Impaired Platelet Production and Autoantibody-Mediated Platelet Destruction Are Two Major Causes for Prolonged Thrombocytopenia after Allogeneic HSCT.

Prolonged thrombocytopenia is one of late complications in patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its pathogenic process is unclear in the majority of cases. In this study, mechanisms for thrombocytopenia in allo-HSCT recipients were examined using a series of parameters useful for discriminating immune thrombocytopenia from bone marrow failure. Forty-one patients who underwent allo-HSCT and survived for >100 days without recurrence were enrolled. Of these, 20 (49%) had prolonged thrombocytopenia (<100 x 10⁹/L for ≥3 months). As controls, 81 with idiopathic thrombocytopenic purpura (ITP), 12 with aplastic anemia (AA), 41 healthy donors were used. Circulating B cells producing anti-GPIIb/IIIa antibodies, an index for plasma glycocalicin normalized for the individual platelet count (GCI) and plasma thrombopoietin (TPO) were measured as indices of anti-platelet autoantibody response, platelet turnover and platelet production, respectively. A period between HSCT and blood examination was shorter in allo-HSCT with thrombocytopenia than in those without (P = 0.02), but other clinical characteristics, including age, underlying disease, stem cell source, GVHD prophylaxis regimen, and the presence or absence of chronic GVHD, were not different. Anti-GPIIb/IIIa antibody-producing B cells in allo-HSCT were significantly more frequent than those in AA (P = 0.002) and healthy controls (P < 0.001), but were less frequent than those in ITP (P = 0.002). GCI in allo-HSCT was higher than that in healthy controls (P = 0.01), but was lower than GCI in ITP (P < 0.001). Allo-HSCT recipients had a higher TPO level compared with ITP (P = 0.01) and healthy controls (P = 0.02), but had a lower level compared with AA (P = 0.004). In allo-HSCT, anti-GPIIb/IIIa antibody-producing B cell frequency, TPO and GCI were greater in patients with thrombocytopenia than those without (P = 0.01, < 0.001 and < 0.001, respectively). In addition, there were a negative correlation between platelet count and GCI (r = 0.66, P < 0.001), or TPO (r = 0.52, P < 0.001). Step-wise multiple regression analysis revealed that GCI and TPO were factors independently associated with platelet count in allo-HSCT. ITP and AA patients and healthy controls were classified based on levels of GCI and TPO: 72% of 32 ITP showed GCI^high/TPO^low; 67% of 9 AA showed GCI^low/TPO^high; and all 17 healthy controls showed GCI^low/TPO^low. Eighteen allo-HSCT recipients with thrombocytopenia represented heterogeneous distribution: 3 with GCI^high/TPO^low (ITP-like), 6 with GCI^low/TPO^high (AA-like), 6 with GCI^high/TPO^high (mixed features) and 3 with GCI^low/TPO^low. A therapeutic response to immunosuppressive treatment was observed in 2 of 2 GCI^high/TPO^low, one of 4 GCI^low/TPO^high, 2 of 6 GCI^high/TPO^high, and none of one GCI^low/TPO^low. In an allo-HSCT recipient with GCI^high/TPO^low, platelet count responded to high-dose prednisolone and anti-GPIIb/IIIa antibody-producing B cells and GCI were negatively correlated with platelet count during the course, compatible with immune thrombocytopenia. In summary, mechanisms for prolonged thrombocytopenia after allo-HSCT are heterogeneous, but mainly caused by impaired platelet production, autoantibody-mediated platelet destruction, or a combination of both. GCI and TPO are useful markers for evaluating a pathogenic process for thrombocytopenia and predicting a therapeutic response to immunosuppressive therapies in allo-HSCT recipients.