From www.bloodjournal.org by guest on May 22, 2019. For personal use only.

weight, or behavior. Although this study has myeloid leukemia. N Engl J Med. 2016;374(23): groups: small water-soluble compounds,
2209-2221.
remarkable clinical implications, some issues middle molecules, and protein-bound
4. Stein EM, Tallman MS. Emerging therapeutic drugs
have to be addressed. It would be interesting solutes, with the common characteristic of
for AML. Blood. 2016;127(1):71-78.
to investigate a putative ddC-induced being difficult to eliminate by conventional
5. Eron JJ Jr, Johnson VA, Merrill DP, Chou TC,
resistance in the treatment of AML due to Hirsch MS. Synergistic inhibition of replication of RRTs.5 IS, a protein-bound uremic toxin
the onset of mutations in mtDNA. human immunodeficiency virus type 1, including that derived from the amino acid tryptophan, is
of a zidovudine-resistant isolate, by zidovudine and
Conflict-of-interest disclosure: The author declares 29,39-dideoxycytidine in vitro. Antimicrob Agents Chemother.
produced by the intestinal flora and is 1 of
no competing financial interests. n 1992;36(7):1559-1562. the clinical factors thought to contribute to
6. Boultwood J, Fidler C, Mills KI, et al. Amplification CKD progression.
REFERENCES of mitochondrial DNA in acute myeloid leukaemia. Yang et al conducted a series of
Br J Haematol. 1996;95(2):426-431.
1. Liyanage SU, Hurren R, Voisin V, et al. Leveraging experiments to examine IS triggering of
increased cytoplasmic nucleoside kinase activity to target 7. Nawrocki ST, Kelly KR, Smith PG, et al. The
NEDD8-activating enzyme inhibitor MLN4924 disrupts
platelet activation and thrombosis both in
mtDNA and oxidative phosphorylation in AML. Blood.
2017;129(19):2657-2666. nucleotide metabolism and augments the efficacy of vitro and in vivo in a mouse model. The
cytarabine. Clin Cancer Res. 2015;21(2):439-447. authors present convincing data of platelet
2. Döhner H, Weisdorf DJ, Bloomfield CD. Acute
myeloid leukemia. N Engl J Med. 2015;373(12): hyperactivity caused by IS, as demonstrated
1136-1152. DOI 10.1182/blood-2017-03-773200
by an enhanced response to the platelet
3. Papaemmanuil E, Gerstung M, Bullinger L, et al.
Genomic classification and prognosis in acute © 2017 by The American Society of Hematology agonists thrombin and collagen; increased
P-selectin expression; release of platelet
microparticles; formation of heterotypic
l l l THROMBOSIS AND HEMOSTASIS
platelet-monocyte aggregates; and higher
Comment on Yang et al, page 2667 platelet adhesion in a thrombosis model of
carotid artery occlusion. The platelet effect

Indoxyl sulfate, a uremic of IS, which is an activator of oxidative stress,

seems likely to be mediated through the

trigger for platelets

-----------------------------------------------------------------------------------------------------
production of reactive oxygen species (ROS)
and the activation of the inflammation-related
protein p38 MAPK.
Maribel Diaz-Ricart HOSPITAL CLINIC Furthermore, the authors show that
Klotho protein modulates the effect of IS
In this issue of Blood, Yang et al explore the effects of the uremic toxin indoxyl sulfate (IS) on platelet hyperactivity and thrombus
triggering platelet hyperactivity in chronic kidney disease (CKD). In their mouse model of formation, protecting against IS-induced
disease, the aging suppressor protein Klotho acts as an antidote for the toxin effects.1 atherosclerosis in apoE null mice. The role of
Klotho in this setting is intriguing. Klotho is

H emostasis is in a delicate equilibrium

in CKD patients. Deficient hemostasis
coexists paradoxically with accelerated
Accelerated atherothrombosis in
CKD has a complex etiology (see figure).
Endothelial dysfunction coexists with a
known to be an aging suppressor protein that
acts as a scavenger for ROS overproduction.
It is highly expressed in the kidney, and
atherosclerosis and an enhanced thrombotic chronic inflammatory state and oxidative CKD is a state of Klotho deficiency, with
risk. Uremic bleeding is multifactorial and stress in uremic patients.3,4 In the negative systemic effects on numerous
has been attributed to platelet dysfunction, development of these pathological processes, organs, including the cardiovascular system.
impaired platelet–vessel wall interactions, there are at least 2 components: humoral Results provided by Yang et al, together
and altered rheological properties of the and cellular. The humoral component with recently generated evidence,6
blood flow. Treatment with erythropoiesis- consists of the presence of uremic toxins and indicate that this protein could be a future
stimulating agents was introduced in the mid- those factors released by the activation of prophylactic and therapeutic target to
1980s with a very favorable impact, not only blood cells. The uremic toxins are present modify or prevent the progression from
in reducing the frequency of bleeding, but in patients with CKD, independent of acute to CKD with its associated
also in improving patients’ overall quality treatment with renal replacement therapies cardiovascular risk.
of life.2 The prothrombotic state in CKD (RRTs), and alter the function of the There are a number of publications
may be related to an imbalance between different cell populations involved in exploring the effect of IS on different cell
coagulation factors and coagulation hemostasis (endothelial cells, platelets, types, such as endothelial cells, myoblast
inhibitors, decreased fibrinolytic activity, and leukocytes). These activated cellular cells, and smooth muscle cells. IS is
platelet hyperactivity, and endothelial elements release cytokines that enrich the a protein-bound toxin, and high free
dysfunction. At present, although the humoral component. In addition, RRTs concentrations of these compounds and/or
incidence of bleeding is apparently themselves promote cell activation and excessively low albumin concentrations may
decreasing, the thrombotic complications further production and release of cytokines, distort the interpretation of the results
have become the main causes of mortality further propelling the inflammatory reaction. obtained and therefore overestimate the toxic
in this population. Uremic toxins can be classified into 3 main impact of IS.7

BLOOD, 11 MAY 2017 x VOLUME 129, NUMBER 19 2599

 From www.bloodjournal.org by guest on May 22, 2019. For personal use only.

REFERENCES
UREMIC MILIEU: 1. Yang K, Du C, Wang X, et al. Indoxyl sulfate
Toxins RRTs induces platelet hyperactivity and contributes to
chronic kidney disease–associated thrombosis in mice.
+
Blood. 2017;129(19):2667-2679.
Cytokines
2. Moia M, Mannucci PM, Vizzotto L, Casati S, Cattaneo
M, Ponticelli C. Improvement in the haemostatic defect
of uraemia after treatment with recombinant human
erythropoietin. Lancet. 1987;2(8570):1227-1229.

3. Escolar G, Dı́az-Ricart M, Cases A. Uremic platelet

dysfunction: past and present. Curr Hematol Rep. 2005;
4(5):359-367.

4. Caballo C, Palomo M, Cases A, et al. NFkB in the

development of endothelial activation and damage in
uremia: an in vitro approach. PLoS One. 2012;7(8):
e43374.

5. Duranton F, Cohen G, De Smet R, et al; European

Uremic Toxin Work Group. Normal and pathologic
concentrations of uremic toxins. J Am Soc Nephrol. 2012;
23(7):1258-1270.
Subendothelial adhesive proteins 6. Hu MC, Shi M, Gillings N, Flores B, Takahashi M,
Kuro-O M, Moe OW. Recombinant a-Klotho may be
Activated platelets
prophylactic and therapeutic for acute to chronic kidney
disease progression and uremic cardiomyopathy.
Heterotypic aggregates Kidney Int. 2017;91(5):1104-1114.

Adhesion receptors 7. Vanholder R, Schepers E, Pletinck A, Nagler EV,

Glorieux G. The uremic toxicity of indoxyl sulfate and
p-cresyl sulfate: a systematic review. J Am Soc Nephrol.
Illustration representing a longitudinal section of a vascular vessel. In CKD, toxins and cytokines are present in the circulation. 2014;25(9):1897-1907.
RRTs, although necessary, contribute to activate circulating blood cells with the release of cytokines that enrich the toxic
environment. Chronic inflammation and oxidative stress coexist with endothelial dysfunction in CKD. The hematocrit is 8. Briskey D, Tucker P, Johnson DW, Coombes JS. The
decreased because of the anemia. Activated platelets circulate and form heterotypic aggregates with monocytes. Platelet role of the gastrointestinal tract and microbiota on uremic
hyperactivity contributes to thrombus formation. From Yang et al, the uremic toxin indoxyl sulfate seems to play a crucial role in toxins and chronic kidney disease development. Clin Exp
the activation of these processes, and Klotho protein could be a promising strategy to prevent them. Nephrol. 2017;21(1):7-15.

DOI 10.1182/blood-2017-03-773218
The findings by Yang et al give insight Conflict-of-interest disclosure: The author declares
into the pathogenesis of CKD-associated no competing financial interests. n © 2017 by The American Society of Hematology
thrombosis and accelerated atherosclerosis
and suggest new strategies for their
l l l TRANSPLANTATION
treatment. Correction of Klotho deficiency
may be a promising strategy to prevent, Comment on Schroeder et al, page 2680
retard, and decrease the burden of
comorbidity in CKD. The results obtained
through this study offer different
Mobilizing plasmacytoid dendritic cells
-----------------------------------------------------------------------------------------------------
scenarios for promising future research.
Translational studies on humans are needed Edmund K. Waller WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
to confirm the results obtained in
the mouse model. CKD is a very complex In this issue of Blood, Schroeder et al demonstrate striking mobilization of
pathological situation, and alterations plasmacytoid dendritic cell progenitors (pre-pDCs) and mature plasmacytoid
occurring in those cells constantly exposed dendritic cells (pDCs) into the vascular compartment along with CD341
to the humoral blood components are hematopoietic progenitor cells following administration of single-agent plerixafor
multifactorial. IS is just 1 of the multiple in sibling donors.1
toxins present in the circulation of CKD
patients. There is emerging evidence
on the influence of gut bacteria on the
production of uremic toxins and the
P lerixafor is a small-molecule CXCR4
antagonist that interferes with binding
between CXCR4, expressed on hematopoietic
progenitor cells from the bone marrow (BM)
into the vascular space of patients undergoing
autologous stem cell transplantation, facilitating
development of CKD.8 The search for new cells, and CXCL12, expressed on marrow their collection by apheresis.3 The use of single-
strategies to diminish the concentrations stromal cells.2 Plerixafor is US Food and Drug agent plerixafor in the setting of stem cell
of these uremic toxins will benefit the Administration approved for administration mobilization from allogeneic donors is
management of CKD and end-stage renal in combination with 5 days of granulocyte inherently attractive, as it could avoid the need
disease patients in which there is still residual colony-stimulating factor (G-CSF) to enhance for G-CSF administration and the attendant
renal function. the mobilization of CD341 hematopoietic side effects of bone pain, splenomegaly,

2600 BLOOD, 11 MAY 2017 x VOLUME 129, NUMBER 19

 From www.bloodjournal.org by guest on May 22, 2019. For personal use only.

2017 129: 2599-2600

doi:10.1182/blood-2017-03-773218

Indoxyl sulfate, a uremic trigger for platelets

Maribel Diaz-Ricart

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