Abstract

This review will discuss how 2 common and morbid conditions, renal disease and liver disease, alter platelet number and function. It will review the impact of thrombocytopenia on bleeding complications in patients with these disorders and whether the low platelet count actually correlates with bleeding risk. Emerging data also suggest that platelets are much more than bystanders in both renal and liver disease, but instead play an active role in the pathobiology of these disorders. This review will briefly cover the emerging information on novel roles of platelets in the biology of renal and liver disease.

Learning Objectives
  • List the common manifestations of platelet dysfunction in renal disease and liver disease

  • Compare the causes of thrombocytopenia in renal disease and liver disease

  • Understand the role of platelets in the pathobiology of renal disease and liver disease

Introduction

Renal and liver diseases in hematology texts and reviews of platelet disorders are reported to be common causes of acquired platelet dysfunction. Additionally, thrombocytopenia is a typical problem in patients with some types of both renal and liver disease and may limit therapeutic or diagnostic options. Bleeding may complicate care of patients with both end-stage renal disease (ESRD) and cirrhosis. In patients with uremia, mucosal bleeding including gastrointestinal bleeding, as well as pleural and pericardial hemorrhage into effusions in the presence of impaired hemostasis, may make management of patients with severe disease more difficult. Reported bleeding in ESRD varies from 24% to 50% of patients on hemodialysis.1  Thrombocytopenia has been found in 16% to 55% of patients with uremia.2  In liver disease, 5% to 7% of hospitalized patients may have bleeding,3  mainly from acute esophageal variceal bleeding, which is associated with up to 20% mortality.4  Up to 76% may have thrombocytopenia.5  In this review, we will discuss the impact of thrombocytopenia and platelet dysfunction on patients with liver and renal disease. We will also touch on emerging data extending our understanding of the role of platelets in the pathobiology of liver and renal disease. Using several demonstrative cases, we will discuss the major issues seen in patients with renal and liver disease and discuss some management issues.

Normal platelet production and function

Platelets are produced in the bone marrow by megakaryocytes in a process that is regulated mainly by thrombopoietin (TPO).6  TPO is produced mainly by the liver,7  although TPO mRNA can be expressed in kidney and smooth muscle, and in adults, under inflammatory conditions, bone marrow stromal cells can produce significant amounts of TPO.8  Generally, platelets and megakaryocytes regulate TPO levels by acting as a “sink” for the majority of the TPO produced by the liver, absorbing, internalizing, and destroying the protein through the ligand expressed primarily on these cells: c-MPL.9  Usually, therefore, the lower the platelet mass, the higher the amount of TPO available to stimulate megakaryopoiesis.6,10  This concept becomes important in the thrombocytopenia often seen in severe liver disease.

Normal platelet activities include: adhesion to vascular endothelium using receptors for von Willebrand factor and collagen (GPIb-V-IX complex and both GPVI and integrin α2β1, respectively), aggregation of platelets (by fibrinogen linking by GPIIb/IIIa), and release of their granule contents (requiring signaling through several receptors but resulting in release of adenosine diphosphate [ADP], serotonin, and thromboxane A2 [TxA2]).11  All of these processes are required for proper hemostasis. ADP and serotonin release from granule stores potentiates platelet activation and recruits more platelets to the developing platelet aggregate.12  This causes further platelet and endothelial cell activation and releases more granule contents from both endothelial cells and platelets by activation of the adrenergic receptors P2Y1 and P2Y12 (common pharmacologic targets of platelets).13  Platelet-vascular wall interactions are critical to normal hemostasis because they initiate hemostasis, and lacking these interactions results in bleeding as evidenced by the bleeding diatheses of Bernard Soulier syndrome, a platelet disorder with significantly decreased expression of the GPIb-V-IX complex, resulting in loss of interactions with von Willebrand factor,14  and von Willebrand disease, the quantitative or qualitative deficiency of von Willebrand factor.15 

Vascular endothelium also responds to platelet activation by releasing nitric oxide (NO) and prostacyclin (PGI2) to inhibit further platelet reactivity and modulate the endothelial response. NO increases platelet cyclic guanylyl monophosphate levels, resulting in decreased platelet aggregation to collagen.16  Simultaneously, PGI2 release results in increases in platelet cyclic adenosine monophosphate (cAMP) levels and subsequent decreased platelet reactivity to multiple reagents, inhibition of platelet shape change, and vasodilation.17  Interestingly, and perhaps important to understanding why patients with renal disease and liver disease have an increased tendency to bleed, blockade of the P2Y12 receptor by pharmacologic therapy leads to 1000- to 100 000-fold increased sensitivity of platelets to the inhibitory effect of NO.18  It is not clear whether endogenous loss of platelet ADP–mediated P2Y12 activation results in a similar increased NO/PGI2 sensitivity, but it is a reasonable hypothesis to explain the variable bleeding because endothelial cell activation varies in each patient.

What has also become more apparent is that platelets not only modulate hemostasis, but they also play an important role in the inflammatory response important in both liver fibrosis and renal disease, recruiting inflammatory cells such as neutrophils and monocytes19,20  and releasing inflammatory modulators.21,22 

Platelets and ESRD

Patients with ESRD are prone to both bleeding and thrombosis. A major morbidity in ESRD is thrombosis, with more than half of all grafts developing thrombosis within 2 years,23  and cardiovascular disease is a significant cause of mortality in these patients, accounting for 45% to 50% of deaths among patients on dialysis.24  Paradoxically, 24% to 55% of patients with ESRD have increased bleeding complications.25  This is a result of the combination of the effects of uremia and ESRD on platelet function. Balancing bleeding risk and thrombosis in ESRD may be quite difficult.

Early studies of patients with ESRD showed high prevalence of bleeding complications caused by uremia complicated by significant anemia. Current nephrology practice mitigates some of these issues with dialysis and management of anemia, but allows patients to be potentially older, with increased comorbidities such as hypertension and atherosclerotic vascular disease.26  In addition to the attendant increased risk of bleeding associated with aging, these comorbidities may also increase risk of bleeding.27  Additionally, some studies continue to report mild to moderate thrombocytopenia in patients with ESRD in 16% to 55% of patients.2  There is not a clear relationship between prognosis and platelet counts in patients with ESRD (unlike with liver disease).

The pathophysiology of bleeding in patients with uremia is still not well understood, but several mechanisms appear to play a role in platelet-mediated bleeding associated with uremia. This is independent of platelet count (not related to thrombocytopenia). First, there appears to be a defect in platelet adhesion mediated by GPIb-V-IX–vWF interactions, which can be overcome by increasing vWF levels28  (by administration of desmopressin29 ). Second, there appears to be a defect in platelet secretion, mediated perhaps by increased PGI2 and NO levels in uremic patients30  and associated with increased platelet cAMP levels. Simultaneously, platelets from uremic patients contain less ADP, serotonin, and TxA2, suggesting an acquired storage pool defect caused by the uremia (perhaps in part because of abnormal production of these components, again because of the elevated cAMP levels).31,32  Next, there is a defect in the function of the major platelet receptor GPIIb-IIIa, which plays critical roles to mediate both platelet aggregation by platelet-platelet linking through fibrinogen and signaling through receptor-mediated signal transduction. Small peptides containing the Arg-Gly-Asp binding sequence of fibrinogen required for receptor activation and platelet bridging have been shown to accumulate in patients with renal failure and may explain this aspect of abnormal platelet function.33 

Other factors associated with bleeding in renal patients

Anemia.

In patients with renal disease, significant anemia has been associated with increased risk of bleeding.34  This is attributed to vascular rheology, indicating that during normal laminar flow, red cells flow in the center of the vessel, displacing plasma and therefore platelets, radially and increasing platelet-vessel wall interactions.35  Additionally, red blood cells release ADP and TxA236,37  (which may contribute to platelet activation) and scavenge NO (which inhibits platelet aggregation and promotes vasodilation).38 

Antiplatelet and anticoagulant therapy.

Patients with ESRD are often placed on either antiplatelet or anticoagulant therapy for vascular access maintenance39-41  or to prevent recurrence of acute coronary syndromes.42  Patients with ESRD have increased rates of bleeding compared with the general population. In a study of 579 ambulatory patients treated with warfarin therapy (target international normalized ratio 2-3), chronic renal insufficiency was identified as an independent predictor of major hemorrhage (hazard risk [HR], 2.6; 95% confidence interval [CI], 1.3-5.2; P = .008).43  But even milder degrees of renal insufficiency are associated with an increased risk of bleeding on anticoagulation and were also recently associated with an increased likelihood that physicians would discharge a patient without prescribing recommended pharmacotherapy after percutaneous coronary intervention, so that patients with renal insufficiency are both at increased risk of complications and of receiving less than the recommended therapy.44 

The role of platelets in glomerulopathy

Platelets are found in glomerular structures in glomerulonephritis. During this process, they are activated and their secretory products localize within glomerular structures. In some animal models of nephritis, plasma and urinary levels of platelet proteins correlated with proteinuria and renal histologic abnormalities.45  In addition, platelets release cytokines and growth factors that can directly influence glomerular mesangial cell proliferation, migration, contraction, and extracellular matrix protein synthesis.46,47  However, data from clinical trials using antiplatelet therapies in patients with glomerulonephritis have not been conclusive and at this time, no antiplatelet therapy is standard treatment of glomerulopathy.

Platelets and liver disease

Platelets play an important role in liver disease. Recent evidence suggests that in the injured liver, platelets are present and interact with sinusoidal endothelial cells, influencing the recruitment and activation of other (inflammatory) cells.19,21  Hepatic sinusoids are lined by a unique endothelium, which is fenestrated, exposed to minimal shear stress, and may display scavengerlike functions.48  Several studies have suggested that platelets may be sequestered within the liver sinusoids49-51  and may play a role to assist in leukocyte recruitment during inflammation.48,52  In several types of hepatic injury, neutrophils play a key role in the pathogenesis of liver injury. Current research suggests that circulating platelet-neutrophil aggregates may play a role in driving organ damage in patients with cirrhosis.53,54  Interestingly, the role of platelets in liver disease appears to be time-specific in that induction of thrombocytopenia in some models of chronic liver disease can worsen liver function by causing hepatic fibrosis, and in other forms of liver disease, antiplatelet therapy may mitigate liver injury.55,56  With this information in mind, we can examine the more classical, hemostatic role of platelets in liver disease.

Patients with liver disease often have thrombocytopenia, and this correlates with severity of liver dysfunction and fibrosis in many studies.57-59  Prevalence of thrombocytopenia depends on the exact definitions used and the patient population studied with noncirrhotic patients, with chronic liver disease having lower rates of thrombocytopenia (6%).60  In cirrhotic liver disease, mild to moderate thrombocytopenia is common, occurring in as much as 76% of patients, although only 13% of patients will have more severe thrombocytopenia (platelet counts <50 × 109/L).5  Platelet dysfunction has also been reported in some patients with significant liver disease, including defects of TxA2 synthesis, storage pool deficiency, and GPIb abnormalities.61-63  In contrast to patients with uremia in whom studies of coagulation (activated partial thromboplastin time and prothrombin time) are generally not significantly altered, patients with liver disease often have prolongation of both the prothrombin time and activated partial thromboplastin time because multiple coagulation factors are low in plasma in proportion to the degree of dysfunction in protein synthesis. These abnormalities traditionally lead many clinicians to infer that hemostasis is globally impaired, and this is the main cause of bleeding in this patient population, despite the fact that this testing does not predict the onset or severity of bleeding. Thrombosis is also a concern in many patients, with portal vein thrombosis developing in 10% to 20% of patients with cirrhosis,64,65  as well as many reports of deep vein thrombosis and embolic disease developing.66,67  Growing evidence suggests that there is instead a rebalancing of bleeding/thrombosis risk but a very tenuous balance that may be more easily upset than in patients without liver disease.68 

Thrombocytopenia

Thrombocytopenia in liver disease is multifactorial: caused by splenomegaly and splenic sequestration,69  relatively reduced production of TPO for the degree of thrombocytopenia,70  consumption of platelets owing to autoantibodies directed against platelets,71  or because of bone marrow suppression.72,73  Bleeding in patients with liver disease, in fact, correlates better with platelet count than with standard measures of coagulation,5  although other (global) measures may represent bleeding risk even better. When trying to assess risk of bleeding, investigators looked at thrombin generation in patients with liver disease and thrombocytopenia and found that thrombin generation in platelet-rich plasma from patients with cirrhosis remained normal down to platelet counts ∼60 × 109/L.74  In addition, thromboelastography, which attempts to measure global hemostasis, may not be substantially altered by a standard platelet transfusion in adult patients with platelet counts <50 × 109/L.75 

Thrombocytopenia in liver disease not only potentially contributes to bleeding risk in patients with liver disease, but also complicates therapy. In patients with virally-associated liver disease, therapeutic options may be limited in the setting of severe thrombocytopenia, and pharmacologic intervention to increase platelet count may be needed to allow for treatment of the underlying viral hepatitis or to allow for the performance of needed procedures. Treatment with thrombopoietin receptor agonists, such as eltrombopag, avatrombopag, or romiplostim, can result in significant increases in platelet counts.76-80  Eltrombopag has been studied for longer courses of therapy in several clinical trials77  but has also been associated with more complications including thrombosis (and portal vein thrombosis) and hepatotoxicity.76,77,81  It is not clear whether the increased thrombosis risk is caused by the increased platelet count or the medication itself, and the clinical trial with avatrombopag also reported 1 patient with portal vein thrombosis.79  Clinicians need to carefully examine thrombotic risk in patients before initiation of any platelet-elevating pharmacologic therapy.

Platelet dysfunction

Separate from the thrombocytopenia, some patients with liver disease display platelet dysfunction on laboratory testing. Older studies focused on examining specific aspects of platelet function and found defects in some patients in TxA2 synthesis, storage pool deficiency, and GPIb abnormalities.61-63,82  More recent studies, however, question the conclusions drawn from these early studies (eg, although platelet TxA2 synthesis is decreased, urinary exretion of TxB2, a stable metabolite of TxA2, is increased in cirrhosis, suggesting the platelets can be normally activated83  and total production of TxA2 must be normal). More recent examination of platelets by flow cytometry also supports platelet activation and suggests that in some types of liver disease, platelets may show increased reactivity.84,85  In addition, compensating for possible alterations in platelet function (and for thrombocytopenia), patients with liver disease often have increased von Willebrand factor levels,86  and, as a result of a relative deficiency of ADAMTS activity, the large multimers of von Willebrand factor are increased,87  providing relatively increased hemostatic potency.

Predicting bleeding

Variceal size and severe liver failure predicted bleeding in patients without prior hemorrhage and cirrhosis in a prospective study.88 

Summary

Renal and liver diseases are both associated with altered platelet numbers and function. In both patient populations, it may be difficult to balance risk of bleeding and thrombosis. Current evidence suggests that the role of platelets in these disorders is more complex than originally thought, as well with platelets not only mediating bleeding risk but also contributing to the underlying pathophysiology.

Correspondence

Michele P. Lambert, Division of Hematology, The Children's Hospital of Philadelphia, ARC, Room 316B, 3615 Civic Center Blvd, Philadelphia, PA 19104; e-mail: lambertm@e-mail.chop.edu.

References

References
1.
Pavord
S
,
Myers
B
.
Bleeding and thrombotic complications of kidney disease
.
Blood Rev
.
2011
;
25
(
6
):
271
-
278
.
2.
Boccardo
P
,
Remuzzi
G
,
Galbusera
M
.
Platelet dysfunction in renal failure
.
Semin Thromb Hemost
.
2004
;
30
(
5
):
579
-
589
.
3.
Ha
NB
,
Regal
RE
.
Anticoagulation in Patients With Cirrhosis: Caught Between a Rock-Liver and a Hard Place
.
Ann Pharmacother
.
2016
;
50
(
5
):
402
-
409
.
4.
Deltenre
P
,
Trépo
E
,
Rudler
M
, et al
.
Early transjugular intrahepatic portosystemic shunt in cirrhotic patients with acute variceal bleeding: a systematic review and meta-analysis of controlled trials
.
Eur J Gastroenterol Hepatol
.
2015
;
27
(
9
):
e1
-
e9
.
5.
Gangireddy
VG
,
Kanneganti
PC
,
Sridhar
S
,
Talla
S
,
Coleman
T
.
Management of thrombocytopenia in advanced liver disease
.
Can J Gastroenterol Hepatol
.
2014
;
28
(
10
):
558
-
564
.
6.
Kaushansky
K
.
Thrombopoietin
.
N Engl J Med
.
1998
;
339
(
11
):
746
-
754
.
7.
Qian
S
,
Fu
F
,
Li
W
,
Chen
Q
,
de Sauvage
FJ
.
Primary role of the liver in thrombopoietin production shown by tissue-specific knockout
.
Blood
.
1998
;
92
(
6
):
2189
-
2191
.
8.
Sakamaki
S
,
Hirayama
Y
,
Matsunaga
T
, et al
.
Transforming growth factor-beta1 (TGF-beta1) induces thrombopoietin from bone marrow stromal cells, which stimulates the expression of TGF-beta receptor on megakaryocytes and, in turn, renders them susceptible to suppression by TGF-beta itself with high specificity
.
Blood
.
1999
;
94
(
6
):
1961
-
1970
.
9.
Fielder
PJ
,
Gurney
AL
,
Stefanich
E
, et al
.
Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets
.
Blood
.
1996
;
87
(
6
):
2154
-
2161
.
10.
Hitchcock
IS
,
Kaushansky
K
.
Thrombopoietin from beginning to end
.
Br J Haematol
.
2014
;
165
(
2
):
259
-
268
.
11.
Rao
AK
.
Inherited platelet function disorders: overview and disorders of granules, secretion, and signal transduction
.
Hematol Oncol Clin North Am
.
2013
;
27
(
3
):
585
-
611
.
12.
Rendu
F
,
Brohard-Bohn
B
.
The platelet release reaction: granules’ constituents, secretion and functions
.
Platelets
.
2001
;
12
(
5
):
261
-
273
.
13.
Metharom
P
,
Berndt
MC
,
Baker
RI
,
Andrews
RK
.
Current state and novel approaches of antiplatelet therapy
.
Arterioscler Thromb Vasc Biol
.
2015
;
35
(
6
):
1327
-
1338
.
14.
Andrews
RK
,
Berndt
MC
.
Bernard-Soulier syndrome: an update
.
Semin Thromb Hemost
.
2013
;
39
(
6
):
656
-
662
.
15.
Ng
C
,
Motto
DG
,
Di Paola
J
.
Diagnostic approach to von Willebrand disease
.
Blood
.
2015
;
125
(
13
):
2029
-
2037
.
16.
Moro
MA
,
Russel
RJ
,
Cellek
S
, et al
.
cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase
.
Proc Natl Acad Sci USA
.
1996
;
93
(
4
):
1480
-
1485
.
17.
Armstrong
RA
.
Platelet prostanoid receptors
.
Pharmacol Ther
.
1996
;
72
(
3
):
171
-
191
.
18.
Kirkby
NS
,
Lundberg
MH
,
Chan
MV
, et al
.
Blockade of the purinergic P2Y12 receptor greatly increases the platelet inhibitory actions of nitric oxide
.
Proc Natl Acad Sci USA
.
2013
;
110
(
39
):
15782
-
15787
.
19.
Lalor
PF
,
Herbert
J
,
Bicknell
R
,
Adams
DH
.
Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment
.
Am J Physiol Gastrointest Liver Physiol
.
2013
;
304
(
5
):
G469
-
G478
.
20.
Nurden
AT
.
Platelets, inflammation and tissue regeneration
.
Thromb Haemost
.
2011
;
105
(
suppl 1
):
S13
-
S33
.
21.
Morrell
CN
,
Aggrey
AA
,
Chapman
LM
,
Modjeski
KL
.
Emerging roles for platelets as immune and inflammatory cells
.
Blood
.
2014
;
123
(
18
):
2759
-
2767
.
22.
Gros
A
,
Ollivier
V
,
Ho-Tin-Noé
B
.
Platelets in inflammation: regulation of leukocyte activities and vascular repair
.
Front Immunol
.
2015
;
5
:
678
.
23.
Brahmbhatt
A
,
Remuzzi
A
,
Franzoni
M
,
Misra
S
.
The molecular mechanisms of hemodialysis vascular access failure
.
Kidney Int
.
2016
;
89
(
2
):
303
-
316
.
24.
Agrawal
H
,
Aggarwal
K
,
Littrell
R
, et al
.
Pharmacological and non pharmacological strategies in the management of coronary artery disease and chronic kidney disease
.
Curr Cardiol Rev
.
2015
;
11
(
3
):
261
-
269
.
25.
Lutz
J
,
Menke
J
,
Sollinger
D
,
Schinzel
H
,
Thürmel
K
.
Haemostasis in chronic kidney disease
.
Nephrol Dial Transplant
.
2014
;
29
(
1
):
29
-
40
.
26.
Levin
A
,
Djurdjev
O
,
Barrett
B
, et al
.
Cardiovascular disease in patients with chronic kidney disease: getting to the heart of the matter
.
Am J Kidney Dis
.
2001
;
38
(
6
):
1398
-
1407
.
27.
Janssen
MJ
,
van der Meulen
J
.
The bleeding risk in chronic haemodialysis: preventive strategies in high-risk patients
.
Neth J Med
.
1996
;
48
(
5
):
198
-
207
.
28.
Zwaginga
JJ
,
Ijsseldijk
MJ
,
Beeser-Visser
N
,
de Groot
PG
,
Vos
J
,
Sixma
JJ
.
High von Willebrand factor concentration compensates a relative adhesion defect in uremic blood
.
Blood
.
1990
;
75
(
7
):
1498
-
1508
.
29.
Mannucci
PM
,
Remuzzi
G
,
Pusineri
F
, et al
.
Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia
.
N Engl J Med
.
1983
;
308
(
1
):
8
-
12
.
30.
Noris
M
,
Remuzzi
G
.
Uremic bleeding: closing the circle after 30 years of controversies?
Blood
.
1999
;
94
(
8
):
2569
-
2574
.
31.
Eknoyan
G
,
Brown
CH
III
.
Biochemical abnormalities of platelets in renal failure. Evidence for decreased platelet serotonin, adenosine diphosphate and Mg-dependent adenosine triphosphatase
.
Am J Nephrol
.
1981
;
1
(
1
):
17
-
23
.
32.
Schafer
AI
,
Levine
S
,
Handin
RI
.
Regulation of platelet arachidonic acid oxygenation by cyclic AMP
.
Blood
.
1980
;
56
(
5
):
853
-
858
.
33.
Zwaginga
JJ
,
IJsseldijk
MJ
,
de Groot
PG
,
Vos
J
,
de Bos Kuil
RL
,
Sixma
JJ
.
Defects in platelet adhesion and aggregate formation in uremic bleeding disorder can be attributed to factors in plasma
.
Arterioscler Thromb
.
1991
;
11
(
3
):
733
-
744
.
34.
Sohal
AS
,
Gangji
AS
,
Crowther
MA
,
Treleaven
D
.
Uremic bleeding: pathophysiology and clinical risk factors
.
Thromb Res
.
2006
;
118
(
3
):
417
-
422
.
35.
Turitto
VT
,
Baumgartner
HR
.
Platelet interaction with subendothelium in a perfusion system: physical role of red blood cells
.
Microvasc Res
.
1975
;
9
(
3
):
335
-
344
.
36.
Valles
J
,
Santos
MT
,
Aznar
J
, et al
.
Erythrocytes metabolically enhance collagen-induced platelet responsiveness via increased thromboxane production, adenosine diphosphate release, and recruitment
.
Blood
.
1991
;
78
(
1
):
154
-
162
.
37.
Santos
MT
,
Valles
J
,
Marcus
AJ
, et al
.
Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment
.
J Clin Invest
.
1991
;
87
(
2
):
571
-
580
.
38.
Azarov
I
,
Huang
KT
,
Basu
S
,
Gladwin
MT
,
Hogg
N
,
Kim-Shapiro
DB
.
Nitric oxide scavenging by red blood cells as a function of hematocrit and oxygenation
.
J Biol Chem
.
2005
;
280
(
47
):
39024
-
39032
.
39.
Abramson
S
,
Niles
JL
.
Anticoagulation in continuous renal replacement therapy
.
Curr Opin Nephrol Hypertens
.
1999
;
8
(
6
):
701
-
707
.
40.
Kaufman
JS
,
O’Connor
TZ
,
Zhang
JH
, et al. 
;
Veterans Affairs Cooperative Study Group on Hemodialysis Access Graft Thrombosis
.
Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis
.
J Am Soc Nephrol
.
2003
;
14
(
9
):
2313
-
2321
.
41.
Mokrzycki
MH
,
Jean-Jerome
K
,
Rush
H
,
Zdunek
MP
,
Rosenberg
SO
.
A randomized trial of minidose warfarin for the prevention of late malfunction in tunneled, cuffed hemodialysis catheters
.
Kidney Int
.
2001
;
59
(
5
):
1935
-
1942
.
42.
Freeman
RV
,
Mehta
RH
,
Al Badr
W
,
Cooper
JV
,
Kline-Rogers
E
,
Eagle
KA
.
Influence of concurrent renal dysfunction on outcomes of patients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors
.
J Am Coll Cardiol
.
2003
;
41
(
5
):
718
-
724
.
43.
McMahan
DA
,
Smith
DM
,
Carey
MA
,
Zhou
XH
.
Risk of major hemorrhage for outpatients treated with warfarin
.
J Gen Intern Med
.
1998
;
13
(
5
):
311
-
316
.
44.
Maree
AO
,
Margey
RJ
,
Selzer
F
,
Bajrangee
A
,
Jneid
H
,
Marroquin
OC
, et al
.
Renal insufficiency, bleeding and prescription of discharge medication in patients undergoing percutaneous coronary intervention in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry
.
Cardiovasc Revasc Med
.
2016
;
17
(
5
):
302
-
307
.
45.
Macconi
D
,
Noris
M
,
Benfenati
E
,
Quaglia
R
,
Pagliarino
G
,
Remuzzi
G
.
Increased urinary excretion of platelet activating factor in mice with lupus nephritis
.
Life Sci
.
1991
;
48
(
15
):
1429
-
1437
.
46.
Abboud
HE
.
Growth factors in glomerulonephritis
.
Kidney Int
.
1993
;
43
(
1
):
252
-
267
.
47.
Barnes
JL
,
Hevey
KA
.
Glomerular mesangial cell migration. Response to platelet secretory products
.
Am J Pathol
.
1991
;
138
(
4
):
859
-
866
.
48.
Meyer
J
,
Lejmi
E
,
Fontana
P
,
Morel
P
,
Gonelle-Gispert
C
,
Bühler
L
.
A focus on the role of platelets in liver regeneration: Do platelet-endothelial cell interactions initiate the regenerative process?
J Hepatol
.
2015
;
63
(
5
):
1263
-
1271
.
49.
Lang
PA
,
Contaldo
C
,
Georgiev
P
, et al
.
Aggravation of viral hepatitis by platelet-derived serotonin
.
Nat Med
.
2008
;
14
(
7
):
756
-
761
.
50.
Iannacone
M
,
Sitia
G
,
Isogawa
M
, et al
.
Platelets mediate cytotoxic T lymphocyte-induced liver damage
.
Nat Med
.
2005
;
11
(
11
):
1167
-
1169
.
51.
Lesurtel
M
,
Graf
R
,
Aleil
B
, et al
.
Platelet-derived serotonin mediates liver regeneration
.
Science
.
2006
;
312
(
5770
):
104
-
107
.
52.
Wong
J
,
Johnston
B
,
Lee
SS
, et al
.
A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature
.
J Clin Invest
.
1997
;
99
(
11
):
2782
-
2790
.
53.
Sturgeon
JP
,
Manakkat Vijay
GK
,
Ryan
J
,
Bernal
W
,
Shawcross
DL
.
Could abnormal neutrophil-platelet interactions and complex formation contribute to oxidative stress and organ failure in cirrhosis?
Hepatology
.
2015
;
62
(
4
):
1323
-
1324
.
54.
Taylor
NJ
,
Manakkat Vijay
GK
,
Abeles
RD
, et al
.
The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90-day and 1-year mortality
.
Aliment Pharmacol Ther
.
2014
;
40
(
6
):
705
-
715
.
55.
Kodama
T
,
Takehara
T
,
Hikita
H
,
Shimizu
S
,
Li
W
,
Miyagi
T
, et al
.
Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice
.
Gastroenterology
.
2010
;
138
(
7
):
2487
-
2498
, 98 e1-7.
56.
Sitia
G
,
Iannacone
M
,
Guidotti
LG
.
Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma
.
J Hepatol
.
2013
;
59
(
5
):
1135
-
1138
.
57.
Giannini
EG
,
Zaman
A
,
Kreil
A
, et al
.
Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study
.
Am J Gastroenterol
.
2006
;
101
(
11
):
2511
-
2519
.
58.
Lu
SN
,
Wang
JH
,
Liu
SL
, et al
.
Thrombocytopenia as a surrogate for cirrhosis and a marker for the identification of patients at high-risk for hepatocellular carcinoma
.
Cancer
.
2006
;
107
(
9
):
2212
-
2222
.
59.
van der Meer
AJ
,
Veldt
BJ
,
Feld
JJ
, et al
.
Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis
.
JAMA
.
2012
;
308
(
24
):
2584
-
2593
.
60.
Maan
R
,
de Knegt
RJ
,
Veldt
BJ
.
Management of Thrombocytopenia in Chronic Liver Disease: Focus on Pharmacotherapeutic Strategies
.
Drugs
.
2015
;
75
(
17
):
1981
-
1992
.
61.
Rubin
MH
,
Weston
MJ
,
Langley
PG
,
White
Y
,
Williams
R
.
Platelet function in chronic liver disease: relationship to disease severity
.
Dig Dis Sci
.
1979
;
24
(
3
):
197
-
202
.
62.
Weston
MJ
,
Langley
PG
,
Rubin
MH
,
Hanid
MA
,
Mellon
P
,
Williams
R
.
Platelet function in fulminant hepatic failure and effect of charcoal haemoperfusion
.
Gut
.
1977
;
18
(
11
):
897
-
902
.
63.
Rubin
MH
,
Weston
MJ
,
Bullock
G
, et al
.
Abnormal platelet function and ultrastructure in fulminant hepatic failure
.
Q J Med
.
1977
;
46
(
183
):
339
-
352
.
64.
Amitrano
L
,
Brancaccio
V
,
Guardascione
MA
, et al
.
Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia
.
Endoscopy
.
2002
;
34
(
7
):
535
-
538
.
65.
Fimognari
FL
,
Violi
F
.
Portal vein thrombosis in liver cirrhosis
.
Intern Emerg Med
.
2008
;
3
(
3
):
213
-
218
.
66.
Gulley
D
,
Teal
E
,
Suvannasankha
A
,
Chalasani
N
,
Liangpunsakul
S
.
Deep vein thrombosis and pulmonary embolism in cirrhosis patients
.
Dig Dis Sci
.
2008
;
53
(
11
):
3012
-
3017
.
67.
Søgaard
KK
,
Horváth-Puhó
E
,
Grønbaek
H
,
Jepsen
P
,
Vilstrup
H
,
Sørensen
HT
.
Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study
.
Am J Gastroenterol
.
2009
;
104
(
1
):
96
-
101
.
68.
Hartmann
M
,
Szalai
C
,
Saner
FH
.
Hemostasis in liver transplantation: Pathophysiology, monitoring, and treatment
.
World J Gastroenterol
.
2016
;
22
(
4
):
1541
-
1550
.
69.
Aster
RH
.
Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrombocytopenia
.
J Clin Invest
.
1966
;
45
(
5
):
645
-
657
.
70.
Giannini
EG
,
Peck-Radosavljevic
M
.
Platelet dysfunction: status of thrombopoietin in thrombocytopenia associated with chronic liver failure
.
Semin Thromb Hemost
.
2015
;
41
(
5
):
455
-
461
.
71.
Pereira
J
,
Accatino
L
,
Alfaro
J
,
Brahm
J
,
Hidalgo
P
,
Mezzano
D
.
Platelet autoantibodies in patients with chronic liver disease
.
Am J Hematol
.
1995
;
50
(
3
):
173
-
178
.
72.
Ballard
HS
.
Hematological complications of alcoholism
.
Alcohol Clin Exp Res
.
1989
;
13
(
5
):
706
-
720
.
73.
Peck-Radosavljevic
M.
Thrombocytopenia in liver disease
.
Can J Gastroenterol
.
2000
;
14
(
Suppl D
):
60D
-
66D
.
74.
Tripodi
A
,
Primignani
M
,
Chantarangkul
V
, et al
.
Thrombin generation in patients with cirrhosis: the role of platelets
.
Hepatology
.
2006
;
44
(
2
):
440
-
445
.
75.
Tripodi
A
,
Primignani
M
,
Chantarangkul
V
, et al
.
Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion
.
Liver Int
.
2013
;
33
(
3
):
362
-
367
.
76.
McHutchison
JG
,
Dusheiko
G
,
Shiffman
ML
, et al. 
;
TPL102357 Study Group
.
Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C
.
N Engl J Med
.
2007
;
357
(
22
):
2227
-
2236
.
77.
Afdhal
NH
,
Dusheiko
GM
,
Giannini
EG
,
Chen
PJ
,
Han
KH
,
Mohsin
A
, et al
.
Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy
.
Gastroenterology
.
2014
;
146
(
2
):
442
-
452
e1.
78.
Fukushima-Shintani
M
,
Suzuki
K
,
Iwatsuki
Y
, et al
.
AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist
.
Eur J Haematol
.
2009
;
82
(
4
):
247
-
254
.
79.
Terrault
NA
,
Hassanein
T
,
Howell
CD
, et al
.
Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure
.
J Hepatol
.
2014
;
61
(
6
):
1253
-
1259
.
80.
Moussa
MM
,
Mowafy
N
.
Preoperative use of romiplostim in thrombocytopenic patients with chronic hepatitis C and liver cirrhosis
.
J Gastroenterol Hepatol
.
2013
;
28
(
2
):
335
-
341
.
81.
Afdhal
NH
,
Giannini
EG
,
Tayyab
G
, et al. 
;
ELEVATE Study Group
.
Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia
.
N Engl J Med
.
2012
;
367
(
8
):
716
-
724
.
82.
Laffi
G
,
Cominelli
F
,
Ruggiero
M
, et al
.
Altered platelet function in cirrhosis of the liver: impairment of inositol lipid and arachidonic acid metabolism in response to agonists
.
Hepatology
.
1988
;
8
(
6
):
1620
-
1626
.
83.
Davì
G
,
Ferro
D
,
Basili
S
, et al
.
Increased thromboxane metabolites excretion in liver cirrhosis
.
Thromb Haemost
.
1998
;
79
(
4
):
747
-
751
.
84.
Ogasawara
F
,
Fusegawa
H
,
Haruki
Y
,
Shiraishi
K
,
Watanabe
N
,
Matsuzaki
S
.
Platelet activation in patients with alcoholic liver disease
.
Tokai J Exp Clin Med
.
2005
;
30
(
1
):
41
-
48
.
85.
Sayed
D
,
Amin
NF
,
Galal
GM
.
Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis
.
Thromb Res
.
2010
;
125
(
5
):
e228
-
e233
.
86.
Lisman
T
,
Bongers
TN
,
Adelmeijer
J
, et al
.
Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity
.
Hepatology
.
2006
;
44
(
1
):
53
-
61
.
87.
Violi
F
,
Basili
S
,
Raparelli
V
,
Chowdary
P
,
Gatt
A
,
Burroughs
AK
.
Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?
J Hepatol
.
2011
;
55
(
6
):
1415
-
1427
.
88.
Basili
S
,
Ferro
D
,
Leo
R
, et al
.
Bleeding time does not predict gastrointestinal bleeding in patients with cirrhosis. The CALC Group. Coagulation Abnormalities in Liver Cirrhosis
.
J Hepatol
.
1996
;
24
(
5
):
574
-
580
.

Author notes

Conflict-of-interest disclosure: The author declares no competing financial interests.

Off-label drug use: None disclosed.