, Long GL, Scott BT, Bovill EG. Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-de®cient family. J Thromb Haemost 2004; 2: 242±7. heritabilityof single coagulation factors and measures of a Summary. Background: Earlier studies found strong support prethrombotic state. Hemostatic markers with statistically for a genetic basis for regulation of coagulation factor levels and signi®cant heritabilityconstitute potential targets for the iden- measures of a prethrombotic state (D-dimer, prothrombin frag- ti®cation of novel genes involved in the control of quantitative ment 1.2). Objectives: Estimation of how much of the variation trait loci. in the levels of coagulation factors and measures of a pre- thrombotic state, including measures of protein C activation and Keywords: coagulation, hereditaryprotein C de®ciency,herit- inactivation, could be attributed to heritabilityand household ability. effect. Patients and methods: Blood samples were collected from 330 members of a large kindred of French-Canadian origin with type I protein C de®ciency. Heritability and common Introduction household effect were estimated for plasma concentrations of prothrombin, factor (F)V, factor VIII, factor (F)IX, ®brinogen, Over a centuryago, Virchow postulated that thrombosis was von Willebrand factor (VWF), antithrombin, protein C, protein caused byalteration in the vessel wall, blood ¯ow or the S, protein Z, protein Z-dependent protease inhibitor (ZPI), composition of the blood [1]. Several hereditaryprothrombotic ®brinopeptide A (FPA), protein C activation peptide (PCP), defects have been identi®ed in the last four decades associated activated protein C±protein C inhibitor complex (APC±PCI), with a change in the composition of the blood. The ®rst activated protein C±a1-antitrypsin complex (APC±a1AT), hereditarydefects described were mutations in clot-preventing prothrombin fragment 1.2 (F1.2) and D-dimer, using the factors (antithrombin, protein C and protein S) [2±4]. In 1994 variance component method in sequential oligo-genic linkage and 1996, two highlyprevalent mutations, the factor (F)V analysis routines (SOLAR). Results: The highest heritability Leiden mutation (FV G1691A) and the factor II G20210A was found for measures of thrombin activity(PCP and mutation, were reported [5,6]. The latter two mutations are FPA). High estimates were also found for prothrombin, FV, associated with resistance to inactivation of activated FV and FIX, protein C, protein Z, ZPI, APC±PCI and APC±a1AT. elevated concentrations of prothrombin, respectively. Elevated An important in¯uence of shared household effect on pheno- concentrations of other procoagulant factors, such as ®brino- typic variation was found for VWF, antithrombin, protein S gen, factor (F)VIII, factor (F)IX and factor (F)XI have been and F1.2. Conclusions: We found strong evidence for the shown to increase the risk of venous thrombosis [7±10]. Several polymorphisms are known to in¯uence plasma levels of ®bri- nogen [11]. For high levels of FVIII, evidence for a genetic Correspondence: E. G. Bovill, Department of Pathology, University of determination byfactors other than blood group and von Wille- Vermont, Given Building #E208, 89 Beaumont Avenue, Burlington, VT 05405, USA. brand factor (VWF) has been found [12,13]. However, no Tel.: 1 802 656 0359; fax: 1 802 656 8892; e-mail: edwin.bovill@ polymorphisms have been discovered yet in the FVIII gene uvm.edu that can account for high levels of FVIII [14]. For FIX and FXI it is still unclear whether genetic factors contribute or not, and to Received 18 September 2003, accepted 31 October 2003 what extent. # 2004 International Societyon Thrombosis and Haemostasis Heritability of the coagulation system 243 Recent studies have demonstrated a genetic basis for the SCAT-1 (25 mM PPACK, 200 kIU mLÀ1 aprotinin, 4.5 mM regulation of plasma concentrations of coagulation factors and EDTA; Hematologic Technologies, Essex, VT, USA). Plate- markers of a prethrombotic state [D-dimer and prothrombin let-poor plasma from freshlydrawn whole blood was produced activation fragment 1.2 (F1.2)] byestimating heritabilitywithin within 1 h bycentrifugation at 3000  g for 10 min at room healthyindividuals or relatives of individuals with arterial or temperature and stored at À70 8C. Frozen plasma samples were venous thrombosis [15±18]. Previously, we published prelimin- thawed at 37 8C just before assayperformance. arydata demonstrating strong evidence for the heritabilityof levels of markers of protein C activation and inactivation in a Assay methodology large familyfrom French Canadian descent with TypeI protein C de®ciency[19]. All assays were performed in the investigators' laboratories The present paper describes the ®nalized analysis on the either byELISA: FV antigen [coef®cient of variation (CV) heritabilityof levels of coagulation factors and measures of a 5.8%] [21], FVIII antigen (CV 7.8%), FIX antigen (CV 10%), prethrombotic state with the addition of important information VWF (CV 3%) [22], protein Z (CV 6.5%) [24], ZPI (CV 7.2%) on household in¯uence. Heritabilityand common household [24], APC±a1AT complex (CV 12.4%) [25] and APC±PCI effect were estimated for plasma concentrations of prothrom- complex (CV 11.7%) [25], or radioimmunoassay: prothrombin bin, FV, FVIII, FIX, ®brinogen, VWF, antithrombin, protein C, (CV 8%) [26], antithrombin (CV 5%) [27,28], protein S (CV protein S, protein Z, protein Z-dependent protease inhibitor 9.8%) [29], F1.2 (CV 8%) [28], PCP (CV 14%) [28] and FPA (ZPI), ®brinopeptide A (FPA), protein C activation peptide (CV 8%) [28], the Clauss method for ®brinogen (CV 1.7%) (PCP), activated protein C±protein C inhibitor complex [30,31] using the ST4 instrument (Diagnostica Stago, Parsi- (APC±PCI), activated protein C±a1-antitrypsin complex panny, NJ, USA), a clot-based functional assay for protein C: (APC±a1AT), F1.2 and D-dimer. (CV 5.5%) [20,23] or micro latex bead agglutination for D- dimer (CV 9.2%) (Biomerieux, Durham, NC, USA) [32,33]. FV antigen analysis was performed with an in-house assay Materials and methods [21]. The kits for FVIII antigen, FIX antigen, protein C and VWF were provided byDiagnostica Stago, and assayswere Participants and inclusion criteria performed following the manufacturers' instructions. The as- Blood samples were collected from 330 members of a large says for APC±PCI complex and APC±a1AT complex were kindred of French-Canadian origin with type I protein C performed using a commerciallyavailable assayat Af®nity de®ciency, including spouses of family members with children. Biologicals Inc. (Ancaster, Ontario, Canada). The ascertainment and evaluation of the familymembers was The number of individuals per assayvaried, based on the described previously[20]. All subjects completed question- availabilityof appropriate stored samples from 83 to 287. naires and were personallyinterviewed regarding their medical historyin general, their risk factors for thrombosis (e.g. use of Statistical analysis birth control pills, pregnancy, surgery, trauma, infection) and their thrombosis history. We classi®ed a history of venous To reduce skewness and kurtosis, we applied log transformation thrombosis as veri®ed when subjects were hospitalized and to the levels of FV, VWF, antithrombin, FPA, PCP, APC±a1AT treated for venous thrombosis with an objectivelydiagnosed complex, APC±PCI complex and D-dimer, square root trans- deep venous thrombosis or pulmonaryembolism. All partici- formation to the levels of FVIII antigen and F1.2, and reciprocal pating subjects gave informed consent, or if individuals were transformation to the levels of FIX antigen. under 18 years, a parent or legal guardian gave informed
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