Autoantibodies in immune thrombocytopenia affect the physiological interaction between megakaryocytes and bone marrow extracellular matrix proteins

GOETTE NP; HELLER PG; DI BUDUO CA; SOPRANO PM; MARTA RF; GRODZIELSKI M; LEV PR; BALDUINI A

BRITISH JOURNAL OF HAEMATOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2017

0007-1048

Immune thrombocytopenia (ITP) is characterized by itsheterogeneity among patients with regard to both clinicalfeatures and response to treatment. Although there isstill much to investigate, this heterogeneity could be thereflection of multiple mechanisms contributing to thrombo-cytopenia, affecting individual patients in variable propor-tions. These mechanisms include increased platelet clearanceby autoantibodies targeting main platelet glycoproteins(GPs) (IIbIIIa, IbIX and IaIIa) and impaired megakary-opoiesis (McMillanet al, 2004). Recently, we reported thatITP plasma samples inhibit proplatelet (PP) formation bynormal megakaryocytes (MKs) (Levet al, 2014), demon-strating that thrombopoiesis, the key step of platelet pro-duction, is altered, a finding further confirmed by others(Iraqiet al, 2015). In agreement with these experimentaldata, studies on platelet kinetics show inadequate plateletproduction according to the degree of thrombocytopenia(Ballemet al, 1987).Interaction between these GP receptors of the megakary-ocytic lineage and their corresponding extracellular matrixligands is essential for MK development and platelet produc-tion in the bone marrow (BM). Proof of the relevance of thisinteraction include the abnormalities in platelet generationfound in several inherited conditions: (i) patients withMYH9-related thrombocytopenia (Pecciet al, 2009) carryingmutations in myosin IIA (MYH9), downstream of collagentype I receptor, GPIaIIa; (ii) macrothrombocytopenia due tomutations that partially activate fibrinogen receptor, GPII-bIIIa (Kunishimaet al, 2011); and (iii) mutations in GPI-bIXV, the von Willebrand factor (VWF) receptor, leading toBernard-Soulier syndrome (Strasselet al, 2009).Given that the main ITP autoantibodies target GPIIbIIIa,GPIbIX and GPIaIIa, we hypothesized that their bindingcould impair GP function, altering MK interaction withextracellular matrix proteins and thus, megakaryocytic beha-viour within the BM environment. In order to test thisassumption, we studied the effect of ITP plasma on normalMK adhesion, spreading, activation of downstream signallingpathways and thrombopoiesis