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  • Open Access

Tumour necrosis factor, interleukin-6 and interleukin-10 are possibly involved in Plasmodium vivax-associated thrombocytopaenia in southern Pakistani population

  • 1,
  • 2,
  • 1,
  • 1 and
  • 1Email author
Malaria Journal201413:323

https://doi.org/10.1186/1475-2875-13-323

  • Received: 24 May 2014
  • Accepted: 5 August 2014
  • Published:

Abstract

Background

In Pakistan, Plasmodium vivax is endemic causing approximately 70% of the malaria cases. A number of haematological changes, especially thrombocytopaenia have been reported for P. vivax. Several host factors including cell-mediated immune cells, such as IL-1, IL-6 and IL-10 have been documented for P. vivax-induced thrombocytopaenia. However, study on correlation of cytokines and thrombocytopaenia in P. vivax, particularly in patients with severe signs and symptoms has not been reported from Pakistan.

Methods

A case control study to correlate TNF, IL-6 and IL-10 in healthy controls and thrombocytopaenic P. vivax-infected patients (both uncomplicated and complicated cases) from southern Pakistan was carried out during January 2009 to December 2011. One Hundred and eighty two patients presenting with microscopy-confirmed asexual P. vivax mono-infection and 100 healthy controls were enrolled in the study at Aga Khan University Hospital, Karachi. Enzyme-linked immunosorbent assay (ELISA) was performed for determination of TNF, IL-6 and IL-10 levels.

Results

Out of 182 cases, mild thrombocytopaenia (platelet count 100,000-150,000 mm3) was observed in ten (5.5%), moderate (50,000-100,000 mm3) in 93 (51.1%), and profound thrombocytopaenia (<50,000 mm3) was detected in 79 (43.4%) patients. IL-6 and IL-10 levels were found approximately three-fold higher in the mild cases compared to healthy controls. Two-fold increase in TNF and IL-10 (p < 0.0001) was observed in profound thrombocytopaenic when compared with moderate cases, while IL-6 was not found to be significantly elevated.

Conclusion

Cytokines may have a possible role in P. vivax-induced thrombocytopaenia in Pakistani population. Findings from this study give first insight from Pakistan on the role of cytokines in P.vivax-associated thrombocytopaenia. However, further studies are required to understand the relevance of cytokines in manifestations of thrombocytopaenia in P. vivax malaria.

Keywords

  • Plasmodium vivax
  • Thrombocytopaenia
  • Cytokines

Background

Plasmodium vivax malaria is an important public health problem worldwide causing an estimated 80–215 million clinical cases annually [1]. Malaria is endemic throughout Pakistan with an estimated 4.5 million suspected cases reported by the World Health Organization (WHO). Both P. vivax and Plasmodium falciparum co-exist, with P. vivax being the major contributor (70%) of malaria burden in all areas [1].

Clinical symptoms commonly associated with vivax malaria include fever, malaise, chills, acute respiratory distress (ARDS), acute renal failure, coma, death, while frequent haematological disturbance observed include anaemia and thrombocytopaenia [2]. Various malaria-endemic countries, including Indonesia, Columbia, Kenya, India, and Pakistan, have documented high frequency of thrombocytopaenia in malaria patients [313]. Furthermore, case reports describing clinical manifestations of thrombocytopaenia due to P. vivax have been described indicating the significance of the respective parameter in vivax malaria [1421]. Recent studies have also highlighted the usefulness of thrombocytopaenia as a plausible clinical marker of malaria diagnosis with significant sensitivity, specificity, positive, and negative predictive values [2224].

Thrombocytopaenia in P. vivax is frequently observed (24-94%) however; mechanisms associated with malaria thrombocytopaenia are not clear at present. Speculated mechanisms include coagulopathy, splenic sequestration of injured platelets, bone-marrow alterations, platelet aggregation, antibody-mediated platelet destruction and oxidative stress [3, 25]. Association of cell-mediated immune cells, such as interlukin-1 (IL-1), IL-6, IL-10, tumour necrosis factor (TNF) and transforming growth factor-β (TGF-β) and thrombocytopaenia have been documented in various studies [3, 2628]. There is a paucity of baseline data on various aspects of P. vivax, including cytokine profile, correlation of immunological response and haematological manifestations. Therefore, the aim of this study was to determine and correlate baseline levels of TNF, IL-6 and IL-10 in healthy controls and thrombocytopaenic P. vivax-infected patients from southern Pakistan. The cytokines data presented in this study is part of ongoing project previously published baseline profiles of biomarkers in malaria patients. (37) In this study cytokine data was used for correlation with thrombocytopaenia.

Methods

Study design, settings and case definitions

A case control study using plasma samples from well characterized groups suffering from P. vivax infection including uncomplicated cases (n = 100), complicated cases (n = 82) and healthy controls (n = 100) was conducted during January 2009 to December 2011 at The Aga Khan University and Hospital, Karachi. Baseline plasma levels of TNF, IL-6 and IL-10 were compared and correlated between healthy controls and thrombocytopaenic P. vivax-infected patients (both complicated and uncomplicated cases). Thrombocytopaenia was categorized as mild, moderate and profound on the basis of reference ranges used in The Aga Khan University and Hospital, Karachi.

Reference ranges for thrombocytopaenia:

Mild: platelet count range between 100,000 mm3 and 150,000 mm3

Moderate: platelet count range between 50,000 mm3 and 100,000 mm3

Profound: platelet count range <50,000 mm3

Case definitions

Healthy controls

Individuals tested negative on screening test for Hepatitis B, C, human immunodeficiency virus (HIV), syphilis, malaria and having platelet counts >150,000 mm3 were recruited as healthy controls.

Uncomplicated malaria

Febrile patients tested slide and PCR positive for P. vivax infection but no malarial complication were recruited as uncomplicated cases.

Complicated malaria

Patients tested slide and PCR positive for P. vivax infection and admitted to the Aga Khan University Hospital, Karachi with one or more symptoms of complicated malaria (WHO guidelines) were enrolled as complicated cases.

Both complicated and uncomplicated cases were further stratified on the basis of thrombocytopaenia status. Cases and controls with no co-morbid/associated diagnosis were enrolled in the study. Pregnant women were excluded from the study.

Ethical considerations

The study was approved by the Ethical Review Committee of Aga Khan University Hospital and conducted in accordance with the Good Clinical Practice of Declaration of Helsinki [29]. Informed consent was obtained from enrolled patients.

Sample collection and microcopy

Approximately 2 ml of intravenous blood sample in EDTA tube was collected. Initial presence of malaria parasites was established by Leishman’s staining while further species identification was determined by Giemsa staining of thick and thin blood smears [30]. Plasma was collected by centrifuging remaining blood at 3,500 rpm for 15 minutes. Blood and plasma aliquots were stored at -80°C until further analysis. Platelet count of cases and controls was performed using coulter counter (Beckman Coulter Inc, USA).

DNA extraction and PCR

DNA was extracted from 200 μl of whole blood using QiAamp DNA Mini Kit according to manufacturer’s instructions (Qiagen, USA). Confirmation of P. vivax mono-infection was performed using a species-specific PCR [31].

ELISA for quantification of inflammatory cytokines

TNF, IL-6 and IL-10 were detected in plasma of healthy controls and cases by using standards and ELISA reagents obtained from Endogen (Rockford, IL, USA). Cytokines were measured using a sandwich ELISA technique according to the manufacturer’s instructions and as reported previously [32]. Recombinant human cytokine was used to obtain a dose response curve with a range of detection from 3.9-1,000 pg/ml. All experimental samples were tested in duplicate.

Statistical analysis

Data were entered in Microsoft Excel and Graph Pad Prism version 5.0 was used for performing further analysis. Arithmetical means and medians were calculated, where applicable, for all continuous baseline demographic variables. Kruskal-Wallis test with Dunn’s multiple comparison was used to compare concentrations of cytokines between study groups. Mann Whitney U test was used to verify differences between cases and controls. Correlation between cytokines and thrombocytopaenia in complicated cases was performed using Spearman’s Rank correlation analysis.

Results

Baseline demographics

A total of 200 microscopically confirmed P. vivax cases were enrolled in the study. Amongst these, 182 samples tested PCR positive for P. vivax mono-infection and were thus further analysed. One-hundred healthy controls were also enrolled for the study.

Thrombocytopaenia profile

Thrombocytopaenia of varying intensity was detected in all cases. Out of 182 cases, mild thrombocytopaenia was observed in ten (5.5%), moderate thrombocytopaenia in 93 (51.1%), and profound thrombocytopaenia was detected in 79 (43.4%) patients. Comparison of haematological parameters between moderate and profound thrombocytopaenia groups showed significant decrease in haemoglobin and red blood cell count while other parameters did not show any significant difference between the study groups. Baseline demographics and haematological parameters of healthy controls and enrolled patients are given in Table 1.
Table 1

Baseline demographics and hematological parameters of the study groups

 

Healthy Controls (HC)

Malaria cases (thrombocytopaenia)

P value

Mild (MI)

Moderate (M)

Profound (P)

M vs P

N

100

10

93

79

 

Haemoglobin

12.29 ± 1.99

12.38 ± 1.80

12.65 ± 1.63

11.68 ± 2.19

0.002*

RBC

4.38 ± 0.43

4.46 ± 0.69

4.39 ± 0.50

4.05 ± 0.70

0.000*

WBC

5.94 ± 2.43

7.05 ± 2.31

5.99 ± 2.72

5.8 ± 3.11

0.658

Neutrophils

63.5 ± 15

59.38 ± 12.3

72.0 ± 13.78

68.44 ± 14.2

0.098

Lymphocytes

21.7 ± 11.4

26.56 ± 9.93

19.25 ± 11.16

22.27 ± 11.19

0.079

Eosinophils

0.97 ± 1.16

0.66 ± 0.55

0.82 ± 1.22

0.92 ± 0.96

0.554

Monocytes

8.98 ± 5.07

12.94 ± 3.24

7.62 ± 4.6

8.28 ± 5.42

0.387

Platelets

175 ± 45.78

102.60 ± 32.97

74.76 ± 27.1

32.17 ± 11.19

0.000*

Values represent medians ± standard deviation.

Reference units used:

Haemoglobin = gm/dl; RBC = 1012/L; WBC = 106/L; Platelets = 109/L.

Neutrophils, lymphocytes, eosinophils, monocytes =%.

* = singificant (p-value <0.05).

Baseline cytokine levels between healthy controls, uncomplicated and complicated Plasmodium vivax thrombocytopaenic cases

Median concentrations of TNF, IL-6 and IL-10 were compared between healthy controls and thrombocytopaenic uncomplicated and complicated P. vivax cases. Comparison of TNF level between healthy controls and and uncomplicated mild cases did not show any significant difference in mild thrombocytopaenic group, while it was found to be elevated approximately two-fold in moderate and profound group. In complicated cases, TNF was found to be approximately three fold elevated in profound group. IL-6 was found to be 7 fold increased while IL-10 levels were found to be > 20 fold higher in the respective groups. Comparison of profound thrombocytopaenia between uncomplicated and complicated cases showed a two-fold increase in TNF and IL-10 (p < 0.0001) while IL-6 was not found to be significantly elevated (Table 2).
Table 2

Comparison of cytokine levels between healthy controls, uncomplicated and complicated Plasmodium vivax cases

Cytokines

Healthy controls

Uncomplicated malaria

Complicated malaria

P-value

Mild

Moderate

Profound

Mild

Moderate

Profound

UM vs CM

TNF

178 (57–296)

165 (116–310)

235 (168–647)

482 (320–685)

177 (110–306)

249 (181–664)

652 (339–705)

<0.0001*

IL-6

87 (79–93)

215 (219–357)

229 (105–1,107)

313 (149–858)

238 (225–428)

253 (123–1,118)

438 (157–855)

0.352

IL-10

37 (21–88)

498 (316–825)

1,079 (428–2,152)

2,552 (995–6,400)

556 (326–886)

1,223 (459–2,269)

4,250 (958–6,750)

<0.0001*

Values represent medians with interquartile ranges (25th and 75th percentile). Mann–Whitney U test used to determine significant differences between groups. * = singificant (p-value <0.05).

Correlation of cytokines and thrombocytopenia in complicated Plasmodium vivax cases

Spearman Rank correlation analysis was performed in complicated P. vivax cases exhibiting mild, moderate and profound thrombocytopaenia to determine whether complex interactions between cytokines and thrombocytopaenia exist in complicated P. vivax cases. No significant correlation was observed between cytokines levels and mild thrombocytopaenia. However, significant negative correlation was observed between IL-6 and IL-10 (p = 0.02) in moderate cases. In profound cases, highly significant positive correlation was observed between TNF and IL-10 (p < 0.0001) while highly significant negative correlation was observed between IL-6 and IL-10 (p < 0.0001) (Table 3).
Table 3

Correlation of cytokines with thrombocytopaenia in complicated Plasmodium vivax cases

 

IL-6

IL-10

TNF-α

Mild

   

IL-6

1.00

0.756

-0.108

IL-10

 

1.00

0.764

TNF- α

  

1.00

Moderate

   

IL-6

1.00

-0.02*

-0.158

IL-10

 

1.00

0.158

TNF

  

1.00

Profound

   

IL-6

1.00

-0.0001**

0.0001**

IL-10

 

1.00

0.336**

TNF

  

1.00

Spearman rank correlation was performed. p <0.05 considered significant.

* = significant.

** = highly significant.

Comparison of severe symptoms with thrombocytopaenia

Comparison of severe signs and symptoms in complicated cases with thrombocytopaenia revealed that profound thrombocytopaenia was most common in patients suffering from respiratory distress/pulmonary oedema and metabolic acidosis (Table 4) while moderate thrombocytopaenia was observed in patients suffering from jaundice and haemoglobinuria.
Table 4

% positivity of thrombocytopaenia in complicated cases

Complications

No. of patients

% positivity

Pulmonary oedema/respiratory distress

31

11.2

Metabolic acidosis

20

6.8

Jaundice

26

21.8%

Haemoglobinuria

5

5.2%

Discussion

In this study, baseline levels of cytokines were examined in healthy controls, uncomplicated and complicated P. vivax cases exhibiting varying intensities of thrombocytopaenia. Furthermore, cytokines levels were correlated with thrombocytopaenia status in complicated cases to determine whether complex interactions exist between these molecules and manifestations of disease symptoms in thrombocytopaenic P. vivax cases. In this study, thrombocytopaenia was detected in all cases. Moderate and profound thrombocytopaenia was most frequently observed (51.1 and 43.4%, respectively) while mild thrombocytopaenia was observed in only 5.5% of the patients. This finding is consistent with previously reported observations from South America and south Asia where P. vivax is endemic [2]. Clinical complications such as disseminated intravascular coagulation (DIC), platelet associated IgG increase (PAIgG), immune thrombocytopaenia purpura (ITP), acute renal failure, pulmonary oedema, splenomegaly, cerebral malaria, and seizures have been reported in P. vivax cases exhibiting profound thrombocytopaenia [1519, 21]. In these cases, bleeding was observed in a few cases, indicating that thrombocytopaenia in P. vivax does not always lead to bleeding complications. In this study, complications including metabolic acidosis, pulmonary oedema, jaundice, haemglobunuria were observed in 45% (82/182) of the patients. Of these, profound thrombocytopenia was observed in 18% of the patients of which 11.2% suffered from respiratory distress/pulmonary oedema, while 6.8% suffered from metabolic acidosis. Moderate thrombocytopenia was observed in the remaining cases. Bleeding was observed infrequently in complicated cases exhibiting profound thrombocytopenia indicating that P. vivax-associated thrombocytopaenia in Pakistan demonstrates a similar trend of low bleeding tendencies as observed worldwide.

To determine the role of cytokines in thrombocytopaenia, baseline concentrations of pro- and anti-inflammatory cytokines TNF, IL-6, IL-10 were evaluated in healthy controls, uncomplicated and complicated P. vivax cases exhibiting mild, moderate and profound thrombocytopaenia. A significant increase of TNF level was observed between uncomplicated and complicated cases exhibiting profound thrombocytopenia while no significant difference was observed between healthy controls and mild cases. This finding corroborates with previously reported data in which thrombocytopaenia was observed in patients exhibiting high TNF levels [33]. It has been postulated that TNF induced thrombocytopaenia is a result of platelet trapping and consumption that occurs in inflamed blood vessels [34]. In P. falciparum, this process is well documented and has been associated with immunologically mediated endothelial activation that allows platelet adherence via endothelial adhesion molecules on the blood lining [35]. In P. vivax, thrombocytopaenia due to platelet consumption via endothelial adherence/destruction and coagulopathy has also been documented [36, 37]. Elevated levels of TNF in this study imply a similar role of this cytokine in P. vivax-associated thrombocytopaenia. However, further studies are required to understand the role of TNF in platelet consumption.

Insignificant increase in IL-6 levels (p value = 0.352) was observed in uncomplicated and complicated cases exhibiting profound thrombocytopaenia. This finding concurs with previous studies that document the role of IL-6 in platelet production [38, 39]. Increased IL-6 levels have been reported in patients with reactive thrombocytosis [4042]. Furthermore, administration of IL-6 in humans has been associated with increase in circulating platelet counts [4349]. Thus, a finding of non-significant increase in IL-6 levels in mild, moderate and profound thrombocytopaenic cases implies that regulation of platelet production by IL-6 is disturbed in P. vivax cases leading to worsening thrombocytopaenia status.

A significant increase of IL-10 in moderate and profound uncomplicated and complicated P. vivax cases was observed in this study. This finding corroborates with previously reported data that reports elevated IL-10 levels in malaria thrombocytopaenia [3, 25, 33]. Furthermore, decreased platelet production in humans in response to administration of recombinant IL-10 has also been documented. The same study postulated that IL-10-induced reduction in platelet count is possibly due to reduction in platelet production [50]. It is possible that similar mechanism of reduced platelet production due to high IL-10 levels is responsible for P. vivax-associated thrombocytopaenia in this study. Regulatory cytokines, such as IL-10, are required to reduce the risk of severe disease or more tissue injury in malaria. Therefore, intrinsic IL-10 response induced in response to protecting the host against injury results in down regulation of platelet production mechanisms, thus leading to manifestation of thrombocytopaenia.

To understand complex interaction between cytokines and platelet counts in complicated cases, Spearman rank correlation analysis was performed. It was observed that negative correlation existed between IL-6 and IL-10 in both moderate and profound cases indicating that as IL-10 levels increase, IL-6 levels decrease leading to reduction/disturbance in platelet production. Consequently, this elevated anti-inflammatory bias results in aggravation of thrombocytopaenia in P. vivax cases. A significant positive correlation between IL-10 and TNF-α in profound cases further strengthens the role of respective cytokines in platelet consumption, trapping and dysregulation of platelet production. Thus, findings from this study corroborate previously reported data and indicate a possible role of pro- and anti-inflammatory cytokines in manifestation of thrombocytopaenia in P. vivax malaria.

Though this study was performed and analyzed keeping all aspects in perspective, however, there are certain limitations in this study. Reference ranges for thrombocytopenia utilized for this study were derived from those used in The Aga Khan University laboratory. Secondly, parasitaemias and patient data, such as days of fever and temperature at admission, was not documented and, therefore, could not be used for analysis as done previously in other studies [5, 51, 52]. Hence, it was not possible to evaluate differences in parasitaemia in relation to thrombocytopaenia and cytokine levels. Furthermore, some studies have also reported age to significantly affect platelet count in malaria patients. In this study, the average age of the patients was between 33–42 years. Since no significant differences with respect to age were observed therefore data was not analyzed for age. However, to better understand the dynamics of thrombocytopenia and cytokine levels future studies focusing on all these aspects in P. vivax is suggested.

Conclusion

Findings from this study give an insight from Pakistan on the role of cytokines in P. vivax-associated thrombocytopaenia. However, further studies are required to understand the relevance of cytokines in manifestations of thrombocytopaenia in P. vivax malaria.

Declarations

Acknowledgements

This work was supported by Aga Khan University Research Council grant (grant ID: 102017P&M). We are thankful to the study participants for their participation. We are also grateful to The Aga Khan University for providing core facilities in MDL laboratory for performing experiments.

Authors’ Affiliations

(1)
Department of Pathology and Microbiology, Aga Khan University, Stadium Road, PO Box 3500, Karachi, 74800, Pakistan
(2)
Dow University of Health Sciences, Civil Hospital, Karachi, 74800, Pakistan

References

  1. WHO: World Malaria Report 2011. 2011, Geneva: World Health Organization, 246-xiiGoogle Scholar
  2. Lacerda MV, Mourao MP, Coelho HC, Santos JB: Thrombocytopenia in malaria: who cares?. Mem Inst Oswaldo Cruz. 2011, 106 Suppl 1: 52-63.View ArticlePubMedGoogle Scholar
  3. Casals-Pascual CKO, Newton CR, Peshu N, Roberts DJ: Thrombocytopenia in falciparum malaria is associated with high concentrations of IL-10. Am J Trop Med Hyg. 2006, 75: 434-436.PubMedGoogle Scholar
  4. Echeverri M, Tobon A, Alvarez G, Carmona J, Blair S: Clinical and laboratory findings of Plasmodium vivax malaria in Colombia, 2001. Rev Inst Med Trop Sao Paulo. 2003, 45: 29-34.View ArticlePubMedGoogle Scholar
  5. González BRH, De Donato M, Berrizbeitia M, Gómez C, González L: Hematologic variations in patient with malaria caused by Plasmodium vivax before, during and after treatment. Invest Clin. 2009, 50: 187-201.PubMedGoogle Scholar
  6. Jadhav UM, Patkar VS, Kadam NN: Thrombocytopenia in malaria–correlation with type and severity of malaria. J Assoc Physicians India. 2004, 52: 615-618.PubMedGoogle Scholar
  7. Ladhani S, Lowe B, Cole AO, Kowuondo K, Newton CR: Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome. Br J Haematol. 2002, 119: 839-847.View ArticlePubMedGoogle Scholar
  8. Mohanty D, Ghosh K, Nandwani SK, Shetty S, Phillips C, Rizvi S, Parmar BD: Fibrinolysis, inhibitors of blood coagulation, and monocyte derived coagulant activity in acute malaria. Am J Hematol. 1997, 54: 23-29.View ArticlePubMedGoogle Scholar
  9. Mohapatra MK, Padhiary KN, Mishra DP, Sethy G: Atypical manifestations of Plasmodium vivax malaria. Indian J Malariol. 2002, 39: 18-25.PubMedGoogle Scholar
  10. Rasheed ASS, Khan SA: Clinical and laboratory findings in acute malaria caused by various plasmodium species. J Pak Med Assoc. 2009, 59: 220-223.PubMedGoogle Scholar
  11. Shaikh QH, Ahmad SM, Abbasi A, Malik SA, Sahito AA, Munir SM: Thrombocytopenia in malaria. J Coll Physicians Surg Pak. 2009, 19: 708-710.PubMedGoogle Scholar
  12. Srivastava S, Ahmad S, Shirazi N, Kumar Verma S, Puri P: Retrospective analysis of vivax malaria patients presenting to tertiary referral centre of Uttarakhand. Acta Trop. 2011, 117: 82-85.View ArticlePubMedGoogle Scholar
  13. Taylor WR, Widjaja H, Basri H, Ohrt C, Taufik T, Tjitra E, Baso S, Fryauff D, Hoffman SL, Richie TL: 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. 2008, 7: 259-PubMed CentralView ArticlePubMedGoogle Scholar
  14. Bhatia V, Bhatia J: Severe thrombocytopenia with bleeding manifestations in two children secondary to Plasmodium vivax. Platelets. 2010, 21: 307-309.View ArticlePubMedGoogle Scholar
  15. Harish R, Gupta S: Plasmodium vivax malaria presenting with severe thrombocytopenia, cerebral complications and hydrocephalus. Indian J Pediatr. 2009, 76: 551-552.View ArticlePubMedGoogle Scholar
  16. Lacerda MV, Hipolito JR, Passos LN: Chronic Plasmodium vivax infection in a patient with splenomegaly and severe thrombocytopenia. Rev Soc Bras Med Trop. 2008, 41: 522-523.View ArticlePubMedGoogle Scholar
  17. Lacerda MVAM, Santos PD, Arcanjo AR, Alecrim WD, Alecrim MGC: Idiopathic thrombocytopenic purpura due to vivax malaria in the Brazilian Amazon. Acta Trop. 2004, 90: 187-190.View ArticlePubMedGoogle Scholar
  18. Parakh A, Agarwal N, Aggarwal A, Aneja A: Plasmodium vivax malaria in children: uncommon manifestations. Ann Trop Paediatr. 2009, 29: 253-256.View ArticlePubMedGoogle Scholar
  19. Song JY, Park CW, Jo YM, Kim JY, Kim JH, Yoon HJ, Kim CH, Lim CS, Cheong HJ, Kim WJ: Two cases of Plasmodium vivax Malaria with the clinical picture resembling toxic shock. Am J Trop Med Hyg. 2007, 77: 609-611.PubMedGoogle Scholar
  20. Thapa R, Biswas B, Mallick D, Sardar S, Modak S: Childhood Plasmodium vivax malaria with severe thrombocytopenia and bleeding manifestations. J Pediatr Hematol Oncol. 2009, 31: 758-759.View ArticlePubMedGoogle Scholar
  21. Yamaguchi S, Kubota T, Yamagishi T, Okamoto K, Izumi T, Takada M, Kanou S, Suzuki M, Tsuchiya J, Naruse T: Severe thrombocytopenia suggesting immunological mechanisms in two cases of vivax malaria. Am J Hematol. 1997, 56: 183-186.View ArticlePubMedGoogle Scholar
  22. D’Acremont V, Landry P, Mueller I, Pecoud A, Genton B: 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. 2002, 66: 481-486.PubMedGoogle Scholar
  23. Lathia TBJR: Can hematological parameters discriminate malaria from nonmalarious acute febrile illness in the tropics?. Indian J Med Sci. 2004, 58: 239-244.PubMedGoogle Scholar
  24. Patel U, Gandhi G, Friedman S, Niranjan S: Thrombocytopenia in malaria. J Natl Med Assoc. 2004, 96: 1212-1214.PubMed CentralPubMedGoogle Scholar
  25. Coelho HCLS, Pimentel JP, Nogueira PA, Costa FT, Siqueira AM, Melo GC, Monteiro WM, Malheiro A, Lacerda MV: Thrombocytopenia in Plasmodium vivax malaria is related to platelets phagocytosis. PLoS One. 2006, 8: e63410-View ArticleGoogle Scholar
  26. Grau GE, Piguet PF, Gretener D, Vesin C, Lambert PH: Immunopathology of thrombocytopenia in experimental malaria. Immunology. 1988, 65: 501-506.PubMed CentralPubMedGoogle Scholar
  27. Kaser A, Brandacher G, Steurer W, Kaser S, Offner FA, Zoller H, Theurl I, Widder W, Molnar C, Ludwiczek O, Atkins MB, Mier JW, Tilg H: Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001, 98: 2720-2725.View ArticlePubMedGoogle Scholar
  28. Wenisch C, Linnau KF, Looaresuwan S, Rumpold H: Plasma levels of the interleukin-6 cytokine family in persons with severe Plasmodium falciparum malaria. J Infect Dis. 1999, 179: 747-750.View ArticlePubMedGoogle Scholar
  29. Williams JR: The Declaration of Helsinki and public health. Bull World Health Organ. 2008, 86: 650-652.PubMed CentralView ArticlePubMedGoogle Scholar
  30. Warhurst DC, Williams JE: Laboratory diagnosis of malaria. J Clin Pathol. 1996, 49: 533-538.PubMed CentralView ArticlePubMedGoogle Scholar
  31. Snounou GVS, Jarra W, Thaithong S, Brown KN: Identification of the four human malaria parasite species in field samples by the polymerase chain reaction and detection of a high prevalence of mixed infections. Mol Biochem Parasitol. 1993, 58: 283-292.View ArticlePubMedGoogle Scholar
  32. Hussain RKA, Shahid F, Dojki M, Jamil B, Mehmood H, Dawood G, Dockrell HM: Cytokine profiles using whole-blood assays can discriminate between tuberculosis patients and healthy endemic controls in a BCG vaccinated population. J Immunol Meth. 2002, 264: 95-108.View ArticleGoogle Scholar
  33. Park JWPS, 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: Serum cytokine profiles in patients with Plasmodium vivax malaria: a comparison between those who presented with and without thrombocytopenia. Ann Trop Med Parasitol. 2003, 97: 339-344.View ArticlePubMedGoogle Scholar
  34. Angulo I, Fresno M: Cytokines in the pathogenesis of and protection against malaria. Clin Diagn Lab Immunol. 2002, 9: 1145-1152.PubMed CentralPubMedGoogle Scholar
  35. Bridges DJBJ, van Mourik JA, Grau G, Preston RJ, Molyneux M, Combes V, O’Donnell JS, de Laat B, Craig A: Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings. Blood. 2010, 115: 1472-1474.PubMed CentralView ArticlePubMedGoogle Scholar
  36. 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, Araújo MO, Russell B, Suwanarusk R, Snounou G, Rénia L, Costa FT: On the cytoadhesion of Plasmodium vivax-infected erythrocytes. J Infect Dis. 2010, 202: 638-647.View ArticlePubMedGoogle Scholar
  37. Raza AGN, Sarwar Zubairi AB, Raheem A, Nizami S, Beg M: Tumor necrosis factor -α, interleukin-10, intercellular and vascular adhesion molecules are possible biomarkers of disease severity in complicated Plasmodium vivax isolates from Pakistan. PLoS One. 2013, 8: e81363-PubMed CentralView ArticlePubMedGoogle Scholar
  38. Baatout S: Interleukin-6 and megakaryocytopoiesis: an update. Ann Hematol. 1996, 73: 157-162.View ArticlePubMedGoogle Scholar
  39. Hollen CW, Henthorn J, Koziol JA, Burstein SA: Serum interleukin-6 levels in patients with thrombocytosis. Leuk Lymphoma. 1992, 8: 235-241.View ArticlePubMedGoogle Scholar
  40. Heits F, Katschinski DM, Wilmsen U, Wiedemann GJ, Jelkmann W: Serum thrombopoietin and interleukin 6 concentrations in tumour patients and response to chemotherapy-induced thrombocytopenia. Eur J Haematol. 1997, 59: 53-58.View ArticlePubMedGoogle Scholar
  41. Heits F, Stahl M, Ludwig D, Stange EF, Jelkmann W: Elevated serum thrombopoietin and interleukin-6 concentrations in thrombocytosis associated with inflammatory bowel disease. J Interferon Cytokine Res. 1999, 19: 757-760.View ArticlePubMedGoogle Scholar
  42. Hollen CW, Henthorn J, Koziol JA, Burstein SA: Elevated serum interleukin-6 levels in patients with reactive thrombocytosis. Br J Haematol. 1991, 79: 286-290.View ArticlePubMedGoogle Scholar
  43. D’Hondt VHY, Guillaume T, Baatout S, Chatelain C, Berlière M, Longueville J, Feyens AM, de Greve J, Van Oosterom A: Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebo-controlled, randomized phase Ib study. Blood. 1995, 85: 2347-2353.PubMedGoogle Scholar
  44. Gordon MS, Nemunaitis J, Hoffman R, Paquette RL, Rosenfeld C, Manfreda S, Isaacs R, Nimer SD: A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. Blood. 1995, 85: 3066-3076.PubMedGoogle Scholar
  45. Lazarus HMWE, Williams SF, Grinblatt D, Campion M, Cooper BW, Gunn H, Manfreda S, Isaacs RE: Phase I multicenter trial of interleukin 6 therapy after autologous bone marrow transplantation in advanced breast cancer. Bone Marrow Transplant. 1995, 15: 935-942.PubMedGoogle Scholar
  46. Schrezenmeier H, Marsh JC, Stromeyer P, Muller H, Heimpel H, Gordon-Smith EC, Raghavachar A: A phase I/II trial of recombinant human interleukin-6 in patients with aplastic anaemia. Br J Haematol. 1995, 90: 283-292.View ArticlePubMedGoogle Scholar
  47. van Gameren MM WP, Mulder NH, Limburg PC, Groen HJ, Vellenga E, de Vries EG: Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. Blood. 1994, 84: 1434-1441.PubMedGoogle Scholar
  48. Veldhuis GJWP, Sleijfer DT, van der Graaf WT, Groen HJ, Limburg PC, Mulder NH, de Vries EG: Toxicity and efficacy of escalating dosages of recombinant human interleukin-6 after chemotherapy in patients with breast cancer or non-small-cell lung cancer. J Clin Oncol. 1995, 13: 2585-2593.PubMedGoogle Scholar
  49. Weber J, Yang JC, Topalian SL, Parkinson DR, Schwartzentruber DS, Ettinghausen SE, Gunn H, Mixon A, Kim H, Cole D: Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol. 1993, 11: 499-506.PubMedGoogle Scholar
  50. Sosman JA, Verma A, Moss S, Sorokin P, Blend M, Bradlow B, Chachlani N, Cutler D, Sabo R, Nelson M, Bruno E, Gustin D, Viana M, Hoffman R: Interleukin 10-induced thrombocytopenia in normal healthy adult volunteers: evidence for decreased platelet production. Br J Haematol. 2000, 111: 104-111.View ArticlePubMedGoogle Scholar
  51. Maina RN, Walsh D, Gaddy C, Hongo G, Waitumbi J, Otieno L, Jones D, Ogutu BR: Impact of Plasmodium falciparum infection on haematological parameters in children living in Western Kenya. Malar J. 2010, 9 Suppl 3: S4-View ArticlePubMedGoogle Scholar
  52. Saravu K, Docherla M, Vasudev A, Shastry BA: Thrombocytopenia in vivax and falciparum malaria: an observational study of 131 patients in Karnataka, India. Ann Trop Med Parasitol. 2011, 105: 593-598.PubMed CentralView ArticlePubMedGoogle Scholar

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© Raza et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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