Molekularbiologie und Hämostase

Zusammenfassung

Für die Diagnostik von Erkrankungen spielen molekularbiologische Methoden bei schweren angeborenen Krankheiten (z. B. Hämophilie A oder B) eine wichtige Rolle. Auch zur Diagnostik polygenetischer Erkrankungen (z. B. venöse und arterielle Thrombosen) sind sie unentbehrlich. Neben der Analyse der zwei häufigsten genetischen Defekte (Inversion im Intron 22 und Intron 1) im Faktor-VIII-Gen als Ursache der schweren Hämophilie A wurde in den vergangenen Jahren die Sequenzierung des Faktor-VIII-Gens in mehreren Zentren eingeführt und wird nun in der Hämophilie- und Überträgerinnen- Diagnostik eingesetzt. Bei Patienten mit Thrombophilie trägt der Nachweis von Mutationen im Protein-C- und Protein-S-Gen zur Verbesserung der Diagnostik bei bekanntem familiären Protein-C- bzw. -S-Mangel bei. Die Analysen der Arg506Gln-Mutation im Faktor-V-Gen (Faktor-V-Leiden) und die 20210G>A-Mutation im Prothrombin-Gen, die das Risiko für venöse Thrombose beeinflussen, können potenziell helfen, das individuelle Risiko für eine Thrombose bzw. Rezidivthrombose besser einzuschätzen. Allerdings führt die unkritische Untersuchung genetischer Ursachen der Thrombose zu keinem wesentlichen Informationsgewinn hinsichtlich Behandlung und Beratung der Patienten und kostet Zeit und Geld. Daher sollen immer nur jene Tests durchgeführt werden, die medizinische bzw. therapeutische Konsequenzen nach sich ziehen. Trotz der Bedeutung der molekulargenetischen Diagnostik sind die Einsatzmöglichkeiten der Mutationsdiagnostik im klinischen Alltag eines Gerinnungslabors begrenzt. Große Studien haben gezeigt, dass eine Mutation nicht bei jedem Menschen die gleiche Auswirkung hat, da endogene und exogene modulierende Faktoren den Phänotyp beeinflussen. Da sehr wenig über modulierende Faktoren bekannt ist, ist es häufig schwierig, die Auswirkung einer Mutation in ihrer Tragweite zu bewerten. Es ist daher von außerordentlicher Wichtigkeit, die Forschung voranzutreiben, um Gen- Gen- und Gen-Umwelt-Interaktionen zu verstehen, damit in Zukunft eine zuverlässige Interpretation der Mutationsergebnisse möglich wird.

Summary

Molecular biological methods have become increasingly important not only in the diagnostics of inherited monogenetic diseases such as hemophilia A or B but also in the diagnostics of polygenetic diseases e.g. venous and arterial thrombosis. In haemophilia A, sequencing of the factor VIII gene has been established in addition to the analysis of the two most frequent genetic abnormalities, the inversions in intron 22 and intron 1, in several centers. Molecular testing has proved helpful to identify haemophilia patients at high risk to develop inhibitors as well as in carrier analysis. In patients with familial protein C or protein S deficiency mutation analysis contributes to the verification of the diagnosis. The frequently performed tests for the factor V Leiden mutation and the prothrombin 20210G>A variation can potentially support the estimation of the thrombotic risk as well as the risk of recurrence. However, any uncritical application of these genetic tests does not improve diagnostics nor does it support therapeutic decision making or counselling of the patient. Therefore, one should only do genetic tests with medical or therapeutic consequences. The applicability of mutation analysis in the daily routine is still limited in spite of the importance of molecular diagnostics in the understanding of pathomechanisms of haemostatic disorders. As has been demonstrated in large studies, the phenotypic effects of mutations can vary significantly between individuals. Endogenous and exogenous modulators that are still largely unknown, play a role. Currently, the understanding of these modulators is limited, and large multicenter studies and meta-analyses are needed for a better understanding of gene-gene and gene-environment interactions.

Schlüsselwörter

Blutgerinnung - Molekularbiologie - Thrombophilie - angeborene Blutungsneigung

Keywords

Blood coagulation - genetics - thrombophilia - inherited bleeding disorders

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