Kongenitale amegakaryozytäre Thrombozytopenie (CAMT) - ein Defekt des Thrombopoetin-Rezeptors c-Mpl

Zusammenfassung.

Bei der angeborenen amegakaryozytären Thrombozytopenie (CAMT) handelt es sich um ein seltenes „bone marrow failure”-Syndrom, bei dem eine zunächst isoliert auftretende Thrombozytopenie mit hypomegakaryozytärem Knochenmark im Laufe der ersten Lebensjahre in eine Panzytopenie übergeht. Die Knochenmarktransplantation stellt der-zeit die einzige kurative Behandlungsmethode dar. Thrombopoetin (TPO) ist der wichtigste Wachstumsfaktor für die Regulation der Megakaryozytopoese und Thrombozytopoese. Wir führten Laboruntersuchungen an Blutplasma, hämatopoetischen Vorlauferzellen und Thrombozyten von CAMT-Patienten durch, um die TPO-Produktion und die Reaktivität der verschiedenen Zellen auf diesen Botenstoff zu testen. Obwohl wir im Plasma von CAMT-Patienten, wie auch bei anderen hypomegakaryozytären Thrombozytopenien, hohe TPO-Serumspiegel nachweisen konnten, zeigten die untersuchten Zellen keine Reaktivität auf TPO: Weder die hämatopoetischen Vorläuferzellen im Knochenmark noch die Thrombozyten ließen sich durch TPO in vitro stimulieren. Mit Hilfe durchflusszytometrischer Untersuchungen konnten wir diese fehlende TPO-Reaktivität von Thrombozyten bei CAMT-Patienten auf die defekte Expression des TPO-Rezeptors c-Mpl auf der Oberfläche der Thrombozyten zurückführen. Ursache hierfür sind Mutationen im c-mpl-Gen, die entweder zu einem kompletten Ausfall oder zu einer strukturellen Veränderung des c-Mpl-Proteins mit Funktionseinschränkung führen. TPO spielt nicht nur in der Megakaryozytopoese, sondern auch in der Regulation früher, multipotenter hämatopoetischer Zellen eine wichtige Rolle. Der Defekt im TPO-Rezeptor c-Mpl bei CAMT scheint demzufolge auch für die Ausweitung des hämatopoetischen Defekts auf die anderen Zellreihen und die Entwicklung der Panzytopenie verantwortlich zu sein.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a very rare bone marrow failure syndrome presenting with isolated hypomegakaryocytic thrombocytopenia at birth developing into a pancytopenia during the first years of life. Bone marrow transplantation is the only curative therapy for this disease so far. Thrombopoietin (TPO) is the most important hematopoietic growth factor for the regulation of megakaryopoiesis and thrombopoiesis. We investigated TPO production and reactivity in CAMT patients. TPO plasma levels were high like in other forms of thrombocytopenia due to ineffective megakaryopoiesis. However, we found a defective reactivity to TPO: Neither hematopoietic progenitor cells in the bone marrow nor platelets from the peripheral blood did respond to TPO. Flow cytometric investigations demonstrated a lack of expression of the TPO receptor c-Mpl on the surface of platelets. Accordingly, we found mutations in the c-mpl gene, which are predicted to lead to a complete or at least partial loss of function of the TPO receptor. TPO is not only involved in the regulation of megakaryocytopoiesis but also in early hematopoiesis. This seems to be the reason for the general defect in hematopoiesis in CAMT leading to the development of pancytopenia.

Schlüsselwörter

Kongenitale amegakaryozytäre Thrombozytopenie - TPO - c-Mpl - Hämatopoese - Panzytopenie

Key words

Congenital amegakaryocytic thrombocytopenia - TPO - c-Mpl - hematopoiesis - pancytopenia

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