Thrombotic Microangiopathy in Haematopoietic Stem Cell Transplantation: Diagnosis and Treatment

• Published in: Drugs (New York, N.Y.) N.Y.), 2009-01, Vol.69 (2), p.183-198
• Main Authors: Choi, Cecilia M., Schmaier, Alvin H., Snell, Michael R., Lazarus, Hillard M.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Apheresis; Biological and medical sciences; Blood; Blood circulation disorders; Blood platelets; Bone marrow; Dehydrogenases; Diagnosis; Dosage and administration; Drug therapy; Enzymes; Etiology; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; Humans; Immunoglobulin G - therapeutic use; Immunosuppressive agents; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Microcirculation; Miscellaneous; Mortality; Pathophysiology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Plasma Exchange - methods; Polydeoxyribonucleotides - therapeutic use; Prognosis; Purpura; Risk Factors; Rituximab; Stem cell transplantation; Steroids; Syndrome; Therapy in Practice; Thrombocytopenia; Thrombosis - etiology; Thrombosis - physiopathology; Thrombosis - therapy; Transplantation
• ISSN: 0012-6667; 1179-1950
• DOI: 10.2165/00003495-200969020-00004

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% 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.