Experiences in Routine Genetic Analysis of Hereditary Hemorrhagic, Thrombotic, and Platelet Disorders

Abstract

Hemostasis is a complex and tightly regulated system that attempts to maintain a homeostatic balance to permit normal blood flow, without bleeding or thrombosis. Hemostasis reflects the subtle balance between procoagulant and anticoagulant factors in the pathways of primary hemostasis, secondary hemostasis, and fibrinolysis. The major components in this interplay include the vascular endothelium, platelets, coagulation factors, and fibrinolytic factors. After vessel wall injury, the subendothelium is exposed to the blood stream, followed by rapid activation of platelets via collagen binding and von Willebrand factor–mediated platelet adhesion to the damaged vessel wall through platelet glycoprotein receptor Ib/IX/V. Activated platelets change their shape, release bioactive molecules from their granules, and expose negatively charged phospholipids on their surface. For a proper function of this process, an adequate number of functional platelets are required. Subsequently, a rapid generation of sufficient amounts of thrombin begins; followed by activation of the coagulation system and its coagulation factors (secondary hemostasis), generating fibrin that consolidates the platelet plug. To maintain equilibrium between coagulation and anticoagulation, the naturally occurring anticoagulants such as protein C, protein S, and antithrombin keep this process in balance. Deficiencies (inherited or acquired) at any level of this fine-tuned system result in pathologic bleedings or increased hypercoagulability states leading to thrombosis. This review will focus on genetic diagnosis of inherited bleeding, thrombotic, and platelet disorders, discussing strengths and limitations of existing diagnostic settings and genetic tools and highlight some important considerations necessary for clinical application.

Zusammenfassung

Die Hämostase ist ein komplexes und streng reguliertes System, das dazu dient ein homöostatisches Gleichgewicht aufrecht zu erhalten und einen normalen Blutfluss ohne Blutungen oder Thrombosen zu ermöglichen. Die Hämostase stellt das fein balancierte Gleichgewicht zwischen gerinnungsfördernden und gerinnungshemmenden Faktoren in der primären Hämostase, der sekundären Hämostase und der Fibrinolyse dar. Zu den wichtigsten Komponenten in diesem Zusammenspiel gehören das Gefäßendothel, die Thrombozyten, die Gerinnungsfaktoren und die fibrinolytischen Faktoren. Nach einer Verletzung der Gefäßwand wird das Subendothel dem Blutstrom ausgesetzt, gefolgt von einer raschen Aktivierung der Thrombozyten durch Kollagenbindung und VWF-vermittelte Thrombozytenadhäsion an der beschädigten Gefäßwand durch den Thrombozyten-Glykoproteinrezeptor Ib/IX/V. Aktivierte Thrombozyten verändern ihre Form, setzen bioaktive Moleküle aus ihren Granula frei und legen negativ geladene Phospholipide auf ihrer Oberfläche frei. Dieser Prozessder primären Hämostase setzt eine ausreichende Anzahl funktionstüchtiger Thrombozyten voraus. Anschließend beginnt eine rasche Bildung großer Mengen von Thrombin, gefolgt von einer Aktivierung der prokoagulatorischen Gerinnungsfaktoren (sekundäre Hämostase), wodurch Fibrin entsteht, das den initialen Thrombozytenpfropf verfestigt. Um das Gleichgewicht zwischen Gerinnung und Antikoagulation aufrechtzuerhalten, halten die natürlich vorkommenden Antikoagulanzien wie Protein C, Protein S und Antithrombin diesen Prozess im Gleichgewicht. Defizite (vererbt oder erworben) auf irgendeiner Ebene dieses so fein abgestimmten Systems führen zu pathologischen Blutungen oder einer erhöhten Hyperkoagulabilität, die zu Thrombosen führt. Diese Übersichtsarbeit fokussiert die genetische Diagnose von vererbten Blutungs-, Thrombose- und Thrombozytenstörungen, wobei die Stärken und Limitationen bestehender diagnostischer Verfahren und genetischer Techniken erörtert und wichtige Überlegungen für die klinische Anwendung gegeben werden.

Keywords

platelet pathology/inherited - acquired - thrombosis - inherited coagulation disorders - gene mutations - diagnosis management

Schlüsselwörter

Blutplättchen Krankheitsbild/vererbt - erworben - Thrombose - angeborene Blutgerinnungsstörungen - Genmutationen - Diagnosemanagement

Publikationsverlauf

Eingereicht: 08. November 2021

Angenommen: 20. Dezember 2021

Artikel online veröffentlicht:
28. Februar 2022

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