Markers of Hereditary Thrombophilia with Unclear Significance

Abstract

Thrombophilia leads to an increased risk of venous thromboembolism. Widely accepted risk factors for thrombophilia comprise deficiencies of protein C, protein S, and antithrombin, as well as the factor V “Leiden” mutation, the prothrombin G20210A mutation, dysfibrinogenemia, and, albeit less conclusive, increased levels of factor VIII. Besides these established markers of thrombophilia, risk factors of unclear significance have been described in the literature. These inherited risk factors include deficiencies or loss-of-activity of the activity of ADAMTS13, heparin cofactor II, plasminogen, tissue factor pathway inhibitor (TFPI), thrombomodulin, protein Z (PZ), as well as PZ-dependent protease inhibitor. On the other hand, thrombophilia has been linked to the gain-of-activity, or elevated levels, of α2-antiplasmin, angiotensin-converting enzyme, coagulation factors IX (FIX) and XI (FXI), fibrinogen, homocysteine, lipoprotein(a), plasminogen activator inhibitor-1 (PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI). With respect to the molecular interactions that may influence the thrombotic risk, more complex mechanisms have been described for endothelial protein C receptor (EPCR) and factor XIII (FXIII) Val34Leu. With focus on the risk for venous thrombosis, the present review aims to give an overview on the current knowledge on the significance of the aforementioned markers for thrombophilia screening. According to the current knowledge, there appears to be weak evidence for a potential impact of EPCR, FIX, FXI, FXIII Val34Leu, fibrinogen, homocysteine, PAI-1, PZ, TAFI, and TFPI on the thrombotic risk.

Zusammenfassung

Eine Thrombophilie führt zu einem erhöhten Risiko für venöse thromboembolische Ereignisse. Weithin anerkannte Risikofaktoren für eine Thrombophilie sind ein Mangel an Protein C, Protein S und Antithrombin, sowie die Faktor-V-“Leiden”-Mutation, die Prothrombin-G20210A-Mutation, eine Dysfibrinogenämie und, weniger eindeutig, erhöhte Faktor VIII-Aktivitäten. Neben diesen etablierten Markern sind in der Literatur auch Risikofaktoren von eher unklarem Stellenwert beschrieben. Zu diesen Risikofaktoren, bzw. Markern, gehören der Funktionsverlust (loss-of-activity), bzw. der Mangel, der Aktivität von ADAMTS13, Heparin-Cofaktor II (HCII), Plasminogen, Tissue Factor Pathway Inhibitor (TFPI), Thrombomodulin (TM), Protein Z (PZ) sowie des Protein Z-abhängigen Proteaseinhibitors (ZPI). Andererseits wurde eine Thrombophilie mit einem gain-of-activity, bzw. erhöhten Aktivitäten, von α2-Antiplasmin (a2-AP), Angiotensin-konvertierendem Enzym (ACE), den Gerinnungsfaktoren IX (FIX) und XI (FXI), Fibrinogen, Homocystein, Lipoprotein(a), Plasminogenaktivator-Inhibitor-1 (PAI-1) sowie dem Thrombin-aktivierbaren Fibrinolyse-Inhibitor (TAFI) in Verbindung gebracht. Im Hinblick auf die zugrundeliegenden molekularen Interaktionen, die einen Einfluss auf das Thromboserisiko haben könnten, stellen sich die Mechanismen für den endothelialen Protein-C-Rezeptor (EPCR) und den Faktor-XIII-(FXIII) Val34Leu komplexer dar. In der vorliegenden Arbeit soll ein Überblick über den aktuellen Wissensstand zur Bedeutung dieser Marker für das Thrombophilie-Screening bei Patienten mit venösen thromboembolischen Ereignissen gegeben werden. Hierbei zeigt sich nach derzeitigem Kenntnisstand eine schwache Evidenz für einen möglichen Einfluss von EPCR, F IX, F XI, F XIII Val34Leu, Fibrinogen, Homocystein, PAI-1, PZ, TAFI und TFPI auf das Thromboserisiko.

Keywords

thrombophilia - risk factors - unclear evidence

Publication History

Received: 06 June 2022

Accepted: 23 August 2022

Article published online:
22 December 2022

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