Thrombotic microangiopathy following allogeneic bone marrow transplantation is associated with intensive graft-versus-host disease prophylaxis

Abstract

Summary:Thrombotic microangiopathy (TM), manifesting clinically as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, is an uncommon complication after bone marrow transplantation (BMT). A retrospective analysis of potential risk factors for TM following allogeneic BMT was performed. Clinical data were analyzed from seven patients diagnosed with severe TM and 409 patients who underwent BMT during the same time period and who survived for at least 100 days afterwards. Six of the seven patients with TM received intensive GVHD prophylaxis consisting of cyclosporine, methotrexate and glucocorticoids, whereas only 66 of the 409 patients without TM received this regimen (P Ͻ 0.001, Fisher's exact test). This regimen was administered to patients older than 40 years, or recipients of a mismatched or unrelated allograft. Univariate analysis also revealed an increased risk of TM associated with the use of an unrelated bone marrow donor (P = 0.02), but no significant association with patient age or gender, diagnosis, amount of prior chemotherapy, transplant conditioning regimen or severity of GVHD. A multivariate exact logistic regression analysis revealed that only the type of GVHD prophylaxis had a significant impact on the risk for TM. The combined use of cyclosporine, methotrexate and glucocorticoids as GVHD prophylaxis may predispose to the development of TM following BMT. Keywords: thrombotic thrombocytopenic purpura; hemolytic uremic syndrome; bone marrow transplantation; graftversus-host disease Thrombotic microangiopathy (TM) is a pathological process characterized by occlusion of the microvasculature by hyaline thrombi resulting in microangiopathic hemolytic anemia, thrombocytopenia and end organ dysfunction. Clinically, TM manifests as hemolytic uremic syndrome (HUS) when the renal vasculature is primarily affected, or as thrombotic thrombocytopenic purpura (TTP) when there is diffuse vascular involvement. The onset of TM has been associated with infection by a variety of bacterial or viral pathogens. 1 There is a well-documented association between infection with E. coli strain O157:H7 and the occurrence of HUS. 2,3 Individuals infected with the human immunodeficiency virus have an increased incidence of TTP. 4 TM also occurs in relation to pregnancy; TTP tends to occur in the ante-partum period while HUS is more frequent post-partum. 1 Administration of chemotherapy, especially mitomycin C, has been associated with the development of HUS. 5 These various etiologies are thought to share the ability to induce injury to the vascular endothelium. Plasma exchange is highly effective therapy for TTP; HUS may also respond to this therapy. 3,6 TM is an uncommon complication of allogeneic bone marrow transplantation (BMT). More than 63 cases of TM have been reported to occur in this setting. 7 The first case of TM following allogeneic BMT was observed during the earliest use of cyclosporine (CsA) prophylaxis for graftversus-host disease (GVHD). 8 Subsequently, the occurrence of TM was found to be signifi...

Transplant-associated microangiopathy (TAM) in recipients of allogeneic hematopoietic stem cell transplants

“…The strongest risk factors for TAM were age and HSCT from unrelated donors, 1,4,[6][7][8]15,20 both risk factors for aGvHD. TAM was correlated with aGvHD severity.…”

“…Reduced metalloprotease activity is not the pathophysiologic mechanism in TAM 25, 28 and plasma exchange is generally ineffective. 4,29 There is no validated definition for this syndrome. 14 Outcome of this complication may be variable, but little is known about causes and factors determining outcome of affected patients.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Thrombotic microangiopathy is characterized by systemic or intrarenal platelet aggregation and a microangiopathic hemolytic anemia, with red blood cell (RBC) fragmentation and a negative direct antiglobulin test. Increased platelet consumption leads to thrombocytopenia.…”

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

“…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. 22 Although cyclosporine prophylaxis was discontinued in all of our patients when the diagnosis of TTP was made, it was restarted for signs of GVHD exacerbation in seven. In none of these seven patients was there any evidence for TTP exacerbation and TTP was not the cause of death in any of these patients.…”

Transplantation-associated thrombotic microangiopathy: twenty-two years later

“…The observation that TA-TMA may occur in autologous blood stem cell transplant recipients suggests that high-dose chemotherapy alone may be responsible for some cases of this disorder. 6 Others have associated total body irradiation, 10 GVHD 11 and intensive immunosuppression 12 with the development of this syndrome. Infections such as CMV and HHV-6 have been associated in case reports with TA-TMA.…”