Mem Inst Oswaldo Cruz, Rio de Janeiro, 106 (Suppl.I) August 2011
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

Page: 52-63 DOI: 10.1590/S0074-02762011000900007
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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.

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 ?-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-1?, IL-6, interferon-? 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)-?1 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-? (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.




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.



Aggarwal A, Rath S, Shashiraj 2005. Plasmodium vivax malaria presenting with severe thrombocytopenia. J Trop Pediatr 51: 120-121.

Alecrim MGC 2000. Clinical aspects, resistance and parasitary polymorphism of Plasmodium vivax malaria in Manaus, PhD Thesis, Universidade de Brasília, Brasília, 176 pp.

Alexandre MA, Ferreira CO, Siqueira AM, Magalhaes BL, Mourao MPG, Lacerda MVG, Alecrim MGC 2010. Severe Plasmodium vivax malaria, Brazilian Amazon. Emerg Infect Dis 16: 1611-1614.

Almeida AJ 2003. Trombocitopenia associada ao HCV: aspectos clínico-laboratoriais e virológicos, MD Thesis, Fundação Oswaldo Cruz, Rio de Janeiro, 110 pp.

Andrade BB, Reis-Filho A, Souza-Neto SM, Clarencio J, Camargo LM, Barral A, Barral-Netto M 2010. Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance. Malar J 9: 13.

Anstey NM, Currie BJ, Dyer ME 1992. Profound thrombocytopenia due to Plasmodium vivax malaria. Aust N Z J Med 22: 169-170.

Araujo CF, Lacerda MV, Abdalla DS, Lima ES 2008. The role of platelet and plasma markers of antioxidant status and oxidative stress in thrombocytopenia among patients with vivax malaria. Mem Inst Oswaldo Cruz 103: 517-521.

Araújo Filho JA, Bressan FR, Tourinho TM, Souza MVL, Pereira LI 2003. Plaquetopenia acentuada associada à malária pelo P. vivax. Anais do XIII Congresso Brasileiro de Infectologia, Goiânia. Braz J Infect Dis 7 (Suppl. 1): 25.

Bashawri LA, Mandil AA, Bahnassy AA, Ahmed MA 2002. Malaria: hematological aspects. Ann Saudi Med 22: 372-376.

Batista D 1946. O paludismo na Amazônia: contribuição à epidemiologia, à protozoologia e à clínica; estudo sôbre a febre biliosa-hemoglobinúrica; síntese, Imprensa Nacional, Rio de Janeiro, 212 pp.

Beale PJ, Cormack JD, Oldrey TB 1972. Thrombocytopenia in malaria with immunoglobulin (IgM) changes. BMJ 1: 345-349.

Becchi C, Al Malyan M, Fabbri LP, Marsili M, Boddi V, Boncinelli S 2006. Mean platelet volume trend in sepsis: is it a useful parameter? Minerva Anestesiol 72: 749-756.

Bhatia V, Bhatia J 2010. Severe thrombocytopenia with bleeding manifestations in two children secondary to Plasmodium vivax. Platelets 21: 307-309.

Blajchman MA 2003. Substitutes and alternatives to platelet transfusions in thrombocytopenic patients. J Thromb Haemost 1: 1637-1641.

Brown KM, Kreier JP 1982. Plasmodium berghei malaria: blockage by immune complexes of macrophage receptors for opsonized plasmodia. Infect Immun 37: 1227-1233.

Campos FM, Franklin BS, Teixeira-Carvalho A, Filho AL, de Paula SC, Fontes CJ, Brito CF, Carvalho LH 2010. Augmented plasma microparticles during acute Plasmodium vivax infection. Malar J 9: 327.

Carvalho BO, Lopes SC, Nogueira PA, Orlandi PP, Bargieri DY, Blanco YC, Mamoni R, Leite JA, Rodrigues MM, Soares IS, Oliveira TR, Wunderlich G, Lacerda MV, Del Portillo HA, Araujo MO, Russell B, Suwanarusk R, Snounou G, Renia L, Costa FT 2010. On the cytoadhesion of Plasmodium vivax-infected erythrocytes. J Infect Dis 202: 638-647.

Casals-Pascual C, Kai O, Newton CR, Peshu N, Roberts DJ 2006. Thrombocytopenia in falciparum malaria is associated with high concentrations of IL-10. Am J Trop Med Hyg 75: 434-436.

Chagas C 1903. Hematological studies of impaludism, MD Thesis, Manguinhos Institute, Rio de Janeiro, 143 pp.

Chotivanich K, Sritabal J, Udomsangpetch R, Newton P, Stepniewska KA, Ruangveerayuth R, Looareesuwan S, Roberts DJ, White NJ 2004. Platelet-induced autoagglutination of Plasmodium falciparum-infected red blood cells and disease severity in Thailand. J Infect Dis 189: 1052-1055.

Combes V, Coltel N, Faille D, Wassmer SC, Grau GE 2006. Cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier. Int J Parasitol 36: 541-546.

Conte R, Tassi C, Belletti D, Ricci F, Tazzari PL 2003. Autoimmune thrombocytopenia in malaria. Vox Sang 85: 221.

Cummins D, Faint R, Yardumian DA, Dawling S, Mackie I, Machin SJ 1990. The in vitro and ex vivo effects of chloroquine sulphate on platelet function: implications for malaria prophylaxis in patients with impaired haemostasis. J Trop Med Hyg 93: 112-115.

D'Acremont V, Landry P, Mueller I, Pecoud A, Genton B 2002. Clinical and laboratory predictors of imported malaria in an outpatient setting: an aid to medical decision making in returning travelers with fever. Am J Trop Med Hyg 66: 481-486.

Daniel-Ribeiro CT 2000. Is there a role for autoimmunity in immune protection against malaria? Mem Inst Oswaldo Cruz 95: 199-207.

Daniel-Ribeiro CT, Zanini G 2000. Autoimmunity and malaria: what are they doing together? Acta Trop 76: 205-221.

Davidson RA 1985. Immunology of parasitic infections. Med Clin North Am 69: 751-758.

de Paula LV, Klafke A, Bordin R, Pereira JPM, Job FM 1993. Avaliação da eficácia das transfusões de concentrados de plaquetas nos Serviços de Hematologia e Hemoterapia do Hospital de Clínicas de Porto Alegre. Bol Soc Bras Hematol Hemoter 15: 9-13.

del Portillo HA, Lanzer M, Rodriguez-Malaga S, Zavala F, Fernandez-Becerra C 2004. Variant genes and the spleen in Plasmodium vivax malaria. Int J Parasitol 34: 1547-1554.

Dennis LH, Eichelberger JW, Inman MM, Conrad ME 1967. Depletion of coagulation factors in drug-resistant Plasmodium falciparum malaria. Blood 29: 713-721.

Doi T, Homma H, Mezawa S, Kato J, Kogawa K, Sakamaki S, Niitsu Y 2002. Mechanisms for increment of platelet associated IgG and platelet surface IgG and their implications in immune thrombocytopenia associated with chronic viral liver disease. Hepatol Res 24: 23.

Echeverri M, Tobon A, Alvarez G, Carmona J, Blair S 2003. Clinical and laboratory findings of Plasmodium vivax malaria in Colombia 2001. Rev Inst Med Trop Sao Paulo 45: 29-34.

Engwerda CR, Beattie L, Amante FH 2005. The importance of the spleen in malaria. Trends Parasitol 21: 75-80.

Erel O, Kocyigit A, Bulut V, Avci S, Aktepe N 1998. Role of lipids, lipoproteins and lipid peroxidation in thrombocytopenia in patients with vivax malaria. Haematologia (Budap) 29: 207-212.

Erel O, Vural H, Aksoy N, Aslan G, Ulukanligil M 2001. Oxidative stress of platelets and thrombocytopenia in patients with vivax malaria. Clin Biochem 34: 341-344.

Essien EM, Ebhota MI 1981. Platelet hypersensitivity in acute malaria (Plasmodium falciparum) infection in man. Thromb Haemost 46: 547-549.

Fajardo LF, Tallent C 1974. Malarial parasites within human platelets. J Am Med Assoc 229: 1205-1207.

Franchini M 2005. Pathophysiology, diagnosis and treatment of disseminated intravascular coagulation: an update. Clin Lab 51: 633-639.

George P, Alexander LM 2010. A study on the clinical profile of complicated Plasmodium vivax mono-infections. Asian Pac J Trop Med 3: 560-562.

Gerardin P, Rogier C, Ka AS, Jouvencel P, Brousse V, Imbert P 2002. Prognostic value of thrombocytopenia in African children with falciparum malaria. Am J Trop Med Hyg 66: 686-691.

Gonzalez B, Rodulfo H, De Donato M, Berrizbeitia M, Gomez C, Gonzalez L 2009. Hematologic variations in patient with malaria caused by Plasmodium vivax before, during and after treatment. Invest Clin 50: 187-201.

Gonzalez LM, Guzman M, Carmona J, Lopera T, Blair S 2000. Clinical and epidemiologic characteristics of 291 hospitalized patients for malaria in Medellin (Colombia). Acta Med Colomb 25: 163-170.

Grau GE, Piguet PF, Gretener D, Vesin C, Lambert PH 1988. Immunopathology of thrombocytopenia in experimental malaria. Immunology 65: 501-506.

Greenwood BM 1968. Autoimmune disease and parasitic infections in Nigerians. Lancet 2: 380-382.

Grynberg P, Fernandes Fontes CJ, Braga EM 2007. Association between particular polymorphic residues on apical membrane antigen 1 (AMA-1) and platelet levels in patients with vivax malaria. Clin Microbiol Infect 13: 1089-1094.

Harish R, Gupta S 2009. Plasmodium vivax malaria presenting with severe thrombocytopenia, cerebral complications and hydrocephalus. Indian J Pediatr 76: 551-552.

Hill GJ, Knight V, Jeffery GM 1964. Thrombocytopenia in vivax malaria. Lancet 39: 240-241.

Hoffman SL, Rustama D, Punjabi NH, Surampaet B, Sanjaya B, Dimpudus AJ, McKee KT, Jr., Paleologo FP, Campbell JR, Marwoto H 1988. High-dose dexamethasone in quinine-treated patients with cerebral malaria: a double-blind, placebo-controlled trial. J Infect Dis 158: 325-331.

Holland BH, Walker AN, Collier L, Stephens JL 2004. Severe thrombocytopenia and epistaxis secondary to Plasmodium vivax infection. Internet J Infect Dis 3. Available from:

Honda S, Saito M, Dimaano EM, Morales PA, Alonzo MT, Suarez LA, Koike N, Inoue S, Kumatori A, Matias RR, Natividad FF, Oishi K 2009. Increased phagocytosis of platelets from patients with secondary dengue virus infection by human macrophages. Am J Trop Med Hyg 80: 841-845.

Huang DB, DuPont HL 2005. Problem pathogens: extra-intestinal complications of Salmonella enterica serotype typhi infection. Lancet Infect Dis 5: 341-348.

Inyang AL, Sodeinde O, Okpako DT, Essien EM 1987. Platelet reactions after interaction with cultured Plasmodium falciparum infected erythrocytes. Br J Haematol 66: 375-378.

Jadhav UM, Patkar VS, Kadam NN 2004. Thrombocytopenia in malaria - correlation with type and severity of malaria. J Assoc Physicians India 52: 615-618.

Jaff MS, McKenna D, McCann SR 1985. Platelet phagocytosis: a probable mechanism of thrombocytopenia in Plasmodium falciparum infection. J Clin Pathol 38: 1318-1319.

Kakar A, Bhoi S, Prakash V, Kakar S 1999. Profound thrombocytopenia in Plasmodium vivax malaria. Diagn Microbiol Infect Dis 35: 243-244.

Karpatkin S 2002. HIV-1 related thrombocytopenia. In AD Michelson, Platelets, Elsevier Academic Press, California, p. 559-570.

Karpatkin S, Nardi MA, Hymes KB 1995. Sequestration of anti-platelet GPIIIa antibody in rheumatoid factor immune complexes of human immunodeficiency virus 1 thrombocytopenic patients. Proc Natl Acad Sci USA 92: 2263-2267.

Katira B, Shah I 2006. Thrombocytopenia in Plasmodium vivax infected children. J Vector Borne Dis 43: 147-149.

Kaur D, Wasir V, Gulati S, Bagga A 2007. Unusual presentation of Plasmodium vivax malaria with severe thrombocytopenia and acute renal failure. J Trop Pediatr 53: 210-212.

Kelton JG, Keystone J, Moore J, Denomme G, Tozman E, Glynn M, Neame PB, Gauldie J, Jensen J 1983. Immune-mediated thrombocytopenia of malaria. J Clin Invest 71: 832-836.

Khan FY, Lutof AK, Yassin MA, Khattab MA, Saleh M, Rezeq HY, Almaslamani M 2009. Imported malaria in Qatar: a one year hospital-based study in 2005. Travel Med Infect Dis 7: 111-117.

Kochar DK, Das A, Kochar A, Middha S, Acharya J, Tanwar GS, Gupta A, Pakalapati D, Garg S, Saxena V, Subudhi AK, Boopathi PA, Sirohi P, Kochar SK 2010. Thrombocytopenia in Plasmodium falciparum, Plasmodium vivax and mixed infection malaria: a study from Bikaner (Northwestern India). Platelets 21: 623-627.

Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV, Das A 2005. Plasmodium vivax malaria. Emerg Infect Dis 11: 132-134.

Koltas IS, Demirhindi H, Hazar S, Ozcan K 2007. Supportive presumptive diagnosis of Plasmodium vivax malaria. Thrombocytopenia and red cell distribution width. Saudi Med J 28: 535-539.

Komoda M, Fujimoto T, Kawaguchi Y, Tsushima H, Fukushima T, Hata T, Miyazaki Y, Tsukasaki K, Tomonaga M 2006. Plasmodium vivax malaria with clinical presentation mimicking acute type idiopathic thrombocytopenic purpura (abstract). Rinsho Ketsueki 47: 1453-1456.

Kortepeter M, Brown JD 1998. A review of 79 patients with malaria seen at a military hospital in Hawaii from 1979 to 1995. Mil Med 163: 84-89.

Kreil A, Wenisch C, Brittenham G, Looareesuwan S, Peck-Radosavljevic M 2000. Thrombopoietin in Plasmodium falciparum malaria. Br J Haematol 109: 534-536.

Kumar A, Shashirekha 2006. Thrombocytopenia: an indicator of acute vivax malaria. Indian J Pathol Microbiol 49: 505-508.

Lacerda MV, Alexandre MA, Santos PD, Arcanjo AR, Alecrim WD, Alecrim MGC 2004. Idiopathic thrombocytopenic purpura due to vivax malaria in the Brazilian Amazon. Acta Trop 90: 187-190.

Lacerda MV, Hipolito JR, Passos LN 2008. Chronic Plasmodium vivax infection in a patient with splenomegaly and severe thrombocytopenia. Rev Soc Bras Med Trop 41: 522-523.

Lacerda MVG 2007. Manifestações clínicas e patogênese da plaquetopenia na malária, PhD Thesis, Universidade de Brasília, 439 pp.

Lacerda MVG, Cavalcante TB, Silva AC, Macêdo VO 2006. Avaliação das indicações de transfusão de concentrado de plaquetas. Anais do XLII Congresso da Sociedade Brasileira de Medicina Tropical, Teresina. Rev Soc Bras Med Trop 39 (Suppl. I): 104.

Lacerda MVG, Mourão MPG, Alecrim WD, Alecrim MGC 2001. Clinical study of patients with falciparum malaria admitted to the Tropical Medicine Foundation of Amazonas - Brazil. Annals of the 50th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Atlanta (USA). Am J Trop Med Hyg 65: 336.

Lacerda MVG, Oliveira SL, Alecrim MGC 2007. Splenic hematoma in a patient with Plasmodium vivax malaria. Rev Soc Bras Med Trop 40: 96-97.

Ladhani S, Lowe B, Cole AO, Kowuondo K, Newton CR 2002. Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome. Br J Haematol 119: 839-847.

Lathia TB, Joshi R 2004. Can hematological parameters discriminate malaria from nonmalarious acute febrile illness in the tropics? Indian J Med Sci 58: 239-244.

Lee SH, Looareesuwan S, Chan J, Wilairatana P, Vanijanonta S, Chong SM, Chong BH 1997. Plasma macrophage colony-stimulating factor and P-selectin levels in malaria-associated thrombocytopenia. Thromb Haemost 77: 289-293.

Li Z, Nardi MA, Karpatkin S 2005. Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood 106: 572-576.

Llanos C, Quintero G, Castellanos A, Arévalo-Herrera M, Herrera S 2006. Surgical bone marrow aspiration in Aotus lemurinus griseimembra. J Med Primatol 35: 131-135.

Lou J, Donati YR, Juillard P, Giroud C, Vesin C, Mili N, Grau GE 1997. Platelets play an important role in TNF-induced microvascular endothelial cell pathology. Am J Pathol 151: 1397-1405.

Maina RN, Walsh D, Gaddy C, Hongo G, Waitumbi J, Otieno L, Jones D, Ogutu BR 2010. Impact of Plasmodium falciparum infection on haematological parameters in children living in Western Kenya. Malar J 9 (Suppl. 3): S4.

Makkar RP, Mukhopadhyay S, Monga A, Gupta AK 2002. Plasmodium vivax malaria presenting with severe thrombocytopenia. Braz J Infect Dis 6: 263-265.

Marques HO 2004. Alterações da hemostasia em pacientes com malária, MSc Thesis, Universidade Federal de São Paulo, São Paulo, 140 pp.

Marques HO, Alexandre MAA, Oliveira VM, Marreira L, Lacerda MVG, Alecrim MGC, Morelli VM, Lourenço DM 2005. Hemostatic changes in patients with malaria. Annals of the XX Congress of the International Society on Thrombosis and Hemostasis, Sydney (Australia). J Thromb Haemost 3 (Suppl. I): 1452.

Martin-Jaular L, Ferrer M, Calvo M, Rosanas-Urgell A, Kalko S, Graewe S, Soria G, Cortadellas N, Ordi J, Planas A, Burns J, Heussler V, Del Portillo HA 2011. Strain-specific spleen remodelling in Plasmodium yoelii infections in Balb/c mice facilitates adherence and spleen macrophage-clearance escape. Cell Microbiol 13: 109-122.

Mast Q, de Groot PG, van Heerde WL, Roestenberg M, van Velzen JF, Verbruggen B, Roest M, McCall M, Nieman AE, Westendorp J, Syafruddin D, Fijnheer R, van Dongen-Lases EC, Sauerwein RW, van der Ven AJ 2010. Thrombocytopenia in early malaria is associated with GP1b shedding in absence of systemic platelet activation and consumptive coagulopathy. Br J Haematol 151: 495-503.

Mast Q, Groot E, Lenting PJ, de Groot PG, McCall M, Sauerwein RW, Fijnheer R, van der Ven A 2007. Thrombocytopenia and release of activated von Willebrand Factor during early Plasmodium falciparum malaria. J Infect Dis 196: 622-628.

Menendez C, Fleming AF, Alonso PL 2000. Malaria-related anaemia. Parasitol Today 16: 469-476.

Mohanty D, Ghosh K, Nandwani SK, Shetty S, Phillips C, Rizvi S, Parmar BD 1997. Fibrinolysis, inhibitors of blood coagulation, and monocyte derived coagulant activity in acute malaria. Am J Hematol 54: 23-29.

Mohanty D, Marwaha N, Ghosh K, Sharma S, Garewal G, Shah S, Devi S, Das KC 1988. Functional and ultrastructural changes of platelets in malarial infection. Trans R Soc Trop Med Hyg 82: 369-375.

Mohanty S, Patel DK, Pati SS, Mishra SK 2006. Adjuvant therapy in cerebral malaria. Indian J Med Res 124: 245-260.

Mohapatra MK, Padhiary KN, Mishra DP, Sethy G 2002. Atypical manifestations of Plasmodium vivax malaria. Indian J Malariol 39: 18-25.

Monath TP 2001. Yellow fever: an update. Lancet Infect Dis 1: 11-20.

Moulin F, Lesage F, Legros AH, Maroga C, Moussavou A, Guyon P, Marc E, Gendrel D 2003. Thrombocytopenia and Plasmodium falciparum malaria in children with different exposures. Arch Dis Child 88: 540-541.

Mourão MP, Lacerda MV, Macedo VO, Santos JB 2007. Thrombocytopenia in patients with dengue virus infection in the Brazilian Amazon. Platelets 18: 605-612.

Mourão MPG, Lacerda MVG, Magalhães L, Alecrim WD, Alecrim MGC 2001. Estudo clínico em crianças internadas com malária (P. falciparum) na FMT-AM. Anais do XXXVII Congresso da Sociedade Brasileira de Medicina Tropical, Salvador. Rev Soc Bras Med Trop 34 (Suppl. 1): 71.

Muniz-Junqueira MI 2007. Immunomodulatory therapy associated to anti-parasite drugs as a way to prevent severe forms of malaria. Curr Clin Pharmacol 2: 59-73.

Muniz-Junqueira MI, Silva FO, de Paula Júnior MR, Tosta CE 2005. Thalidomide influences the function of macrophages and increases the survival of Plasmodium berghei-infected CBA mice. Acta Trop 94: 128-138.

Murthy GL, Sahay RK, Srinivasan VR, Upadhaya AC, Shantaram V, Gayatri K 2000. Clinical profile of falciparum malaria in a tertiary care hospital. J Indian Med Assoc 98: 160-162.

Nardi MA, Liu LX, Karpatkin S 1997. GPIIIa(49-66) is a major pathophysiologically relevant antigenic determinant for anti-platelet GPIIIa of HIV-1-related immunologic thrombocytopenia. Proc Natl Acad Sci USA 94: 7589-7594.

Naveira JB 1970. Malária - aspectos hematológicos, Associate professorship Thesis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 104 pp.

Nicodemo AC 1993. Análise de aspectos microscópicos, imuno-histoquímicos e ultra-estruturais do pulmão na leptospirose para a compreensão da patogenia da plaquetopenia, PhD Thesis, Universidade de São Paulo, São Paulo, 153 pp.

Noronha EF 1998. Estudo clínico-epidemiológico da malária falciparum em crianças de 0 a 14 anos, atendidas no Instituto de Medicina Tropical do Amazonas em Manaus - AM - Brasil, MSc Thesis, Universidade de Brasília, Brasília, 126 pp.

Oh MD, Shin H, Shin D, Kim U, Lee S, Kim N, Choi MH, Chai JY, Choe K 2001. Clinical features of vivax malaria. Am J Trop Med Hyg 65: 143-146.

Ohtaka M, Ohyashiki K, Iwabuchi H, Iwabuchi A, Lin KY, Toyama K 1993. A case of vivax malaria with thrombocytopenia suggesting immunological mechanisms. Rinsho Ketsueki 34: 490-492.

Pain A, Ferguson DJ, Kai O, Urban BC, Lowe B, Marsh K, Roberts DJ 2001. Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc Natl Acad Sci USA 98: 1805-1810.

Panasiuk A 2001. Autoimmune thrombocytopenia in recurrent polietiological malaria (Plasmodium falciparum, Plasmodium vivax). Wiad Parazytol 47: 85-89.

Pankoui Mfonkeu JB, Gouado I, Fotso Kuate H, Zambou O, Amvam Zollo PH, Grau GE, Combes V 2010. Elevated cell-specific microparticles are a biological marker for cerebral dysfunctions in human severe malaria. PLoS ONE 5: e13415.

Parakh A, Agarwal N, Aggarwal A, Aneja A 2009. Plasmodium vivax malaria in children: uncommon manifestations. Ann Trop Paediatr 29: 253-256.

Park CHL, Ferreira CB, Bianchi CP, Fazio FS, Costa JC, Padilha A, Fonseca MO, Boulos M 2002. Plaquetopenia em pacientes com malária por Plasmodium vivax. Anais do XXXVIII Congresso da Sociedade Brasileira de Medicina Tropical, Foz do Iguaçu. Rev Soc Bras Med Trop 35 (Suppl. 1): 370.

Park JW, Park SH, Yeom JS, Huh AJ, Cho YK, Ahn JY, Min GS, Song GY, Kim YA, Ahn SY, Woo SY, Lee BE, Ha EH, Han HS, Yoo K, Seoh JY 2003. Serum cytokine profiles in patients with Plasmodium vivax malaria: a comparison between those who presented with and without thrombocytopenia. Ann Trop Med Parasitol 97: 339-344.

Patel U, Gandhi G, Friedman S, Niranjan S 2004. Thrombocytopenia in malaria. J Natl Med Assoc 96: 1212-1214.

Peck-Radosavljevic M 2001. Hypersplenism. Eur J Gastroenterol Hepatol 13: 317-323.

Piguet PF, Da Laperrousaz C, Vesin C, Tacchini-Cottier F, Senaldi G, Grau GE 2000. Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice. Infect Immun 68: 3822-3829.

Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Hasanuddin A, Warikar N, Sugiarto P, Tjitra E, Anstey NM, Price RN 2009. Vivax malaria: a major cause of morbidity in early infancy. Clin Infect Dis 48: 1704-1712.

Prasad R, Das BK, Pengoria R, Mishra OP, Shukla J, Singh TB 2009. Coagulation status and platelet functions in children with severe falciparum malaria and their correlation of outcome. J Trop Pediatr 55: 374-378.

Rasheed A, Saeed S, Khan SA 2009. Clinical and laboratory findings in acute malaria caused by various plasmodium species. J Pak Med Assoc 59: 220-223.

Rebulla P 2000. Trigger for platelet transfusion. Vox Sang 78 (Suppl. 2): 179-182.

Rebulla P 2001. Revisitation of the clinical indications for the transfusion of platelet concentrates. Rev Clin Exp Hematol 5: 288-310.

Rifakis PM, Hernandez O, Fernandez CT, Rodriguez-Morales AJ, Von A, Franco-Paredes C 2008. Atypical Plasmodium vivax malaria in a traveler: bilateral hydronephrosis, severe thrombocytopenia, and hypotension. J Travel Med 15: 119-121.

Rios-Orrego A, Alvarez-Castillo T, Carmona-Fonseca J, Blair-Trujillo S 2005. Temporal evolution of platelets and anti-platelet antibodies in patients of endemic area with non complicated malaria. An Med Interna 22: 561-568.

Robinson P, Jenney AW, Tachado M, Yung A, Manitta J, Taylor K, Biggs BA 2001. Imported malaria treated in Melbourne, Australia: epidemiology and clinical features in 246 patients. J Travel Med 8: 76-81.

Rodriguez-Morales AJ, Sanchez E, Vargas M, Piccolo C, Colina R, Arria M 2006. Anemia and thrombocytopenia in children with Plasmodium vivax malaria. J Trop Pediatr 52: 49-51.

Rodriguez-Morales AJ, Sanchez E, Vargas M, Piccolo C, Colina R, Arria M, Franco-Paredes C 2005. Occurrence of thrombocytopenia in Plasmodium vivax malaria. Clin Infect Dis 41: 130-131.

Rogier C, Gerardin P, Imbert P 2004. Thrombocytopenia is predictive of lethality in severe childhood falciparum malaria. Arch Dis Child 89: 795-796.

Samuel H, Nardi M, Karpatkin M, Hart D, Belmont M, Karpatkin S 1999. Differentiation of autoimmune thrombocytopenia from thrombocytopenia associated with immune complex disease: systemic lupus erythematosus, hepatitis-cirrhosis, and HIV-1 infection by platelet and serum immunological measurements. Br J Haematol 105: 1086-1091.

Santana Filho FS, Arcanjo AR, Chehuan YM, Costa MR, Martinez-Espinosa FE, Vieira JL, Barbosa MG, Alecrim WD, Alecrim MG 2007. Chloroquine-resistant Plasmodium vivax, Brazilian Amazon. Emerg Infect Dis 13: 1125-1126.

Santos MC, Lacerda MVG, Benedetti SM, Albuquerque BC, Aguiar Filho AA, Elkhoury MR, Rosa ES, Vasconcelos PF, Medeiros DB, Mourao MPG 2006. Human hantavirus infection, Brazilian Amazon. Emerg Infect Dis 12: 1165-1167.

Santos PD 2000. Correlação entre níveis séricos de Intermediários Reativos de Nitrogênio (IRN) e malária em pacientes da Fundação de Medicina Tropical do Amazonas (FMT/IMT-AM), MSc Thesis, Universidade Federal do Amazonas, Manaus, 133 pp.

Scaradavou A 2002. HIV-related thrombocytopenia. Blood Rev 16: 73-76.

Schlossberg HR, Herman JH 2003. Platelet dosing. Transfus Apher Sci 28: 221-226.

Shaikh QH, Ahmad SM, Abbasi A, Malik SA, Sahito AA, Munir SM 2009. Thrombocytopenia in malaria. J Coll Physicians Surg Pak 19: 708-710.

Shear HL 1984. Murine malaria: immune complexes inhibit Fc receptor-mediated phagocytosis. Infect Immun 44: 130-136.

Silva IBA 2004. Malária vivax: manifestações clínicas e laboratoriais relacionadas com o fator de necrose tumoral alfa, PhD Thesis, Universidade Federal do Pará, Belém, 128 pp.

Silva SBR 2009. Avaliação da frequência e dos fatores associados à plaquetopenia causada pelo Plasmodium vivax, MSc Thesis, Universidade Federal do Mato Grosso, 64 pp.

Silva SL, Santana Filho FS, Arcanjo ARL, Alecrim WD, Alecrim MGC 2000. Perfil clínico e hematológico dos pacientes internados com malária por Plasmodium vivax e plaquetopenia, na Fundação de Medicina Tropical do Amazonas, no período de janeiro de 1997 a setembro de 1999. Anais do XXXVI Congresso da Sociedade Brasileira de Medicina Tropical, São Luís do Maranhão , Rev Soc Bras Med Trop 33 (Suppl. 1): 348.

Skudowitz RB, Katz J, Lurie A, Levin J, Metz J 1973. Mechanisms of thrombocytopenia in malignant tertian malaria. BMJ 2: 515-518.

Song JY, Park CW, Jo YM, Kim JY, Kim JH, Yoon HJ, Kim CH, Lim CS, Cheong HJ, Kim WJ 2007. Two cases of Plasmodium vivax malaria with the clinical picture resembling toxic shock. Am J Trop Med Hyg 77: 609-611.

Srichaikul T, Pulket C, Sirisatepisarn T, Prayoonwiwat W 1988. Platelet dysfunction in malaria. Southeast Asian J Trop Med Public Health 19: 225-233.

Srichaikul T, Puwasatien P, Karnjanajetanee J, Bokisch VA, Pawasatien P 1975. Complement changes and disseminated intravascular coagulation in Plasmodium falciparum malaria. Lancet 1: 770-772.

Srivastava S, Ahmad S, Shirazi N, Kumar Verma S, Puri P 2011. Retrospective analysis of vivax malaria patients presenting to tertiary referral centre of Uttarakhand. Acta Trop 117: 82-85.

Suarez-Mutis MC, Cuervo P, Leoratti FM, Moraes-Avila SL, Ferreira AW, Fernandes O, Coura JR 2007. Cross sectional study reveals a high percentage of asymptomatic Plasmodium vivax infection in the Amazon Rio Negro area, Brazil. Rev Inst Med Trop Sao Paulo 49: 159-164.

Sun G, Chang WL, Li J, Berney SM, Kimpel D, van der Heyde HC 2003. Inhibition of platelet adherence to brain microvasculature protects against severe Plasmodium berghei malaria. Infect Immun 71: 6553-6561.

Takaki K, Aoki T, Akeda H, Kajiwara T, Honda S, Maeda Y, Okada K, Sawae Y 1991. A case of Plasmodium vivax malaria with findings of DIC. Kansenshogaku Zasshi 65: 488-492.

Tan SO, McGready R, Zwang J, Pimanpanarak M, Sriprawat K, Thwai KL, Moo Y, Ashley EA, Edwards B, Singhasivanon P, White NJ, Nosten F 2008. Thrombocytopaenia in pregnant women with malaria on the Thai-Burmese border. Malar J 7: 209.

Taylor WR, Widjaja H, Basri H, Ohrt C, Taufik T, Tjitra E, Baso S, Fryauff D, Hoffman SL, Richie TL 2008. Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria. Malar J 7: 259.

Terrazzano G, Cortese L, Piantedosi D, Zappacosta S, Di Loria A, Santoro D, Ruggiero G, Ciaramella P 2006. Presence of anti-platelet IgM and IgG antibodies in dogs naturally infected by Leishmania infantum. Vet Immunol Immunopathol 110: 331-337.

Thapa R, Biswas B, Mallick D, Sardar S, Modak S 2009. Childhood Plasmodium vivax malaria with severe thrombocytopenia and bleeding manifestations. J Pediatr Hematol Oncol 31: 758-759.

Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, Lampah DA, Price RN 2008. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia. PLoS Med 5: e128.

Touze JE, Mercier P, Rogier C, Hovette P, Schmoor P, Dabanian C, Campiadgi S, Laroche R 1990. Platelet antibody activity in malaria thrombocytopenia. Pathol Biol (Paris) 38: 678-681.

Tribulatti MV, Mucci J, Van Rooijen N, Leguizamon MS, Campetella O 2005. The trans-sialidase from Trypanosoma cruzi induces thrombocytopenia during acute Chagas' disease by reducing the platelet sialic acid contents. Infect Immun 73: 201-207.

Tyagi P, Biswas S 1999. Naturally occurring plasmodia-specific circulating immune complexes in individuals of malaria endemic areas in India. Indian J Malariol 36: 12-18.

Urban BC, Hien TT, Day NP, Phu NH, Roberts R, Pongponratn E, Jones M, Mai NTH, Bethell D, Turner GDH, Ferguson D, White NJ, Roberts DJ 2005. Fatal Plasmodium falciparum malaria causes specific patterns of splenic architectural disorganization. Infect Immun 73: 1986-1994.

van der Heyde HC, Gramaglia I, Sun G, Woods C 2005. Platelet depletion by anti-CD41 (alphaIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering the levels of pathogenic cytokines. Blood 1

Received 1 April 2011
Accepted 26 May 2011
Financial support: CAPES (scholarship for HCCC), CNPq (MVGL is a level 2 research productivity fellow), ASH


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