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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 106, Num. s1, 2011, pp. 52-63
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Memórias do Instituto Oswaldo Cruz, Vol. 106, Special Issue, pp. 52-63
Original Article
Thrombocytopenia
in malaria: who cares?
Marcus Vinícius
Guimarães LacerdaI, II, I, +; Maria Paula
Gomes MourãoI, II, III; Helena Cristina Cardoso CoelhoII;
João Barberino SantosIV
IFundação
de Medicina Tropical Dr. Heitor Vieira Dourado, Av. Pedro Teixeira 25, 69040-000
Manaus, AM, Brasil
IIUniversidade do Estado do Amazonas, Manaus, AM, Brasil
IIIUniversidade Nilton Lins, Manaus, AM, Brasil
IVUniversidade de Brasília, Brasília, DF, Brasil
+ Corresponding author: marcuslacerda.br@gmail.com
Received 1 April
2011
Accepted 26 May 2011
Abstract
Despite not being
a criterion for severe malaria, thrombocytopenia is one of the most common complications
of both Plasmodium vivax and Plasmodium falciparum malaria. In
a systematic review of the literature, platelet counts under 150,000/mm3
ranged from 24-94% in patients with acute malaria and this frequency was not
different between the two major species that affected humans. Minor bleeding
is mentioned in case reports of patients with P. vivax infection and
may be explained by medullary compensation with the release of mega platelets
in the peripheral circulation by megakaryocytes, thus maintaining a good primary
haemostasis. The speculated mechanisms leading to thrombocytopenia are: coagulation
disturbances, splenomegaly, bone marrow alterations, antibody-mediated platelet
destruction, oxidative stress and the role of platelets as cofactors in triggering
severe malaria. Data from experimental models are presented and, despite not
being rare, there is no clear recommendation on the adequate management of this
haematological complication. In most cases, a conservative approach is adopted
and platelet counts usually revert to normal ranges a few days after efficacious
antimalarial treatment. More studies are needed to specifically clarify if thrombocytopenia
is the cause or consequence of the clinical disease spectrum.
Key words:
Plasmodium falciparum - Plasmodium vivax - malaria - thrombocytopenia
- platelets
Malaria affects
almost all blood components and is a true haematological infectious disease.
Anaemia and thrombocytopenia are the most frequent malaria-associated haematological
complications (Wickramasinghe & Abdalla 2000) and have received more attention
in the scientific literature due to their associated mortality. On the other
hand, thrombocytopenia is less studied, causes negligible mortality and is an
isolated phenomenon; there is no report of a single patient in the literature
who has died only because of malaria-associated thrombocytopenia.
In the current
field of Travel Medicine, the rapid increase in the number of people travelling
to tropical areas has added a great challenge for malaria diagnosis because
the thick blood smear (the standard diagnosis in endemic areas) has high specificity
but only when performed by experienced microscopists. The presence of thrombocytopenia
in acute febrile travellers returning from tropical areas has become a highly
sensitive clinical marker for malaria diagnosis (D'Acremont et al. 2002). Another
study has reported 60% sensitivity and 88% specificity of thrombocytopenia for
malaria diagnosis in acute febrile patients (Lathia & Joshi 2004). The sensitivity
of thrombocytopenia together with the acute febrile syndrome was 100% for malaria
diagnosis, with a specificity of 70%, a positive predictive value of 86% and
a negative predictive value of 100% (Patel et al. 2004).
Thrombocytopenia
is a well-documented and frequent complication in Plasmodium vivax malaria.
In one study, platelet count normalised after treatment and only one patient,
concomitant with the lowest platelet count, exhibited "purpuric lesions" on
the lower extremities (Hill et al. 1964).
Since the beginning
of the 1970s, there have been reports proposing that malaria-associated thrombocytopenia
is quite similar in P. vivax and Plasmodium falciparum infections
(Beale et al. 1972). However, more recent data in India has shown how thrombocytopenia
exhibited a heightened frequency and severity among patients with P. vivax
infection (Kochar et al. 2010).
In 1903, the young
physician Carlos Chagas (who become more famous afterwards for the discovery
of American trypanosomiasis, which is named after him), published his MD thesis
on the Hematological Studies on Paludism (Chagas 1903). Within it, he described
anaemia and leukocyte abnormalities, but also normal megakaryocytes in the bone
marrow were referred to in patients with acute and chronic malaria from Rio
de Janeiro. He also drew our attention to evidence of bleeding in the 46 patients
he followed.
In the city of
Manaus, state of Amazonas, located in the Western Brazilian Amazon, Djalma Batista
authored Paludism in the Amazon, a book in which he described observations about
patients with malaria seen at his private clinics (Batista 1946). Similar to
Carlos Chagas, there is no mention of platelet count in his study because it
was not routinely performed. However, there is a vivid description of haemostasis
disorders in some patients. Particularly noteworthy is the presence of huge
spleen enlargement and prolonged bleeding time accompanied by recurrent gingival
bleeding.
Data on the real
burden of thrombocytopenia associated with malaria is contradictory in the literature
and it is not usually considered when conducting patient selection. Table
I shows the major publications estimating the frequency of thrombocytopenia.
Most of these data were published in the late 1990s, probably in time with the
surge in the availability of affordable automated machines capable of performing
full blood counts (FBC). Manual platelet counting is time-consuming and usually
needs to be requested by the physician with the routine blood count in most
of the endemic areas for malaria. In only three publications is there an adequate
randomised enrollment of patients with appropriate sample size calculation to
estimate the frequency of bleeding and its association with the respective platelet
count (Lacerda 2007, Silva 2009, Kochar et al. 2010). Only one study has ruled
out other common causes of thrombocytopenia that are also endemic in the studied
area (Lacerda 2007). There is a wide range of thrombocytopenia occurrence in
these reports, which may be explained by distinct selection criteria of the
enrolled patients. There are also differences in the selection of outpatients
or inpatients from tertiary care centres that tend to present with severe thrombocytopenia.
Furthermore, clinical manifestations of thrombocytopenia are usually described
as case reports and most of these are due to P. vivax (Table
II).
In 2005, 138 of
684 (20.1%) malarial cases hospitalised in a tertiary care centre in Manaus
had thrombocytopenia as the cause of admission, which corresponded to 6.8% of
hospitalisations due to all causes in this reference institution (unpublished
observations). Hospitalisation, however, does not add any benefit to the patient
and because there is no evidence for any intervention, this simply increases
public health costs in underdeveloped and under-resourced areas.
Pathogenesis
of malarial thrombocytopenia - Coagulation disturbances - A study
based on 31 American soldiers in Vietnam with chloroquine-resistant falciparum
malaria noted the following changes in the acute phase of the disease using
the same patients as their own controls during convalescence: decrease in the
platelet count and prothrombim activation time, increase in the activated thromboplastin
time, and reduction in factors V, VII and VIII with normal fibrinogen (Dennis
et al. 1967). This report suggested that thrombocytopenia was simply a consequence
of the coagulation disorders presented by these patients, an idea that persisted
for many decades in the literature. In another series of 21 patients with falciparum
malaria, six had developed disseminated intravascular coagulation (DIC). The
authors noted that the patients with more severe thrombocytopenia also had DIC
and that there was correlation between platelet count and C3 protein levels.
However, the reduction in C3 was proportional to that in parasitaemia, suggesting
that thrombocytopenia was not independently associated with C3 (Srichaikul et
al. 1975). In Manaus, 2004, a study with falciparum and vivax patients demonstrated
a negative correlation between platelet counts, thrombin-anti-thrombin complex
and D-dimers, suggesting that the activation of coagulation could be partially
responsible for thrombocytopenia (Marques et al. 2005).
Splenomegaly
- The spleen in malaria has played a crucial role in the immune response against
the parasite, as well as controlling parasitaemia due to the phagocytosis of
parasitised red blood cells (RBCs) (Engwerda et al. 2005). Some data suggested
that platelets were sequestered in the spleen during the acute infection (Skudowitz
et al. 1973). In the experimental model with Plasmodium chabaudi, thrombocytopenia
was absent in splenectomised mice, showing that the spleen was essential for
thrombocytopenia (Watier et al. 1992). The term hypersplenism was proposed to
describe the clinical picture of the enlarged spleen followed by the decrease
in one or more peripheral blood lineages (usually reverted after splenectomy),
probably due to sequestration or destruction of cells inside the spleen, in
liver diseases, which lead to increased portal system pressure. However, it
is recently believed that not only mechanical alterations take place, but also
compromise of haematopoietic growth factors produced in the liver (Peck-Radosavljevic
2001). On the other hand, the isolated spleen enlargement does not explain per
se the destruction of cells as formerly believed. This organ represents
outstanding architectural organisation and controls, with great sophistication,
the exposure of cells screened by it. In patients with malaria, the increase
in the macrophage-colony stimulating factor is associated to thrombocytopenia,
suggesting that macrophages play a role in the destruction of these particles
(Lee et al. 1997). In the comparison of spleens from patients with severe falciparum
malaria vs. those of control and septic patients, it was shown that splenic
dendritic cells are increased in malaria and there is a reduction in B lymphocytes
and macrophages in the splenic cords (Urban et al. 2005). The mechanisms related
to the formation of splenic hematomas are mostly associated with P. vivax
infection and the interface with thrombocytopenia is noted to be imprecise (Lacerda
et al. 2007). In vivax malaria, the role of the spleen in the expression of
vir genes is still unrecognised. P. vivax passing through the
spleen would activate the transcription of polymorphic Vir proteins to escape
from macrophage destruction in this organ. On the other hand, these same proteins
would permit the binding of parasitised RBCs to barrier cells, creating an isolated
microenvironment in the spleen that would be rich in reticulocytes (del Portillo
et al. 2004). More recent studies with the murine model of Plasmodium yoelii
evidenced that there was higher parasite accumulation, reduced motility, loss
of directionality, increased residence time and altered magnetic resonance only
in the spleens of mice infected with the non-lethal 17X strain (Martin-Jaular
et al. 2011). This same model has never been used to study the role of the spleen
in thrombocytopenia, but opens new avenues for functional and structural studies
of this lymphoid organ.
Bone marrow
alterations - The finding of a P. vivax trophozoite inside a human
platelet suggested that thrombocytopenia could be the result of invasion of
these particles by the parasites themselves, similar to what was classically
proposed for RBCs. As these same authors did not find parasites inside megakaryocytes,
they proposed that the penetration took place in the peripheral circulation
(Fajardo & Tallent 1974). However, this observation was never seen again
in the literature. Likewise, a "dysmegakaryopoiesis" was proposed, similar to
what happened in the human malarial anaemia model, where dyserythropoiesis was
triggered by cytokines (Menendez et al. 2000). In the few studies that examined
the bone marrow for this purpose, megakaryocytic lineage was apparently preserved
(Naveira 1970, Beale et al. 1972). Thrombopoietin indeed seems to rise during
the acute disease even in the presence of liver compromise, suggesting that
no bone marrow inhibition is seen (Kreil et al. 2000). Additional data from
FBC samples in vivax patients showed that there is a significant negative correlation
between platelet count and mean platelet volume (Lacerda 2007), suggesting that
megakaryocytes are able to release mega platelets in the circulation to compensate
for the low absolute number of platelets in the periphery. Similar results were
shown in children with falciparum malaria (Maina et al. 2010). These mega platelets
are probably able to sustain a good primary haemostasis that could explain the
low frequency of severe bleeding in malarial patients, as shown in Table
II. Non-human primates, on the other hand, are an unexplored model to study
megakaryopoiesis alterations and its implication on thrombocytopenia (Llanos
et al. 2006).
Antibody-mediated
platelet destruction - There is evidence that platelet-associated IgG (PAIgG)
is increased in malaria and is associated with thrombocytopenia. However, this
is a generic definition for all types of IgGs that may be found on the platelet
surface, including antibodies stored inside platelet α-granules.
Therefore, increased PAIgG could also be interpreted as platelet activation
and exposition of IgGs on the surface, and not necessarily auto-immunity, as
suggested in anecdotal case reports where antibodies against glycoproteins were
detected in malaria (Panasiuk 2001, Conte et al. 2003). The detection of auto-antibodies
against platelets by flow cytometry (Rios-Orrego et al. 2005) should not be
seen as specific for malaria, as natural auto-antibody formation is a common
defence of the infected organism and is frequently seen in most viral, bacterial
and parasitic diseases without any repercussion (Daniel-Ribeiro & Zanini
2000). Molecular mimicry, however, provides evolutionary advantage for microorganisms
that escape immune aggression (Daniel-Ribeiro 2000). The relationship between
malaria and auto-immunity has been discussed in the literature and the first
epidemiological association was made based on the presence of fewer auto-immune
diseases in malarigenous areas (Greenwood 1968). The formation of circulating
immune complexes (CIC) in vivo in malaria, as well as in other infectious diseases,
is a continuous process from antigens and antibodies and/or complement elements.
CIC seems to modulate the immune response to several antigens that remain sequestered
in B lymphocyte or dendritic cell-rich follicles for a longer time, which contributes
to the formation of B-cell immunological memory, as seen in vaccine studies
(Davidson 1985). During acute malaria, thrombocytopenia is most probably associated
with the binding of parasite antigens to the surface of platelets to which antimalarial
antibodies also bind, leading to the in situ formation of immune complexes
(ICs) (Kelton et al. 1983). In an experimental model with Plasmodium berghei,
the same correlation between platelet count and IC's was evidenced (Grau et
al. 1988). No association was found with IgM (Beale et al. 1972). It is clear
that CICs are elevated in vivax and falciparum malaria, but their role in the
development of thrombocytopenia is still obscure (Touze et al. 1990, Tyagi &
Biswas 1999) as well as its immune suppressing effect (Brown & Kreier 1982,
Shear 1984). Because the generation of IC's is proportional to the amount of
available antigen, the negative correlation between platelet count and peripheral
parasitaemia reported in many studies (Lacerda 2007, Silva 2009) corroborates
ICs as a potential mechanism of platelet destruction. The presence of amino
acid residues tyrosine 193 [9Y(193)] and serine 210 [S(210)]
on apical membrane antigen-1 (AMA-1) was significantly associated with normal
platelet counts in P. vivax malaria independent of the level of parasitaemia
that also provides supporting evidence for this (Grynberg et al. 2007). In only
one study, circulating monocytes were found to phagocytose platelets, but this
mechanism still needs to be associated to thrombocytopenia more closely (Jaff
et al. 1985). The finding of immune thrombocytopenic purpura (ITP) secondary
to malarial infection is rare and may be due to idiosyncratic auto-immune mechanisms
not well understood (Lacerda et al. 2004).
Oxidative stress
- Free radicals may play an important role in the platelet destruction in malarial
infection. There is evidence that the decrease in total cholesterol in vivax
malaria is due to lipidic peroxidation (Erel et al. 1998). Also, in vivax malaria,
there is a negative correlation between platelet count and platelet lipid peroxidation
in addition to the positive correlation between platelet count and the activity
of gluthatione peroxidase and superoxide dismutase, which are considered anti-oxidant
enzymes (Erel et al. 2001). In a study of 103 patients with acute falciparum
malaria, there was a negative correlation between platelet count and nitrogen
reactive intermediates (Santos 2000). There is also a strong association between
platelet count and intra-platelet gluthatione peroxidase, suggesting that a
compensatory mechanism is presented by platelets to face the oxidative burst
found in malaria (Araujo et al. 2008).
Platelet aggregation
- Platelets from patients with acute malaria are highly sensitive to adenosine
diphosphate (ADP) addition in vitro (Essien & Ebhota 1981), and it is believed
that ADP release following haemolysis could contribute to higher platelet aggregation.
Actually, the incubation of platelets with P. falciparum-parasitised
RBCs also increases platelet aggregation per se in vitro, especially
after ADP and thromboxane A2 addition (Inyang et al. 1987). Even
electron microscopic examination of non-stimulated, fresh platelets from malarial
patients show centralisation of dense granules, glycogen depletion and microaggregates
and phylopoids as a sign of in vivo activation, which could be responsible for
a pseudo-thrombocytopenia due to sequestration of these activated particles
in the interior of the vessels (Mohanty et al. 1988). Contradictory data were
presented showing aggregation impairment in severe falciparum patients after
ADP addition in vitro (Srichaikul et al. 1988). P. falciparum induces
systemic acute endothelial cell activation and the release of activated von
Willerbrand factor (vWF) immediately after the onset of the blood-stage infection
(Mast et al. 2007). Even without consumptive coagulopathy, the increase in soluble
glycoprotein-1b (GP1b) concentrations results from vWF-mediated GP1b shedding,
a process that may prevent excessive adhesion of platelets and parasitised erythrocytes
(Mast et al. 2010). Antimalarial drugs have also been shown as potential inhibitors
of platelet aggregation in vivo and in vitro, what precludes careful inclusion
and exclusion criteria of patients to be used in clinical research (Cummins
et al. 1990).
The relationship
between thrombocytopenia and severe malaria - Severe thrombocytopenia (platelet
count under 50,000/mm3), despite not being considered severe malaria
according to World Health Organization criteria (WHO 2010) due to the inability
to cause death per se, has been occasionally associated with severity
(Gerardin et al. 2002, Rogier et al. 2004) or not (Moulin et al. 2003). But
thrombocytopenia has also been described in severe vivax patients (Kochar et
al. 2005, Andrade et al. 2010). In 17 patients from Manaus affected by any of
the WHO malaria severity criteria with confirmed P. vivax monoinfection,
14 presented with thrombocytopenia, suggesting that this haematological complication
can be explored as a marker of the severity for this species (Alexandre et al.
2010). From the case reports described in Table II,
the association between severe cases with thrombocytopenia is evident. However,
that can be due to bias publication, where prospective studies would be needed
to validate this association. On the other hand, considering that many studies
point to a clear negative correlation between platelet count and parasitaemia
(Grynberg et al. 2007, Silva 2009), it should be investigated if thrombocytopenia
could be used in the surveillance of drug resistance, where higher parasitaemias
for prolonged periods are usually found. Interestingly, in areas where thrombocytopenia
and other types of clinical severity are frequently reported, resistant parasites
are also being simultaneously detected (Santana Filho et al. 2007, Tjitra et
al. 2008), possibly explaining why the prevalence of thrombocytopenia worldwide
is not homogeneous.
On the other side
of the clinical presentation of plasmodial infection, platelet counts were never
performed in asymptomatic parasite carriers. However, due to the very low parasitaemia
(sometimes submicroscopic) presented by these patients, it is possible that
platelet counts are normal and parallel clinical symptoms (Suarez-Mutis et al.
2007).
Avoiding the consensual
understanding that platelets are particles devoted to the maintenance of primary
haemostasis, it has been shown that platelets participate in the pathogenesis
of microvascular malaria, adhering to the endothelium when it is previously
stimulated with tumor necrosis factor (TNF) (Lou et al. 1997). Even in the non-stimulated
cerebral endothelium, platelets may adhere and facilitate the adhesion of P.
falciparum-parasitised RBCs, through CD36 is ubiquitous in endothelial cells
and, coincidentally, platelets (Wassmer et al. 2004). Platelets therefore act
by stabilising and strengthening bridges between RBCs and endothelial cells,
which is considered the cornerstone of severe falciparum malaria. Rosetting
of parasitised RBCs is also mediated through CD36 in platelets in severe malaria
(Pain et al. 2001, Chotivanich et al. 2004). In mice infected with P. berghei
ANKA, mice deficient of tissue and uroquinase plasminogen activators demonstrated
less capillary sequestration of platelets and less severe malaria (Piguet et
al. 2000). Blocking GPIIb with anti-CD41 monoclonal antibodies in the first
day of murine infection with P. berghei also led to higher production
of interleukin (IL)-10, IL-1α,
IL-6, interferon-α
and TNF and less mortality among mice, suggesting that platelets may act as
cofactors of severe malaria (Sun et al. 2003, van der Heyde et al. 2005). There
was also an inverse correlation between platelet count and TNF in patients with
vivax infection and no association between specific mutation G→A
in the position 308 in the TNF gene (a polymorphism whose functional
effect upon severe disease is hypothesised) and platelet count was observed.
More severe patients presented more severe thrombocytopenia and higher TNF levels
(Silva 2004). Platelets stimulated by parasitised RBCs may also trigger apoptosis
in endothelial cells pre-treated with TNF in a pathway mediated by tumor growth
factor (TGF)-β1
from platelets (Wassmer et al. 2006a, b). Recent evidence showing P. vivax-infected
RBCs adhering to lung endothelial cells and to the placental tissue ex vivo
indicates that in vivax, mechanisms similar to those associated with falciparum
severity may be involved (Carvalho et al. 2010). The contribution of platelets
to this adhesion, however, requires further investigation.
In children in
Kenya suffering from falciparum malaria, an inverse correlation between platelet
count and plasmatic IL-10 was seen (Casals-Pascual et al. 2006). This interpretation
is not straightforward, because IL-10 is generally associated with protection
against severe disease. The authors hypothesise, though, that IL-10 could reduce
platelet counts to avoid infected-RBC adhesion to the endothelium, as if thrombocytopenia
was a mechanism of defence against severe disease and not the cause. Studies
of vivax infection have shown thrombocytopenia to be associated with an increase
in IL-1, IL-6, IL-10 and TGF-β
(Park et al. 2003).
The role of platelet-derived
microparticles (MPs) (submicron-sized vesicles released from cells upon activation
or apoptosis) has yet to be determined in vivo. There is evidence that these
MPs participate in the endothelial activation responsible for severe cerebral
malaria in murine models (Combes et al. 2006). MPs were also associated with
coma and thrombocytopenia in severe falciparum malaria patients (Pankoui Mfonkeu
et al. 2010). Apparently, there is an increase in the amount of MPs in vivax
malaria patients, which may play a role in the acute inflammatory symptoms of
this disease (Campos et al. 2010); this role requires further investigation.
Clinical management
of malarial thrombocytopenia - To date, there is no robust evidence on how
to manage patients with malaria and thrombocytopenia. Platelet transfusion has
been widely followed, but with no confirmed efficacy. The indication of prophylactic
platelet transfusion when platelet counts are under 10,000/mm3 probably
applies only when the bone marrow is compromised and is not able to release
efficacious platelets (Rebulla 2000). This does not seem to be the case in malaria.
Keeping platelet counts between 50,000 and 100,000/mm3 is a formal
indication only in patients undergoing surgical procedures (Rebulla 2001). In
a tertiary care centre in the Western Brazilian Amazon over a 12-month period,
10.4% (20/191) of patients who received platelet transfusion were diagnosed
with vivax or falciparum malaria (Lacerda et al. 2006). The dosage was usually
below that recommended in the literature (Schlossberg & Herman 2003). In
40% of patients, the only justifications for transfusion were maintaining a
platelet count below 10,000/mm3 and discrete bleeding. In a further
6% of patients, only a very low platelet count was described. In this group
of 40% of patients, the alleged reason was minor bleeding despite having non-severe
thrombocytopenia; in 33%, no indication was verified. These data point to the
little existing evidence of the recommendations for platelet transfusion in
these patients. The corrected count increment to evaluate transfusion efficacy
was not calculated for any patient. The low efficacy of platelet transfusion
in general is well described for several acute infectious diseases (de Paula
et al. 1993), probably due to peripheral immune mechanisms of destruction that
do not spare the transfused platelets. Indications for platelet transfusion
in cases when DIC is suspected and diagnosed, the formal clinical indication
persists, as recommended elsewhere (Franchini 2005). Due to the impossibility
of using frozen platelets in routine clinical practice, other platelet substitutes
and preparations are being investigated (Blajchman 2003). Except in atypical
cases of ITP with severe bleeding, there is no evidence for the use of human
intravenous immunoglobulin, even in cases of severe thrombocytopenia (Lacerda
et al. 2004).
The use of corticoids
has never been followed, probably due to the fact that the recovery of thrombocytopenia
following antimalarial treatment is seen in almost all cases, with good prognosis
for all species that infect humans (Lacerda 2007) and with the lack of robust
evidence of immune-mediated destruction of platelets as a major mechanism. It
was also found that in patients with cerebral falciparum malaria, dexamethasone
exacerbated the neurological symptoms and increased the frequency of gastrointestinal
bleeding (Warrell et al. 1982, Hoffman et al. 1988). However, in none of these
studies was platelet recovery analysed as a secondary endpoint.
Immune modulators
are also candidates in the adjuvant antimalarial therapy (Muniz-Junqueira et
al. 2005, Mohanty et al. 2006), based on the drug-induced inhibition of adhesion
molecules in RBCs and platelets (Muniz-Junqueira 2007). The exploration of drugs
known by their anti-inflammatory effect, modulating TNF, e.g., pentoxyfylline
and thalidomide, upon severe malaria, could not only contribute to the understanding
of the mechanisms of severity but also clarify the association between platelets
and severe disease.
Thrombocytopenia
in other infectious diseases - Many other acute and chronic infectious diseases
share similar thrombocytopenia as part of the clinical picture and these mechanisms
may be used by proxy to explain malarial disease.
Chronic thrombocytopenia
is found in approximately 10% of patients with human immunodeficiency virus
(HIV)-1 infection and in one-third of those with acquired immunodeficiency syndrome
(Scaradavou 2002). The first cases of homosexuals with profound thrombocytopenia
in New York were classified as ITP (Karpatkin 2002), involving the presence
of serum IgG anti-GPIIIa (Karpatkin et al. 1995). Later on, this IgG was found
to be directed against GPIIIa49-66 (Nardi et al. 1997). More recently,
molecular mimicry was proposed between nef HIV-1 protein and GPIIIa49-66
(Li et al. 2005). Other chronic infectious diseases known to cause
thrombocytopenia include chronic viral hepatitis, where CIC (Samuel et al. 1999)
and PAIgG (Doi et al. 2002) are also implicated. In the case of hepatitis C
virus infection, the blockage in the maturation of megakaryocytes is mediated
by the viral RNA itself (Almeida 2003). Despite an associated medullary compromise
in visceral leishmaniasis in the canine model of Leishmania infantum
infection, anti-platelet IgG and IgM were also observed (Terrazzano et al. 2006).
In acute infection with Trypanosoma cruzi, frequent thrombocytopenia
is related to the presence of parasite trans-sialidase (Tribulatti et al. 2005).
Furthermore, during infection with any of the four dengue viruses, thrombocytopenia
is frequent and is supposed to be a criterion of dengue hemorrhagic fever (Mourão
et al. 2007). Platelet phagocytosis ex vivo has already been shown as a potential
mechanism in this acute viral disease (Honda et al. 2009). Thrombocytopenia
is also observed in leptospirosis (Nicodemo 1993), typhoid fever (Huang &
DuPont 2005), hantavirus infection (Santos et al. 2006), yellow fever (Monath
2001) and sepsis (Becchi et al. 2006), whose mechanisms are poorly understood.
The high frequency of thrombocytopenia in other infectious diseases, as a rule,
changes the paradigm that platelets are essential only to haemostasis, supporting
their role as important contributors to modulate the immune response. In any
case, studies focusing on the pathogenesis of thrombocytopenia in malarial patients
should always rule out other concomitant infectious diseases, which is difficult
in socio-economically deprived study populations suffering large burdens of
multiple diseases.
The frequency of
thrombocytopenia (i.e., platelet count below 150,000/mm3) in malarial
infection ranges from 24-94% in the literature, despite the low occurrence of
severe bleeding, even in the case of severe malaria. It is still unclear whether
this haematological complication is more frequent in P. vivax or P.
falciparum malaria. In Figure, the major mechanisms involved
in the pathogenesis are highlighted, but further studies are still needed to
clarify the impact of each mechanism and its clinical relevance. The clinical
management of malarial thrombocytopenia is expectant and the level of evidence
for platelet transfusion is insufficient to recommend this practice. It is not
clear whether platelets are diminished during acute malarial infection as a
consequence of the immune response to the parasite present or whether platelets
are actually involved in the generation of severe disease.
Acknowledgements
To Alex Kumar,
for critical and linguistic review of the manuscript, and to Mary Galinski,
for inspiring the title. This review is dedicated to Simon Karpatkin and Vanize
Oliveira Macêdo.
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