Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe and often fatal
complication of allogeneic hematopoietic stem cell transplantation (HSCT), often associated
with or preceded by graft-versus-host disease (GVHD). Diagnostic criteria proposed
by an International Working Group include all of the following: (1) > 4% schistocytes
on blood smear; (2) thrombocytopenia < 50 × 109/L or > 50% reduction from previous count; (3) increased serum lactate dehydrogenase;
(4) decrease of hemoglobin concentration; and (5) decreased serum haptoglobin.[1] The group proposed the name TAM (transplant-associated microangiopathy) for the
condition but the designation of TA-TMA has been more widely accepted.[2]
Shortly after the discovery of the von Willebrand factor-cleaving protease, a disintegrin
and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and
its severe deficiency as the diagnostic hallmark of acquired or congenital thrombotic
thrombocytopenic purpura in the late 1990s, it became evident that TA-TMA was not
associated with severe ADAMTS13 deficiency. Instead, endothelial cell injury induced
by chemotherapy, radiotherapy, calcineurin inhibitor treatment, GVHD caused by donor
cytotoxic T cells, and infections was evoked as pathogenetically most relevant. Recently,
variants in several genes involved in complement activation pathways were reported
to strongly predispose to TA-TMA.[3]
Gavriilaki et al,[4] in this issue of Thrombosis and Haemostasis, set out to elucidate the pathogenesis of TA-TMA. Over 3.5 years, they consecutively
recruited 10 patients developing TA-TMA, 10 being diagnosed with GVHD and 10 control
HSCT patients, and studied complement activation markers, extracellular deoxyribonucleic
acid (DNA) and DNA-myeloperoxidase (MPO) complexes as remnants of neutrophil extracellular
traps (NETs), soluble thrombomodulin and soluble vascular cell adhesion molecule-1
as endothelial injury parameters, and thrombin–antithrombin (TAT) complex as marker
of coagulation activation.
The sC5b-9, DNA and DNA-MPO, and TAT complex levels were found to be significantly
higher in the patients with TA-TMA compared with the controls, whereas those with
GVHD showed values not different from controls. In contrast, soluble thrombomodulin
was similarly increased over control levels in both TA-TMA and GVHD patients.
The data are interpreted to suggest that complement activation, neutrophil activation
with NETs release, and coagulation activation may all contribute to the pathogenesis
of TA-TMA. How exactly the various overactive defense systems interact and influence
each other remains to be investigated. Whether complement activation or NET markers
will become useful diagnostic tools to distinguish TA-TMA from GVHD remains to be
studied in much larger prospective cohorts of HSCT patients.
