Thrombotic Microangiopathy in Haematopoietic Stem Cell Transplantation

Abstract

Each year in the US, more than 10 000 patients benefit from allogeneic haematopoietic stem cell transplantation (HSCT), a modality that offers an excellent chance of eradicating malignancy but confers a higher risk of treatment-related mortality. An uncommon but devastating consequence of HSCT is transplantation-associated thrombotic microangiopathy (TA-TMA). The incidence of TA-TMA ranges from 0.5% to 76%, with a mortality rate of 60-90% despite treatment. Although there appears to be a consistent treatment approach to idiopathic thrombotic thrombocytopenic purpura (TTP) using plasma exchange, corticosteroids and rituximab, the treatment strategies for TA-TMA are perplexing, in part, because the literature regarding this complex condition does not provide true consensus for incidence, aetiology, diagnostic criteria, classification and optimal therapy. The classic definition of idiopathic TTP includes schistocytes on the peripheral blood smear, thrombocytopenia and increased serum lactate dehydrogenase. Classic idiopathic TTP has been attributed to deficient activity of the metalloproteinase responsible for cleaving ultra-large von Willebrand factor multimers. This protease is a member of the 'a disintegrin and metalloprotease with thrombospondin type 1 motif' family and is subsequently named ADAMTS-13. Severely deficient ADAMTS-13 activity (<5% of normal) is associated with idiopathic TTP in 33-100% of patients. In constrast to the pathophysiology of idiopathic TTP, patients with TA-TMA have >5% ADAMTS-13 serum activity. These data may explain why plasma exchange, a standard treatment modality for idiopathic TTP that restores ADAMTS-13 activity, is not effective in TA-TMA. TA-TMA has a multifactorial aetiology of endothelial damage induced by intensive conditioning therapy, irradiation, immunosuppressants, infection and graft-versus-host disease. Treatment consists of substituting calcineurin inhibitors with an alternative immunosuppressive agent that possesses another mode of action. One candidate may be daclizumab, especially in those with mild to moderate TMA. Rituximab therapy or the addition of defibrotide may also be beneficial. In general, plasma exchange is not recommended.

Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT

“…None of these treatments have produced consistently beneficial results. 3,13 The general consensus in the literature is that plasmapheresis is not effective in TA-TMA. However, this conclusion may be biased because patients are usually diagnosed late and may have already suffered significant or irreversible vascular damage.…”

“…12 However, responses are variable and often unsatisfactory and mortality rates can approach 60%. 3,13 TA-TMA is less commonly reported following auto-SCT. 4,14,15 In the pediatric population, HDC followed by auto-SCT is the standard treatment for high-risk neuroblastoma.…”

Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy

“…[1][2][3] These conditions share a common end point of microthrombotic vascular endothelial cell injury, but with differing underlying pathophysiologic mechanisms. The TMA in TTP is related to severely deficient ADAMTS13 activity and the resulting ultra-large Von Willebrand factor multimers that aggregate platelets in conditions of high shear forces.…”

“…7,8 Common treatment approaches to HCT-TMA are largely ineffective and include withdrawal of calcineurin inhibitors, plasma exchange and intravenous immune globulin (IVIG), resulting in high mortality and morbidity rates. 3,9 We report a retrospective study of five patients who developed HCT-TMA and were treated with complement inhibition using eculizumab.…”

Acute kidney injury in HCT: an update

“…54,72,73 Discontinuation of offending causative agents such as calcineurin inhibitors, plasma infusion and plasma exchange, rituximab and defibrotide are frequently described as valid treatment options for TA-TMA. 76 Thrombotic microangiopathy is often linked to calcineurin inhibitor toxicity; therefore, their withdrawal is required. Contrary to classic thrombotic thrombocytopenic purpura, plasma infusion or plasma exchange is usually ineffective in post-HCT thrombotic microangiopathy.…”