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Heparinresistenz und Antithrombinmangel*

Heparin Resistance and Antithrombin Deficiency

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Zusammenfassung

Das Phänomen der Heparinresistenz (HR) ist gekennzeichnet durch das Erfordernis hoher Dosen von unfraktioniertem Heparin (UFH) zur Erzielung therapeutisch erwünschter Bereiche der aktivierten partiellen Thromboplastinzeit (aPTT) bzw. der aktivierten Gerinnungszeit (ACT) oder die Unmöglichkeit, dieses Ziel zu erreichen. Ab einer UFH-Dosis > 35 000 IE/d sollte man eine HR in Erwägung ziehen. Die häufigste Ursache für eine HR ist der Mangel an Antithrombin (AT), dessen Vorhandensein für die antikoagulatorische Wirksamkeit des UFH notwendig ist. Zur Überwindung einer AT-abhängigen HR kann AT als Konzentrat verabreicht werden. Klinisch relevante Situationen einer AT-abhängigen HR mit einer eventuellen Indikation zur AT-Substitution sind vor allem der hereditäre AT-Mangel, die Asparaginasetherapie, die disseminierte intravasale Gerinnung (DIC) und die hochdosierte Heparingabe bei extrakorporaler Zirkulation, wobei hier wegen der Notwendigkeit einer sehr hohen ACT (> 400 s) der Einsatz der Herz-Lungen-Maschine mit einer HR-Inzidenz von ca. 20% von Bedeutung ist. Besteht keine DIC oder extrakorporale Zirkulation, empfiehlt sich folgendes Procedere: Bei HR-Verdacht und einer AT-Aktivität ≤ 60% sollten zur Vermeidung von Blutungskomplikationen zunächst UFH auf 500 IE/h reduziert und dann AT substituiert werden. Hierunter sollte die AT-Aktivität > 80% liegen. Unter normalisierter und konstanter AT-Aktivität ist die UFH-Dosis so zu adjustieren, dass die aPTT 60–100 s beträgt. Falls eine längerfristige Antikoagulation indiziert ist, sollte so rasch als möglich überlappend eine orale Antikoagulation mit einem Vitamin-K-Antagonisten eingeleitet werden.

Abstract

The phenomenon of heparin resistance (HR) is characterized by high doses of unfractionated heparin (UFH) being required to bring activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) within therapeutically desired ranges, or by the impossibility of reaching these ranges. At UFH dosages > 35,000 IU/d, HR should be considered a factor. The most frequent cause of HR is deficiency of antithrombin (AT), the presence of which is essential for UFH to exert its anticoagulatory effect. AT in concentrate form may be applied to overcome AT-dependent HR. The main clinically relevant situations in which AT-dependent HR occurs, with possible indication of AT substitution, are congenital AT deficiency, asparaginase therapy, disseminated intravascular coagulation (DIC) and administration of high doses of heparin during extracorporeal circulation, where it is significant, due to the need to maintain a very high ACT (> 400 s), that use of heart-lung machines is associated with an HR incidence of approximately 20%. The following procedure is recommended when there is no DIC and when extracorporeal circulation is not used: if HR is suspected and AT activity is ≤ 60%, UFH should first be reduced to 500 IU/h (to prevent bleeding complications), before AT is substituted. AT activity should then exceed 80%. Under normalized and stable AT activity, the UFH dose should be adjusted such that aPTT is within a range of 60–100 s. If anticoagulation over a longer term is indicated, then overlapping anticoagulation with a vitamin K antagonist should be started as quickly as possible.

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  1. KfH-Nierenzentrum Neuwied, Neuwied, Germany

    Norbert Maurin

  2. Internist/Nephrologie, Intensivmedizin, KfH-Nierenzentrum Neuwied, Engerser Landstraße 78, 56564, Neuwied, Germany

    Norbert Maurin

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* Herrn Prof. Dr. med. Heinz-Günter Sieberth zur Vollendung seines 75. Lebensjahres gewidmet.

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Maurin, N. Heparinresistenz und Antithrombinmangel*. Med Klin 104, 441–449 (2009). https://doi.org/10.1007/s00063-009-1093-8

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