Biomarkers for arterial and venous thrombotic disorders

Summary

The haemostatic system maintains the blood in a fluid state, but allows rapid clot formation at sites of vascular injury to prevent excessive bleeding. Unbalances within the haemostatic system can lead to thrombosis. Inspite of successful research our understanding of the disease pathogenesis is still incomplete. There is great hope that genetic, genomic, and epigenetic discoveries will enhance the diagnostic capability, and improve the treatment options. During the preceding 20 years, the identification of polymorphisms and the elucidation of their role in arterial and venous thromboses became an important area of research. Today, a large body of data is available regarding associations of single nucleotide polymorphisms (SNPs) in candidate genes with plasma concentrations and e. g. the risk of ischaemic stroke or myocardial infarction. However, the results for individual polymorphisms and genes are often controversial. It is now well established that besides acquired also hereditary risk factors influence the occurrence of thrombotic events, and environmental factors may add to this risk. Currently available statistical methods are only able to identify combined risk genotypes if very large patient collectives (>10 000 cases) are tested, and appropriate algorithms to evaluate the data have yet to be developed. Further research is needed to understand the functional effects of genetic variants in genes of blood coagulation proteins that are critical to the pathogenesis of arterial and venous thrombotic disorders. In this review genetic variants in selected genes of the haemo static system and their relevance for arterial and venous thrombosis will be discussed.

Zusammenfassung

Das Gerinnungssystem stellt sicher, dass das fließende Blut im Falle von Verletzungen sehr rasch ein Gerinnsel bilden kann, Wunden verschließt und damit einen Blutverlust großen Ausmaßes verhindert. Dies wird durch ein feinst ausgewogenes Gleichgewicht zwischen pro- und antikoagulatorischer Aktivität gewährleistet. Jedwede Verschiebung der Balance kann zu Thrombosen oder Blutungen führen. Trotz umfangreicher Forschungsaktivitä-ten sind die pathogenetischen Ursachen dafür nicht gut verstanden. Es besteht die Hoffnung, dass genetische, genomische und epigeneti-sche Erkenntnisse das Wissen vertiefen, die Diagnostik schärfen und schließlich die Therapie verbessern werden. Im Laufe der vergangenen 20 Jahre wurden zahlreiche genetischen Varianten identifiziert und hinsichtlich ihrer Bedeutung für arterielle und venöse Thrombosen wissenschaftlich untersucht. Heute liegen uns umfangreiche Daten zur Assoziation verschiedenster polymorpher Varianten von zahlreichen Kandidatengenen mit den Plas-makonzentrationen der entsprechenden Proteine und z. B. dem Risiko für Schlaganfall und Herzinfarkt vor. Allerdings sind die publizierten Ergebnisse zur Rolle verschiedener Polymorphismen und ihrem Beitrag zum Auftreten von Thrombosen oft kontrovers. Das mag zum Teil mit dem Einfluss externer Fak-toren auf das Thromboserisiko zusammen-hängen, es liegt aber wahrscheinlich auch an den statistischen Analyseverfahren und der erforderlichen großen Zahl der Patienten. Zur Erreichung signifikanter Ergebnisse benötigt man sehr große Kohorten (>10 000 Fälle), die oft sehr heterogen sind. Ohne Zweifel bedarf es neuer Algorithmen, um die immer umfangreicheren Daten sinnvoll auszuwerten und die verschiedenen funktionellen Effekte, die für die Pathogenese arterieller und venöser Thrombosen verantwortlich sind, zu verste-hen.

In diesem Übersichtsbeitrag werden verschiedene Varianten in ausgewählten Genen des Hämostasesystems vorgestellt und ihre Relevanz für arterielle und venöse Thrombosen kritisch diskutiert.

Keywords

Genetics - single nucleotide polymorphisms - thrombotic disorders - haemostasis

Schlüsselwörter

Genetik - Einzelnukleotidpolymorphismen - thrombotische Erkrankungen - Hämostase

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