Download Pathogenesis of liver involvement during dengue viral infections

Transactions of the Royal Society of Tropical Medicine and Hygiene (2006) 100, 608—614
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
REVIEW
Pathogenesis of liver involvement during dengue
viral infections
S.L. Seneviratne a,∗, G.N. Malavige b, H.J. de Silva c
a
Department of Clinical Immunology, Level 7, John Radcliffe Hospital, Oxford OX3 9DU, UK
Department of Microbiology, Faculty of Medicine, University of Jayawardenapura, Sri Lanka
c
Department of Medicine, Faculty of Medicine, University of Kelaniya, Sri Lanka
b
Received 9 August 2005 ; received in revised form 21 October 2005; accepted 21 October 2005
Available online 17 February 2006
KEYWORDS
Dengue;
Liver;
Transaminases;
Immune mechanisms;
Clinical observations
Summary The dengue virus can infect many cell types and cause diverse clinical and pathological effects. We describe clinical and experimental observations that suggest that liver
involvement occurs during dengue infections, and we outline the possible role played by host
immune responses in this process.
© 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights
reserved.
1. Introduction
Dengue is epidemic or endemic in virtually every tropical country. It is the most important viral haemorrhagic
fever in the world. Infection may be clinically asymptomatic
or give rise to undifferentiated fever, dengue fever (DF),
dengue haemorrhagic fever (DHF) or dengue shock syndrome
(DSS).
The dengue virus, an RNA virus, belongs to the Flaviviridae family, and consists of four serotypes (DEN1—4). The
virus can infect many cell types and cause diverse clinical
and pathological effects. Its main effects are on the vascular,
muscular and haematological systems. However, both clinical and experimental observations suggest that there is liver
involvement during dengue infection. This liver dysfunction
could be a direct viral effect on liver cells or be an adverse
∗ Corresponding author. Tel.: +44 1865 225993;
fax: +44 1865 225990.
E-mail address: [email protected] (S.L. Seneviratne).
consequence of dysregulated host immune responses against
the virus.
In this mini-review we outline the clinical and experimental observations of liver involvement during dengue infections, and discuss the possible role played by host immune
responses in this process.
2. Clinical observations
Clinical evidence of liver involvement in dengue infections
includes the presence of hepatomegaly and increased serum
liver enzymes. Hepatomegaly is frequent and is commoner
in patients with DHF than in those with DF. Several studies
document raised serum transaminase levels in dengue infection. Transaminase levels are also higher in DHF/DSS than in
DF and tend to return to normal 14—21 d after infection.
Kuo et al. (1992) evaluated 270 dengue patients and
found abnormal aspartate transaminase (AST) and alanine
aminotransaminase (ALT) levels in 93.3 and 82.2%, respectively. Most had mild to moderate increases, while levels
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doi:10.1016/j.trstmh.2005.10.007
Liver involvement in dengue infections
more than 10 times the normal upper limit were seen in
11.2 and 7.4% of patients. Nimmannitya (1987), investigating 145 dengue patients, found ALT levels to be normal,
slightly elevated or significantly elevated in 74, 18 and 8%
of patients, respectively. No mention of AST levels were
found in this report. Wahid et al. (2000) studied 50 serologically confirmed cases of dengue (25 cases each of DF
and DHF), and found serum AST and ALT levels to be significantly higher in patients with DHF. In addition, Mohan et
al. (2000), who evaluated children with dengue (37 cases of
DF, 16 with DHF and 8 with DSS), found abnormal transaminases in 96%, with higher levels in DHF/DSS. Of 1585 dengue
patients (65% with primary dengue, 91% with DF) studied
by Souza et al. (2004), during a dengue epidemic in Rio
de Janeiro, Brazil, alterations in AST and ALT were seen in
63.4 and 45% of patients, with 3.8% having transaminase levels >10 times the upper limit of normal. Fulminant hepatic
failure complicating severe DHF/DSS has also been documented, and is associated with a poor prognosis (Alvarez
and Ramirez-Ronda, 1985; Lawn et al., 2003; Lum et al.,
1993; Munasinghe and Rajasuriya, 1967; Nguyen et al., 1997;
Subramanian et al., 2005). Nimmannitya et al. (1987) have
reported 18 DHF cases with jaundice and encephalopathy,
of whom 10 died.
Varying abnormalities in liver enzymes appear to be
present in most patients with symptomatic dengue infections, but they tend to recover soon (Pancharoen et al.,
2002). There does not appear to be chronic liver damage as with the hepatitis B and C viruses. In a subgroup
of predominantly DHF/DSS patients, severe liver dysfunction occurs and is a marker of poor prognosis. During some
dengue epidemics, greater degrees of liver damage are seen
(Ehrenkranz et al., 1971). Although this may be a consequence of different dengue serotypes having varying tissue
trophism, this has not been widely studied.
Some investigators suggest that liver damage may be
potentiated by the intake of drugs (such as acetaminophen
and anti-emetics) during the early phase of the illness, but
others do not see this (Suvatte et al., 1990). The course
appears not to be influenced by concomitant hepatitis virus
infection (Chung et al., 1992). Although hepatitis B virus
(HBV) is hyperendemic in parts of South America and in the
Far East, no evidence exists that HBV infection acts as a
co-factor for hepatic damage in dengue infections.
In dengue infections, elevations in serum AST appear to
be greater than ALT levels. This differs from the pattern in
viral hepatitis, in which ALT levels are usually higher than or
equal to AST levels (Gholson et al., 1990), but it is similar
to that seen with alcoholic hepatitis. The exact significance
of this pattern seen in dengue is uncertain. It has been suggested that it may be due to excess release of AST from
damaged myocytes during dengue infections (Chung et al.,
1992), but this has not been formally tested. Simultaneous measurement of muscle isoforms of lactate dehydrogenase and creatinine kinase may help further clarify this
observation. The elevated AST levels tend to return to normal more rapidly than ALT levels. This is possibly because
AST (12.5—22 h) has a shorter half-life than ALT (32—43 h)
(Hawker, 1991).
Histological changes reported in the liver in dengue
include: microvesicular steatosis, hepatocellular necrosis,
Kupffer cell hyperplasia and destruction, Councilman bodies
609
and cellular infiltrates at the portal tract (Bhamarapravati,
1989; Burke, 1968). Most reports are based on small numbers of samples obtained from fatal cases. The presence of
thrombocytopenia and coagulative dysfunction makes it difficult to obtain samples from others. As such, one is unsure of
the degree of changes present in those with milder disease.
Steatosis occurs frequently in hepatitis of viral origin and
no special significance can be attributed to this process in
dengue infections. Hepatocellular necrosis in dengue generally affects the midzonal area and sometimes the centrolobular area. Reasons for this pattern may be that hepatocytes
in this zone are more sensitive to anoxia or the products of
an immune response (e.g. cytokines and chemokines) or that
the dengue virus preferentially infects cells in this zone. In
fact, dengue viral RNA and protein have been detected in
midzonal hepatocytes, mostly around necrotic foci. Councilman (acidophilic) bodies correspond to hepatocytes showing
the characteristic morphology of apoptosis. Inflammatory
mononuclear cell infiltrates (of varying intensity) are seen
in most specimens studied so far.
The dengue virus has been isolated from the liver of fatal
cases (Burke, 1968; Rosen et al., 1989; Sumarmo et al.,
1983). Some find it the main organ from which virus could be
isolated (Bhamarapravati, 1997; Huerre et al., 2001; Rosen
et al., 1989). For instance, using mosquito inoculation techniques, DEN-2 or DEN-3 viruses were recovered from the
livers of 5 of 17 fatal cases, but rarely from other tissues
(Rosen et al., 1989).
Using dengue-specific RT-PCR on liver samples from fatal
cases, dengue RNA was detected in 11 of 15 (Rosen et al.,
1999). Dengue RT-PCR has been done on paraffin-embedded
samples from autopsies of 10 children with a clinical diagnosis of DHF/DSS 17 years after their death. In 44, 80
and 43% of cases, DEN-2 RNA was detected in the liver,
spleen and lymph nodes (Sariol et al., 1999). Dengue viral
RNA has also been detected in midzonal hepatocytes of
archived paraffin-embedded autopsy tissues using an in-situ
PCR method (Kangwanpong et al., 1995).
Immunohistochemistry and in-situ hybridization have
been used to localize dengue antigens in naturally infected
human tissues (Jessie et al., 2004), with immunoperoxidase
methods suggested to be reliable and specific in diagnosing
dengue or yellow fever infection from human archive samples (Hall et al., 1991).
Clinical manifestations in severe dengue disease and
yellow fever are similar. Viruses causing them are closely
related (both are flaviruses, transmitted by the same group
of vectors). Overall liver pathology in dengue appears to
be similar to that observed during the early stages of yellow fever (Bhamarapravati, 1997). However, in yellow fever,
liver cell necrosis tends to be more severe and extensive. In
addition, immunofluorescence patterns in infected HepG2
cells differ. While dengue viral antigens are found as large
perinuclear inclusions and small cytoplasmic foci, yellow
fever antigens are homogeneously distributed throughout
the cytoplasm (Marianneau et al., 1998). DEN-2 infection
of HepG2 cells leads to the release of only a small amount
of infectious particles and a slight increase in the number
of viral antigen-containing cells over time. By contrast, yellow fever viruses replicated to high titres and infected all
exposed cells (Marianneau et al., 1998). Furthermore, while
dengue virus-infected cells died rapidly by apoptosis, the
610
highly productive yellow fever virus-infected cells did not
show early cytopathic changes (Marianneau et al., 1998).
It is possible that early apoptosis of infected hepatocytes
followed by their rapid clearance by surrounding phagocytic cells may help to limit the spread of the dengue virus.
By contrast, the delayed appearance of apoptotic liver cell
death in yellow fever may occur too late. At this stage most
cells may have already been infected, causing severe liver
destruction.
The dengue virus is able to replicate in both hepatocytes
and Kupffer cells (Huerre et al., 2001). Although dengue
viruses can enter human Kupffer cells efficiently, replicative infection of these cells appears not to be very efficient (Marianneau et al., 1999). This may be because most
viral particles enter such cells by phagocytosis, a process
known to lead to viral degradation. In the smaller number of Kupffer cells in which virus replication can occur,
the virus probably enters by receptor-mediated endocytosis
and fusion. Two phases of Kupffer cell activation have been
described. The first phase occurs shortly after infection with
nitric oxide and IFN-␣ production, with a second a few hours
later, involving IL-6 and TNF-␣ synthesis (Marianneau et al.,
1999).
Infection of hepatic cell lines HepG2 and THLE-3 with
ChemiVaxTM -DEN1—4 and their parent viruses, wild-type
DEN1—4 and YF17D, showed significant differences in growth
kinetics (Brandler et al., 2005). The YF17D virus produced
higher titres and caused extensive cytopathic effects earlier
than ChemiVaxTM -DEN1—4 or wild-type DEN1—4 viruses. The
lack of growth of chimeric viruses in human hepatic cells
suggests that these viruses may be less hepatotrophic than
YF17D virus vaccine in humans.
3. Experimental observations
To infect cells, dengue viruses need first to attach to host
cell surfaces. This attachment process is considered a major
determinant of the viral host range and tissue tropism.
The dengue viral envelope protein has been implicated as
the viral attachment protein (Chen et al., 1996). Following
penetration, internalization occurs by either endocytosis or
direct fusion. Evidence exists for both receptor-mediated
and non-receptor-mediated entry pathways.
There is considerable interest in determining the nature
of cellular proteins used by different viruses to enter cells.
Identification of such proteins may allow us to rationally
design small peptide-based molecules that are able to prevent or modify such interactions. In the case of the dengue
viruses, some of these molecules include: DC-specific ICAM3 grabbing non-integrin (DC-SIGN) used by the virus to
gain entry into monocyte-derived dendritic cells (NavarroSanchez et al., 2003); the Fc␥ receptor used in cases of secondary infection to gain entry into monocytes (Daughaday et
al., 1981); and monocyte—macrophage complement receptors (CR3) mediating IgM-dependent enhancement of flavivirus replication (Cardosa et al., 1983).
Several viruses are able to bind heparan sulphate (HS),
a ubiquitous glycosaminoglycan found on the surface of
cells. HS may act directly as a virus receptor or serve as
a low-affinity virus-binding site, allowing the virus to accumulate before transfer to its high-affinity receptor (Chen
S.L. Seneviratne et al.
et al., 1997; Germi et al., 2002). HS is reported to be
involved in entry of all four dengue serotypes into HepG2
cells (Thepparit et al., 2004). However, the degree of internalization varied between serotypes.
At present, exact mechanisms of interaction (including
the nature of molecules that facilitate entry) between the
dengue virus and liver cells are poorly defined. Glucose
regulated protein 78 (GRP78) was reported to be used by
DEN-2 to gain entry into HepG2 cells (a human hepatoblastoma cell line) (Jindadamrongwech et al., 2004). Thepparit
and Smith (2004) suggested that the DEN-1 virus (but not
the other dengue serotypes) used the 37/67 high-affinity
laminin receptor to enter liver cells. This is a non-integrin
cell surface molecule expressed on normal human liver cells,
with upregulated levels on liver carcinoma cells. Laminin
receptor binding appeared to occur both directly or via HSdependent interactions. Interestingly, a similar mechanism
has been previously proposed for entry of prion proteins
(Gauczynski et al., 2001) and Sindbis viruses (Wang et al.,
1992) into cells. Hilgard and Stockert (2000), studying DEN1 binding protein expression using the Huh7 liver cell line,
found the virus able to bind two membrane proteins (approximately 33 and 37 kDa in size). It is possible that the 37-kDa
protein described in this report is similar to the molecule
described by Thepparit and Smith (2004).
The permissiveness of a cell to infection by a virus is considered to be due to two factors: the ability of the virus to
enter the cell, and the factors within the cell that enable
the virus to replicate successfully. Cellular permissiveness
to dengue virus infection appears to be modulated by viral
serotype, strain and cell type. HepG2 cells show a marked
influence of cell physiology, with cells in the G2 phase of
the cell cycle having a higher susceptibility to infection and
a higher rate of virus production per cell (Phoolcharoen and
Smith, 2004). The link between the cell cycle and the permissiveness of liver cells to infection with the dengue virus
may point the way to understanding the greater susceptibility of children towards the more severe forms of dengue
infection (Phoolcharoen and Smith, 2004).
Under experimental conditions, HepG2 cell binding
of DEN-1 and DEN-2 was found to be non-saturable
(Suksanpaisan and Smith, 2003), in keeping with results using
Huh7 cells (Hilgard and Stockert, 2000). It is suggested there
is a degree of cooperation in dengue virus binding onto liver
cells. The binding of one virus to a liver cell serves to facilitate binding of further virus particles, thus making it easier
for successive particles to bind. It does this is by inducing
conformational changes in cell surface binding molecules.
Dengue viruses have varying effects on liver cell lines in
vitro. DEN-2 were able to attach equally well to five liver cell
lines, but rates of replication and levels of virion production
were higher in the differentiated cell lines (Hul7, PLC, M3B
and Chang) than in a de-differentiated cell line (HA22T) (Lin
et al., 2000b). It is possible that specific cell differentiation
factors may play important roles in viral replication within
hepatocytes. Studies aimed at identifying such factors may
allow us to understand this process better. Heparin is able
to inhibit DEN-2 virus invasion of the different liver cell lines
(Lin et al., 2002). Dengue viruses have differential susceptibility to heparin inhibition. This property may be used for
screening and selecting mutant viruses for use in different
animal models.
Liver involvement in dengue infections
RANTES (regulated upon activation, normal T cell
expressed and secreted), a CC chemokine has chemotactic activity for T cells, monocytes, natural killer cells and
eosinophils. Levels are higher in patients infected with
the dengue virus. Correlation between DEN-2 infection and
upregulated RANTES gene expression in liver cells has been
shown in vitro (Lin et al., 2000a). It has been hypothesized that dengue infection of liver cells upregulates RANTES
mRNA expression by oxidant-dependent and -independent
pathways.
Following dengue infection, cellular apoptosis in the liver
has been seen both in vivo and in vitro (Couvelard et al.,
1999; Marianneau et al., 1996, 1997). The Councilman bodies are believed to be the remains of cells undergoing
apoptosis (Huerre et al., 2001). Dengue virus infection of
primary cultures of human Kupffer cells and a hepatoma
cell line induces apoptosis, as evidenced by DNA laddering
(Marianneau et al., 1997, 1999). Activation of the transcription factor NF-␬B has been implicated in the induction of
apoptosis (Marianneau et al., 1997). NF-␬B decoys were able
to inhibit HepG2 apoptosis, further pointing to the important
role played by the NF-␬B pathway in this process. Modulating this activity may have future therapeutic potential in
patients with severe dengue-induced liver dysfunction.
Several mechanisms may be involved in dengue-induced
liver cell apoptosis. These include direct cytopathic effects
of the virus, mitochondrial dysfunction due to low flow
hypoxia and the influence of cellular and humoral immune
factors in the liver (as is observed in other types of viral hepatitis). The apoptotic process appears to be independent of
p53 (Thongtan et al., 2004). Increased levels of endoplasmic
reticulum stress have been speculated to induce apoptosis
in dengue, as has been previously proposed with Japanese
encephalitis, another member of the Flavivirus genus (Su
et al., 2002). Recently, dengue virus-induced TRAIL (tumour
necrosis factor-related apoptosis-inducing ligand) expression has been suggested to be partly responsible for causing
apoptosis (Matsuda et al., 2005). DEN-2 infection was shown
to cause TRAIL promotor activation, whereas a proteosome
inhibitor and TRAIL antibody were able to inhibit DEN-2induced apoptosis.
An animal model for dengue was established by transplanting a human HepG2 cell line into severe combined
immunodeficient (SCID) mice, followed by intraperitoneal
infection with DEN-2 virus 8 weeks later (An et al., 1999).
During the early post-infection stages, high viral titres were
found in the liver and serum but not the brain. Paes et al.
(2005) have used BALB/c mice to study liver injury following inoculation with a DEN-2 virus isolated from a human
patient. Although the mice did not present with clinical
signs and survived the infection, hepatic injury was seen
in all individuals. Dengue viral antigens were found in the
liver. Elevated transaminase levels correlating with a peak
of viraemia were noted.
4. Immunopathogenic mechanisms
An excellent review on current knowledge of dengue pathogenesis has been recently published (Stephenson, 2005).
Therefore, in this article, we will only describe salient features of the immune response during dengue infections and
611
attempt to outline its relationship to liver involvement in
dengue.
Both innate and adaptive host immune responses play
important roles in determining the natural history of viral
infections. Innate immune responses are induced rapidly
and act as first-line defences until specific adaptive immune
responses come into play. Differences in antibody, T-cell and
cytokine responses are seen among patients with uncomplicated DF or DHF/DSS.
The immune enhancement and viral virulence hypotheses have been put forward to explain the causation of severe
dengue disease. Antibody-dependent enhancement (ADE)
attempts to explain the observation that individuals experiencing a secondary infection with a heterologous dengue
viral serotype have a significantly higher risk of developing
DHF/DSS. During secondary dengue infections, preexisting
non-neutralizing antibodies may form complexes with the
virus and enhance its uptake and replication in macrophages
(Halstead and O’Rourke, 1977). The viral virulence hypothesis is based on the observation that some dengue viruses
have greater epidemic potential than others. These virulent strains replicate faster and to higher concentrations and
hence cause higher levels of viraemia.
Effective CD4+ and CD8+ T-cell responses have been suggested to play an important role in clearance of acute
dengue viraemia. Following primary dengue, both serotypespecific and serotype-cross-reactive memory T cells are
formed. On secondary exposure to a different viral serotype,
most serotype-cross-reactive CD4+ and CD8+ T cells are able
to augment infection by producing various cytokines (Kurane
et al., 1990).
During dengue infection, monocytes, B cells, T cells and
mast cells produce large amounts of cytokines. Serum concentrations of TNF-␣, IL-2, IL-6 and IFN-␥ are highest in the
first three days of illness while IL-10, IL-5 and IL-4 tend
to appear later (Chaturvedi et al., 1999). It has been suggested that predominant Th2 responses (IL-4, IL-5) occur in
DHF/DSS, whereas Th1 (IFN-␥) responses seem to protect
against severe infections.
Using MHC class I tetrameric complexes loaded with a
peptide from the NS3 protein, expansion of CD8+ T cells with
relatively low affinity for the currently infecting virus and
higher affinity for serotypes presumed to have been encountered in the past were found (Mongkolsapaya et al., 2003).
This was thought to result from the detrimental effects of
original antigenic sin. It was argued that these ‘inappropriate’ T cells contribute to immunopathology while doing
little to clear the virus. Another explanation suggested for
these findings was that high antigenic load associated with
a second dengue infection (due to immune enhancement),
may preferentially drive high-affinity T cells into apoptosis,
which would in turn increase the frequency of lower-affinity
cells (Mongkolsapaya et al., 2003).
T-cell responses in dengue infections need to be well
regulated, to avoid specific downsides. For instance, in the
process of viral elimination, damage to vital target organs
may occur. As in the case of the other hepatitis viruses,
dengue virus-specific CD4+ and CD8+ T cells may cause liver
cell damage by direct cytolytic and/or cytokine-mediated
effects. Cytokines produced during the immune response
may also have ill effects, such as promoting the excessive
deposition of extracellular matrix.
612
Bhamarapravati et al. (1967) examined the liver pathology of 100 fatal paediatric DHF cases (aged 5 months to 14
years) and reported that cellular infiltration was noted in 64
cases. Lymphocytoid cells, megakaryocytes and rarely neutrophils were observed in the sinusoids. Cellular infiltration
around the portal tract comprised lymphocytes, plasmacytoid cells and some histiocytes. In a recent study by Huerre
et al. (2001), in five fatal paediatric cases (aged 10 months
to 6 years), little or no inflammatory infiltrate was found in
four cases and a moderate periportal infiltrate in one.
Chen et al. (2004) infected immunocompetent C57BL/6
mice with high titres of DEN-2 strain 16681 and studied lymphocyte activation and hepatic cellular infiltration. T cells in
the infected mice were found to be activated and functionally active, as evidenced by the production of IFN-␥. Most
of the activated cells were CD8+ T cells. Liver enzyme elevation and hepatic T-cell infiltration were found to coincide
with the kinetics of T-cell activation. Hepatic cellular infiltrates consisted predominantly of T cells. While most CD4+
T cells clustered around the portal vein, most CD8+ T cells
were scattered in the hepatic acinus. Flow cytometric analysis of liver infiltrating T cells showed that nearly two-thirds
were CD8+ T cells.
Gagnon et al. (1999) have postulated that CD4+ cytotoxic
T cells (CTLs) may mediate liver damage in dengue through a
mechanism involving bystander lysis. CD4+ T-cell-mediated
cytotoxicity is thought to occur via two main pathways:
release of perforin and granzymes from the activated CTL
or the interaction of Fas ligand on T cells with Fas on the
target cell. The Fas/Fas-L pathway could contribute to the
destruction of cells presenting viral antigens as well as nonantigen-presenting bystander cells that express Fas. Dengue
viral capsid-protein-specific CD4+ T-cell clones were able to
mediate bystander lysis of HepG2 and Jurkat cells. It has
been suggested that dengue virus-specific CTL may be activated by dengue virus-infected Kupffer cells, and in turn
lyse hepatocytes via a bystander mechanism. However, such
bystander lysis has still not been demonstrated in vivo.
At present, the part played by the host immune response
in liver damage is unclear. Differences in the intensity of
mononuclear cell infiltrates in the liver have been reported
in human and animal studies. Although it has been suggested
that cellular infiltrates are lower following arboviral infections than following hepatitis B or C infection, reports in
human and animal models of dengue suggest significant infiltrates may occur. It is known that activated viral-specific T
cells are able to bind specific receptors on virus-infected
cells and induce their apoptosis. It is possible that some
T cells that enter the liver may cause damage and either
undergo apoptosis or leave the liver. They may also produce
a range of cytokines/chemokines, and cause damage to target organs (such as the liver) at a distance from the site of
immune activation.
5. Conclusion
In summary, clinical and experimental observations suggest
that liver involvement occurs during dengue infections. Clinical evidence includes hepatomegaly and increased serum
liver enzymes, with liver involvement being more pronounced in the more severe forms of infection. Dengue viral
S.L. Seneviratne et al.
antigens have been found within hepatocytes, and the virus
appears to be able to replicate in both hepatocytes and
Kupffer cells, and dysregulated host immune responses may
play an important causative role in liver damage. Modulating
these immune responses may have a therapeutic potential.
There are limitations in the investigation of liver involvement in dengue infection. Immunopathological lesions in the
liver are difficult to study in patients with thrombocytopenia and coagulative dysfunction; present knowledge is based
mainly on post-mortem specimens and animal models.
Conflicts of interest statement
The authors have no conflicts of interest concerning the work
reported in this paper.
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