Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children

Abstract

Summary:Thrombotic microangiopathy (TMA) is a serious complication of BMT. Several factors are important in the etiology of TMA, such as cyclosporin A, GVHD, irradiation, intensive conditioning chemotherapy and infection, which cause damage to vascular endothelial cells leading to activation of these cells. We describe two young children with TMA following high-dose chemotherapy with autologous BMT. Development of TMA was accompanied by reactivation of HHV-6, which was identified by both an increase in the copy number of HHV-6 DNA in the peripheral blood and a significant increase in antibody titers to HHV-6. Thus, it was suggested that reactivation of HHV-6 together with highdose chemotherapy played an important role in the pathogenesis of TMA in these patients. Since HHV-6 is known to infect vascular endothelial cells, and CMV which is virologically closely related to HHV-6, has been reported to be a pathogen that causes TMA, infection with HHV-6 of vascular endothelial cells may induce TMA via damage and activation of these cells.

Endothelial damage caused by cytomegalovirus and human herpesvirus-6

“…23 With regard to HHV-6, it has been reported that infection of vascular endothelial cells with this virus leads to cell damage or activation, which may predispose to the development of TMA. 24 The findings obtained in the present study suggest that vascular endothelial cells are both stimulated and injured by infection with CMV and HHV-6. The levels of these parameters might have increased secondary to their reactivation rather than to infection with these viruses.…”

Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes

“…7 Furthermore, at the time of diagnosis of the TTP-like syndrome, they actually experienced a greater frequency of transplant-related complications, severe acute GVHD and systemic infections, also similar to previous reports. 7,8 These data suggest that acute GVHD 7,8 or infections complications 7,14 could have been the actual etiology for the signs and symptoms, which were interpreted as diagnostic for TTP. However patients with TTP-like syndromes were not older than other BMT patients, as may have been expected among patients with more complications.…”

“…19 Even if absent, VWF-cleaving protease activity and unusually large VWF multimers were demonstrated in patients following BMT, the diagnosis of TTP would still be uncertain since these abnormalities may be common among patients with disseminated malignancy who do not have clinical features of TTP. 20 Other disorders complicating BMT, such as acute GVHD and sepsis, may be associated with diffuse endothelial damage and disseminated microthrombi, 7,14,21 therefore the clinical features may resemble TTP. Intensity of GVHD prophylactic treatment has also been associated with TTP-like syndromes, but this may merely have reflected the increased diagnosis of TTP-like syndromes in patients with unrelated donors.…”

Transplantation-associated thrombotic microangiopathy: twenty-two years later

“…Infections such as CMV and HHV-6 have been associated in case reports with TA-TMA. 13,14 Recent reports have also documented the occurrence of TA-TMA in solid organ and bone marrow transplant recipients receiving immunosuppression with tacrolimus. 15 Two recent case-control studies have examined risk factors for TA-TMA in allogeneic bone marrow transplant recipients in more detail.…”