We have investigated the interaction of iron oxide nanoflowers with blood components, focusing on the primary biological changes of PLTs. By employing fresh human blood, we selected different IONFs concentration levels, and studied the effects on RBCs, WBCs and PLTs. From the biological standpoint, only PLTs were appreciably affected by incubation with the highest IONFs concentration for 30 minutes. This activation, however, disappeared after further incubation. Conversely, RBC and WBC homeostasis were not affected at any incubation time or at any IONFs concentration. From MRI measurements, a substantial reduction of the T1 and T2 relaxation times for IONFs-C1 was seen when compared to the control cases in both PLT and RBC populations. Lower concentrations of IONFs (IONFs-C3) induced negligible effects compared to the control. Finally, TEM images showed that PLT-rich plasma exposed to IONFs-C1 could internalize IONFs within PLTs. Accordingly, we conclude that IONF concentrations close to C1 in human blood can induce temporary morphological changes in PLTs. These results show that the selected IONFs may be promising candidates for further theranostic applications in whole blood for thromboembolic diseases.