Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis.
Severe leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thr...
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doaj-3aabf7a21cb841d8ac44c277f4ce31652020-11-25T02:12:57ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352017-09-01119e000591510.1371/journal.pntd.0005915Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis.Rahajeng N TunjungputriMuhammad Hussein GasemWillemijn van der DoesPandu H SasongkoBambang IsbandrioRolf T UrbanusPhilip G de GrootAndre van der VenQuirijn de MastSevere leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thrombocytopenia, but also to platelet dysfunction, and that increased binding of von Willebrand factor (VWF) to platelets is involved in both platelet dysfunction and increased platelet clearance.A prospective study was carried out in Semarang, Indonesia, enrolling 33 hospitalized patients with probable leptospirosis, of whom 15 developed clinical bleeding, and 25 healthy controls. Platelet activation and reactivity were determined using flow cytometry by measuring the expression of P-selectin and activation of the αIIbβ3 integrin by the binding of fibrinogen in unstimulated samples and after ex vivo stimulation by the platelet agonists adenosine-diphosphate (ADP) and thrombin-receptor activating peptide (TRAP). Platelet-VWF binding, before and after VWF stimulation by ristocetin, as well as plasma levels of VWF, active VWF, the VWF-inactivating enzyme ADAMTS13, thrombin-antithrombin complexes (TAT) and P-selectin were also measured. Bleeding complications were graded using the WHO bleeding scale. Our study revealed that platelet activation, with a secondary platelet dysfunction, is a feature of patients with probable leptospirosis, especially in those with bleeding manifestations. There was a significant inverse correlation of bleeding score with TRAP-stimulated P-selectin and platelet-fibrinogen binding (R = -0.72, P = 0.003 and R = -0.66, P = 0.01, respectively) but not with platelet count. Patients with bleeding also had a significantly higher platelet-VWF binding. Platelet counts were inversely correlated with platelet-VWF binding (R = -0.74; P = 0.0009. There were no correlations between platelet-VWF binding and the degree of platelet dysfunction, suggesting that increased platelet-VWF binding does not directly interfere with the platelet αIIbβ3 signaling pathway in patients with probable leptospirosis.Platelet dysfunction is common in probable leptospirosis patients with manifest bleeding. Increased VWF-platelet binding may contribute to the activation and clearance of platelets.http://europepmc.org/articles/PMC5626517?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rahajeng N Tunjungputri Muhammad Hussein Gasem Willemijn van der Does Pandu H Sasongko Bambang Isbandrio Rolf T Urbanus Philip G de Groot Andre van der Ven Quirijn de Mast |
spellingShingle |
Rahajeng N Tunjungputri Muhammad Hussein Gasem Willemijn van der Does Pandu H Sasongko Bambang Isbandrio Rolf T Urbanus Philip G de Groot Andre van der Ven Quirijn de Mast Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. PLoS Neglected Tropical Diseases |
author_facet |
Rahajeng N Tunjungputri Muhammad Hussein Gasem Willemijn van der Does Pandu H Sasongko Bambang Isbandrio Rolf T Urbanus Philip G de Groot Andre van der Ven Quirijn de Mast |
author_sort |
Rahajeng N Tunjungputri |
title |
Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. |
title_short |
Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. |
title_full |
Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. |
title_fullStr |
Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. |
title_full_unstemmed |
Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. |
title_sort |
platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Neglected Tropical Diseases |
issn |
1935-2727 1935-2735 |
publishDate |
2017-09-01 |
description |
Severe leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thrombocytopenia, but also to platelet dysfunction, and that increased binding of von Willebrand factor (VWF) to platelets is involved in both platelet dysfunction and increased platelet clearance.A prospective study was carried out in Semarang, Indonesia, enrolling 33 hospitalized patients with probable leptospirosis, of whom 15 developed clinical bleeding, and 25 healthy controls. Platelet activation and reactivity were determined using flow cytometry by measuring the expression of P-selectin and activation of the αIIbβ3 integrin by the binding of fibrinogen in unstimulated samples and after ex vivo stimulation by the platelet agonists adenosine-diphosphate (ADP) and thrombin-receptor activating peptide (TRAP). Platelet-VWF binding, before and after VWF stimulation by ristocetin, as well as plasma levels of VWF, active VWF, the VWF-inactivating enzyme ADAMTS13, thrombin-antithrombin complexes (TAT) and P-selectin were also measured. Bleeding complications were graded using the WHO bleeding scale. Our study revealed that platelet activation, with a secondary platelet dysfunction, is a feature of patients with probable leptospirosis, especially in those with bleeding manifestations. There was a significant inverse correlation of bleeding score with TRAP-stimulated P-selectin and platelet-fibrinogen binding (R = -0.72, P = 0.003 and R = -0.66, P = 0.01, respectively) but not with platelet count. Patients with bleeding also had a significantly higher platelet-VWF binding. Platelet counts were inversely correlated with platelet-VWF binding (R = -0.74; P = 0.0009. There were no correlations between platelet-VWF binding and the degree of platelet dysfunction, suggesting that increased platelet-VWF binding does not directly interfere with the platelet αIIbβ3 signaling pathway in patients with probable leptospirosis.Platelet dysfunction is common in probable leptospirosis patients with manifest bleeding. Increased VWF-platelet binding may contribute to the activation and clearance of platelets. |
url |
http://europepmc.org/articles/PMC5626517?pdf=render |
work_keys_str_mv |
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