Prospective study on the behaviour of the metalloprotease ADAMTS13 and of von Willebrand factor after bone marrow transplantation

Abstract

Summary Thrombotic microangiopathies (TMAs) are rare but serious complications of bone marrow transplantation (BMT). Clinical manifestations are similar to those of thrombotic thrombocytopenic purpura (TTP), but prognosis is generally poorer despite plasma exchange. The enzymatic activity of the plasma metalloprotease ADAMTS13, which cleaves ultralarge thrombogenic multimers of von Willebrand factor (VWF) derived from activated endothelial cells, is very low or undetectable in patients with classic TTP, and protease deficiency is thought to play a mechanistic role in the formation of platelet thrombi in the microcirculation. This is the first prospective study to evaluate the incidence of TMA in 46 consecutively recruited patients undergoing autologous or allogeneic BMT and explore in parallel the behaviour of ADAMTS13, VWF antigen and VWF multimer size. The incidence of post‐BMT TMA was 6% (three of 46); all cases occurred after allogeneic BMT. Compared with baseline values plasma ADAMTS13 activity was significantly reduced in patients undergoing BMT, particularly after the conditioning regimen (mean values: 50 ± 22 vs. 77 ± 32%; P < 0·0001). In the three patients who developed TMA, ADAMTS13 decreased after conditioning, but was very low in one case only (8%). VWF antigen levels progressively increased after the conditioning regimen (228 ± 75 vs. 178 ± 76% at baseline, P = 0·002). The mean proportion of high‐molecular weight VWF multimers did not change in the various stages of BMT, even though ultralarge multimers were transiently found in same cases with and without TMA. Hence, the measurements evaluated in this study are not clinically useful to predict the occurrence of post‐BMT TMA.

Transplantation-associated thrombotic microangiopathy: effect of concomitant GVHD on efficacy of therapeutic plasma exchange

“…34 Why should PE be effective in management of TA-TMA, when, unlike idiopathic TTP, TA-TMA has not been associated with autoantibody production and/or severe deficiency of the plasma protease ADAMTS13? 8,[27][28][29] Although the exact mechanisms involved in pathogenesis of TA-TMA in different clinical settings post-SCT are not currently known, the development of endothelial cell injury or dysfunction seems to represent a final common pathway in the pathogenesis of MAHA post-SCT. 2,3 Several drugs used in SCT, and various cytokines associated with GVHD and other post-SCT complications, can potentially induce endothelial cell apoptosis and/or dysfunction, including calcinuria inhibitors, IL-1 and TNFa.…”

“…2,3,8 Unlike idiopathic TTP, TA-TMA has only rarely been associated with severe deficiency of the plasma protease ADAMTS13. 8,[27][28][29] Current therapeutic recommendations of TA-TMA revolve around treatment of and/or elimination of conditions resulting in endothelial insult. 2,3 These recommendations include immediate cessation of potential culprit medications and aggressive treatment of associated GVHD and/or infection.…”

Cyclosporin A Impairs the Secretion and Activity of ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeat)

“…Indeed, numerous reports suggest that the use of CsA in transplant patients may be associated with TTP (12)(13)(14)(15)(16), although some other reports reveal no interrelationship between CsA treatment and TTP development and found no influence of CsA treatment on ADAMTS13 levels (17). Nevertheless, it has been demonstrated that reduced activity and/or deficiency of ADAMTS13 can clinically manifest as TTP (18).…”

Rituximab in thrombotic microangiopathy

“…Furthermore, Au et al (2007) found no change in ADAMTS13 and anti-ADAMTS13 after treatment with rituximab. The genesis of TM after transplant may be more related to endothelial damage rather than an antibodymediated lowering of ADAMTS13 levels (Peyvandi et al, 2006).We wonder whether rituximab was really responsible for the regression of TM in this small cohort of patients, rather than possible alternative contributory factors, e.g. the replacement of ciclosporin with tacrolimus and the use of steroids, which can probably control graft-versus-host disease (a known risk factor for TM), in three out of four responding patients.…”

“…Furthermore, Au et al (2007) found no change in ADAMTS13 and anti-ADAMTS13 after treatment with rituximab. The genesis of TM after transplant may be more related to endothelial damage rather than an antibodymediated lowering of ADAMTS13 levels (Peyvandi et al, 2006).…”