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Thrombocytopenia in malaria: who cares? Heitor Vieira Dourado, Av. Despite not being a criterion for severe malaria, thrombocytopenia is one of the most common complications of both Plasmodium vivax and Plasmodium falciparum malaria.

Minor bleeding is mentioned in case reports of patients with P. 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. 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. 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.

Since the beginning of the s, there have been reports proposing that malaria-associated thrombocytopenia is quite similar in P. However, more recent data in India has shown how thrombocytopenia exhibited a heightened frequency and severity among patients with P. In , 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 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 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 s, 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 , Silva , Kochar et al. Only one study has ruled out other common causes of thrombocytopenia that are also endemic in the studied area Lacerda 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. In , of 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.

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.

In Manaus, , 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. 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.

Some data suggested that platelets were sequestered in the spleen during the acute infection Skudowitz et al. In the experimental model with Plasmodium chabaudi , thrombocytopenia was absent in splenectomised mice, showing that the spleen was essential for thrombocytopenia Watier et al. 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 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. In the comparison of spleens from patients with severe falciparum malaria vs. The mechanisms related to the formation of splenic hematomas are mostly associated with P. In vivax malaria, the role of the spleen in the expression of vir genes is still unrecognised. 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.

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. 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. 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. In the few studies that examined the bone marrow for this purpose, megakaryocytic lineage was apparently preserved Naveira , Beale et al.

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. Additional data from FBC samples in vivax patients showed that there is a significant negative correlation between platelet count and mean platelet volume Lacerda , 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. 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. Antibody-mediated platelet destruction - There is evidence that platelet-associated IgG PAIgG is increased in malaria and is associated with thrombocytopenia.

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 , Conte et al. The detection of auto-antibodies against platelets by flow cytometry Rios-Orrego et al.

Molecular mimicry, however, provides evolutionary advantage for microorganisms that escape immune aggression Daniel-Ribeiro 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 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 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.

In an experimental model with Plasmodium berghei , the same correlation between platelet count and IC's was evidenced Grau et al. No association was found with IgM Beale et al.

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. 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 , Silva corroborates ICs as a potential mechanism of platelet destruction.

The presence of amino acid residues tyrosine [9Y ] and serine [S ] on apical membrane antigen-1 AMA-1 was significantly associated with normal platelet counts in P. 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.

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. 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. 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.

In a study of patients with acute falciparum malaria, there was a negative correlation between platelet count and nitrogen reactive intermediates Santos 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.

Actually, the incubation of platelets with P. 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.

Contradictory data were presented showing aggregation impairment in severe falciparum patients after ADP addition in vitro Srichaikul et al. 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.

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.

But thrombocytopenia has also been described in severe vivax patients Kochar et al. 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. 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.

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.

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. Even in the non-stimulated cerebral endothelium, platelets may adhere and facilitate the adhesion of P.

Platelets therefore act by stabilising and strengthening bridges between RBCs and endothelial cells, which is considered the cornerstone of severe falciparum malaria.

In mice infected with P.


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