Plasminogen activator inhibitor (PAI-1) antigen levels in primary TTP and secondary TTP post-bone marrow transplantation

Abstract

Our objectives were to measure and compare plasminogen activator inhibitor levels (PAI-1) in primary adult thrombotic thrombocytopenic purpura (TTP) and in secondary TTP associated with bone marrow transplantation (BMT)-TTP. PAI-1 antigen levels were measured by an enzyme linked immunosorbent assay on platelet poor plasma samples obtained from patients at the time of diagnosis of the TTP disorder and from a group of normal volunteers. The samples were frozen at -70 degrees C. Patients with TTP secondary to bone marrow transplantation had their grade determined by percentage fragmented cells and lactate dehydrogenase levels. The primary TTP samples were contributed by investigators in the multi-institutional North American TTP Group, and the bone marrow transplant samples were obtained from an adult bone marrow transplant program. Nineteen patients with adult TTP, and 47 patients with bone marrow transplant-TTP were evaluated. Of the latter, 14 had Grade 2, 13 had Grade 3, and 20 had Grade 4 BMT-TTP. PAI-1 levels were elevated compared to control volunteers in both primary adult TTP and BMT-TTP, P < 0.001. Levels did not differ from normal in Grade 2 BMT-TTP (median = 16 ng/ml; quartiles = 9-20). PAI-1 levels were similar in primary TTP (median = 32 ng/ml; quartiles = 25-51) and Grade 3 BMT-TTP (median = 35 ng/ml; quartiles = 19-48 ng/ml), P = 0.7. However, PAI-1 levels were significantly higher in Grade 4 BMT-TTP (median = 83 ng/ml; quartiles = 60-143) than Grade 3 BMT-TTP, and primary TTP, P < 0.001. PAI-1 levels are high in primary TTP and secondary bone marrow transplant-TTP (Grades 3-4). In contrast, normal levels are seen in Grade 2 BMT-TTP, which is a self-limited disorder. Therefore, high PAI-1 levels may contribute to hypofibrinolysis in the pathogenesis of primary TTP and of moderate to severe TTP (Grades 3-4) following bone marrow transplantation.

Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation

“…Endothelial damage in this setting is a crucial triggering factor, supported by the presence of high levels of thrombomodulin, P-selectin, plasminogen activator inhibitor (PAI-1) which, in the presence of unusually large von Willebrand factors, can contribute to an increased quantity of hyaline thrombi, mostly due to aggregated platelets. [25][26][27] Some of these coagulation disorders have been demonstrated, especially in unrelated BMT. 28 The current study also found a correlation between elevated LDH peak values during the course of TTP and a worse prognosis of TTP (P = 0.001).…”

“…With regard to the treatment of TTP in BMT patients, there are a few promising reports regarding the use of defibrotide, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] which seems to have a considerable antithrombotic effect due to its profibrinolytic activity, 36,37 based on its ability to induce release of plasminogen activator factor from the vascular tissue 38 and to decrease blood concentration of plasminogen activator inhibitor. 39 These and other defibrotide-related effects, the most important of which concerns inhibition of platelet aggregation, have recently been acknowledged to be of benefit in post-BMT venoocclusive disease, 40 which, like TTP, can occur as a result of endothelial damage.…”

Chronic Kidney Disease in Long-Term Survivors of Hematopoietic Cell Transplantation

“…PAI-1 levels are normal in patients without complications after HCT (62); however, there is some evidence that these levels are elevated in post-HCT patients at the time of diagnosis of TTP (63) and also may be elevated in patients with sinusoidal obstruction syndrome and sepsis after HCT. Tissue plasminogen activator antigen remained normal in these patients (64).…”

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.…”