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Significance of elevation in cell-derived microparticles after allogeneic stem cell transplantation: transient elevation of platelet-drived microparticles in TMA/TTP

Although stem cell transplantation (SCT) is being used for hematopoietic reconstitution following high-dose chemotherapy for malignancy, it involves some serious transplant-related complications.1 For example, graft-versus-host disease (GVHD), and vascular disorders such as veno-occlusive disease (VOD), pulmonary vasculopathy, thrombotic microangiopathy (TMA) and capillary leak syndrome, are considered to be very important. In particular, TMA is a well-recognized disorder, and several factors contribute to the onset of this complication.2 In the case of SCT, patients generally receive granulocyte colony-stimulating factor (G-CSF) after chemotherapy. The administration of G-CSF can affect serum cytokine levels of these patients,3 resulting in the generation of procoagulant factors such as platelet-derived microparticles (PDMP).4 In addition, some cytokines, such as G-CSF, IL-6 and thrombopoietin, modulate platelet activation.5 When TMA is described in patients who have undergone allogeneic SCT, it is often implied that the clinical diagnosis of TMA is similar to that of thrombotic thrombocytopenic purpura (TTP). However, TMA exhibits no symptoms at the initial stage in most cases. If it advances to a further progressive stage, a TTP-like symptom occurs. And the decrease of vWF-CPase activity is hardly recognized in TTP after bone marrow transplantation. PDMPs have been associated with TTP, and endothelial cells and monocytes can develop the same microparticles. We measured and compared the levels of microparticles and soluble factors in patients undergoing allogeneic SCT.

The subjects were 21 patients who underwent allogeneic SCT from June 2001 to February 2005 in our institutions. One of the cases developed TMA/TTP after SCT, but the other 20 cases did not. All non-TMA/TTP cases experienced degree I or II acute GVHD. In addition, none developed TMA/TTP induced by cyclosporin A. The sCD40L ELISA kit from Chemicon International Inc. (Temecula, CA, USA), and the sIL-2R, sVCAM-1 and sE-selectin ELISA kit from BioSource International, Inc. (CA, USA) were used. PDMP, monocyte-derived microparticles (MDMP), and endothelial cell-derived microparticles (EDMP) were detected by flow cytometry using a modified version of the previously reported method.6 In brief, they were detected using FITC-stained cell-specific monoclonal antibodies and PE-stained Annexin V by two color flow cytometric analysis.

Table 1 shows changes in the soluble factors and microparticles. The levels of sCD40L and PDMP continued to increase up to 4 weeks in non-TMA/TTP case. However, the TMA/TTP patient exhibited their peak at 2 weeks, and then began to decline. The levels of sIL-2R, sVCAM-1 and sE-selectin continued to increase up to 4 weeks in both non-TMA/TTP cases and the TMA/TTP case. In particular, these increases in the TMA/TTP case were very remarkable. The levels of MDMP and EDMP also continued to increase up to 4 weeks in both non-TMA/TTP cases and the TMA/TTP case. In particular, the increase of EDMP in the TMA/TTP case was very remarkable.

Table 1 Changes of soluble factors and microparticles with SCT

Cellular microparticles are fragments that shed almost spontaneously from the plasma membrane blebs of virtually all cell types when submitted to a number of stress conditions.7, 8 In addition, these microparticles have more recently been shown to reflect in vitro cell stimulation, and testify to cellular activation and/or tissue degeneration occurring in vivo under a variety of pathophysiologic circumstances.7, 8 Therefore, there is a possibility that cellular microparticles exhibit the dynamic change after SCT. In contrast, diagnosing vascular complications in patients undergoing SCT is challenging, and damage to endothelial cells is regarded as the common feature of these complications.9 Furthermore, endothelial damage, perpetuated by cytotoxic lymphocytes, has been linked to chronic GVHD.9 In the present study, we found a continuous increase of endothelial cell-related soluble factors such as sVCAM-1 and sE-selectin up to 4 weeks after SCT. The GVHD marker, sIL-2R, also demonstrated the same change. In addition, both MDMP and EDMP exhibited a continuous increase up to 4 weeks after SCT. On the other hand, sCD40L and PDMP showed a transient elevation in the TMA/TTP case, although these exhibited continuous increases in non-TMA/TTP cases. There has been a study demonstrating a significant correlation between TMA/TTP and cyclosporin A, in which this immunosuppressive agent was used for GVHD control purposes.10 However, in the present study, there was no TMA/TTP case by cyclosporin A treatment. Recently, Inbal et al11 reported that there were no significant differences in cellular microparticles in the period between conditioning treatment and day zero of SCT. They concluded that the conditioning treatment did not cause hypercoagulability by cellular microparticle development. However, they did not demonstrate the change in cellular microparticles after SCT. Our results showed that cellular microparticles were significantly elevated after SCT. However, we could not ascertain whether the elevation of microparticles was a peculiar feature after SCT or linked with TMA/TTP. Further examination will be necessary for the validation as to whether cellular microparticles are the predictable marker for vascular complications after SCT.

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Nomura, S., Ishii, K., Kanazawa, S. et al. Significance of elevation in cell-derived microparticles after allogeneic stem cell transplantation: transient elevation of platelet-drived microparticles in TMA/TTP. Bone Marrow Transplant 36, 921–922 (2005). https://doi.org/10.1038/sj.bmt.1705150

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