Pathobiology and Treatment of Hepatitis Virus-Related
Roberto Stasi, Lian Wea Chia, Pallavi Kalkur, Robert Lowe and Muriel S.
Department of Haematology, St George’s Hospital, London, UK
Dr. Roberto Stasi, Department of Haematology, St George's
Hospital, Blackshaw Road, SW17 0QT, London, United Kingdom. Telephone:
+44 208 725 1172; Fax: +44 208 725 2859. E-mail: email@example.com
Published: November 25, 2009
Received: September 10, 2009
Accepted: September 25, 2009
Medit J Hemat Infect Dis 2009, 1(3): e2009023 DOI 10.4084/MJHID.2009.023
This article is available from: http://www.mjhid.org/article/view/5119
This is an Open Access article
distributed under the terms of the
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is a well recognized complication of infections, including those from
hepatotropic viruses. Thrombocytopenia may actually be the only
manifestation of vital hepatitis, which should therefore be considered
in the differential diagnosis of primary immune thrombocytopenia (ITP).
The mechanisms of thrombocytopenia associated with viral hepatitis vary
widely depending on the specific infectious agent and the severity of
liver disease. Most of the studies have described thrombocytopenia in
association with chronic hepatitis C virus (HCV) infection, the most
common cause of chronic infection worldwide. Studies have shown that
treatment of HCV infection often results in substantial improvement or
complete recovery of the thrombocytopenia. In patients with
thrombocytopenia associated with HCV-related chronic liver disease, the
use of eltrombopag, a thrombopoietin receptor agonist, normalizes
platelet levels thereby permitting the initiation of antiviral therapy.
either alone or in combination with other hematologic abnormalities, is
commonly associated with infectious diseases 
However, only a few
studies have specifically investigated this condition in patients with
viral hepatitis 
The onset of the thrombocytopenia is rarely abrupt and severe during
acute viral hepatitis A (HAV)[2-5]
, B (HBV)[5-7]
and E (HEV)[9-11]
This appears to have a course similar to that of the thrombocytopenia
associated with self-limiting infections in children, such as
varicella, rubella, or mumps 
. It is, at least in
part, mediated by
immune complexes and generally resolves spontaneously within 2 to 8
weeks. In occasional individuals it may persist for months before
remitting. Virus-associated hemophagocytic syndrome has been reported
in several cases of HAV infection [8-11]
, and rarely
in association with
HBV and HCV infections [12-14]
On the other hand, persistent thrombo-cytopenia is more typically
associated with chronic infection from HBV or HCV. Despite chronic HBV
infection is still highly endemic in areas such as South East Asia and
, there is a paucity of data about HBV
and thrombocytopenia. In
one study in treatment-na´ve patients with chronic hepatitis B,
thrombocytopenia (defined as a platelet counts below 150 x 109/l) was
observed in 17.7% of 219 patients with chronic active hepatitis B and
10.6% of 123 HBV inactive carriers 
of HBV infection with
interferon-alpha (IFN-alpha) is also frequently complicated with
thrombo-cytopenia, which in some series has been described in over 60%
of cases 
However, most of the recent literature pertaining to thrombocytopenia
is about chronic hepatitis C, which will be the focus of our review.
Natural History of HCV Infection.
HCV is now recognized as the most common viral infection causing
chronic liver disease in humans. The 3rd National Health and Nutrition
Examination Survey (NHANES III) estimated that nearly 3.2 million
persons in the general population of the United States are infected
with HCV 
. Worldwide, an estimated 145 million
individuals (2.2% of
the world’s population) are infected 
infection evolves towards a
chronic state in approximately 85% of patients as demonstrated by the
persistence of HCV-RNA in serum 
severe and long-term
complications of chronic HCV infection such as liver cirrhosis,
end-stage liver disease, and hepatocellular carcinoma develop only in a
proportion of infected patients, after a period that can exceed 10 to
20 years 
. Chronic HCV infection has also been
reported to be
associated with the development of several extrahepatic alterations,
including thrombo-cytopenia 
summarizes the results on the prevalence of HCV infection from several
cross-sectional studies in adult patients fulfilling the diagnostic
criteria for immune thrombocytopenia (ITP) of the American Society of
Hematology (ASH) 
. Altogether, serologic
evidence of HCV infection was
found in 159 of 799 (20%) cases. The major series published to date
evaluated 250 patients 
. A positive serology was
found in 76 (30%) of
While retrospective studies [24,25]
suggest that the
prevalence of ITP
among HCV patients is greater than would be expected by chance, the
prevalence of HCV-positive ITP patients in some cohorts may be
indirectly related to the background prevalence of HCV infection
reported in the general populations [23,26-28]
Chiao et al calculated the
incidence rate of ITP among 120,691 HCV-infected and 454,905 matched
HCV-uninfected US veterans who received diagnoses during the period
1997 to 2004 
. Their results indicate that HCV
infection is actually
associated with an elevated risk of developing ITP (HR, 1.8; 95% CI,
1.4-2.3) among both untreated and treated patients. Pockros et al
retrospectively identified 7 ITP cases among 3440 new HCV patients seen
over a 56-month period 
. They estimated that the
prevalence of CITP
among their HCV patients was much greater than would be expected by
chance (P < .00001). Even in the presence of active liver disease,
patients with HCV infection present with lower platelet counts when
compared with patients with HBV or alcoholic liver disease [23,25]
Thrombocytopenia either pre-exists and prevents the initiation of
treatment with pegylated interferon (PEG-IFN) or develops as a
consequence of PEG-IFN treatment, leading to dose modification in 19%
of cases and discontinuation in 2% of cases 
cirrhosis, thrombocytopenia complicates antiviral treatment much more
frequently than in patients with HCV infection without cirrhosis 
A variety of pathogenic mechanisms are reported to be implicated in
thrombocytopenia related to chronic HCV infection. These include: 1)
sequestration of platelets in the enlarged spleen secondary to portal
hypertension (hyper-splenism); 2) reduced hepatic production of
thrombopoietin; 3) bone marrow suppression by HCV or antiviral
treatment; and 4) increased platelet destruction mediated by immune
mechanisms involving anti-platelet autoantibodies and
platelet-associated immune complexes.
is a common finding in patients with advanced liver disease (especially
cirrhotic patients), who develop portal hypertension ultimately
resulting in an enlarged spleen and subsequent platelet sequestration.
The increased portal pressure causes redistribution of blood to the
spleen, subsequent pooling of platelets, and the increased clearance of
platelets from the circulation . There is an
between spleen size and platelet count in patients with chronic liver
disease, the vast majority of whom have HCV infection [33,34].
splenic platelet pooling does not fully account for the occurrence of
thrombocytopenia in chronic liver disease. In fact, approximately one
third of patients with splenomegaly have normal platelet counts ,
hypersplenism is not a consistent finding in patients with HCV-positive
patients with thrombocytopenia [26,35],
spleen volume and platelet count
have not been closely correlated in cirrhotic patients with end-stage
liver disease and thrombocytopenia , and
thrombocytopenia has been
shown to persist after surgical portal decompression in cirrhotic
hepatic production of the thrombopoietin (TPO) may be one of the
contributing causes of thrombocytopenia during chronic liver diseases.
TPO, the growth factor that primarily regulates megakaryocyte
maturation and platelet formation, is produced mainly by hepatocytes,
and is normally released at a constant rate into the circulation .
Circulating TPO binds to the TPO receptor (also referred to as c-Mpl)
on hematopoietic stem cells and on megakaryocytes, and promotes all
stages of platelet production, from early megakaryocyte proliferation
to mega-karyocytic maturation and platelet formation. TPO also binds to
platelets and enhances platelet activation and function. In turn,
platelets not only bind TPO, but also internalize and degrade TPO.
Thus, serum levels of TPO are normally regulated by the total platelet
mass, including platelets sequestered in the spleen, rather than by the
production rate of TPO . Under normal
conditions, if platelet
production decreases, the circulating platelet count subsequently
falls, less TPO is bound to platelets, and consequently the plasma TPO
concentration increases. As a result, megakaryocytopoiesis increases to
restore platelet homeostasis, resulting in more platelets produced and
released. Once the platelet count increases, excess TPO is bound by
circulating platelets, and TPO levels decrease to normal levels.
However, in patients with extensive liver cirrhosis and⁄or fibrosis and
subsequent reduction in functioning hepatocytes (clinically manifested
as severe impairment of liver function), production of TPO can be
reduced [34,40]. Studies have
demonstrated an inverse correlation between
serum TPO levels and liver fibrosis grade (r = 0.50; P < 0.0001),
with thrombocytopenia occurring with greater frequency and severity in
patients with grade 3 or 4 liver fibrosis than in those with grades 0–2
liver fibrosis [34,40]. A
correlation between low TPO serum level and
decreases in global liver function (r = 0.52; P = 0.01) has also been
demonstrated40. One study of thrombocytopenic patients with cirrhotic
liver disease demonstrated a reduction in platelet production in the
bone marrow in the presence of low blood TPO levels .
suggests that the bone marrow of such patients may produce fewer
platelets because of decreased TPO levels, resulting in
thrombocytopenia. Furthermore, after successful orthotopic liver
transplantation, when the dysfunctional liver is replaced by a
functioning organ, plasma TPO levels increase, followed by increased
platelet production and by an improvement in thrombocytopenia [36,42].
Increased degradation of TPO, mediated by the binding of TPO to
platelets sequestered in the enlarged spleen, may also contribute to
thrombocytopenia in patients with cirrhosis. Serum TPO levels and
platelet counts can increase significantly after partial splenic
embolization and the normal physiological relationship between TPO and
platelet count has been restored following this procedure .
levels in patients with chronic liver disease do not reflect TPO
production because of the complex interactions between TPO production,
TPO degradation, platelet turnover and thrombocytopenia. In this
patient population, serum TPO levels have been variously reported to be
low, normal or elevated, in the presence of thrombocytopenia, without
close correlation between TPO and platelet counts [43,44].
patients with high grade (grades 3–4) liver fibrosis have significantly
lower TPO levels than patients with less severe fibrosis (liver
fibrosis grades 0–2), reflecting decreased production of the TPO by the
damaged liver .
production of platelets secondary to HCV infection is thought to be a
contributing factor in the development of thrombocytopenia. In a study
using reticulated platelets in peripheral blood as a marker of
thrombopoiesis, patients with liver cirrhosis had low platelet
production . Also, the decrease in HCV viral
load following interferon
(IFN)-alpha treatment correlates with significant increases in platelet
count  in the absence of hypersplenism or
serological evidence of
platelet autoantibodies in some cases . Finally,
recent data on
short-term CFU-MK assays in patients with chronic hepatitis C showed an
evident depression in the number of colony-forming unit-megakaryocyte
(CFU-meg). The whole of these data suggest that HCV can directly affect
megakaryopoiesis.However, antiviral therapy is itself associated with
thrombocytopenia. IFN admin-istration can induce a rapid and sustained
reduction in peripheral platelet count. Peck-Radosavljevic and
colleagues demonstrated that the platelet count decreased by nearly 28%
in subjects treated with at least one dose of standard IFN and
pegylated interferon (PEG) . They also found
that despite a
corresponding increase in serum TPO levels, the reticulated platelet
count did not change or actually decreased among subjects continuously
exposed to PEG. These data indicate that bone marrow suppression,
rather than increased platelet consum-ption, is the primary mechanism
responsible for IFN-related thrombocytopenia. Interestingly, IFN-alpha
treatment may also suppress the production or secretion of TPO .
Concomitant ribavirin therapy appears to have a protective effect
against IFN-induced reductions in platelet count. In randomized
controlled trials of PEG with or without ribavirin (RBV), the median
decrease in platelet count was smaller among those receiving RBV
therapy compared with those receiving only PEG .
Overall, in such
trials, severe grade 4 thrombocytopenia (less than 20 x 109/l) was not
observed, and platelet counts less than 50 x 109/l rarely were
observed. Current guidelines therefore recommend the management of
mild-to-moderate thrombocytopenia with PEG dose reduction and the
discontinuation of HCV therapy in cases of severe thrombocytopenia,
which typically is seen only in the setting of cirrhosis.
there is a higher prevalence of thrombocytopenia and anti-platelet
antibodies in patients with liver disease caused by HCV than in
patients with hepatitis B infection , the
pathogenic significance of
anti-platelet antibodies is uncertain . Using a
antibody-specific immobilization of platelet antigen assay (MAIPA),
detectable platelet antibodies were found in 32 of 48 (66%)
HCV-infected individuals at various stages of disease .
common target was glycoprotein IIb/IIIa, but all other glycoproteins
were also targets. However, platelet autoantibodies lack specificity
and do not assist in the diagnosis of immune thrombocytopenia.
Recently, however, the pathogenetic role of platelet antibodies has
been supported by an elegant study showing that HCV core envelope
1 can induce thrombocytopenia by molecular mimicry with an epitope on
platelet surface integrin GPIIIa, GPIIIa49-6647.Other studies have
shown that HCV-RNA can be detected in washed platelets of infected
individuals, particularly if thrombocytopenic .
Furthermore, there is
a non-saturable binding of HCV to platelets .
High affinity binding of
HCV to platelet membrane with subsequent binding of anti-HCV antibody
could theoretically lead to “innocent bystander” phagocytosis of
platelets . The improvement of thrombocytopenia
interferon therapy supports this kind of mechanism.
In one study from Japan 
the platelet counts in
were lower than in the HCV-negative patients (26
9 vs 49
109/l, respectively; P<0.02). Conversely, in an American study
carried out in the Los Angeles area23, fewer HCV-positive patients had
severe thrombocytopenia, defined as platelet count ≤10 x 109/l (4% vs.
46% for ITP, P≤0.001). However, 
had a platelet count
≤50 x 109/l. Symptoms and signs of thrombocytopenia were less frequent
in HCV-positive ITP, but major bleeding was more frequent (25% vs. 10%,
P=0.0059). Serum cryoglobulins and anticardiolipin antibodies were more
frequent in HCV-positive ITP (90% and 62% respectively), but rare in
HCV-negative ITP (7% and 15%, P≤0.001 compared with HCV-positive ITP).
In the French 
and Chinese 
studies the characteristics of ITP in
HCV-positive patients did not differ from HCV-negative ones.
case series of patients with HCV infection and chronic immune
thrombo-cytopenia have reported a greater than 50% platelet response to
. Only in
the study from Sakuraya et al none of the
10 HCV-positive patients treated with prednisolone achieved a
. Response to splenectomy was not found
significantly between HCV-positive and HCV-negative patients in two
studies describing patients with chronic ITP [27,50]
Rajan et al noted that only a minority of HCV-positive patients
received some form of treatment for thrombocytopenia [29 (38%) vs. 158
(91%) for HCV-negative ITP]
. Of the seven
patients treated with
prednisone (4 responded, 57%), six developed elevations of hepatic
transaminases of greater than twice pretreatment levels while receiving
prednisone. All six patients had a documented increase in HCV viral
load. Two patients developed elevated serum bilirubin levels, with one
patient developing overt jaundice. Treatment with either intravenous
immunoglobulin (IVIG) or anti-RhD Ig proved effective in increasing
platelet counts in both the HCV seropositive and seronegative patients.
Of five HCV-positive patients treated with interferon-alpha (IFN-a
four responded with increased platelet counts. Responders to IFN-a
could be distinguished from the non-responder by a decrease in HCV
quantitative RNA, hepatic transaminases and cryoglobulins 
In the report of Garcia-Suarez et al each of 6 HCV patients treated
responded with a
significant increase in platelet count 
Iga et al reported significant increases in the platelet counts of 12
HCV infected patients who were complete responders to interferon alpha
) treatment, but no
improvement in the platelet counts of 11
patients who failed IFN-a
therapy assessed by viral load 
Considering the results of these various studies [26,35,54]
half HCV-positive adult ITP patients treated with IFN-a
a rise in platelet count.
Research has focused on developing compounds specifically to stimulate
thrombopoietin (TPO) activity in order to prevent or treat
thrombocytopenia in chronic liver diseases. Eltrombopag is a
small-molecule nonpeptide oral platelet growth factor that acts as an
agonist to the thrombopoietin-receptor 
. A phase
randomized trial of daily eltrombopag in patients with HCV-associated
thrombocytopenia and compensated liver disease showed that after 4
weeks of therapy platelet count increased to ≥100 x 109/L in 75%, 79%,
and 95% of patients treated with 30 mg, 50 mg, and 75 mg eltrombopag,
respectively, compared to no response in placebo patients (P <
. Significantly more patients in the
groups (36%, 53%, and 65% in the 30-mg, 50-mg, and 75-mg groups)
completed 12 weeks of antiviral therapy compared with 6% of placebo
patients and 75% of these patients had platelet counts above baseline
values at the end of the antiviral treatment phase. The most common
adverse event during the initial 4 weeks was headache, reported in 36%,
16%, and 17% of patients who received 30 mg of eltrombopag, 50 mg of
eltrombopag, and 75 mg of eltrombopag, respectively, as well as in 17%
of patients who received placebo. Thereafter, the adverse events were
those expected with interferon-based therapy (influenza-like illness,
fatigue, chills, and headache).
Since eltrombopag has shown remarkable activity in chronic ITP as
well57, this agent appears to be an adequate candidate for the
management of HCV-related chronic thrombocytopenia.
acute and chronic viral hepatitis may be associated with isolated
thrombocytopenia and should be considered in the differential diagnosis
of ITP when isolated thrombocytopenia is present. Most of the studies
have described thrombo-cytopenia in association with chronic HCV
infection, by far the most common cause of chronic hepatitis. Several
potential mechanisms can contribute to the thrombocytopenia in chronic
HCV infection, including accelerated platelet clearance due to immune
complex disease, cross-reactivity of anti-platelet glycoprotein
antibodies and viral or bacterial antibodies, defective platelet
production, and splenic sequestration of platelets secondary to portal
hypertension and decreased production of thrombopoietin.
Serologic evaluation for HCV infection is
indicated in patients with
ITP because of the potential adverse effect of prolonged corticosteroid
usage on the underlying infection and the utility of antiviral therapy
in treating the both the underlying infection and the thrombocytopenia.
Treatment with eltrombopag, a second generation thrombopoietin receptor
agonist, appears to be very efficacious in elevating the platelet count
and is well tolerated. Ongoing phase III studies in HCV-related chronic
thrombocytopenia will better define the benefits of this agent compared
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