von Willebrand Factor Proteolysis Is Deficient in Classic, but not in Bone Marrow Transplantation–Associated, Thrombotic Thrombocytopenic Purpura

Abstract

Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) differs from classic TTP in its clinical course and therapy. A characteristic of classic TTP is the inhibition of a plasma protease that specifically cleaves von Willebrand factor (vWF), thus reducing its multimeric size. We investigated whether this protease was also inhibited in BMT-associated TTP. Plasma from patients with classic or BMT-associated TTP was incubated with recombinant vWF R834Q, a vWF mutant with enhanced sensitivity to the protease. The proteolysis of vWF multimers was analyzed and quantified on Western blot. Metalloprotease activity was strongly inhibited in the classic TTP patient group. However, metalloprotease activity was normal in the BMT-associated TTP patient group. The difference in activity between the two patient groups was highly significant (P = .0016). The results indicate that the etiologies of classic and BMT-associated TTP are indeed different and provide an explanation for the lack of success of plasma exchange in BMT-associated TTP.

Plasmapheresis in Thrombotic Microangiopathy‐Associated Syndromes: Review of Outcome Data Derived from Clinical Trials and Open Studies

“…The endothelial injury is hypothetically induced by total body irradiation and/or toxicity of cyclosporin A and FK506, which are used to prevent graft-versus-host disease (GvHD) (76). It is also interesting to note that inhibition of the 300 kDa metalloprotease could not be demonstrated in this particular group of patients (17). Mortality attributable to TTP/HUS ranged between 60% to 90% in four case series despite intensive PEX/FFP treatment.…”

“…In HELLP syndrome, neither the inciting agent of TMA nor the role of the 300 kDa metalloprotease has yet been determined. The 300 kDa metalloprotease was found to be active in the development of TTP/HUS after bone marrow transplantation (17). In this case, total body irradiation is thought to cause TMA analogous to local radiation nephritis.…”

Thrombotic microangiopathy in blood and marrow transplant patients receiving tacrolimus or cyclosporine A

“…At least one study has failed to show decreased activity of vWF-cleaving enzyme in BMT-related TMA patients. 24 Other investigators have described platelet-aggregating properties of calpain 33 and a correlation between BMT-associated TMA and serum calpain levels. 34 The lack of an association with decreased levels of vWF-cleaving protein suggests little rationale for the use of plasmapheresis, despite its clear efficacy in sporadic TTP.…”

“…20,21 Interestingly, although recent studies have identified deficiencies of vWF-cleaving protein in patients with familial or sporadic thrombotic thrombocytopenic purpura (TTP), 22,23 this has not been observed with BMT-related TMA. 24 Renal biopsies, which are useful for confirming the diagnosis of TMA in solid organ transplant recipients, are rarely performed in BMT patients. Thus, there is no "gold standard" diagnostic test that is specific for BMT-related TMA, and studies of this interesting condition continue to use clinical definitions to identify cases.…”

Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF‐cleaving protease activity

“…38 Severely decreased or absent vWF-CPase activity has been observed in classic TTP, whereas its activity has been found to be normal in patients with marrow transplantation-associated TTP. 39 In this study, some of the non-…”