DEFICIENT IN-VITRO MEGAKARYOCYTOPOIESIS AND DECREASED IN-VIVO PLATELET TURNOVER IN CHILDREN AND YOUNG-ADULTS WITH CHRONIC THROMBOCYTOPENIA

Purpose: Chronic thrombocytopenia is uncommon in children and frequent ly thought to be secondary to chronic idiopathic thrombocytopenic purp ura (ITP), which is considered an immune disorder. However, not all ch ildren with chronic ITP respond to immunosuppressive therapy. Platelet survival and megakaryocyte growth were studied to determine if there is a failure of platelet production in children with chronic thrombocy topenia who carry a presumptive diagnosis of chronic ITP. Patients and Methods: In vitro megakaryocyte growth using a plasma clot system and in vivo survival of In-111-labeled autologous platelets were studied in seven patients (aged 2 days to 17 years at diagnosis; aged 2 to 28 years at time of megakaryocyte study) with chronic isolated thrombocyt openia (range 1,000 to 130,000/mu l). Results: All seven patients exhi bited elevated platelet-associated immunoglobulin G early in the cours e of their disease and showed normal marrow morphology with normal num bers of morphologically typical megakaryocytes on initial marrow biops y. Occasional dysplastic-appearing megakaryocytes were noted in three of the seven patients at diagnosis and all patients were noted to have dysplastic megakaryocytes, reduced megakary ocytes, or both during fo llow-up (range 5 to 16 years). Either morphologic or karyotypic abnorm alities indicative of myelodysplasia subsequently developed in three p atients. No patient exhibited any significant megakaryocyte colony gro wth under basal conditions. In one patient, megakaryocytic colonies si gnificantly increased when grown in the presence of serum from aplasti c patients and growth factors (granulocyte-macrophage colony-simulatin g factor, interleukin-3, and interleukin-6). Erythroid colony growth w as markedly deficient in four of five patients studied and myeloid col onies were normal in two of three patients studied. Five of the seven patients underwent platelet survival studies. Platelet survival was < 6 days in the 4 patients with platelet counts < 100,000/mu l (range 2 to 60,000/mu l; survival range 92 to 137 hours) and was normal in the patient whose platelet count was > 100,000/mu l (platelets 132,000/mu l; survival 253 hours). All five patients had either overtly low or in appropriately low platelet turnovers (range 100 to 1423 platelets/mu l per hour; normal range 1200 to 1600 platelets/mu l per hour). The pat ient with the lowest platelet count and platelet turnover had previous ly undergone a splenectomy without benefit. Conclusions: Megakaryocyte dysfunction resulting in subnormal production of platelets may play a significant role in the thrombocytopenia noted in some patients who h ave an isolated thrombocytopenia and a clinical picture that suggests ITP. Determination of platelet turnover may help to identify these pat ients. These data suggest the presence of a stem cell defect which may progress to myelodysplasia or overt marrow failure in these patients.