Genomische Diagnostik thrombophiler Gerinnungsstörungen bei Frauen

Zusammenfassung

Die Aufklärung der DNA-Sequenzen sowohl der Gerinnungsfaktoren als auch der Gerinnungsinhibitoren hat die Erforschung genetischer Ursachen einer venösen Thromboseneigung ermöglicht. Da die Entstehung venöser Thrombosen ein multifaktorielles Geschehen ist, weisen Frauen auf Grund frauenspezifischer Risikosituationen (z. B. hormonale Kontrazeption, Schwangerschaft, Wochenbett) in bestimmten Lebensphasen ein zusätzliches expositionelles Thromboserisiko auf. Von wesentlicher Bedeutung ist es, die thrombophilen Neigungen zu definieren, bei denen eine genetische Diagnostik von besonderer klinischer Relevanz ist, zumal auch eine habituelle Abortneigung, schwangerschaftsinduzierte hypertensive Erkrankungen und frustrane In-vitro-Fertilisationen in Zusammenhang mit einer Thrombophilie gebracht werden. Trotz der vielfältigen Möglichkeiten einer genomischen Diagnostik ist eine DNA-Analyse nur in wenigen Fällen klinisch notwendig: Sinnvoll ist eine Mutationsanalytik bezüglich einer Faktor- V-Leiden-Mutation, da die Risiken zwischen homo- und heterozygoter Ausprägung differieren und von klinischer Relevanz in der Schwangerschaft und bei Schwangerschaftskomplikationen sind. Ebenso bewiesen ist dies für die Prothrombinmutation G20210A, wobei die Datenlage für deren homozygote im Vergleich zur heterozygoten Form auf Grund der Seltenheit unzureichend ist.

Die Analytik der homozygoten Form der MTHFR-Mutation C677T ist nicht zu empfehlen, da die klinische Relevanz für die meisten Indikationen nicht ausreichend belegt ist. Für angeborene Mangelzustände von Antithrombin, Protein C und Protein S ist die Datenlage auf Grund ihrer geringen Inzidenzen selbst in venösen Thrombosekollektiven sehr gering. Die Mutationsanalytik kommt hier nur in Frage, wenn die Aktivitätsuntersuchungen der Proteine trotz wiederholter Messungen keine eindeutige Beurteilung zulassen. Alle übrigen Mutationsanalysen (z. B. PAI-1-Polymorphismus, Faktor-XIII-Val34Leu-Polymorphismus) sind bei Frauen zurzeit ohne klinische Relevanz.

Summary

The detection of the DNA-sequence of human coagulation factors and inhibitors has introduced the possibility of differentiated mutation analysis in patients with venous thrombosis. Since venous thromboembolism is a multifactorial disease, women are at an increased risk to develop venous thrombosis due to hormonal contraception, during pregnancy and the puerperium. In addition, pregnancy complications like early or late fetal loss, pregnancy-induced hypertensive disorders and very recently recurrent embryo implantation failure have been suspected to be associated with thrombophilia. Therefore, it is of major importance to define inherited thrombophilic disorders, in which genetic diagnosis is of clinical relevance. While most of the genetic defects described so far represent a risk factor for venous thrombosis, only a minority of these defects actually needs DNA analysis to be detected: Mutation analysis is clinically relevant, when factor V Leiden mutation is suspected, because relative risks concerning venous thrombosis as well as pregnancy complications clearly differ between homozygote and heterozygote forms of this frequently observed mutation. Similarly detection of the prothrombin mutation G20210A is of clinical relevance, although data for the very rarely observed homozygote variant are not sufficiently available.

In contrast, detection of the homozygote variant of the MTHFR-mutation C677T is not useful, since clinical relevance could not be proven in a majority of studies concerning women specific risk situations. Inherited deficiencies of antithrombin, protein C and protein S are rare with high rates of different mutations. Genetic analysis seems only useful in patients with wide intraindividual variations of coagulation inhibitor activities. Genetic analysis concerning the PAI-1 4G/5G polymorphism or the factor XIII Val34Leu polymorphism can not be recommended in women specific risk situations because of insufficient data.

Schlüsselwörter

Thrombophilie - Mutationsanalyse - Frauen

Keywords

Thrombophilia - mutation analysis - women

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