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Review the Prothrombin G20210A Mutation - a Common Cause of Thrombophilia? Die Prothrombin G20210A-Mutation - Häufige Ursache Thrombophiler Diathesen?

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Review the Prothrombin G20210A Mutation - a Common Cause of Thrombophilia? Die Prothrombin G20210A-Mutation - Häufige Ursache Thrombophiler Diathesen? Review The Prothrombin G20210A Mutation - A Common Cause of Thrombophilia? Die Prothrombin G20210A-Mutation - Häufige Ursache thrombophiler Diathesen? R. Junker1·2, Ulrike Nowak-Göttl3 Summary: Human prothrombin is a vitamin K-depen- Ickulargewicht von 72 kDa. Die Gensequenz für Pro- dcntly synthcsized 72 kDa giycoprotein. The 2l kb se- thrombin umfaßt 21 kB und befindet sich auf Chro- quence of thc prothrombin gene has been mapped in mosom 11 (Ilpll-ql2). Im Jahre 1996 konnte eine the chromosomal region llpll-qJ2. In 1996 a single Punktmutation (G/A) in Position 20210 der 3'-nicht nucleotidc change (G to A transition) at position 20210 codierenden Sequenz des Prothrombin-Gens als Risi- in the sequence of the 3'-untranslated region has been kofaktor für venöse Thrombosen identifiziert werden. identified äs a risk factor for venous thrombosis. Co- Das gemeinsame Vorliegen dieser Mutation mit einem inheritance with deficiency of protein S, protein C, an- weiteren prothrombotischen Risikofaktor (Protein S-, tithrombin, or the coagulation factor V G1691A muta- Protein C- oder Antithrombinmangel, Faktor V tion led to a further increase of the thrombotic risk. G1691A-Mutation) führt zu einem weiteren Anstieg Moreover, the G20210A mutation, if in combination des Thromboserisikos. Heterozygote Träger der with other established risk factors (e. g. smoking, me- G20210A-Mutation haben ein erhöhtes Risiko für tabolic parameters), was found more frequently in Myokardinfarkte, sofern weitere, etablierte Risiken myocardial infarction patients than in healthy controls. (Rauchen, metabolische Risikofaktoren) vorhanden An association with arterial cerebrovascular thrombo- sind. Ein häufigeres Auftreten von arteriellen Schlag- sis in young patients has been shown in one study. anfällen bei jungen Trägern der Prothrombin-Variante Geographical and ethnical differences in carrier fre-' konnte bislang nur in einer Studie gezeigt werden. Der quencies of the prothrombin G20210A mutation ap- prozentuale Anteil der Mutationsträger an der gesun- peared between healthy populations, with a trend to- den Bevölkerung variiert etwa zwischen 0 und 4%; in- wards lower frequencies from south to norm of Euro- nerhalb Europas ist eine Zunahme von Nord nach Süd pe (ränge approximately from 0 to 4%). Screening for zu erkennen. Ein generelles Screening auf Vorliegen presence of the mutation should be performed at least der Mutation ist derzeit weder zu empfehlen, noch ab- in cases of otherwise unexplained thrombotic events in zulehnen. In Fällen thrombotischer Ereignisse ohne er- adtilts, äs well äs in all thrombotic events during child- kennbare Ursache beim Erwachsenen, sowie in jedem hood, adolescence or young adults. However, thera- Falle bei Gefäßverschlüssen im Kindes-, Jugend- und peutic strategies for the treatment of thrombosis in car- jungen Erwachsenenalter sollte die Prothrombin-Vari- riers of the prothrombin G20210A mutation have not ante im Rahmen der Thrombophiliediagnostik be- been derived from clinical studies. Meanwhile, treat- stimmt werden. Bisher wurden keine Studien zur Be- ment should be performed similar for thrombosis pati- handlung thrombotischer Ereignisse bei Trägern der ents carrying the coagulation factor V G1691A mutati- Prothrombin G20210A-Mutation durchgeführt. Vor- on or other hereditary prothrombotic risk factors. läufig sollte analog zur Therapie thrombotischer Er- eignisse aufgrund anderer hereditärer Risikofaktoren Keywords: Prothrombin/genetics, Thrombosis/gene- (Protein S-, Protein C- oder Antithrombinmangel, Fak- tics; Risk Factors. tor V G1691A-Mutation) behandelt werden. Zusammenfassung: Prothrombin wird Vitamin K- Schlüsselwörter: Prothrombin/Genetik; Thrombose/ abhängig in der Leber synthetisiert und besitzt ein Mo- Genetik; Risikofaktor-en. 1 Institut für Klinische Chemie und Laboratoriumsmedizin und In- stitut für Arterioskleroseforschung, Westfälische Wilhelms-Univer- uman PT is a single-chain 72 kDa giycoprotein sität Münster and is vitamin K-dependently synthesized in the 2 Correspondence to: Dr. med. Ralf Junker, Institut für Klinische H Chemie und Laboratoriumsmedizin, Westfälische Wilhelms- liver [l, 2]. Its primary structure contains 579 amino Universität Münster, Albert Schweitzer-Straße 33, D-48129 Mün- acids [3]. The mature PT molecule is composed of ster, Germany. Fax: +49-251-8347227. E-mail: junkerr@uni-muen- four domains: a Gla domain (residues 1-40), the ster.de 3 Klinik und Poliklinik für Kinderheilkunde, Westfälische Wilhelms- kringle l domain (residues 41-155), the kringle 2 do- Universität Münster main (residues 156-271) and a serine protease domain Received: May 22, 1998 / Accepted: July 21, 1998 precursor (residues 272-579) [1,2]. 472 J Lab Med 1998; 22 (9): 472-482 © 1998 Blackwell'Wissenschafts-Verlag, Berlin R. Junker, Ulrike Nowak-Göttl: Prothrombin G20210A mutation a) via Fi+2/Prethrombin b) via Meizothombin V _ .. Prothrombinase complex Platelets Monocytes FactorXa Lymphocytes FactorVa 2 rapid Inactivation of free FactorXa by anti'thrombin, Endothelial cells PL,Cä * thus prolhrombin activation is localized to the injury site Figure 1 Role of prothrombin and its regulation mechanisms in. hemostasis PT äs the inactive precursor of thrombin is a central PT is found in plasma concentrations of 100-200 molecule in hemostasis. After activation by coagulati- g/ml and has a plasma half-life of approximately 72- on factor Xa in the presence of coagulation factor Va, 96hours [7,8] (Figure 1). calcium ions, and phospholipids, which are assembled äs a prothrombinase complex on phospholipid surfa- ces, PT is converted into thrombin. The latter is indu- The prothrombin gene and the G20210A ced by hydrolysis of.tvvo internal peptide bonds mutation (Arg27i-Thr and Arg32o-Ue), resulting in the release of 39 kba thrombin from the carboxyl-terminal portion The complete 21 kb sequence of the prothrombin gene of PT, whereas the Gla and the kringle containing re- contains 14 exons (25-315 bp), 13 introns (90% of the gions from the amino-terminal end of PT remain atta- gene, 84-9447 bp), a 5'-untranslated region, and a 34- ched to the phospholipid. Although coagulation factor untranslated region [3,9]. The gene has been mapped Va increases the conversion rate of this pathway dra- on chromosome 11 in the chromosomal region llpll- matically, a mechanism acting slowly and solely with q!2 [10]. factor Xa is probably important for the initial reaction: There are few mutations in the PT gene leading to after conversion of coagulation factor X to Xa, coagu- hypo- or dysprothrombinemia and consequently to lation factor V is proteolyzed by factor Xa to factor bleeding disorders [11]. However, due to the central Va. In addition, factor Xa converts PT to thrombin, role in the hemostatic .System the gene encoding for PT which itself activates_coagulation factor V. Önce fac- might serve äs a candidate gene not only for bleeding tors Va and Xa are avaflable, the prothrombinase com-· disorders but also for hereditary thrombophilia. Hence, plex can assemble on cell membranes. in 1996 Poorr et al. identified a single nucleotide The serine protease thrombin has procoagulant, an- change (G to A transition) at position 20210 in the se- ticoagulant and antifibrinolytic functions. It participa- quence of the 3'-untranslated region äs a risk factor for tes in the final stage of blood coagulation mainly by venous thrombosis [12]. converting fibrinogen to fibrin, forming an insoluble The mechanism leading to an increased thrombotic fibrin clot. Additional functions of thrombin are the risk in carriers of this mutation remains to be clarified. activation of coagulation factors V, VIII, XIII and pro- As localized in the 3'-untranslated region of the gene, tein C, äs well äs Stimulation of platelets, monocytes, there are no structural changes of the protein due to lymphocytes,and endothelial cells [1,2, 4-6]. this mutation. On the one hand elevated levels of PT found in individuals carrying the A allele may consti- tute a risk factor by increasing the amount of thrombin Non Standard abbreviations: Cl, confidence interval; DVT, deep generation and leading to coagulation activation. Thus, venous thrombosis; FV, coagulation factor V; HIND III, restrictipn high levels of PT may be explained by higher transla- endonuclease from haemophilus tnfluenzae; MI, myocardial in- farction; OR, odds ratio; PCR, polymerase chain reaction; PT, pro- tion efficiency or higher stability of .the transcribed thrombin. mRNA [12]. However, up to'now ex perimental results J Lab Med 1998; 22 (9): 472-482 473 R. Junker, Ulrike Nowak-Göttl: Prothrombin G20210A mutation failcd to confirm this hypothcsis |13). On thc othcr hand, it ihereforc may also bc suggested that thc PT M AG A G AG AG AG mulation is linked with a furthcr sequcncc variant in- flucncing genc cxprcssion [12]. - 270 - 148 Genotyping methods F M B P -C Due lo inter- and intraindividual variancc of plasma Figure 2 Gel electrophoresis of allele specific PCR products. PT concentrations, PT levels itself do not allow a con- Upper row: lane A, amplification product of the A allele; lane G amplification product of the G allele; M, marker. Lower row: F, fat- clusion to be drawn on the presence or absence of the her; M, mother; B, brother; P, DVT patient; - C, negative control. mutation. Thcrefore, the PT mutation has to be deter- The patient, his mother and brother are heterozygous carriers of mined by DNA analysis [14]. the PT mutation Poon et al. detected the mutation by direct sequen- cing after PCR amplification
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