Plasma von Willebrand factor antigen (vWF:AG) and thrombomodulin (TM) levels in adult thrombotic thrombocytopenic purpura/hemolytic uremic syndromes (TTP/HUS) and bone marrow transplant-associated thrombotic microangiopathy (BMT-TM)

Abstract

Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndromes (TTP/HUS). The present studies measured two markers of endothelial cell stimulation and/or activation [von Willebrand Factor (vWF:Ag) and thrombomodulin (TM)] in patients with TTP/HUS disorders and compared them to controls. The patient groups consisted of adults with TTP/HUS, with (n = 13) and without (n = 14) peak Cr levels >2.0 mg/dl. Additionally, 52 patients with Bone Marrow Transplant-associated Thrombotic Microangiopathy (BMT-TM) following allogeneic BMT were evaluated. Both vWF:Ag and TM were elevated in all patient groups compared to controls. TTP/HUS patients with peak Cr >2.0 mg/dl had higher TM levels (P < 0.001) than did those with peak Cr levels below 2 mg/dl. However, thrombomodulin/ creatinine (TM/Cr) ratios did not differ in these two groups nor did they differ from controls. BMT-TM pts had higher vWF:Ag levels and higher TM/Cr ratios than controls and TTP/ HUS, P < 0.001. The median TM/Cr ratio in BMT-TM was 91 (range = 34-229) compared to 38 (range = 29-50) in controls, P < 0.001 and 38 (range = 6 to 156) in TTP/HUS, P < 0.001. Additionally both TM (P < 0.001) and TM/Cr (P < 0.02) were higher in patients with Grades 3 and 4 BMT-TM compared to those with Grade 2 BMT-TM. These results suggest that endothelial cell activation occurs in TTP/HUS and BMT-TM. Since TM/Cr ratios were higher in BMT-TM compared to TTP/HUS, these findings suggest that the mechanism of elevated TM in BMT-TM cannot be explained solely by altered renal excretion. Taken together, these findings strongly indicate a role of endothelial cell damage in BMT-TM.

Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy

“…TM is a high-affinity thrombin receptor on the surface of vascular endothelial cells and a cofactor in the activation of protein C. 23 There is a good correlation between TM levels and clinical complications related to endothelial cell injury in septicemia, VOD and GVHD. 16 Increased TM levels in patients with BMT-TMA have been reported by Zeigler et al 15 They tested a ratio of TM:creatinine to provide a measure of the renal contribution to the TM elevation. We similarly evaluated this ratio in our series.…”

“…Recently it has been reported that thrombomodulin is a useful marker to assess endothelial cell injury not only in patients with HUS/TTP but also in BMT-TMA. 15,16 In this study, we measured hemostatic parameters, including thrombomodulin, during BMT in a prospective study to find early predictive factors for the development of TMA.…”

The role of the endothelium in the short-term complications of hematopoietic SCT

“…Catani et al 19 analysed TM and P-selectin weekly from day 0 to day þ 28 and observed normal levels in all patients, except for those developing severe VOD. Zeigler et al 20 observed that VWF and TM were increased in all patients with TAM after HSCT. Salat et al 21 evidenced that VWF and TM rose significantly after conditioning in all patients.…”

Transplantation-associated thrombotic microangiopathy: twenty-two years later

“…It is expected that once extensive endothelial dysfunction occurs it would be more difficult to obtain benefit from risk factor modification and supportive care. It is possible that the demonstration of TA-TMA-associated coagulation abnormalities, such as increased levels of vWF, PAI-1 or of TM, 48,49 or indicators of endothelial dysfunction, such as the generation of endothelial microparticles, 27 may predict the subsequent development of this disorder. Conditioning regimens have been shown to alter levels of vWF, PAI-1 and TM and baseline values for these factors in this context remain to be determined.…”