Human neutrophil peptides inhibit cleavage of von Willebrand factor by ADAMTS13: a potential link of inflammation to TTP

Pillai, Vikram Gopalakrishna; Bao, Jialing; Zander, Catherine B.; McDaniel, Jenny K.; Chetty, Palaniappan Sevugan; Seeholzer, Steven H.; Bdeir, Khalil; Cines, Douglas B.; Zheng, X. Long

doi:10.1182/blood-2015-12-688747

Cited by 60 publications

(71 citation statements)

References 47 publications

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“…38 More recently, we demonstrated that HNP1-3 inhibits proteolytic cleavage of VWF by ADAMTS13. 11 Dramatic increases in plasma HNP1-3 are also reported in patients with myocardial infarction, 39,40 systemic lupus erythematosus, 41 and septic meningitis, 42 suggesting that HNP may also play a role in the pathogenesis of other inflammatory and thrombotic disorders. In TTP patients, we speculate that the massive release of HNP1-3 at the sites of vascular W. Cao et al 1324 haematologica | 2016; 101(11) Figure 4.…”

Section: Discussionmentioning

confidence: 99%

“…Based on our recently published study, wherein we demonstrated that HNP1-3, a group of 29-30 amino acid anti-microbial peptides, potentially released from activated human neutrophils, is a potent inhibitor of ADAMTS13-medidated VWF proteolysis. 11 We hypothesize that the locally released HNP1-3 may play a role in the pathogenesis of acute TTP, particularly in those with severely low circulating ADAMTS13 activity.…”

Section: Human Neutrophil Peptides and Complement Factor Bb In Pathogmentioning

confidence: 97%

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Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

et al. 2016

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A cquired thrombotic thrombocytopenic purpura is primarily caused by the deficiency of plasma ADAMTS13 activity resulting from autoantibodies against ADAMTS13. However, ADAMTS13 deficiency alone is often not sufficient to cause acute thrombotic thrombocytopenic purpura. Infections or systemic inflammation may precede acute bursts of the disease, but the underlying mechanisms are not fully understood. Herein, 52 patients with acquired autoimmune thrombotic thrombocytopenic purpura and 30 blood donor controls were recruited for the study. The plasma levels of human neutrophil peptides 1-3 and complement activation fragments (i.e. Bb, iC3b, C4d, and sC5b-9) were determined by enzyme-linked immunosorbent assays. Univariate analyses were performed to determine the correlation between each biomarker and clinical outcomes. We found that the plasma levels of human neutrophil peptides 1-3 and Bb in patients with acute thrombotic thrombocytopenic purpura were significantly higher than those in the control (P<0.0001). The plasma levels of HNP1-3 correlated with the levels of plasma complement fragment Bb (rho=0.48, P=0.0004) and serum lactate dehydrogenase (rho=0.28, P=0.04); in addition, the plasma levels of Bb correlated with iC3b (rho=0.55, P<0.0001), sC5b-9 (rho=0.63, P<0.0001), serum creatinine (rho=0.42, p=0.0011), and lactate dehydrogenase (rho=0.40, P=0.0034), respectively. Moreover, the plasma levels of iC3b and sC5b-9 were correlated (rho=0.72, P<0.0001), despite no statistically significant difference of the two markers between thrombotic thrombocytopenic purpura patients and the control. We conclude that innate immunity, i.e. neutrophil and complement activation via the alternative pathway, may play a role in the pathogenesis of acute autoimmune thrombotic thrombocytopenic purpura, and a therapy targeted at these pathways may be considered in a subset of these patients.

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Section: Discussionmentioning

confidence: 99%

Section: Human Neutrophil Peptides and Complement Factor Bb In Pathogmentioning

confidence: 97%

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

et al. 2016

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“…Additional conditions associated with inflammation can contribute to acute episodes in patients with acquired or hereditary TTP. [14][15][16] The limitations of our analysis are the small number of patients, the small number of relapses that occurred during our follow-up, and that we only measured remission ADAMTS13 activity annually. However, even this small number of patients followed across many years revealed clinically important observations.…”

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confidence: 99%

Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura

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Hovinga

Terrell³

et al. 2016

Blood

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“…The present study demonstrates that synthetic HNP‐1 may be a potent inhibitor of platelet adhesion/aggregation onto a fibrillar collagen surface or activated endothelium under arterial flow. These findings were somewhat unexpected because our previous study demonstrated that HNP 1–3 inhibit the proteolytic cleavage of VWF by ADAMTS13 and our initially hypothesis was that the addition of HNP 1–3 to a whole blood containing ADAMTS13 would enhance platelet adhesion/aggregation on a VWF‐collagen surface under arterial shear owing to the expected reduction of VWF proteolysis by ADAMTS13. However, the opposite result was obtained reproducibly.…”

Section: Discussionmentioning

confidence: 80%

Human neutrophil peptide‐1 inhibits thrombus formation under arterial flow via its terminal free cysteine thiols

McDaniel

Abdelgawwad

Hargett

et al. 2019

Journal of Thrombosis and Haemostasis

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Biological activity of human neutrophil peptide (HNP)‐1 in hemostasis under physiological conditions is not fully understood. HNP‐1 inhibits the adhesion/aggregation of murine platelets on a fibrillar collagen surface or an activated endothelial cell surface under flow. The anti‐adhesion activity appears to depend on the terminal free thiols of HNP‐1, which may inhibit VWF‐VWF lateral associations. Our results suggest a protective role and potential novel therapeutic use of HNP‐1 for arterial thrombosis. Summary BackgroundHuman neutrophil peptides (HNPs), also known as α‐defensins, are released from degranulated neutrophils and play an important role in innate immunity. However, their biological roles in hemostasis under flow are not fully explored. ObjectiveThis study aims to determine the role of HNP‐1 on platelet adhesion and aggregation on a collagen surface or ultra large von Willebrand factor (ULVWF) on endothelium under flow and elucidate the structural elements required for its activity. MethodsAnticoagulated whole blood from wild‐type or Adamts13−/− mice was incubated with a fluorescein‐conjugated anti‐human CD41 in the presence of increasing concentrations of a synthetic HNP‐1 and perfused over a collagen surface or a tumor necrosis factor (TNF)‐α activated murine endothelial cell surface under arterial flow. The rate of accumulation and the final surface coverage of fluoresceinated murine platelets or the rate of forming platelet‐decorated ULVWF strings were determined using the BioFlux microfluidic system. ResultsHNP‐1 inhibited the rate and final coverage of fluorescein‐labeled murine platelets on a fibrillar collagen surface under flow (100 dyne/cm2) in a concentration‐dependent manner and the anti‐adhesive activity of HNP‐1 depended on its terminal free cysteine thiols. HNP‐1 (20 μM) also dramatically inhibited the formation of platelets‐decorated ULVWF strings on TNF‐α activated murine endothelial surface under arterial flow. ConclusionsOur results demonstrate for the first time an antiplatelet adhesion or antithrombotic activity of HNP‐1; this activity depends on its terminal free thiols, likely affecting VWF‐VWF lateral associations. These findings may suggest a potential novel therapeutic strategy for arterial thrombosis.

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Human neutrophil peptides inhibit cleavage of von Willebrand factor by ADAMTS13: a potential link of inflammation to TTP

Cited by 60 publications

References 47 publications

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura

Human neutrophil peptide‐1 inhibits thrombus formation under arterial flow via its terminal free cysteine thiols

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