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Am. J. Trop. Med. Hyg., 76(4), 2007, pp. 648-654
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene

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CASE REPORT


DISSEMINATED INTRAVASCULAR COAGULATION COMPLICATED BY PERIPHERAL GANGRENE IN A RHESUS MACAQUE (MACACA MULATTA) EXPERIMENTALLY INFECTED WITH PLASMODIUM COATNEYI

ALBERTO MORENO*, ANAPATRICIA GARCÍA, MÓNICA CABRERA-MORA, ELIZABETH STROBERT, AND MARY R. GALINSKI
Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, Georgia

 

ABSTRACT

We report the first case of disseminated intravascular coagulation (DIC) complicated by peripheral gangrene induced by Plasmodium coatneyi in rhesus monkeys. Ten days after experimental challenge, numerous petechiae were noted over the trunk and extremities, with polychromasia, severe anemia, thrombocytopenia, and moderate parasitemia. These changes were accompanied by elevated serum activity of blood urea nitrogen, creatinine, transaminases, and creatinine phosphokinase. The animal received intravenous fluid support, artemether, and blood transfusion. Three days after treatment, the platelet counts returned to normal, and parasitemia was abated. However, several areas of skin discoloration with gangrenous tissue in the hands and the tail were observed. Coagulation profile showed elevated D-dimers and elevated levels of fibrinogen/fibrin degradation products with low levels of protein S functional activity. DIC with peripheral gangrene is very rare in Plasmodium-infected individuals. Our results indicate that the experimental model of P. coatneyi infection of rhesus monkeys is important for studies of malarial anemia and coagulopathy.

 

INTRODUCTION

Plasmodium is responsible for > 500 million clinical cases of malaria annually around the world.1 Although natural human transmission of the simian malaria parasite Plasmodium knowlesi has been described,2–4 four species of Plasmodium are generally attributed to human infection: P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum is responsible for most of the severe cases of malaria estimated in 10% of the total number of clinical cases. Fatal cases have been estimated between 1 and 3 million every year mainly among children younger than 5 years old. Ninety percent of these lethal cases are reported in sub-Saharan Africa.5–7 These numbers have been maintained without dramatic changes owing to the high prevalence of drug-resistant strains of parasites and failure of malaria control programs.1

The World Health Organization (WHO) has established criteria to classify severe malaria.8 The classification of clinical entities associated with the severity of the disease allows comparison in different epidemiologic settings. Severe malaria is defined by seven major syndromes: cerebral malaria, severe anemia, respiratory distress, renal failure, metabolic acidosis, hypoglycemia, and coagulopathy. Cerebral malaria and severe anemia are the most common complications in children and primigravidas.9,10 This is in contrast with the frequent expression of pulmonary edema and renal failure in severe malaria cases in adults.11 Parasite sequestration associated with a pro-inflammatory milieu is a critical pathogenic mechanism leading to multi-organ dysfunction in P. falciparum malaria.12 However, the precise molecular mechanisms associated with this and each of the individual syndromes of severe malaria are not fully understood.

Non-human primates (NHPs) have been extensively used in malaria research as experimental animal models for drug and vaccine development.13–16 The use of NHP for characterizing mechanisms associated with severe malaria is evident in recent studies.17–20 We used simian malaria parasites in rhesus macaques to explore several biologic aspects of the complex parasite–host interactions involved in the pathogenesis of multi-organ failure. P. coatneyi shares several morphologic and biologic features with P. falciparum.21,22 Experimental infections of rhesus monkeys with P. coatneyi reproduce several histopathologic findings reported in humans infected with P. falciparum.17,18,23–25 We describe here the first case of disseminated intravascular coagulation (DIC) and peripheral gangrene in a rhesus macaque experimentally infected with P. coatneyi. Although platelet dysfunction and increased pro-coagulant activity is a common finding in severe malaria, DIC complicated with symmetrical peripheral gangrene is very rare.26 The experimental design that we have used to follow-up infections provided us with a unique opportunity to explore hematologic and immunologic parameters associated with DIC.

 

MATERIALS AND METHODS

Study design and clinical laboratory assays. RIp-8, a 4-year-old male rhesus monkey (Macaca mulatta), was born and raised at the Yerkes National Primate Research Center. This animal was part of an experimental protocol designed to evaluate anemia induced by simian malaria parasite infections (unpublished data). Procedures used were approved by the Emory University’s Institutional Animal Care and Use Committee and followed accordingly. The animal was inoculated with fresh 2 x 104 P. coatneyi–infected erythrocytes/kg (corresponding to a total number of 1.77 x 105) obtained from a donor monkey previously infected with a cryopreserved stabile. The monkey’s temperature was recorded every day after experimental challenge using a subcutaneous transponder chip (Bio Medic Data Systems, Seaford, DE). Capillary blood samples were obtained every day by ear prick and collected into EDTA-coated capillary tubes. Blood samples were used to determine hemoglobin concentration using a HemoCue photometer (HemoCue, Lake Forest, CA) and to quantify the parasite load using Giemsa-stained thin and thick smears. Reticulocyte counts were performed by the new methylene blue stain technique.27 Serum levels of fibrinogen degradation products were determined using a direct latex agglutination assay (Pacific Hemostasis, Middletown, VA). Serum levels of myoglobin were determined by ELISA using monkey-specific reagents (Life Diagnostics, West Chester, PA). On indicated dates, venous blood samples were obtained for a blood coagulation test and blood chemical analysis. Blood platelet counts were obtained by manual quantification using Giemsa-stained thin smears.

Gross pathology and histopathology. Immediately before necropsy, 14 days after experimental challenge, the monkey was sedated using intramuscular inoculation of Ketamine-HCl (15 mg/kg), and a complete physical exam was performed. The animal was euthanized by sodium pentobarbital overdose (Schering-Plough Animal Health, Union, NJ). Tissue samples from all organs including bone marrow and skin were placed in 10% normal buffered formalin and paraffin embedded. Sections (6 µm) were cut and stained with hematoxylin and eosin. To show polymerized fibrin, replicate sections were stained with phosphotungstic acid hematoxylin (PTAH) as described.28

Statistical analysis. Linear correlation was used to evaluate the relationship between hemoglobin concentration, parasitemia, and reticulocyte counts. This approach was also used to evaluate the relationship between hemoglobin concentration and thrombocytopenia. P < 0.05 was considered significant.

 

RESULTS

Clinical evolution. Parasites were identified in peripheral blood smears 48 hours after experimental challenge. Parasitemias followed the described pattern of alternating high and low values (Figure 1Go).29 During the follow-up period, sharp peaks of parasitemia were observed on days post-inoculation (DPI) 2, 4, and 6. The hemoglobin concentration exhibited a sustained decrease from the pre-challenge levels (18.2 g/dL) to reach 8 g/dL on DPI 5 (Figure 1AGo; Table 1Go). A small improvement in hemoglobin level was observed from DPI 6 to DPI 8. On DPI 9, the animal was reluctant to move and began to show signs of severe malaria that included anorexia and tachypnea. On examination, the animal was hypothermic (36.1°C) with mucocutaneous paleness. Blood tests showed thrombocytopenia (46,000 platelets/µL), mild anemia (hemoglobin level of 8.3 g/dL), and a parasitemia level of 356,868 parasites/µL that corresponded to 8.7% infected erythrocytes. In addition, the macaque exhibited a progressive decrease in platelet counts that reached a minimum of 46,000. A negative correlation between the number of platelets and parasitemia was found using linear correlation analysis (r = –0.8, P = 0.028). The animal was treated with a single subcurative dose of artemether (2 mg/kg Artesian; Dafra Pharma, Turn-hout, Belgium) to prevent life-threatening hyperparasitemia.


Figure 1
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  		    FIGURE 1. (A) Course of parasitemia in rhesus macaque RIp-8 experimentally challenged with P. coatneyi infected erythrocytes. The values are plotted with hemoglobin levels determined using a hemoglobin meter and capillary samples obtained daily after infection. The kinetics of parasitemia were determined using Giemsa-stained thick smears and the Earle-Perez method71 and expressed as the number of parasites per microliter of blood (left y-axis). Hemoglobin concentrations are expressed as g/dL (right y-axis). •, parasitemia levels; {blacksquare}, hemoglobin levels. (B) Number of platelets and proportion of reticulocytes in peripheral blood determined at different time-points after experimental infection. Arrow represents the day when the P. coatneyi–infected monkey received complete blood transfusion. {diamondsuit}, number of platelets in capillary blood; {blacktriangleup}, proportion of reticulocytes in red blood cell counts.

 

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TABLE 1
Clinical laboratory features of rhesus monkey RIp-8 experimentally infected with P. coatneyi
 
On DPI 10, the animal had a normal temperature (37.6°C) but showed severe mucocutaneous paleness, and numerous cutaneous petechiae over the trunk and extremities developed. Cardiopulmonary examination revealed holosystolic murmur grade 4 and tachypnea. Blood tests showed severe anemia (hemoglobin level of 4.4 g/dL), thrombocytopenia (67,000 platelets/µL), and parasitemia of 90,242 parasites/µL (2.2%). Thin blood smears revealed polychromasia and a strong medullary response with an erythroblastemia of 15%. However, reticulocyte counts did not correlate with peaks of parasitemia (Figure 1Go). Blood urea nitrogen (BUN) and creatinine values were increased (152 and 6.8 mg/dL, respectively). Elevated transaminase levels, glutamic oxaloacetic (357 U/L), and glutamic pyruvic (207 U/L), were also associated with an increased level of creatinine phosphokinase (CPK, 2,340 U/L). Dipstick urinalysis revealed pigmenturia with hemoglobin recorded as 4+ and only four to six red blood cells per high-power field. The animal was hemodynamically stabilized, and a total volume of 100 mL of blood was transfused. Curative anti-malaria therapy was initiated using artemether at 4 mg/kg followed by 2 mg/kg/day for 4 days.

On DPI 11, the animal was more active, and the parasitemia was recorded as negative. However, the animal appeared reluctant to use the hands on DPI 12. Therefore, buprenorphine was initiated at a dose of 0.01 mg/kg every 6 hours. Discoloration of the digit tips and tail was noted, and the lesions deteriorated by self-inflicted bite injuries that required initiation of ceftriaxone sodium on DPI 13. At this time-point, a blood test showed that platelet counts had increased from 67,000 to 474,000 platelets/µL, and the hemoglobin concentration had increased from 4.4 to 9.0 g/dL. Nevertheless, deep red discoloration was detected on both hands and arms. On DPI 14, the animal’s hands and tail showed deep red tissue discoloration with evidence of gangrene at the margins. Blood tests on DPI 14 showed leukocytosis (absolute number, 21,800/µL) and normal platelet counts (359,000 platelets/µL). BUN, creatinine, CPK, and transaminase levels were normal. Coagulation tests showed elevated D-dimers (1,175 mg/L), elevated fibrinogen/fibrin degradation products (> 40 µg/mL), and decreased functional protein S levels (46%). Functional protein C levels, antithrombin III, and fibrinogen concentration were all within normal limits. Coagulation factors II, IX, and X were at normal levels. This is in contrast with elevated levels of coagulation factors V, VII, VIII, XI, and XII. The myoglobin concentration, determined by ELISA, was elevated (> 652 ng/mL). This clinical laboratory finding, along with evidence of pigmenturia and an elevated activity of serum CPK, reported on DPI 10, suggested acute rhabdomyolysis. In view of the clinical complications and the poor prognosis, euthanasia was elected.

Gross pathologic findings. On gross examination, the animal was in fair to poor body condition. The mucous membranes were pale and slightly yellow. The dorsal aspect of both hands was dark red and had multiple erosions. All of the fingertips and fingernails of both hands were black. The tips of the third, fourth, and fifth fingers of the right hand were ulcerated (Figure 2Go). The second and third toes of the left foot were dark red. The dorsal aspect of both feet was slightly reddened. Three fourths of the tail was dark red and covered with black spots (Figure 2Go). Both lungs were mottled and had a dark green discoloration. The liver was slightly enlarged and diffusely dark red with a green discoloration. There was mild splenomegaly. Both kidneys were diffusely pale with a green discoloration.


Figure 2
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  		    FIGURE 2. Pictures of the right hand and the tail from RIp-8. The dorsal aspect of a hand was dark red with black digit tips and multiple erosions. The tail shows dusk discoloration of the skin caudal portion. This figure appears in color at www.ajtmh.org.

 
Histopathologic findings. Sections of haired skin ranged from diffusely necrotic to focal dermal necrosis with epidermal separation and cleft formation (Figure 3Go). The epidermis was mildly hyperkeratotic. There were multifocal areas of epidermal separation and cleft formation with occasional infiltration of moderate numbers of neutrophils. The superficial dermis had multifocal areas of collagen degeneration and necrosis intermixed with foci of pigmentary incontinence. The external, and occasionally the internal, root sheath of many hair follicles was necrotic. The deep dermis had multifocal to diffuse infiltration of neutrophils. Scattered in the deep dermis were multifocal areas of hemorrhage (Figure 3Go). Occasional blood vessels contained fibrin thrombi. To identify fibrin deposits, we used PTAH staining (Figure 4Go). The renal tubules were markedly eosinophilic, and many contained hyaline casts. In the cortex, occasional tubules contained a basophilic material, consistent with mineral deposition. The medullary tubules had variable numbers of nucleated erythrocytes. Occasional pulmonary blood vessels contained fibrin thrombi. The alveolar spaces had variable numbers of alveolar macrophages. In some sections, the alveolar walls contained a brown-black pigment, consistent with hemozoin deposition. The hepatic sinusoids contained large amounts of a black-brown pigment (hemozoin), free and within macrophages, intermixed with variable numbers of nucleated red blood cells. Scattered in the parenchyma and within sinusoids were small aggregates of extramedullary hematopoiesis (Figure 5Go).


Figure 3
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  		    FIGURE 3. Photomicrograph of a section of haired skin showing dermal necrosis (arrow) and epidermal cleft formation. Inset, Fibrin thrombi within dermal blood vessels. H&E bar = 70 µm. This figure appears in color at www.ajtmh.org.

 

Figure 4
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  		    FIGURE 4. Photomicrograph of a section of skin depicting fibrin thrombi in dermal blood vessels. PTAH bar = 40 µm. This figure appears in color at www.ajtmh.org.

 

Figure 5
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  		    FIGURE 5. Photomicrograph of liver depicting extramedullary hematopoiesis (EMH). Notice the presence of a brown-black pigment (hemozoin). Bar = 90 µm. This figure appears in color at www.ajtmh.org.

 
 
DISCUSSION

Clinical syndromes associated with severe malaria are life-threatening entities that require aggressive clinical management. The WHO has defined severe malaria in patients with confirmed P. falciparum asexual parasitemia and the presence of one or more of the following clinical or laboratory features: prostration, impaired consciousness, respiratory distress, multiple convulsions, circulatory collapse, pulmonary edema, abnormal bleeding, jaundice, hemoglobinuria, or severe anemia.8 Subclinical evidence of hemostasis dysfunction is common in Plasmodium-infected individuals, but severe coagulopathy with DIC and peripheral gangrene is not a common finding in severe cases of malaria. Only P. falciparum has been reported to be associated in rare instances with this clinical presentation.26 The prevalence of DIC can reach 10% of the total number of severe cases of malaria in endemic areas30 and 30% in non-immune patients with imported cases of P. falciparum malaria.31 Clinical expression of DIC in malaria patients is correlated with poor outcome.32 Although several host and parasite factors play a role in the pathogenesis of severe malaria,33 little is known about the molecular mechanisms involved in the physiopathology of the malarial hematologic complications. Novel experimental animal models are essential for defining the mechanisms involved in both coagulopathy and severe anemia. P. coatneyi is a simian malaria parasite that displays several biologic and morphologic features in common with P. falciparum.29,34,35 Most relevantly, macaques experimentally infected with P. coatneyi exhibit clinical complications similar to severe cases of P. falciparum malaria in humans.36 Cerebral malaria, placental malaria, and metabolic complications of severe malaria have all been reported in macaques experimentally infected with P. coatneyi.17,18,24,29,37,38 We report here the clinical profile and pathologic findings of a rhesus macaque that developed severe coagulopathy compatible with DIC after experimental infection with P. coatneyi. To our knowledge, this is the first description of severe coagulopathy in a non-human primate model of malaria. We confirmed that vascular compromise mediated by DIC led to peripheral gangrene and probably acute rhabdomyolysis. The profound hematologic disturbances induced by P. coatneyi in rhesus macaques support the relevance of using this unique host–parasite combination to study the pathogenesis of severe malarial anemia and malarial coagulopathy.

Laboratory criteria pathognomonic for DIC include 1) evidence of procoagulant activation, thrombocytopenia, elevated prothrombin time, partial thromboplastin time or thrombin time, and decreased fibrinogen; 2) evidence of fibrinolytic activation, elevated fibrinogen/fibrin degradation products, and elevated D-dimer; 3) consumption of coagulation inhibitors, low levels of protein C, protein S, and anti-thrombin; and 4) biochemical evidence or organ damage.39 Clinical evidence from endemic areas of malaria indicates that severe malaria patients exhibit lower levels of protein C, protein S, and anti-thrombin III in comparison with patients with mild malaria.40 Consistent with the most common association of severe malaria cases with P. falciparum infection, individuals infected with P. falciparum exhibit lower levels of coagulation inhibitors in comparison with P. vivax–infected individuals.41 Decreased levels of protein C have also been correlated with elevated levels of tumor necrosis factor (TNF)-{alpha} in P. falciparum malaria.42 We found that thrombocytopenia and a high level of fibrin degradation products are a common finding in rhesus macaques experimentally infected with P. coatneyi (unpublished data). Coagulopathy disturbance in this experimental animal model can progress to DIC as reported here. Extensive fibrin thrombus formation progressed to peripheral gangrene. Laboratory findings compatible with DIC in the P. coatneyi–-infected rhesus monkey reported here involved thrombocytopenia, elevated levels of D-dimer, increased levels of fibrinogen/fibrin degradation products, and decreased functional protein S levels.

The number of platelets dropped dramatically during the acute P. coatneyi infection. The origin of thrombocytopenia is multi-factorial in malaria-infected individuals. Reported mechanisms include immunologic platelet clearance mediated by auto-antibodies or enhanced destruction by macrophages.43–45 Platelet destruction can be mediated by elevated levels of macrophage-colony stimulating factor,46 clearance of parasite-infected thrombocytes,47 massive platelet pooling in an enlarged spleen,48 and oxidative stress that induces platelet lipid peroxidation.49 Severe thrombocytopenia seen in the P. coatneyi–infected rhesus monkey reported here is the result of platelet consumption by microthrombi during DIC.

Plasmodium falciparum malaria induces profound hemodynamic changes explained by vascular collapse or obstruction mediated by sequestration of infected erythrocytes and the increased adhesiveness of normal erythrocytes. The erythrocyte membrane is modified during malaria infection by several mechanisms that include expression of parasite antigens on the surface of infected erythrocytes, exposure of erythrocytic cryptic domains, and changes in phospholipid asymmetry.50–52 These erythrocyte membrane changes can result in the cytoadhesive interactions of P. falciparum–infected erythrocytes with endothelial receptors.53 The loss of phospholipid asymmetry, mediated by oxidative stress, causes the exposure of phosphatidylserine (PS) at the outer surface of the cell. PS-exposing erythrocytes cause endothelial activation, retraction, and subsequent exposure of the extracellular matrix.54 Activated endothelial cells can also upregulate the expression of tissue factor (TF) to modulate hemostasis through the activation of the extrinsic coagulation cascade.55,56 Histopathologic analysis using PTAH staining showed extensive intra-vascular fibrin thrombi in the P. coatneyi rhesus reported here as a consequence of extensive activation of the coagulation cascade. Although sequestered infected erythrocytes were not identified in this case, cytoadherence of P. coatneyi–infected erythrocytes to endothelial cells have been reported in cerebral malaria.36 Our lack of observed sequestered parasites could be caused by the timing of the necropsy after anti-malaria treatment.

Systemic endothelial activation is a distinctive feature of Plasmodium-infected individuals.57 Endothelial cell activation causes the release of preformed procoagulant molecules such as the von Willebrand factor (vWF). vWF recruits platelets through its interaction with CD36, a process that results in the magnification of the endothelial perturbation.58 Platelets can also be activated through interaction with damaged endothelial cells. The activation of platelets gives rise to cell agglutination and the release of various vasoactive molecules from platelet granules. Endothelial activation by pro-inflammatory cytokines also promotes the adhesion of neutrophils. Neutrophil adhesion is followed by degranulation and the release of enzymes such as myeloperoxidase and elastase that mediate local injury.59 These events facilitate the additional exposure of procoagulant molecules such as vWF, collagen, and fibronectin.60 Activation of monocytes by pro-inflammatory cytokines also triggers the synthesis of TF, which can be released from the cell in microparticles to modulate the activation of the extrinsic coagulation cascade.56

Criteria used to identify rhabdomyolysis include the clinical evidence of muscle damage associated with elevated creatinine kinase and pigmenturia, associated with the presence of myoglobin or hemoglobin in the urine. Myocyte injury induces the release of intracellular contents that include creatinine, urea, potassium, creatinine kinase, and other enzymes.61 Myoglobin can directly induce tubular necrosis that along with hypovolemia facilitated by massive intramuscular capillary destruction can be involved in renal failure. Skeletal muscle damage associated with increased serum levels of creatinine kinase and myoglobin have been reported in severe cases of malaria.62,63 Nevertheless, severe rhabdomyolysis with myoglobinuria and renal failure is rare.62 The information available for rhabdomyolysis in malaria infection indicate that there is a positive correlation between levels of creatinine and myoglobin.62,64–68 However, the most sensitive clinical laboratory parameter to detect rhabdomyolysis is the increased levels of creatinine phosphokinase.61 The P. coatneyi–infected rhesus monkey reported here exhibited increase levels of creatinine phosphokinase and myoglobin with pigmenturia in the absence of red blood cells. These clinical features are suggestive of rhabdomyolysis. In severe cases of malaria with renal failure, hemoglobin casts have been reported.69 Although hyaline casts were seen histologically in the kidney of this rhesus monkey, special stains for hemoglobin were negative. In addition, reactivity with a myoglobin monoclonal antibody was also negative. The positive reactivity of blood in urine samples suggests the presence of hemoglobinuria and/or myoglobinuria. Although it has been proposed that parasite sequestration plays a leading role in the pathogenesis of rhabdomyolysis,70 we did not identify sequestered parasites in skeletal muscle tissue samples or histologic evidence of myocyte injury. The failure to show parasite sequestration can be explained by the presence of extensive fibrin thrombi in various stages of organization and anti-malarial treatment with an artemisinin derivative.

In this study, we used pathologic and hematologic laboratory studies to elucidate clinical features associated with hemostasis dysfunction in a rhesus macaque experimentally infected with P. coatneyi. To our knowledge, the case that we present here is the first evidence that this simian malaria parasite can induce DIC. The severe coagulopathy induced in a malaria naïve animal lead to peripheral gangrene. The high prevalence of coagulation dysfunction and the prominent clinical presentation seen in a rhesus macaque experimentally infected with P. coatneyi make this parasite–host combination a useful experimental animal model to evaluate the molecular mechanisms involved in the pathogenesis of severe malaria.

Received October 9, 2006. Accepted for publication December 26, 2006.

Acknowledgments: The authors thank Esmeralda V-S Meyer for critical review of the manuscript.

Financial support: This research was supported by NIH/NHLBI Grant 1P01 HL078826-01 and the Yerkes National Primate Research Center Base Grant RR00165 awarded by the National Center for Research Resources of the National Institutes of Health.

* Address correspondence to Alberto Moreno, Emory Vaccine Center, Yerkes National Primate Research Center and Division of Infectious Diseases, Department of Medicine, Emory University, 954 Gatewood Rd., Atlanta, GA 30329. E-mail: amoreno{at}rmy.emory.edu Back

Authors’ addresses: Alberto Moreno and Mary R. Galinski, Emory Vaccine Center, Yerkes National Primate Research Center and Division of Infectious Diseases, Department of Medicine, Emory University, 954 Gatewood Rd., Atlanta, GA 30329. Anapatricia García and Elizabeth Strobert, Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd., Atlanta, GA 30329. Mónica Cabrera-Mora, Emory Vaccine Center, and Yerkes National Primate Research Center Emory University, 954 Gatewood Rd., Atlanta, GA 30329.

Reprint requests: Alberto Moreno, Emory Vaccine Center, Yerkes National Primate Research Center and Division of Infectious Diseases, Department of Medicine, Emory University, 954 Gatewood Rd., Atlanta, GA 30329. E-mail: amoreno{at}rmy.emory.edu.

 

REFERENCES

  1. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI, 2005. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434: 214–217.[Medline]
  2. Vythilingam I, Tan CH, Asmad M, Chan ST, Lee KS, Singh B, 2006. Natural transmission of Plasmodium knowlesi to humans by Anopheles latens in Sarawak, Malaysia. Trans R Soc Trop Med Hyg 100: 1087–1088.[Web of Science][Medline]
  3. Jongwutiwes S, Putaporntip C, Iwasaki T, Sata T, Kanbara H, 2004. Naturally acquired Plasmodium knowlesi malaria in human, Thailand. Emerg Infect Dis 10: 2211–2213.[Web of Science][Medline]
  4. Singh B, Kim Sung L, Matusop A, Radhakrishnan A, Shamsul SS, Cox-Singh J, Thomas A, Conway DJ, 2004. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 363: 1017–1024.[Web of Science][Medline]
  5. Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, Newton C, Winstanley P, Warn P, Peshu N, 1995. Indicators of life-threatening malaria in African children. N Engl J Med 332: 1399–1404.[Abstract/Free Full Text]
  6. Brabin BJ, Premji Z, Verhoeff F, 2001. An analysis of anemia and child mortality. J Nutr 131: 636S–645S.[Abstract/Free Full Text]
  7. Snow RW, Omumbo JA, Lowe B, Molyneux CS, Obiero JO, Palmer A, Weber MW, Pinder M, Nahlen B, Obonyo C, New-bold C, Gupta S, Marsh K, 1997. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 349: 1650–1654.[Web of Science][Medline]
  8. WHO, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94: S1–90.[Web of Science][Medline]
  9. Greenwood BM, Bradley AK, Greenwood AM, Byass P, Jammeh K, Marsh K, Tulloch S, Oldfield FS, Hayes R, 1987. Mortality and morbidity from malaria among children in a rural area of The Gambia, West Africa. Trans R Soc Trop Med Hyg 81: 478–486.[Web of Science][Medline]
  10. Fleming AF, 1989. Tropical obstetrics and gynaecology. 1. Anaemia in pregnancy in tropical Africa. Trans R Soc Trop Med Hyg 83: 441–448.[Web of Science][Medline]
  11. Trang TT, Phu NH, Vinh H, Hien TT, Cuong BM, Chau TT, Mai NT, Waller DJ, White NJ, 1992. Acute renal failure in patients with severe falciparum malaria. Clin Infect Dis 15: 874–880.[Web of Science][Medline]
  12. Berendt AR, Ferguson DJ, Gardner J, Turner G, Rowe A, McCormick C, Roberts D, Craig A, Pinches R, Elford BC, et al., 1994. Molecular mechanisms of sequestration in malaria. Parasitology 108 (Suppl): S19–S28.
  13. Gysin J, 1991. Relevance of the squirrel monkey as a model for experimental human malaria. Res Immunol 142: 649–654.[Web of Science][Medline]
  14. Schmidt LH, 1973. Infections with Plasmodium falciparum and Plasmodium vivax in the owl monkey–model systems for basic biological and chemotherapeutic studies. Trans R Soc Trop Med Hyg 67: 446–474.[Web of Science][Medline]
  15. Young MD, Baerg DC, Rossan RN, 1976. Studies with induced malarias in Aotus monkeys. Lab Anim Sci 26: 1131–1137.[Web of Science][Medline]
  16. Collins WE, 1992. South American monkeys in the development and testing of malarial vaccines—a review. Mem Inst Oswaldo Cruz 87 (Suppl 3): 401–406.[Web of Science][Medline]
  17. Kawai S, Aikawa M, Kano S, Suzuki M, 1993. A primate model for severe human malaria with cerebral involvement: Plasmodium coatneyi-infected Macaca fuscata. Am J Trop Med Hyg 48: 630–636.[Abstract/Free Full Text]
  18. Davison BB, Cogswell FB, Baskin GB, Falkenstein KP, Henson EW, Tarantal AF, Krogstad DJ, 1998. Plasmodium coatneyi in the rhesus monkey (Macaca mulatta) as a model of malaria in pregnancy. Am J Trop Med Hyg 59: 189–201.[Abstract]
  19. Egan AF, Fabucci ME, Saul A, Kaslow DC, Miller LH, 2002. Aotus New World monkeys: model for studying malaria-induced anemia. Blood 99: 3863–3866.[Abstract/Free Full Text]
  20. Makobongo MO, Keegan B, Long CA, Miller LH, 2006. Immunization of Aotus monkeys with recombinant cysteine-rich interdomain region 1 alpha protects against severe disease during Plasmodium falciparum reinfection. J Infect Dis 193: 731–740.[Web of Science][Medline]
  21. Eyles DE, Fong YL, Warren M, Guinn E, Sandosham AA, Wharton RH, 1962. Plasmodium coatneyi, a new species of primate malaria from Malaya. Am J Trop Med Hyg 11: 597–604.[Abstract/Free Full Text]
  22. Vargas-Serrato E, Corredor V, Galinski MR, 2003. Phylogenetic analysis of CSP and MSP-9 gene sequences demonstrates the close relationship of Plasmodium coatneyi to Plasmodium knowlesi. Infect Genet Evol 3: 67–73.[Medline]
  23. Desowitz RS, Miller LH, Buchanan RD, Permpanich B, 1969. The sites of deep vascular schizogony in Plasmodium coatneyi malaria. Trans R Soc Trop Med Hyg 63: 198–202.[Web of Science][Medline]
  24. Smith CD, Brown AE, Nakazawa S, Fujioka H, Aikawa M, 1996. Multi-organ erythrocyte sequestration and ligand expression in rhesus monkeys infected with Plasmodium coatneyi malaria. Am J Trop Med Hyg 55: 379–383.[Abstract/Free Full Text]
  25. Aikawa M, Brown AE, Smith CD, Tegoshi T, Howard RJ, Hasler TH, Ito Y, Collins WE, Webster HK, 1992. Plasmodium coatneyi-infected rhesus monkeys: a primate model for human cerebral malaria. Mem Inst Oswaldo Cruz 87 (Suppl 3): 443–447.[Web of Science][Medline]
  26. Liechti ME, Zumsteg V, Hatz CF, Herren T, 2003. Plasmodium falciparum cerebral malaria complicated by disseminated intravascular coagulation and symmetrical peripheral gangrene: case report and review. Eur J Clin Microbiol Infect Dis 22: 551–554.[Web of Science][Medline]
  27. Riley RS, Ben-Ezra JM, Tidwell A, Romagnoli G, 2002. Reticulocyte analysis by flow cytometry and other techniques. Hematol Oncol Clin North Am 16: 373–420.[Web of Science][Medline]
  28. Momotani E, Yabuki Y, Miho H, Ishikawa Y, Yoshino T, 1985. Histopathological evaluation of disseminated intravascular coagulation in Haemophilus somnus infection in cattle. J Comp Pathol 95: 15.[Web of Science][Medline]
  29. Collins WE, Warren M, Sullivan JS, Galland GG, 2001. Plasmodium coatneyi: observations on periodicity, mosquito infection, and transmission to Macaca mulatta monkeys. Am J Trop Med Hyg 64: 101–110.[Abstract]
  30. Salord F, Allaouchiche B, Gaussorgues P, Boibieux A, Sirodot M, Gerard-Boncompain M, Biron F, Peyramond D, Robert D, 1991. Severe falciparum malaria (21 cases). Intensive Care Med 17: 449–454.[Web of Science][Medline]
  31. Bruneel F, Hocqueloux L, Alberti C, Wolff M, Chevret S, Bedos JP, Durand R, Le Bras J, Regnier B, Vachon F, 2003. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med 167: 684–689.[Abstract/Free Full Text]
  32. Losert H, Schmid K, Wilfing A, Winkler S, Staudinger T, Kletzmayr J, Burgmann H, 2000. Experiences with severe P. falciparum malaria in the intensive care unit. Intensive Care Med 26: 195–201.[Web of Science][Medline]
  33. Schofield L, Grau GE, 2005. Immunological processes in malaria pathogenesis. Nat Rev Immunol 5: 722–735.[Web of Science][Medline]
  34. Coatney GR, 1968. Simian malarias in man: facts, implications, and predictions. Am J Trop Med Hyg 17: 147–155.[Abstract/Free Full Text]
  35. Udomsangpetch R, Brown AE, Smith CD, Webster HK, 1991. Rosette formation by Plasmodium coatneyi-infected red blood cells. Am J Trop Med Hyg 44: 399–401.[Abstract/Free Full Text]
  36. Aikawa M, Brown A, Smith CD, Tegoshi T, Howard RJ, Hasler TH, Ito Y, Perry G, Collins WE, Webster K, 1992. A primate model for human cerebral malaria: Plasmodium coatneyi-infected rhesus monkeys. Am J Trop Med Hyg 46: 391–397.[Abstract/Free Full Text]
  37. Sein KK, Brown AE, Maeno Y, Smith CD, Corcoran KD, Hansukjariya P, Webster HK, Aikawa M, 1993. Sequestration pattern of parasitized erythrocytes in cerebrum, mid-brain, and cerebellum of Plasmodium coatneyi-infected rhesus monkeys (Macaca mulatta). Am J Trop Med Hyg 49: 513–519.[Abstract/Free Full Text]
  38. Nakano Y, Fujioka H, Luc KD, Rabbege JR, Todd GD, Collins WE, Aikawa M, 1996. A correlation of the sequestration rate of Plasmodium coatneyi-infected erythrocytes in cerebral and subcutaneous tissues of a rhesus monkey. Am J Trop Med Hyg 55: 311–314.[Abstract/Free Full Text]
  39. Yu M, Nardella A, Pechet L, 2000. Screening tests of disseminated intravascular coagulation: guidelines for rapid and specific laboratory diagnosis. Crit Care Med 28: 1777–1780.[Web of Science][Medline]
  40. Vogetseder A, Ospelt C, Reindl M, Schober M, Schmutzhard E, 2004. Time course of coagulation parameters, cytokines and adhesion molecules in Plasmodium falciparum malaria. Trop Med Int Health 9: 767–773.[Web of Science][Medline]
  41. 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.[Web of Science][Medline]
  42. Hemmer CJ, Kern P, Holst FG, Radtke KP, Egbring R, Bierhaus A, Nawroth PP, Dietrich M, 1991. Activation of the host response in human Plasmodium falciparum malaria: relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels. Am J Med 91: 37–44.[Web of Science][Medline]
  43. 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.[Web of Science][Medline]
  44. Grau GE, Piguet PF, Gretener D, Vesin C, Lambert PH, 1988. Immunopathology of thrombocytopenia in experimental malaria. Immunology 65: 501–506.[Web of Science][Medline]
  45. Yamaguchi S, Kubota T, Yamagishi T, Okamoto K, Izumi T, Takada M, Kanou S, Suzuki M, Tsuchiya J, Naruse T, 1997. Severe thrombocytopenia suggesting immunological mechanisms in two cases of vivax malaria. Am J Hematol 56: 183–186.[Web of Science][Medline]
  46. 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.[Web of Science][Medline]
  47. Jaff MS, McKenna D, McCann SR, 1985. Platelet phagocytosis: a probable mechanism of thrombocytopenia in Plasmodium falciparum infection. J Clin Pathol 38: 1318–1319.[Free Full Text]
  48. Skudowitz RB, Katz J, Lurie A, Levin J, Metz J, 1973. Mechanisms of thrombocytopenia in malignant tertian malaria. BMJ 2: 515–518.[Abstract/Free Full Text]
  49. 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.[Web of Science][Medline]
  50. Winograd E, Prudhomme JG, Sherman IW, 2005. Band 3 clustering promotes the exposure of neoantigens in Plasmodium falciparum-infected erythrocytes. Mol Biochem Parasitol 142: 98.[Web of Science][Medline]
  51. Moll GN, Vial HJ, Bevers EM, Ancelin ML, Roelofsen B, Comfurius P, Slotboom AJ, Zwaal RF, Op den Kamp JA, van Deenen LL, 1990. Phospholipid asymmetry in the plasma membrane of malaria infected erythrocytes. Biochem Cell Biol 68: 579–585.[Web of Science][Medline]
  52. Simoes AP, Moll GN, Beaumelle B, Vial HJ, Roelofsen B, Op den Kamp JA, 1990. Plasmodium knowlesi induces alterations in phosphatidylcholine and phosphatidylethanolamine molecular species composition of parasitized monkey erythrocytes. Biochim Biophys Acta 1022: 135–145.[Medline]
  53. Sherman IW, Eda S, Winograd E, 2003. Cytoadherence and sequestration in Plasmodium falciparum: defining the ties that bind. Microbes Infect 5: 897–909.[Web of Science][Medline]
  54. Manodori AB, Barabino GA, Lubin BH, Kuypers FA, 2000. Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin. Blood 95: 1293–1300.[Abstract/Free Full Text]
  55. Conway EM, Bach R, Rosenberg RD, Konigsberg WH, 1989. Tumor necrosis factor enhances expression of tissue factor mRNA in endothelial cells. Thromb Res 53: 231–241.[Web of Science][Medline]
  56. Imamura T, Sugiyama T, Cuevas LE, Makunde R, Nakamura S, 2002. Expression of tissue factor, the clotting initiator, on macrophages in Plasmodium falciparum-infected placentas. J Infect Dis 186: 436–440.[Web of Science][Medline]
  57. Turner GD, Ly VC, Nguyen TH, Tran TH, Nguyen HP, Bethell D, Wyllie S, Louwrier K, Fox SB, Gatter KC, Day NP, Tran TH, White NJ, Berendt AR, 1998. Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. Am J Pathol 152: 1477–1487.[Abstract]
  58. Hollestelle MJ, Donkor C, Mantey EA, Chakravorty SJ, Craig A, Akoto AO, O’Donnell J, van Mourik JA, Bunn J, 2006. von Willebrand factor propeptide in malaria: evidence of acute endothelial cell activation. Br J Haematol 133: 562–569.[Web of Science][Medline]
  59. Weiss SJ, 1989. Tissue destruction by neutrophils. N Engl J Med 320: 365–376.[Web of Science][Medline]
  60. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM, 1998. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91: 3527–3561.[Free Full Text]
  61. Warren JD, Blumbergs PC, Thompson PD, 2002. Rhabdomyolysis: a review. Muscle Nerve 25: 332–347.[Web of Science][Medline]
  62. Davis TM, Pongponratan E, Supanaranond W, Pukrittayakamee S, Helliwell T, Holloway P, White NJ, 1999. Skeletal muscle involvement in falciparum malaria: biochemical and ultrastructural study. Clin Infect Dis 29: 831–835.[Web of Science][Medline]
  63. St. John A, Davis TM, Binh TQ, Thu LT, Dyer JR, Anh TK, 1995. Mineral homoeostasis in acute renal failure complicating severe falciparum malaria. J Clin Endocrinol Metab 80: 2761–2767.[Abstract]
  64. Allo JC, Vincent F, Barboteu M, Schlemmer B, 1997. Falciparum malaria: an infectious cause of rhabdomyolysis and acute renal failure. Nephrol Dial Transplant 12: 2033–2034.[Web of Science][Medline]
  65. Knochel JP, Moore GE, 1993. Rhabdomyolysis in malaria. N Engl J Med 329: 1206–1207.[Free Full Text]
  66. Reynaud F, Mallet L, Lyon A, Rodolfo JM, 2005. Rhabdomyolysis and acute renal failure in Plasmodium falciparum malaria. Nephrol Dial Transplant 20: 847.[Free Full Text]
  67. Sinniah R, Lye W, 2000. Acute renal failure from myoglobinuria secondary to myositis from severe falciparum malaria. Am J Nephrol 20: 339–343.[Web of Science][Medline]
  68. Taylor WR, Prosser DI, 1992. Acute renal failure, acute rhabdomyolysis and falciparum malaria. Trans R Soc Trop Med Hyg 86: 361.[Web of Science][Medline]
  69. Rosen S, Hano JE, Inman MM, Gilliland PF, Barry KG, 1968. The kidney in blackwater fever: light and electron microscopic observations. Am J Clin Pathol 49: 358–370.[Web of Science][Medline]
  70. Singh U, Scheld WM, 1996. Infectious etiologies of rhabdomyolysis: three case reports and review. Clin Infect Dis 22: 642–649.[Web of Science][Medline]
  71. Earle WC, Perez M, 1932. Enumeration of parasites in the blood of malarial patients. J Lab Clin Med 17: 1124–1130.[Web of Science]




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