Plasma cytokine levels in thrombotic thrombocytopenic purpura

Wada, Hideo; Kaneko, Toshihiro; Ohiwa, Michiaki; Tanigawa, Motoaki; Tamaki, Shigehisa; Minami, Nobuyuki; Takahashi, Hiroyuki; Deguchi, Katsumi; Nakano, Takeshi; Shirakawa, S

doi:10.1002/ajh.2830400303

Cited by 56 publications

(41 citation statements)

References 22 publications

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“…23,24 In our experience gender, age at BMT, marrow status at BMT, conditioning regimen (with or without TBI) and GVHD did not seem to have an impact on incidence of TTP. This is probably due to the relatively small number of patients in our study but we should not rule out the possibility that different combinations of the above-mentioned factors could favour the occurrence of TTP.…”

Section: Discussionmentioning

confidence: 93%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Uderzo

Fumagalli

Lorenzo

et al. 2000

Bone Marrow Transplant

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Multivariate analysis demonstrated that the risk of TTP was higher in patients who underwent unrelated BMT (P value = 0.02). Acute GVHD, stage of disease at BMT, conditioning with TBI, gender, age, did not appear to be associated with the occurrence of TTP. As to the outcome, TTP resolved in 19 patients while in nine it was the principal cause of death (32.1%). In patients with TTP, LDH peak value was the only statistically significant factor (P = 0.001) related to severe TTP. In conclusion, our experience demonstrates that leukemic children undergoing BMT, especially from an unrelated donor, should be carefully assessed for TTP which appears to be a severe and relatively common transplant-related complication when strict diagnostic criteria are applied. Bone Marrow Transplantation (2000) 26, 1005-1009.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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

Uderzo

Fumagalli

Lorenzo

et al. 2000

Bone Marrow Transplant

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“…These include tumor necrosis factor (TNF)-␣ and interleukin (IL)-1. 5 TNF-␣ and IL-1 also induce release of ultralarge VWF multimers from MVECs, 6,7 another hallmark of TTP. 1 Plasma levels of TNF-␣ and IL-1 are increased at the onset of disease, with normalization following TTP treatment by plasma exchange.…”

Section: Introductionmentioning

confidence: 99%

Synergistic interactions between interferon-γ and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma–associated apoptosis

Stefanescu

Bassett

Modarresi

et al. 2008

Blood

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IntroductionA variety of injuries to microvascular endothelial cells (MVECs) may precipitate episodes of thrombotic thrombocytopenic purpura (TTP) in the setting of deficiency of ADAMTS13 von Willebrand factor (VWF)-cleaving protease activity. 1 However, the specific factors initiating MVEC injury and the mechanism of their lineage specificity are unknown. Autopsy and biopsy studies support the argument that EC lesions characteristic of TTP are primary events, not secondary to microthrombi formation. 2 This injury appears to be apoptotic and restricted to certain lineages of ECs; large vessels are never involved, nor are pulmonary MVECs. 3,4 These pathologic distinctions can be reproduced in vitro by exposure of primary human ECs to plasmas from patients with acute TTP. 4 Cytokines linked to MVEC apoptosis and procoagulant phenotype in vitro are dysregulated during acute TTP in vivo. These include tumor necrosis factor (TNF)-␣ and interleukin (IL)-1. 5 TNF-␣ and IL-1 also induce release of ultralarge VWF multimers from MVECs,6,7 another hallmark of TTP. 1 Plasma levels of TNF-␣ and IL-1 are increased at the onset of disease, with normalization following TTP treatment by plasma exchange. 6,8 In other types of thrombotic microangiopathy, including diarrhea/shigatoxin-associated (D ϩ ) hemolytic uremic syndrome (HUS), significant alterations in these cytokines have not been documented. 9,10 However, levels of IL-1 or TNF-␣ required to induce MVEC apoptosis in vitro are 2-to 3-log-fold greater than those present in TTP plasma.TNF-␣, a related cytokine, TNF-related apoptosis-inducing ligand (TRAIL), and another soluble factor up-regulated during the acute phase of TTP, interferon (IFN)-␥, 8 can interact to elicit apoptosis in several cell types. 11,12 Although the levels required still far exceed those present in TTP, such synergy studies offer insight into modulation of cell-specific cytoprotective pathways that might underlie the differential sensitivity of divergent ECs to injury in TTP.For example, EC viability depends upon several interdependent pathways involving proangiogenic, integrin, and VE-cadherinassociated molecules. 13 These pathways are regulated by NF-B, Akt, and other signaling mechanisms acting through cellular FLICE-like inhibitory protein (c-FLIP), inhibitors of apoptosis (IAP), and Bcl-2. 13,14 Some of these systems may be involved in the EC injury of D ϩ HUS, for which the shiga-like toxins are etiologic agents. Shigatoxins down-regulate Bcl-2 15 and c-FLIP, 16 sensitizing ECs to lipopolysaccharide-induced apoptosis. 15 TNF-␣ and IFN-␥ can facilitate the EC apoptosis-inducing activity of shigatoxin in vitro by up-regulation of shigatoxin receptor CD77 17 and dephosphorylation and subsequent acceleration of ubiquitindependent degradation of Bcl-2 in the proteasome. 18 Yet, levels of TNF-␣ and IFN-␥ required to effect those changes-100 ng/mL TNF-␣ and 200 to 1000 U/mL (20-100 ng/mL) IFN-␥ 15,18 -still far exceed those found in D ϩ HUS or TTP.We had explored the involvement of Bcl-2, Fas, and TNF-␣...

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“…TNF-a, IL-6, IL-1b, and soluble IL-2 receptor were reported to be elevated in TTP patients with significant reduction at complete remission [21]. Cytokine levels at TTP remission, however, were not compared to that of normal controls.…”

Section: Discussionmentioning

confidence: 96%

“…TGF-b1 upregulation has also been reported to be partially protective, suppressing microvascular endothelial cell damage via its anti-apoptotic properties [20]. Measurements of other cytokines including pro-inflammatory cytokines have produced variable results and have been limited to measurements at the disease onset and complete remission [21][22][23][24][25]. In this pilot study, we used a novel multiplexing bead array technique that allowed for simultaneous measurement of multiple cytokines in single serum samples.…”

Section: Introductionmentioning

confidence: 99%

Effect of plasma exchange on cytokines measured by multianalyte bead array in thrombotic thrombocytopenic purpura

2005

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The serum cytokine profile in thrombotic thrombocytopenic purpura (TTP) has not been extensively characterized. In this pilot study, a novel technique was utilized to evaluate multiple cytokines in patients with idiopathic TTP during a course of plasma exchange (PE). Single serum samples were obtained from five TTP patients before and after each PE. Random sera were obtained from nine healthy volunteers who served as controls. The samples were evaluated for 13 cytokines (IL-1B, IL-2 , IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IFN-g , GM-CSF, and TNF-a) using the Luminex bead array (LINCOplex) multianalyte detection system that permits simultaneous detection of multiple cytokines from a single sample. Each patient received 4-6 PEs (Cobe Spectra) with 3.0-4.0 L of fresh frozen plasma as replacement fluid. Four of 5 patients received corticosteroids prior to and during PE. The control group did not receive steroids. Baseline values for IL-8 (182.9 vs. 6.5 pg/mL, P < 0.05) and TNF-a (11.4 vs. 0.9 pg/mL, P < 0.001) were significantly higher in TTP patients compared with controls. Other tested cytokines were not significantly different between the two groups. Comparison of cytokine values pre-and post-PE indicate a substantial decrease after each PE. However, cytokines rebounded to abnormal levels by the following day. There was no correlation between cytokines and serum LDH or platelet count. These findings suggest that certain cytokines, particularly IL-8 and TNF-a, are altered in TTP, and this may indicate a direct role in TTP pathogenesis, reflect ongoing tissue injury, or perhaps indicate an inadequate attempt to limit tissue injury.

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Plasma cytokine levels in thrombotic thrombocytopenic purpura

Cited by 56 publications

References 22 publications

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

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

Synergistic interactions between interferon-γ and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma–associated apoptosis

Effect of plasma exchange on cytokines measured by multianalyte bead array in thrombotic thrombocytopenic purpura

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