High syndecan-1 levels in acute myeloid leukemia are associated with bleeding, thrombocytopathy, endothelial cell damage, and leukocytosis

doi:10.1016/j.leukres.2013.02.015

Leukemia Research

Volume 37, Issue 7, July 2013, Pages 777-783

https://doi.org/10.1016/j.leukres.2013.02.015 Get rights and content

Abstract

The risk of hemorrhage is influenced by multiple factors in acute myeloid leukemia (AML). We investigated whether hemorrhage in AML patients was associated with endothelial perturbation, potentially caused by thrombocytopenia, platelet dysfunction and leukocytosis. Biomarkers of endothelial perturbation, coagulation and platelet activation were analyzed in 49 AML patients, along with previously collected data on bleeding status and platelet activation markers.

High levels of syndecan-1, a marker of endothelial glycocalyx degradation, were associated with bleeding, impaired platelet function, higher age, endothelial cell activation and damage, and leukocytosis. We suggest that platelet dysfunction and leukocytosis in AML causes endothelial perturbation.

Introduction

Infection and bleeding are major causes of morbidity and mortality in acute myeloid leukemia (AML) [1], [2]. About half of all AML patients have moderate or severe bleeding at presentation [3], [4] and patients with the subtype acute promyelocytic leukemia (APL) encounter an even higher incidence of hemorrhage and early hemorrhagic deaths [5], [6].

There is a strong association between platelet count and the risk of hemorrhage in acute leukemia [7], although clinical bleeding can still be evident despite normal platelet counts.

The bleeding tendency is influenced by a multitude of factors such as disseminated intravascular coagulation (DIC), hyperfibrinolysis [8], platelet function defects [9], [10], [11], fever, infection [3], the leukemia phenotype (APL), hyperleukocytosis [12] and administration of drugs that interfere with platelet function [13].

In general, dysfunction of the inner lining of the vessel wall, the endothelium, contributes significantly to capillary leakage and bleeding [14]. In AML patients, bleeding may be partly attributed to direct activation and dysfunction of the endothelium, since leukemic blast cells and thrombocytopenia can both activate or disrupt the endothelium [14], [15]. In support of this suggestion, previous studies reported increased levels of endothelium-derived biomarkers such as endocan and ICAM-1 in AML patients [16], [17].

Endothelial dysfunction contributes significantly to the pathophysiology of systemic critical illness like sepsis [18], [19], [20], [21] and trauma [22], [23]. Furthermore, trauma patients with excessive degradation of the endothelial glycocalyx, determined by the level of circulating syndecan-1, exhibit increased coagulopathy, bleeding and mortality [22].

Syndecan-1 is a transmembrane proteoglycan located on the luminal surface of endothelial cells, and constitutes the “backbone” of the glycocalyx. Syndecan-1 is a recognized marker of glycocalyx degradation, and increased levels of circulating syndecan-1 in the blood are correlated with reduced thickness of the glycocalyx [24]. Syndecan-1 is shed to the blood stream in various conditions such as ischemia/reperfusion injury, cardiac arrest, sepsis, pregnancy, and inflammation.

To our knowledge, no previous studies have investigated the levels of circulating syndecan-1 in AML patients.

Therefore, the primary aim of the present study was to investigate the association between clinical bleeding and endothelial perturbation evidenced by circulating biomarkers of glycocalyx degradation and endothelial cell activation and damage in AML patients.

A secondary aim was to identify biochemical markers associated with endothelial perturbation, hypothesizing that both thrombocytopenia, platelet dysfunction and leukocytosis would be associated with endothelial perturbation.

Endothelial function was assessed by measuring a soluble biomarker of glycocalyx degradation (syndecan-1), markers of endothelial activation and classical adhesion molecules primarily expressed on endothelial cells (inter cellular adhesion molecule-1 (sICAM-1) and sE-selectin), and a marker of endothelial cell damage (thrombomodulin (sTM)).

Section snippets

Patients

All study patients were participants in a previous prospective study of functional platelet defects and hemorrhage in AML conducted by Leinøe and coworkers [4], [10]. All of the subjects in the initial study were included in the period between May 2001 and January 2004 at the Department of Hematology, Copenhagen University Hospital, Herlev, Denmark. Informed consent was given by all patients in accordance with the Second Declaration of Helsinki [4], [10]. Inclusion in the present study without

Study patients

The 49 study patients had a median age of 67 years and 41% (n = 20) were female. Prior to blood sampling no patients had recently taken acetylsalicylic acid or other anti-platelet drugs, whereas 19 patients were treated with antibiotics at the time of blood sampling. None of the patients presented with DIC.

The patients were diagnosed with acute leukemia according to the WHO-classification and were assigned to the FAB-classification categories as follows: M0; three patients, M1; nine patients, M2;

Discussion

The main finding of the present study was that AML patients with clinical bleeding showed enhanced glycocalyx degradation and endothelial cell activation, indicated by higher levels of soluble syndecan-1 and ICAM-1. The patients with the highest degree of glycocalyx degradation had impaired platelet function and more bleeding, despite comparable platelet counts. Furthermore, these patients were older, and had evidence of enhanced endothelial cell activation and damage as indicated by higher

Conclusions

In summary, we found evidence of glycocalyx degradation and endothelial activation in AML patients with clinical bleeding. Patients with enhanced glycocalyx degradation, indicated by high syndecan-1 levels, had more bleeding and impaired platelet function, regardless of platelet counts. Furthermore, patients with high levels of syndecan-1 were older, displayed signs of profound endothelial activation and damage, and had higher leukocyte counts.

The bleeding tendency in AML patients is influenced

Conflict of interest statement

The authors declare no potential conflicts of interests.

Acknowledgements

We thank Karen Dyeremose and Marie Helena Andersson for their skilled technical assistance.

Role of the funding source. No funding was provided for the present study.

Contributions. AL performed statistical analysis, interpreted and analyzed the data and wrote the paper. SRO designed the research, performed statistical analysis, interpreted and analyzed the data and revised the paper. EL included the patients, performed the initial experiments, designed the research and revised the manuscript.

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High syndecan-1 levels in acute myeloid leukemia are associated with bleeding, thrombocytopathy, endothelial cell damage, and leukocytosis

Abstract

Introduction

Section snippets

Patients

Study patients

Discussion

Conclusions

Conflict of interest statement

Acknowledgements

Blood

Leuk Res

Am J Med

Blood Rev

J Thromb Haemost

Blood

Med Hypotheses

Blood

Leuk Res

Br J Anaesth

The risk of bleeding in thrombocytopenic patients with acute myeloid leukemia

Haematologica

Prediction of haemorrhage in the early stage of acute myeloid leukaemia by flow cytometric analysis of platelet function

Br J Haematol

Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin

Blood

The quantitative relation between platelet count and hemorrhage in patients with acute leukemia

N Engl J Med

Platelet function abnormalities in acute leukaemia

Haematologia (Budap)

Multiple platelet defects identified by flow cytometry at diagnosis in acute myeloid leukaemia

Br J Haematol

Clinical course and response to treatment of patients with acute myelogenous leukemia presenting with a high leukocyte count

Cancer

Platelet functions and clinical effects in acute myelogenous leukemia

Thromb Haemost