EVERYDAY BLEEDING DISORDERS

Hemostatic defects in liver and renal dysfunction

Pier Mannuccio Mannucci1 and Armando Tripodi2

1Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca Granda Maggiore
Policlinico Hospital Foundation, Milan, Italy; and 2Angelo Bianchi Bonomi Hemophilia and Thrombosis
Center, IRCCS Ca Granda Maggiore Policlinico Hospital Foundation and Department of Clinical Sciences
and Community Health, University of Milan, Milan, Italy

Multiple and complex abnormalities of hemostasis are revealed by laboratory tests in such common diseases as
cirrhosis and end-stage renal insufficiency. Because these abnormalities are associated with a bleeding tendency, a
causal relationship is plausible. Accordingly, an array of transfusional and nontransfusional medications that improve
or correct these abnormalities is used to prevent or stop hemorrhage. However, recent data indicate that the use of
hemostatic drugs is scarcely justified mechanistically or clinically. In patients with uremia, the bleeding tendency
(mainly expressed by gastrointestinal bleeding and hematoma formation at kidney biopsy) is reduced dramatically by
the improvement of anemia obtained with the regular use of erythropoietin. In cirrhosis, the most severe and frequent
hemorrhagic symptom (acute bleeding from esophageal varices) is not explained by abnormalities in such coagulation
screening tests as the prothrombin and partial thromboplastin times, because formation of thrombin the final
coagulation enzyme is rebalanced by low naturally occurring anticoagulant factors in plasma that compensate for the
concomitant decrease of procoagulants. Rebalance also occurs for hyperfibrinolysis and platelet abnormalities. These
findings are consistent with clinical observations that transfusional and nontransfusional hemostatic medications are
of little value as adjuvants to control bleeding in advanced liver disease. Particularly in uremia, but also in cirrhosis,
thrombosis is becoming a cogent problem.

Introduction of hemostasis tests and that transfusional and nontransfusional

End-stage liver and kidney insufficiency are listed among the causes
of an acquired bleeding tendency in most hematology textbooks. In
uremia, hemorrhagic symptoms span from minor events such as
bruising to severe and life-threatening complications such as upper
gastrointestinal, pericardial, and intracranial bleeding. In cirrhosis,
bleeding from esophageal varices develops in up to 25% of patients,
with a case fatality rate as high as 15%-20%. Moreover, major blood
losses requiring transfusion of blood components occur during and
after operations such as transplantation and hepatectomy. Because
in end-stage liver and renal disease, hemorrhagic symptoms are
associated with multiple abnormalities shown in laboratory tests
exploring the hemostasis system,1,2 a cause-effect relationship was
inferred to be plausible. Therefore, it is common clinical practice to
treat or prevent bleeding in these patients with an array of
transfusional and nontransfusional medications aimed at potentiat-
ing hemostasis (ie, fresh-frozen plasma, platelet concentrates,
antifibrinolytic drugs, prothrombin complex concentrates, and recom-
binant activated factor VII in cirrhosis3-6 and cryoprecipitate,
desmopressin, and conjugated estrogens in uremia7-9). In general,
the capacity of these agents to prevent or stop bleeding is not
validated by randomized clinical trials, but is surmised on the basis
of their demonstrated capacity to improve or correct abnormalities
shown by hemostasis laboratory tests.
With this background, we review herein the pattern of hemostasis
abnormalities in patients with end-stage kidney and liver disease;
changes in these abnormalities induced by the aforementioned
hemostatic agents; and the evidence that, particularly in chronic
liver disease, questions the time-honored paradigm that the bleeding
tendency of these patients is causally related to their abnormalities
hemostatic medications are clinically useful to prevent or stop
bleeding. Both in kidney and liver disease, thrombosis is becoming
a clinical problem, perhaps more prominent than hemorrhage.
Hemostasis defects in uremia
The more than half a million patients in the United States who have
end-stage renal insufficiency requiring maintenance dialysis (with
an estimated yearly cost of 29 billion US dollars) are the epitome of
those who develop bleeding complications. The coagulation phase
of hemostasis, as explored by such screening tests as activated
partial thromboplastin time and prothrombin time, is normal in
uremic patient outside of the period of heparin administration
during dialysis aimed to prevent filter clotting. The most common
and prominent laboratory abnormality is prolongation of the skin
bleeding time,2,10 a term that refers to tests such as the template
bleeding time and the Ivy bleeding time, used as surrogate ex vivo
measurements of defective platelet interactions with the vessel wall
and the delayed formation of the primary hemostatic plug. Thrombo-
cytopenia is a rare cause of prolonged bleeding time, but there are
multiple and complex abnormalities of primary hemostasis in
uremia that help to explain this prolongation (Table 1).2,10 Even
though biochemical platelet alterations and the resulting defects of
aggregation do contribute to slowing the formation of the hemo-
static plug, impaired platelet adhesion to injured vessels is thought
to be the main determinant of the prolonged bleeding time in
uremia. The mechanisms of defective platelet adhesion are complex
and multifactorial (Table 1).
A dysfunction of VWF was thought to be an important culprit in
bleeding disorders11,12 because both cryoprecipitate (a plasma

168 American Society of Hematology

Table 1. Etiologies of platelet dysfunction in patients with renal
disease
Platelet defects
Light transmission aggregometry defects; decreased thromboxane A2
formation; low content of serotonin and ADP; increased cyclic AMP;
impaired Ca2-dependent functions; impaired release of alpha- and
dense-granule contents
Defects of platelet adhesion to the vessel wall
Anemia; VWF dysfunction; enhanced nitric oxide production; uremic
toxins
Medication-induced defects of platelet function
Antiplatelet agents; nonsteroidal anti-inflammatory drugs; beta-lactam
antibiotics; third-generation cephalosporins
product rich in VWF) and desmopressin (a synthetic derivative of
the antidiuretic hormone that increases plasma VWF levels) shorten
the bleeding time in uremia.7,8 A contributory role for the enhanced
endogenous production of nitric oxide (a vasodilator and platelet
function inhibitor) was postulated on the basis of the effect on the
bleeding time induced by conjugated estrogens,9 which quench the
production of nitric oxide.13,14 However, the current thinking is that
anemia, a constant feature in advanced renal insufficiency, is a
critical determinant of defective platelet adhesion to the vessel wall
and the resulting prolongation of the skin bleeding time.
A pioneer observation was made in 1982 by Livio et al, who
demonstrated in uremic patients that the bleeding time is prolonged
in proportion to the degree of anemia, and that this test is shortened
or corrected when the hematocrit is increased to at least 30% by
RBC transfusion.15 The improvement of anemia improves platelet
adhesion because more RBCs in the circulation push more platelets
and leucocytes from the axial center of flowing blood toward the
periphery, thereby enhancing cell contacts with the vessel wall and
the formation of the primary hemostatic plug.16 Additional mecha-
nisms that contribute to the effect exerted by the improvement of
anemia on defective primary hemostasis are the release from RBCs
of ADP, a powerful inducer of platelet aggregation,17 and the
scavenging effect exerted by hemoglobin on nitric oxide.18 The
aforementioned defects of primary hemostasis may be exacerbated
by multiple medications that are taken by uremic patients (Table 1).
Therapeutic control of bleeding in uremia
The adoption of maintenance dialysis was the first step that
improved the bleeding tendency in uremia, although not fully
satisfactorily. The management of spontaneous bleeding and its
prevention at the time of invasive procedures or surgery was further
improved in the 1980s by the demonstration that some drugs
shortened the prolonged bleeding time (ie, desmopressin with a
short-lasting effect8 and conjugated estrogens with a more pro-
longed effect9). Because these medications cannot be administered
prophylactically for prolonged periods of time, the long-lasting
prevention of the bleeding tendency in uremia remained unsettled.
A step forward was the finding in 1987 that the regular use of
recombinant erythropoietin for the management of anemia caused a
marked and sustained shortening of the bleeding time.19 This
positive effect could be obtained after the attainment of hematocrit
values of approximately 30%,20 thereby confirming the early
observations on this critical threshold made by Livio et al9 with
RBC transfusions. In general, clinical experience is that the
improvement of anemia obtained through the regular administration
of erythropoietin has minimized the frequency and severity of
bleeding symptoms in patients with end-stage renal insufficiency
Hematology 2012
beyond the benefits obtained by dialysis. The hematocrit should be
kept at approximately 30%, because higher values and full correc-
tion of anemia increase the risk of atherothrombosis, particularly
myocardial infarction and ischemic stroke.
Are therapeutic weapons other than erythropoietin still being used
to manage uremic bleeding? In patients not on erythropoietin
therapy (eg, in acute or early renal insufficiency) or when the
increase in the hematocrit induced by this drug has not yet been
achieved, desmopressin is the drug of choice to prevent or stop
bleeding at the time of surgery or invasive procedures. An alterna-
tive to desmopressin are conjugated estrogens, which shorten the
bleeding time more slowly than desmopressin but have a more
long-lasting effect.
Table 2 shows the recommended regimens of administration of
drugs that are indicated in the prevention and control of uremic
bleeding for their capacity to shorten the prolonged bleeding time
(ie, the laboratory test that reflects the deranged primary hemostasis
of uremic patients and the underlying defects causing hemorrhage).
A current practical problem is that many laboratories have taken the
bleeding time off of their list of approved tests, so that the
management of uremic bleeding with drugs can no longer be easily
monitored using this test. The successful control of bleeding by
erythropoietin has perhaps thwarted the development and evaluation
in uremia of tests alternative to the bleeding time, with the exception
of PFA-100, the closure time of which has been found to be
prolonged in patients with uremia, but the clinical value of this test
remains to be established.21
Hemostasis defects in cirrhosis
The majority of patients with end-stage liver disease (approximately
400 000 are on the waiting list for transplantation in the United
States) have complex and multifactorial alterations that involve all
of the components of hemostasis.1 With regard to primary hemosta-
sis (Table 3), thrombocytopenia is a frequent finding, with platelet
counts usually ranging between 30 and 100 109/L. Defective
platelet aggregation explains why the skin bleeding time is often
more prolonged than would be predicted from the degree of
thrombocytopenia. At variance with uremia, there are no equivalent
data that anemia plays a role in causing the prolongation of the
bleeding time and the hemorrhagic tendency in liver disease. The
results of screening tests commonly used to explore the coagulation
phase of hemostasis (ie, prothrombin time and partial thromboplas-
tin time) are consistently prolonged because multiple coagulation
factors are low in plasma in proportion to the degree of compro-
mised protein synthetic capacity of the liver. Plasma hyperfibrinoly-
sis is reported in cirrhosis on the basis of the increase of tissue
plasminogen activator and decrease of the naturally occurring
inhibitors of plasmin. These multiple and complex alterations of
Table 2. How I treat bleeding in patients with chronic renal disease
untreated or unresponsive to erythropoietin
Acute bleeding
Desmopressin, 0.3 g/kg IV (added to 50 mL of saline over 30 min) or
subcutaneously (same dosage)
Intranasal desmopressin at a dose of 3 g/kg is also effective
The effect of desmopressin lasts only a few hours and tends to
lose efficacy when repeatedly administered
Chronic bleeding
Conjugated estrogens (a cumulative dose of 3 mg/kg divided as single
IV doses of 0.6 mg/kg for 5 consecutive days)
169
Table 3. Hemostasis rebalance in liver cirrhosis
Hemostasis
component Antihemostatic abnormalities
Primary hemostasis Thrombocytopenia, defective platelet aggregation
on light transmission aggregometry
Blood coagulation Low procoagulant factors (fibrinogen, prothrombin,
factors V, VII, IX, X, XI, XIII)
Fibrinolysis High plasminogen activator, low plasmin inhibitors
laboratory methods have traditionally led the clinician to infer that
in cirrhosis, hemostasis is globally impaired and is the main cause of
the bleeding diathesis seen so frequently in these patients.1
This concept was first challenged by the demonstration that routine
hemostasis tests fail to reflect the bleeding tendency in cirrhosis,
with their poor capacity to predict the onset and severity of bleeding
from esophageal varices, after liver biopsy, and at the time of major
operations such as transplantation. In addition, more recent findings
show unequivocally that the aforementioned laboratory alterations
consistent with an impaired hemostasis are indeed accompanied by
opposing prothrombotic alterations (Table 3).22-24 With regard to
primary hemostasis, thrombocytopenia and thrombocytopathy are
paralleled by a marked increase of plasma VWF, the main platelet-
vessel wall adhesive protein.25 In vitro experiments carried out
under flow conditions that mimic those occurring in vivo demon-
strated that due to high plasma VWF, platelet adhesion to the vessel
wall is normal or even increased in cirrhosis notwithstanding the
presence of thrombocytopenia and platelet function abnormalities.25
Pertaining to blood coagulation, low procoagulant factors are
rebalanced by the concomitant decrease of naturally occurring
anticoagulants in plasma.26 An additional important contribution to
coagulation rebalance is provided by the increase of factor VIII in
plasma.26 Similarly, laboratory changes consistent with hyperfibrin-
olysis tend to be compensated for by antifibrinolytic abnormalities
(Table 3).27 That the concomitant alterations of both prohemostatic
and antihemostatic components in cirrhosis ultimately result in a
restored balance22-24 is unequivocally demonstrated by global tests
such as thrombin generation assays,26,28 which explore both the pro-
and anticoagulant components at the same time. However, these
global tests are not yet standardized, validated, or used widely
enough in the clinical context, making it still premature to propose
them as routine alternatives to the clearly inadequate traditional
tests (prothrombin and partial thromboplastin time).29-31
Therapeutic control of bleeding in cirrhosis
Fresh-frozen plasma is often used to prevent bleeding during liver
biopsy or other potentially hemorrhagic invasive procedures in
patients presenting with a prolonged prothrombin and/or partial
thromboplastin time. Plasma is also used when patients bleed
acutely from esophageal varices, despite no evidence of its efficacy
from randomized clinical trials. The use of plasma is still a common
practice despite the guidelines of the American Association for the
Study of Liver Disease32 and in vitro studies showing that plasma
shortens the prothrombin time but does not affect the amount of
thrombin formed.33 Against the use of plasma stands not only
current knowledge that the abnormalities of standard coagulation
tests do not reflect the bleeding tendency in liver disease,29-31 but
also that plasma may contribute through volume expansion to
increase portal vein hypertension, aggravate decompensation, and
increase the risk of bleeding and rebleeding from esophageal
varices.
170
Prohemostatic abnormalities
High VWF, low ADAMTS-13 (the VWF-cleaving
protease)
High factor VIII, low anticoagulants (antithrombin, protein
C, protein S, tissue factor pathway inhibitor)
Low plasminogen, high plasminogen activator inhibitor
Platelet concentrates are used in the attempt to increase the low
platelet count of cirrhosis patients, even though it is unclear which
count threshold triggers the need for concentrate transfusion. Most
clinicians set this threshold to at least 50 109/L and optimally at
100 109/L, but there are limited laboratory28 and clinical data34
providing evidence that these are the critical values. Neither is it
known which dose of platelet should be transfused; the most
commonly used regimen is one standard adult concentrate (corre-
sponding to approximately 300 33 109 platelets). According to
our clinical experience, this regimen barely increases the platelet
count and fails to ensure the normalization of such global hemosta-
sis tests as thrombin generation and thromboelastography, perhaps
because most transfused platelets are trapped in the spleen and liver.
Preliminary results indicate that the thrombopoietin receptor agonist
eltrombopag increases platelet counts in cirrhosis more markedly
than transfusion, but the study of this drug was interrupted due the
occurrence of thrombotic complications.35
Recombinant activated factor VII (rFVIIa), originally developed
and licensed for the treatment of bleeding in hemophilia A
complicated by alloantibodies inhibiting factor VIII, was also used
off-label for its capacity to generate a strong thrombin burst at the
site of bleeding in clinical conditions such as variceal bleeding and
major surgical operations such as hepatectomy and liver transplanta-
tion. The majority of studies carried out in these settings are
negative with regard to the effect of rFVIIa on clinically relevant
outcomes (ie, arrest of bleeding, reduction of rebleeding, and
mortality),36 with the exception of a modest reduction of transfusion
need and hematocrit loss in liver transplantation.37 Accordingly, the
use of rFVIIa is not recommended as an adjunctive hemostatic
treatment for variceal bleeding, nor for bleeding prophylaxis in
patients undergoing liver biopsy, transplantation, or resection.38,39
Concentrates of vitamin K dependent factors (also called prothrom-
bin complex concentrates) had been used in patients with advanced
liver disease when our current knowledge on the poor clinical
relationship between bleeding and coagulation factor deficiencies
was not available.3 Indeed, these plasma-derived products shorten
or fully correct the prolonged coagulation tests and factor deficien-
cies,3 but their clinical effect on actual bleeding is not substantiated,
and the risk of thrombosis is significant with them and rFVIIa.
Among the antifibrinolytic drugs, a potential candidate is tranexamic
acid, which, given orally or IV, blocks the binding to fibrin of
plasminogen and thus the activation of this fibrinolysis proenzyme
to the enzyme plasmin. According to a Cochrane meta-analysis, this
medication is not effective in the management of acute variceal
bleeding as an adjuvant along with endoscopic therapy and such
drugs as cimetidine and protein pump inhibitors.40 In patients
undergoing orthotopic liver transplantation, tranexamic acid re-
duces to a small degree blood loss and transfusion requirements,41,42
but the overall clinical benefit is generally trivial because the
American Society of Hematology
marked improvement of surgical and anesthesiological methods has
dramatically reduced the need for transfusion during this operation.
Transfusional and nontransfusional hemostatic medications have an
uncertain role in the prevention and treatment of bleeding in an
array of clinical settings associated with end-stage liver disease.
This is not surprising, given the current knowledge that bleeding is
not caused mainly by hemostasis defects, but rather by hemody-
namic alterations of portal hypertension, endothelial dysfunction,
bacterial infections, and renal failure. Therefore, we find it unneces-
sary to provide specific recommendations on how to manage actual
bleeding by hemostatic medication in cirrhosis as we have done
with Table 2, which describes recommendations for uremic bleed-
ing. This negative recommendation is supported by a review article
on handling variceal bleeding, which does not mention any hemo-
static medications,43 whereas specific recommendations are given
on therapeutic approaches based upon vasoconstrictors, antibiotics,
and endoscopic therapy.43
Thrombotic complications in liver and renal disease
Whereas it is known that liver and renal diseases are associated with
a bleeding diathesis, it is less understood that they both share a
thrombotic tendency, that with the aging of the population, is likely
to become more and more clinically relevant. Clinicians tend to
think that because of the prolongation of standard coagulation tests,
patients with chronic liver disease are naturally anticoagulated and
protected from thrombosis. A recent population-based study has
indeed shown that the risk of venous thromboembolism is 2-fold
higher in patients with liver disease than in controls.44 The
corresponding clinical manifestations are not only portal-vein
thrombosis (which has a frequency as high as 8%-25% in patients
with advanced disease who are candidates for liver transplanta-
tion45), but also peripheral vein thrombosis and pulmonary
embolism.44 The occurrence of thrombotic complications in
cirrhosis is consistent with recent findings that these patients
have a procoagulant imbalance related to the impairment of the
thrombomodulin/protein C anticoagulant pathway combined
with very high plasma levels of factor VIII.46 Accordingly,
anticoagulant drugs should be used in patients with liver disease
who develop venous thromboembolism notwithstanding the
widespread belief that these drugs are contraindicated in patients
with severe liver disease. Similarly, patients with cirrhosis are not
protected from clinical manifestations of atherothrombosis (ie,
coronary artery disease and ischemic stroke),47 even though it is
unknown whether they are at higher risk than people with no liver
disease. When atherothrombotic complications occur, antiplatelet
agents should be considered for secondary prophylaxis, even though
in patients with more severe thrombocytopenia ( 50 109/liter),
the risk of bleeding is not trivial.
Chronic kidney disease, even in its early clinical stages, increases by
25%-30% the risk for premature atherothrombotic manifestations of
cardiovascular diseases,48,49 which are in turn the most frequent
clinical outcome in patients with end-stage disease on dialysis,
accounting for approximately 40% of all deaths.50,51 Mechanistic
links between cardiovascular and renal diseases are the high
prevalence of shared risk factors (Table 4). Despite increasing
awareness that patients with chronic renal disease are at very high
risk for incident cardiovascular events, there is a paucity of clinical
trials evaluating whether the adoption of prophylactic and therapeu-
tic measures of consolidated efficacy in patients with cardiovascular
disease without renal dysfunction are also useful in chronic renal
disease. For example, a systematic review and meta-analysis on the
Hematology 2012
Table 4. Thrombosis risk factors shared by cardiovascular and
chronic renal diseases
Old age
Hypertension
Arterial calcifications
Endothelial dysfunction
Obesity
Inflammation
Hemostasis abnormalities
High fibrinogen, factor VIII, and VWF
Low ADAMTS13 (the VWF-cleaving protease)
effect of antiplatelet agents in patients with chronic kidney disease
found that these drugs have uncertain effects on reducing mortality,
but induce a definite increase of bleeding complications.52 It is
important to intervene in these patients with medications and
lifestyle changes to control risk factors for atherothrombosis, such
as high blood pressure, serum LDL cholesterol, body mass index,
and prothrombotic stimuli.53
Conclusions
The association between end-stage kidney and liver disease and a
bleeding tendency has been demonstrated. The pathogenesis of
bleeding in these common diseases is complex and multifactorial
and the hemorrhagic tendency, particularly in cirrhosis, is not
explained by the multiple abnormalities revealed by hemostasis
tests. Anemia in patients with uremia and portal hypertension with
related hemodynamic alterations in those patients with cirrhosis are
much more critical than hemostasis defects in causing the bleeding
tendency. Accordingly, medications that potentiate hemostasis have
a limited role in the prevention and treatment of bleeding. Despite
the bleeding tendency, hypercoagulability and the frequent concomi-
tant presence of atherothrombosis risk factors predispose these
patients to thrombotic complications. Antithrombotic prophylaxis
and treatment should be implemented as needed in these patients,
but the risk of increasing the hemorrhagic diathesis demands careful
evaluation of the balance between benefits and risks in each patient.
Disclosures
Conflict-of-interest disclosure: P.M.M. has been affiliated with the
speakers bureau for Novo Nordisk. A.T. declares no competing
financial interests. Off-label drug use: NovoSeven (rFVIIa).
Correspondence
P. M. Mannucci, Via Pace 9, 20122 Milano, Italy; Phone: 39-02-
55035421, extension 8377; Fax: 39-02-50320723; e-mail:
pmmannucci@libero.it.
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