JCM 10 01530 v2
JCM 10 01530 v2
JCM 10 01530 v2
Clinical Medicine
Review
Thrombocytopenia and Hemostatic Changes in Acute
and Chronic Liver Disease: Pathophysiology, Clinical
and Laboratory Features, and Management
Rüdiger E. Scharf 1,2
1 Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School,
Boston, MA 02115, USA
2 Division of Experimental and Clinical Hemostasis, Hemotherapy, and Transfusion Medicine, Blood and
Hemophilia Comprehensive Care Center, Institute of Transplantation Diagnostics and Cell Therapy,
Heinrich Heine University Medical Center, D-40225 Düsseldorf, Germany; rscharf@uni-duesseldorf.de
Abstract: Thrombocytopenia, defined as a platelet count <150,000/µL, is the most common compli-
cation of advanced liver disease or cirrhosis with an incidence of up to 75%. A decrease in platelet
count can be the first presenting sign and tends to be proportionally related to the severity of hepatic
failure. The pathophysiology of thrombocytopenia in liver disease is multifactorial, including (i)
splenomegaly and subsequently increased splenic sequestration of circulating platelets, (ii) reduced
hepatic synthesis of thrombopoietin with missing stimulation both of megakaryocytopoiesis and
thrombocytopoiesis, resulting in diminished platelet production and release from the bone marrow,
and (iii) increased platelet destruction or consumption. Among these pathologies, the decrease in
thrombopoietin synthesis has been identified as a central mechanism. Two newly licensed oral throm-
bopoietin mimetics/receptor agonists, avatrombopag and lusutrombopag, are now available for
Citation: Scharf, R.E.
targeted treatment of thrombocytopenia in patients with advanced liver disease, who are undergoing
Thrombocytopenia and Hemostatic
invasive procedures. This review summarizes recent advances in the understanding of defective
Changes in Acute and Chronic Liver
but at low level rebalanced hemostasis in stable cirrhosis, discusses clinical consequences and per-
Disease: Pathophysiology, Clinical
sistent controversial issues related to the inherent bleeding risk, and is focused on a risk-adapted
and Laboratory Features, and
Management. J. Clin. Med. 2021, 10,
management of thrombocytopenia in patients with chronic liver disease, including a restrictive
1530. https://doi.org/10.3390/ transfusion regimen.
jcm10071530
Keywords: advanced liver disease; bleeding risk; cirrhosis; hemostasis; thrombocytopenia; throm-
Academic Editor: Hugo ten Cate bopoietin receptor agonists/mimetics
2. Incidence of Thrombocytopenia
An analysis by the Acute Liver Failure Study Group, enrolling 1600 patients, docu-
mented that the median platelet count on admission was approximately 130,000/µL; 60%
of patients had platelets counts <150,000/µL, 35% <100,000/µL, and 10% <50,000/µL [1].
Despite a perceived hemorrhagic diathesis, clinically significant bleeding is rather uncom-
mon in acute liver disease. This observation is confirmed by a recent analysis on adult
1770 patients with acute liver failure by a Dutch Study Group [2]. Despite a median INR
of 2.7 and platelet count of 96,000/µL on admission, hemorrhagic complications occurred
in only 187 patients (11%), including 173 spontaneous and 22 postprocedural bleeding
events. However, 20 subjects among this patient cohort experienced an intracranial hem-
orrhage [2]. Progressive thrombocytopenia in acute liver disease can be an indicator of
impending multi-organ failure, as documented in a retrospective study [3]. Specifically,
an early decrease in platelets (during days 1 to 7 after admission) was proportional to the
grade of hepatic encephalopathy, requirement for treatment with vasopressor agents, and
kidney replacement therapy [3].
In patients with advanced fibrosis or liver cirrhosis, the prevalence of thrombocy-
topenia ranges between 15 and 75% [4–6]. A progressive decrease in platelet count is
considered as a noninvasive indicator for the development of portal hypertension due to
severe liver fibrosis or cirrhosis [7]. Overall, the degree of thrombocytopenia appears to be
proportionally related to the severity of liver disease but is not associated with spontaneous
bleeding, unless platelets counts decrease to <50,000–60,000/µL [8–13].
4. Pathophysiology
Thrombocytopenia in liver disease results from increased splenic sequestration due to
portal hypertension and subsequent hypersplenism [7,8,13,16], decreased thrombopoietin
(TPO) production [6,17–19], and/or from toxic or virus-induced suppression of megakary-
ocytopoiesis [6,19–21]. In the past, low platelet counts in liver disease were mainly at-
tributed to splenic pooling and/or consumption. By contrast, autoantibody-mediated
platelet destruction is of minor importance in most cases with chronic liver disease, but
may be relevant in hepatitis C-induced cirrhosis [6]. In these patients, antiplatelet anti-
bodies are detectable, often at high levels [22]. More recently, the impact of abnormal
rheological conditions, resulting from enhanced portal pressure, is also discussed as an
additional mechanism of increased platelet destruction in chronic liver disease [19]. It is
hypothesized that platelets, upon exposure to high shear stress and subsequent activation,
are rapidly eliminated from the circulation, thereby potentiating thrombocytopenia. How-
ever, this contention is distinct from established high-shear conditions resulting in bleeding
complications due to loss of high-molecular-weight von Willebrand factor [23].
During the past decades, detailed exploration of the association between hepatic
synthesis of TPO and residual hepatic function allowed a more specific insight into the
pathophysiology of thrombocytopenia in liver disease. In fact, TPO levels are near-normal
or even increased in acute hepatic disease [18]. This is in contrast to patients with chronic
liver disease, in whom TPO serum levels are significantly decreased and therefore thought
to be a central pathomechanism to thrombocytopenia in cirrhosis [6,24]. TPO is pre-
J. Clin. Med. 2021, 10, 1530 3 of 17
Figure 1. The concept of rebalanced hemostasis in patients with liver disease. In healthy subjects (A), hemostasis is in stable
equilibrium. In patients with liver disease (B), concomitant changes in pro- and antihemostatic components and pathways
result in rebalance of the hemostatic apparatus despite the quantitative and qualitative disease-related defects, affecting
platelets (primary hemostasis), coagulation (secondary hemostasis), and fibrinolysis. Thus, hemostasis is rebalanced at low
level, but the equilibrium now is extremely labile. In patients with decompensated liver disease (C) and comorbidities,
various stimuli can lead to destabilization and tip the balance toward either bleeding or thrombosis [29]. Modification
of a scheme, taken from Eby and Caldwell [31]. Abbreviations: α2 -AP, α2 -antiplasmin; Antithromb, antithrombin; DIC,
disseminated intravascular coagulation; DVT, deep vein thrombosis; F, factor; PAI-1, plasminogen activator inhibitor-1;
PE, pulmonary embolism; Plt’let, platelet; TAFI, thrombin activatable fibrinolysis inhibitor; t-PA, tissue-type plasminogen
activator; VWF, von Willebrand factor.
J. Clin. Med. 2021, 10, 1530 4 of 17
are at risk for bleeding complications. This is illustrated by a high in-hospital mortality rate
of approximately 15% for each episode of acute gastrointestinal hemorrhage, and variceal
bleeding is the cause of death for approximately 6% of patients with liver cirrhosis [31].
Predictors of a first upper gastrointestinal bleeding in cirrhotic patients include presence of
varices, elevated variceal pressure, and laboratory evidence of decreased hepatocellular
synthesis (with or without manifest coagulopathy), and thrombocytopenia.
Moderate or severe bleeding complications reported after percutaneous liver biopsy
are consistently low with rates of 0.5 to 0.7% in large contemporary series [31,44]. However,
these findings should be considered with caution since most of the data from these studies
are derived from patients in relatively stable or compensated condition of advanced liver
disease. This is also true for attempts to correlate hemostasis test results with clinical
outcome or prediction of bleeding in the setting of invasive procedures.
Drugs represent the most common cause of acquired platelet dysfunction in our
overmedicated society. Apart from typical antiplatelet agents such as aspirin, adenosine
diphosphate receptor antagonists, and integrin αIIbβ3 (GPIIb-IIIa) receptor blockers, other
widely used agents, including non-steroidal anti-inflammatory drugs, antibiotics, cardio-
vascular and lipid-lowering drugs, selective serotonin reuptake inhibitors, and a plethora
of miscellaneous agents, diets, and food additives or spices can affect platelet function and
cause or aggravate a hemorrhagic diathesis [42].
8.1.1. Thromboelastography
TEG allows to dissect the kinetic conversion of fibrinogen into fibrin, the dynamics
of fibrin- and platelet-driven clot formation, and the assessment of clot strength and clot
stability. TEG can also be helpful for detecting abnormal fibrinolysis.
TEG is now widely used in patients with acute and chronic liver disease, specifically
in subjects undergoing liver transplantation to guide replacement therapy with hemo-
static factor concentrates (during the pre-anhepatic and anhepatic phases) and to monitor
treatment of hyperfibrinolysis. However, neither the TEG method nor the hemotherapeu-
tic consequences for correction of TEG parameters are consistently standardized across
transplantation centers [45].
Interestingly, patients with cirrhosis secondary to cholestatic liver disease such as
primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) have been found to
be hypercoagulable by TEG when compared to patients with noncholestatic entities [46,47].
This difference may be due to higher levels of fibrinogen and a still intact platelet function
in the cholestatic stetting despite similar degrees of portal hypertension in the different
J. Clin. Med. 2021, 10, 1530 6 of 17
patient populations [48]. Taken together, these observations may explain the lower rates of
bleeding complications and fewer transfusion needs during liver transplantation in patients
with PBC or PSC than in those with end-stage liver disease of other etiology. Moreover,
several studies have demonstrated that TEG parameters indicative of hypocoagulation
and/or thrombocytopenia are associated with liver disease severity and outcomes [49–51].
9.4.1. Avatrombopag
In two seminal, identically designed, double-blind, randomized, placebo-controlled
phase-3 trials, ADAPT-1 and ADAPT-2, avatrombopag was demonstrated to be superior to
placebo in reducing the need for platelet transfusions or any rescue therapy for bleeding
in 435 patients with thrombocytopenia and chronic liver disease undergoing a scheduled
invasive procedure [82]. In both studies, patients were stratified into two groups based on
lower (<40,000/µL) or higher (>40,000/µL to <50,000/µL) baseline platelet count levels.
The efficacy of avatrombopag was documented in both cohorts with a significantly greater
proportion in drug-treated than in corresponding placebo groups (Table 1). Upon ad-
ministration of the TPO receptor agonist (40 or 60 mg daily for 5 days), platelet counts
increased with a peak effect between days 10 and 13 and returned to baseline levels by day
35 [82]. The overall safety profile was similar for avatrombopag and placebo, except for
hyponatremia reported as the most serious adverse effect.
Table 1. Efficacy of second-generation TPO receptor agonists for the treatment of thrombocytopenia in patients with chronic
liver disease scheduled for invasive procedures. Synopsis of results from four multicentric, randomized, double-blind,
placebo-controlled phase-3 trials [82–84].
9.4.2. Lusutrombopag
Efficacy and safety of lusutrombopag were assessed in two randomized, double-
blind, placebo-controlled trails, L-PLUS-1 and L-PLUS-2, enrolling 96 and 215 cirrhotic
patients undergoing invasive interventions, respectively [83,84]. Key endpoints of the
studies were avoidance of preprocedure platelet transfusions (L-PLUS-1 and -2), avoidance
of rescue therapy for bleeding (L-PLUS-2), and number of days with platelet counts
>50,000/µL (L-PLUS-2). Both trials showed that lusutrombopag (3 mg once daily for up to
7 days) was effective in achieving and maintaining the target platelet count in patients with
thrombocytopenia (<50,000/µL) and chronic liver disease (Table 1). The median time to
reach peak levels in platelet counts was 12 days, and the median duration of platelet levels
over the threshold lasted 19 days [84]. No significant safety concerns were raised in both
J. Clin. Med. 2021, 10, 1530 9 of 17
trials. The most common adverse effect of lusutrombopag was headache, while the most
common serious adverse event was portal-vein thrombosis [84]. However, the number of
thrombotic complications did not differ between drug- and placebo-treated patients (two
in each group).
Figure 2. Proposed management of mild, moderate, and severe thrombocytopenia in patients with chronic liver disease.
Displayed is the compilation of a treatment algorithm, originally designed by Gangireddy et al. [85] and subsequently
adapted by Saab and Brown [25]. In this modification, administration of plasma products (e.g., fibrinogen concentrate,
activated factor VII, prothrombin complex concentrate) as rescue therapy for active bleeding is omitted for clarity. To confirm
no need for treatment, patients with mild thrombocytopenia should have periodic re-examination including complete blood
screening. Of note, for moderate and severe thrombocytopenia, the use of TPO receptor agonists is now considered as
first-choice treatment option, whereas platelet transfusions are restricted to major surgery and control of active hemorrhage.
The star indicates that, upon platelet transfusion, a target platelet count >100,000/µL is aimed at. Abbreviations: CBC,
complete blood cell count; DIC, disseminated intravascular coagulation; LFT, liver function testing; PSE, partial splenic
embolization; TCP, thrombocytopenia; TPO, thrombopoietin.
9.4.4. Thrombotic Risk in Chronic Liver Disease Patients upon Treatment with TPO
Receptor Agonists
Thrombotic events are a key safety concern with the use of either platelet transfusions
or the administration of TPO receptor agonist to raise platelet counts in cirrhotic patients
with severe thrombocytopenia. For example, a phase-3 trial using eltrombopag in this
condition prior to invasive procedures was prematurely terminated because of an increased
rate of thrombotic complications [27]. However, by contrast to subsequent trials evaluat-
ing second-generation TPO receptor agonists in chronic liver disease, eltrombopag was
assessed by the ELEVATE (Eltrombopag Evaluated for its Ability to Overcome Thrombocy-
topenia and Enable Procedures) study group without abdominal imaging for splanchnic
thrombosis at baseline. Thus, it is possible that some of the patients had a subclinical
portal-vein thrombosis at study entry [27].
Several recent reviews and meta-analyses of studies (including more than 2200 pa-
tients in total) that compared the effect of three TPO receptor agonists (eltrombopag,
avatrombopag, and lusutrombopag) and placebo in patients with chronic liver disease and
thrombocytopenia reported on a trend toward increased risk of portal-vein thrombosis
upon preprocedural treatment with the TPO receptor agonist (1.6% overall for the drugs
vs. 0.6% for placebo) [25,86–88]. However, this difference was not statistically significant.
Interestingly, a significant association between portal-vein thrombosis and TPO receptor
agonist was shown for eltrombopag alone but not with avatrombopag or lusutrombopag
treatments. In accord with these results, Michelson et al., reported that avatrombopag
leads to an approximately two-fold increase in platelet counts but not in platelet activation
among thrombocytopenic patients with liver disease [89].
Another analysis reviewed the number of arterial and venous thromboembolic events
in more than 1700 patients treated with either eltrombopag or placebo in the preprocedural
setting and identified a significantly higher rate of thromboembolic events in patients
treated with eltrombopag (3.6%) than in those with placebo (1.1%) [25]. Overall, there are
differences among oral TPO receptor agonists regarding their thrombotic potential, with
eltrombopag carrying a significant thrombotic risk. However, this conclusion is questioned
by others due to the fact that eltrombopag, as discussed above, was studied in the ELEVATE
trial without appropriate pre-screening for portal-vein thrombosis [90].
10.2. Additional Options for Supportive Hemotherapy to Bleeding Patients with Liver Disease
In accord with the “low-volume” concept but by contrast to common practice, a restric-
tive transfusion regimen is required in patients with liver disease to avoid prohemostatic
hemotherapy and treatment-induced thrombotic complications or alloimmunization with
resulting platelet refractoriness. Consequently, recent UK and US guidelines strongly
recommend that blood products should be used sparingly in patients with acute or chronic
liver disease [61,71].
Apart from the hemotherapy-induced increase of portal pressure, the risk of transfusion-
associated circulatory overload, transfusion-related acute lung injury (TRALI), transmission
of pathogens, alloimmunization, and/or transfusion reactions are major concerns. For man-
agement of active bleeding or high-risk invasive procedures the following transfusion
thresholds are currently recommended to improve hemostasis in advanced liver disease:
hematocrit >25%, platelet count >50,000/µL, and fibrinogen >120 mg/dL [61]. Of note,
previously used thresholds for correction of the INR are no longer recommended since
target reductions of INR are not supported by evidence.
10.3.3. Antifibrinolytics
Antifibrinolytics may be useful when cirrhosis-associated hyperfibrinolysis is sus-
pected or proven. Two agents are available, ε-aminocaproic acid (EACA) and tranexamic
acid (TA), both of which abrogate binding of plasminogen or plasmin to fibrin, thus in-
hibiting fibrinolysis. There are only small series of patients and a number of case reports,
demonstrating the efficacy and safety of EACA or TA in liver failure and advanced cirrho-
sis [102,103]. A systematic review and meta-analysis of more than 20 randomized controlled
trials (with a total of 1400 patients) documented a reduction in RBC transfusions during
liver transplantation when comparing TA to placebo, while the efficacy of EACA remained
unproven in this setting (due an unpowered study) [104]. Importantly, this meta-analysis
did not provide evidence for an increased risk of thromboembolic events associated with
antifibrinolytic treatment in liver transplantation [104]. Overall, antifibrinolytic agents
appear to be safe and well tolerated in cirrhotic patients [31].
J. Clin. Med. 2021, 10, 1530 13 of 17
11. Conclusions
Hemostatic dysfunction in acute and chronic liver disease and novel therapeutic
options to control thrombocytopenia are a prime example for the significant progress
that has been made in recent years. According to traditional paradigms, liver cirrhosis
was considered as the epitome of an acquired coagulopathy that in combination with
thrombocytopenia and/or thrombopathy causes hemorrhagic complications. Based on
recent findings, this contention has been revised fundamentally in several aspects.
Firstly, patients with liver failure are also prone to thrombotic events, which may
be even more common than bleeding complications, except for end-stage liver disease.
Secondly, the commensurate decrease in pro- and antihemostatic components can lead
to a rebalanced low-level hemostatic equilibrium. The rebalanced hemostatic system is,
however, labile and can be destabilized by various triggers, which in turn may explain
the occurrence of both bleeding and thrombotic complications. Thirdly, thrombocytopenia
in liver cirrhosis results from multifaceted causes; apart from splenic pooling, decreased
production of TPO plays a major role, as documented by the correlation between TPO
levels and residual hepatic function. Fourthly, defective platelet function as a concomitant
cause of bleeding events in hepatic failure has been overestimated in the past. However,
drug-induced platelet inhibition remains an ongoing concern in this setting. Fifthly, high
levels of plasma von Willebrand factor can restore platelet-vessel wall interaction and
thus rebalance primary hemostasis that may be compromised otherwise in chronic hepatic
disease. Sixthly, rebalanced hemostasis and, all the more, hypercoagulable features in
liver disease have a major impact on the prevention and management of both bleeding
and thrombosis.
This, however, is a challenging demand, which remains difficult to accompl in clinical
practice. Most of routinely available hemostasis screening tests are inconclusive and
without predictive validity in patients with liver disease, and comprehensive hemostasis
profiles have to be restricted in this population to those undergoing high-risk invasive
procedures such as major surgery.
Currently, the platelet threshold required for thrombocytopenic patients, who are
scheduled for higher-risk interventions, is rather “defined” empirically but not based
on study data of appropriate quality. However, recent advances are likely to solve this
issue: the two newly licensed TPO receptor agonists, avatrombopag and lusutrombopag,
were shown to be safe and efficacious at increasing platelet levels and avoiding platelet
transfusions for invasive procedures in patients with thrombocytopenia and chronic liver
disease. It can be expected that both agents will evolve to be the new standard of care for
managing thrombocytopenia in patients with chronic liver disease.
Funding: Work from the author’s laboratory that is cited here was supported by grants from the
Deutsche Forschungsgemeinschaft (Scha 358/3-1; Collaborative Research Center, SFB612). Funding
of the author’s research at Boston Children’s Hospital by a grant from the Society of Thrombosis and
Hemostasis Research (GTH) is also acknowledged.
Acknowledgments: The author is grateful to Dieter Häussinger, Düsseldorf, for stimulating discus-
sion and careful review of the manuscript.
Conflicts of Interest: The author declares no conflict of interest.
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