Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology

The pathophysiology of severe falciparum malaria is complex, but evidence is mounting that its central feature is the old concept of a mechanical microcirculatory obstruction. Autopsy studies, but also in vivo observations of the microcirculation, demonstrate variable obstruction of the microcirculation in severe malaria. The principal cause of this is cytoadherence to the vascular endothelium of erythrocytes containing the mature forms of the parasite, leading to sequestration and obstruction of small vessels. Besides, parasitized red cells become rigid, compromising their flow through capillaries whose lumen has been reduced by sequestered erythrocytes. Adhesive forces between infected red cells (auto-agglutination), between infected and uninfected red cells (rosetting) and between uninfected erythrocytes (aggregation) could further slow down microcirculatory flow. A more recent finding is that uninfected erythrocytes also become rigid in severe malaria. Reduction in the overall red cell deformability has a strong predictive value for a fatal outcome. Rigidity may be caused by oxidative damage to the red blood cell membrane by malaria pigment released at the moment of schizont rupture. Anti-oxidants, such as N-acetylcysteine can reverse this effect and are promising as adjunctive treatment in severe malaria.     

Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin

Sickle trait, the heterozygous state of normal hemoglobin A (HbA) and sickle hemoglobin S (HbS), confers protection against malaria in Africa. AS children infected with Plasmodium falciparum are less likely than AA children to suffer the symptoms or severe manifestations of malaria, and they often carry lower parasite densities than AA children. The mechanisms by which sickle trait might confer such malaria protection remain unclear. We have compared the cytoadherence properties of parasitized AS and AA erythrocytes, because it is by these properties that parasitized erythrocytes can sequester in postcapillary microvessels of critical tissues such as the brain and cause the life-threatening complications of malaria. Our results show that the binding of parasitized AS erythrocytes to microvascular endothelial cells and blood monocytes is significantly reduced relative to the binding of parasitized AA erythrocytes. Reduced binding correlates with the altered display of P. falciparum erythrocyte membrane protein-1 (PfEMP-1), the parasite's major cytoadherence ligand and virulence factor on the erythrocyte surface. These findings identify a mechanism of protection for HbS that has features in common with that of hemoglobin C (HbC). Coinherited hemoglobin polymorphisms and naturally acquired antibodies to PfEMP-1 may influence the degree of malaria protection in AS children by further weakening cytoadherence interactions.     

Cytoadherence of Plasmodium falciparum-infected erythrocytes to human umbilical vein and human dermal microvascular endothelial cells under shear conditions

To investigate the role of hemodynamics in the adherence of Plasmodium falciparum-infected erythrocytes to cerebral endothelium in vivo, we investigated cytoadherence of parasitized erythrocytes to human umbilical vein endothelial cells (HUVEC) under shear conditions in vitro. At 1.0 dyne/cm2 shear stress, parasitized red blood cell (RBC) adherence to HUVEC ranged from 9.9 +/- 1.0 (+/- SEM) to 75.2 +/- 4.8 RBC/mm2 (mean +/- SEM: 35.1 +/- 2.8 RBC/mm2) and was 13-fold greater than uninfected erythrocyte adherence to HUVEC (range 0.1 +/- 0.1 to 6.7 +/- 1.6 RBC/mm2, mean +/- SEM 2.8 +/- 0.8 RBC/mm2). Only erythrocytes infected with trophozoites and schizonts adhered to HUVEC under shear conditions. Parasitized erythrocyte adherence to HUVEC decreased from 28.4 +/- 2.7 RBC/mm2 to 12.7 +/- 2.4 RBC/mm2 when shear stress was increased from 1.0 to 2.0 dynes/cm2. At 4.0 dynes/cm2, parasitized erythrocyte adherence decreased further to 2.0 +/- 1.3 RBC/mm2. In falciparum malaria patients, endothelial cytoadherence predominates in the microcirculation. Therefore, we also investigated adherence of parasitized erythrocytes to human dermal microvascular endothelial cells (MEC). At 1.0 dyne/cm2, cytoadherence of P. falciparum-infected erythrocytes to MEC ranged from 7.9 +/- 1.1 to 60.0 +/- 2.4 RBC/mm2 (mean +/- SEM: 23.0 +/- 1.7 RBC/mm2) and was 10-fold greater than uninfected erythrocyte cytoadherence to MEC (mean +/- SEM: 2.2 +/- 0.6 RBC/mm2). These data indicate that P. falciparum-infected erythrocytes adhere to human umbilical vein and microvascular endothelial cells under shear stress conditions typical of the postcapillary venules in vivo, and that cytoadherence is specific for parasitized erythrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies.

The CD36 molecule expressed by human endothelial cells is a receptor for the adhesion of erythrocytes infected with the human malaria parasite Plasmodium falciparum. A CD36-specific monoclonal antibody, OKM8, inhibits the adhesion of malaria-infected erythrocytes (IRBC) to purified CD36 and cells expressing CD36. Monospecific polyclonal anti-idiotype (anti-Id) antibodies, raised against monoclonal antibody OKM8, expressed determinants molecularly mimicking the CD36 binding domain for the adhesion of IRBC. Purified rabbit anti-Id antibodies reacted with the surface of IRBC by immunofluorescence, directly supported the adhesion of wild-type P. falciparum malaria isolates, and inhibited IRBC cytoadherence to melanoma cells. An approximately 270-kDa protein was immunoprecipitated by the anti-Id antibodies from surface-labeled and metabolically labeled IRBC and was competitively inhibited by soluble CD36. These results support the hypothesis that CD36 is a receptor and the approximately 270-kDa protein, sequestrin, is a complementary ligand involved in the adhesion of IRBC to host-cell endothelium. Sequestrin is a candidate malaria vaccine antigen, and anti-Id antibodies that recognize this molecule may be useful for passive immunotherapy of cerebral and severe P. falciparum malaria.     

In vitro rosetting, cytoadherence, and microagglutination properties of Plasmodium falciparum-infected erythrocytes from Gambian and Tanzanian patients

To understand the molecular mechanisms that lead to sequestration of red blood cells infected with mature stages of Plasmodium falciparum and to examine the relevance of earlier studies on adherence properties of laboratory-derived P falciparum parasites to the natural parasite population, we analyzed Gambian and Tanzanian isolates for in vitro cytoadherence and antibody-mediated microagglutination. Eighteen cryopreserved isolates of ring-stage parasites were cultured for 20 to 30 hours in vitro, in the patients original erythrocytes, to the trophozoite and schizont stage. All parasites were positive in the microagglutination assay with at least one of four African hyperimmune sera. In a rosetting assay, only 2 of the 18 isolates were strongly positive (35% and 41% of parasitized erythrocytes with more than two uninfected cells bound). Thirteen isolates showed either intermediate (5% to 18%) or low (less than 5%) rosetting while three isolates did not form rosettes. Infected cell-binding of the different isolates to immobilized CD36 or thrombospondin, or C32 melanoma cells correlated with the percentage of mature parasites in the blood samples (r = .932 for CD36, r = .946 for thrombospondin, and r = .881 for C32 melanoma cells). There was a high correlation between binding to CD36 and thrombospondin (r = .982). The extent of infected cell rosetting with uninfected cells in these blood samples was not correlated with these other receptor properties. We also observed coexpression of rosetting and cytoadherence receptors on the same parasitized erythrocytes.     

Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes.

Sequestration, the adherence of infected erythrocytes containing late developmental stages of the parasite (trophozoites and schizonts) to the endothelium of capillaries and venules, is characteristic of Plasmodium falciparum infections. We have studied two host factors, the spleen and antibody, that influence sequestration of P. falciparum in the squirrel monkey. Sequestration of trophozoite/schizont-infected erythrocytes that occurs in intact animals is reduced in splenectomized animals; in vitro, when infected blood is incubated with monolayers of human melanoma cells, trophozoite/schizont-infected erythrocytes from intact animals but not from splenectomized animals bind to the melanoma cells. The switch in cytoadherence characteristics of the infected erythrocytes from nonbinding to binding occurs with a cloned parasite. Immune serum can inhibit and reverse in vitro binding to melanoma cells of infected erythrocytes from intact animals. Similarly, antibody can reverse in vivo sequestration as shown by the appearance of trophozoite/schizont-infected erythrocytes in the peripheral blood of an intact animal after inoculation with immune serum. These results indicate that the spleen modulates the expression of parasite alterations of the infected erythrocyte membrane responsible for sequestration and suggest that the prevention and reversal of sequestration could be one of the effector mechanisms involved in antibody-mediated protection against P. falciparum malaria.     

Genes necessary for expression of a virulence determinant and for transmission of Plasmodium falciparum are located on a 0.3-megabase region of chromosome 9.

Virulence of the human malaria parasite Plasmodium falciparum is believed to relate to adhesion of parasitized erythrocytes to postcapillary venular endothelium (asexual cytoadherence). Transmission of malaria to the mosquito vector involves a switch from asexual to sexual development (gametocytogenesis). Continuous in vitro culture of P. falciparum frequently results in irreversible loss of asexual cytoadherence and gametocytogenesis. Field isolates and cloned lines differing in expression of these phenotypes were karyotyped by pulse-field gel electrophoresis. This analysis showed that expression of both phenotypes mapped to a 0.3-Mb subtelomeric deletion of chromosome 9. This deletion frequently occurs during adaptation of parasite isolates to in vitro culture. Parasites with this deletion did not express the variant surface agglutination phenotype and the putative asexual cytoadherence ligand designated P. falciparum erythrocyte membrane protein 1, which has recently been shown to undergo antigenic variation. The syntenic relationship between asexual cytoadherence and gametocytogenesis suggests that expression of these phenotypes is genetically linked. One explanation for this linkage is that both developmental pathways share a common cytoadherence mechanism. This proposed biological and genetic linkage between a virulence factor (asexual cytoadherence) and transmissibility (gametocytogenesis) would help explain why a high degree of virulence has evolved and been maintained in falciparum malaria.     

Plasmodium falciparum intercellular adhesion molecule-1-based cytoadherence-related signaling in human endothelial cells

BACKGROUND: Cytoadherence of Plasmodium falciparum-infected erythrocytes to host endothelium has been associated with pathology in severe malaria, but, despite extensive information on the primary processes involved in the adhesive interactions, the mechanisms underlying disease are poorly understood. METHODS: We compared parasite lines varying in their binding properties to human endothelial cells for their ability to stimulate signaling activity. RESULTS: In human umbilical vein endothelial cells (HUVECs), which rely on adhesion to intercellular adhesion molecule (ICAM)-1 for binding, signaling is related to the avidity of the parasite line for ICAM-1 and can be blocked either through the use of anti-ICAM-1 monoclonal antibodies or HUVECs with altered ICAM-1 binding properties (i.e., ICAM-1(Kilifi)). Human dermal microvascular endothelial cells (HDMECs), which can bind infected erythrocytes via ICAM-1 and CD36, have a more complex pattern of signaling behavior, but this is also dependent on adhesive interactions rather than merely contact between cells. CONCLUSIONS: Signaling via apposition of P. falciparum-infected erythrocytes with host endothelium is dependent, at least in part, on the cytoadherence characteristics of the invading isolate. An understanding of the postadhesive processes produced by cytoadherence may help us to understand the variable pathologies seen in malaria disease.     

Studies of the receptors on melanoma cells for Plasmodium falciparum infected erythrocytes

We investigated whether thrombospondin plays a role in the binding of Plasmodium falciparum parasitized erythrocytes to C32 melanoma cells. Twelve patient isolates bound variably to melanoma cells, with good correlation between the degree of binding to cells and binding to thrombospondin. With a synchronous preparation of asexual parasites, acquisition of the capacity to bind to thrombospondin occurred at the same parasite stage as binding to melanoma cells. Development of parasites to trophozoites and schizonts correlated with binding of parasitized erythrocytes to thrombospondin and melanoma cells. The infected erythrocyte receptor for thrombospondin was destroyed by mild trypsinization, as was the receptor for melanoma cells. Although these results suggest similarity in the melanoma cell receptor and thrombospondin receptor for infected cells, other results showed that thrombospondin cannot alone be the melanoma cell receptor. Binding to other melanoma cell lines did not correlate with thrombospondin secretion: the RPMI 8252 and G361 cell lines bound few or no infected cells, yet secreted 50-100% as much thrombospondin as C32 cells. Iodinated thrombospondin bound in similar amounts to C32 cells and to noncytoadherent C361 melanoma cells. Binding and nonbinding melanoma cells did not differ in quantity of surface thrombospondin by radioimmunoassay. Thus, although purified, immobilized, thrombospondin binds parasitized erythrocytes, expression of thrombospondin alone on melanoma cells is not sufficient to mediate adherence.     

Antibodies to a histidine-rich protein (PfHRP1) disrupt spontaneously formed Plasmodium falciparum erythrocyte rosettes.

Cerebral involvement in Plasmodium falciparum malaria is associated with sequestration of infected red blood cells and occlusion of cerebral vessels. Adhesion of infected erythrocytes along the vascular endothelium as well as binding of uninfected erythrocytes to cells infected with late-stage asexual parasites (rosetting) may be important in erythrocyte sequestration. We report that the recently discovered rosetting phenomenon shares characteristics with other human cell-cell interactions (heparin sensitivity, temperature independence, Ca2+/Mg2+ and pH dependence). Mono- and polyclonal antibodies specific for PfHRP1, a histidine-rich protein present in the membrane of P. falciparum-infected erythrocytes, disrupt rosettes but do not affect attachment of infected erythrocytes to endothelial cells. The inhibitory anti-PfHRP1 antibodies reacted with rosetting parasites in indirect immunofluorescence and with P. falciparum polypeptides of Mr 28,000 and Mr 90,000 in immunoprecipitation and immunoblotting, respectively. No inhibitory effects on erythrocyte rosetting were obtained with antibodies to related histidine-rich or other antigens of P. lophurae or P. falciparum. Whether the epitope that mediates rosetting, and is recognized by the anti-PfHRP1 antibodies, is located on PfHRP1 or on a crossreactive antigen remains to be established. The results suggest that endothelial cytoadherence and erythrocyte rosetting involve different molecular mechanisms.     

脑型疟发生的免疫病理机制

脑型疟(cerebral malaria)是疟疾感染的严重并发症,近年来其发生的免疫病理学机制受到极大关注。早期的研究认为,脑型疟的发生主要与感染疟原虫的红细胞和脑血管内皮细胞黏附,导致脑血管阻塞有关。然而,越来越多的证据表明,脑型疟的发生主要由疟原虫感染后引起的免疫病理反应所导致,与炎症因子的过量释放和免疫细胞在脑血管的浸润密切相关。本文就近年来脑型疟发生的免疫病理机制的研究进展作一综述。     

A primate model for human cerebral malaria: Plasmodium coatneyi-infected rhesus monkeys.

A major factor in the pathogenesis of human cerebral malaria is blockage of cerebral microvessels by the sequestration of parasitized human red blood cells (PRBC). In vitro studies indicate that sequestration of PRBC in the microvessels is mediated by the attachment of knobs on PRBC to receptors on the endothelial cell surface such as CD36, thrombospondin (TSP), and intercellular adhesion molecule-1 (ICAM-1). However, it is difficult to test this theory in vivo because fresh human brain tissues from cerebral malarial autopsy cases are not easy to obtain. Although several animal models for human cerebral malaria have been proposed, none have shown pathologic findings that are similar to those seen in humans. In order to develop an animal model for human cerebral malaria, we studied brains of rhesus monkeys infected with the primate malaria parasite, Plasmodium coatneyi. Our study demonstrated PRBC sequestration and cytoadherence of knobs on PRBC to endothelial cells in the cerebral microvessels of these monkeys. Cerebral microvessels with sequestered PRBC were shown by immunohistochemical analysis to possess CD36, TSP, and ICAM-1. These proteins were not evident in the cerebral microvessels of uninfected control monkeys. Thus, our study indicates, for the first time, that rhesus monkeys infected with P. coatneyi can be used as a primate model to study human cerebral malaria. By using this animal model, we may be able to evaluate strategies for the development of vaccines to prevent human cerebral malaria.     

The resistance to physiological shear stresses of the erythrocytic rosettes formed by cells infected with Plasmodium falciparum

Rosetting forces are believed to be an important contributor to the microcirculatory obstruction that occurs in malaria caused by Plasmodium falciparum. In this study, rosettes of erythrocytes from cultures of this parasite were suspended in different media and exposed to shear stresses corresponding to those encountered on the arterial and venous sides of the human circulation. The rosettes formed by infected erythrocytes in malaria culture medium containing 10% AB serum were disrupted easily (approximately 50% being broken) when exposed to very low shear stresses of < 0.5 Pa. However, use of higher concentrations of serum strengthened the rosetting binding forces considerably. Suspension of rosettes in a viscous colloid (e.g. dextran) increased the adherence forces between infected and uninfected red cells. The results indicate that rosettes do resist the physiological shear forces that are encountered in the venular side of the circulation and could thus contribute to microvascular obstruction in falciparum malaria.     

Cytoadherence in human falciparum malaria as a cause of respiratory distress

The ultrastructure of three cases of fatal human falciparum malaria was studied in order to identify the cytoadherence of the endothelial cells in relation to parasitized red blood cells and septal interstitial changes which could be related to respiratory distress. Two cases showed marked endothelial oedema narrowing the capillary lumen with areas of adherence preferentially related to knobs, accompanied by septal interstitial oedema. One case showed no endothelial cells oedema, no knobs in parasitized red blood cells with no cytoadherence, no septal interstitial oedema and no respiratory distress. Cytoadherence seems to be the mechanism responsible for the septal pulmonary changes in severe falciparum malaria.     

Rolling and stationary cytoadhesion of red blood cells parasitized by Plasmodium falciparum: separate roles for ICAM-1, CD36 and thrombospondin

Summary. Adhesion of parasitized erythrocytes to microvascular endothelium is a central event in the pathogenesis of severe falciparum malaria. We have characterized the adhesion of flowing parasitized red blood cells to three of the known endothelial receptors coated on plastic surfaces (CD36, intercellular adhesion molecule-1 (ICAM-1) and thrombospondin (TSP)), and also to cells bearing these receptors (human umbilical vein endothelial cells (HUVEC) and platelets). All of the surfaces could mediate adhesion at wall shear stress within the physiological range. The great majority of adherent parasitized cells formed rolling rather than static attachments to HUVEC and ICAM-1, whereas static attachments predominated for platelets, CD36 and TSP. Studies with monoclonal antibodies verified that binding the HUVEC was mainly via ICAM-1, and to platelets via CD36. Adhesion via ICAM-1 was least sensitive to increasing wall shear stress, but absolute efficiency of adhesion was greatest for CD36, followed by ICAM-1, and least for TSP. TSP did not give long-lasting adhesion under flow, whereas cells remained adherent to CD36 or ICAM-1. We propose that the different receptors may have complementary roles in modulating adhesion in microvessels. Initial interaction at high wall shear stress may be of a rolling type, mediated by ICAM-1 or other receptors, with immobilization and stabilization occurring via CD36 and/or TSP.     

Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum-infected erythrocytes

In falciparum malaria, the malaria parasite induces changes at the infected red blood cell surface that lead to adherence to vascular endothelium and other red blood cells. As a result, the more mature stages of Plasmodium falciparum are sequestered in the microvasculature and cause vital organ dysfunction, whereas the ring stages circulate in the blood stream. Malaria is characterized by fever. We have studied the effect of febrile temperatures on the cytoadherence in vitro of P. falciparum-infected erythrocytes. Freshly obtained ring-stage-infected red blood cells from 10 patients with acute falciparum malaria did not adhere to the principle vascular adherence receptors CD36 or intercellular adhesion molecule-1 (ICAM-1). However, after a brief period of heating to 40 degrees C, all ring-infected red blood cells adhered to CD36, and some isolates adhered to ICAM-1, whereas controls incubated at 37 degrees C did not. Heating to 40 degrees C accelerated cytoadherence and doubled the maximum cytoadherence observed (P < 0.01). Erythrocytes infected by ring-stages of the ICAM-1 binding clone A4var also did not cytoadhere at 37 degrees C, but after heating to febrile temperatures bound to both CD36 and ICAM-1. Adherence of red blood cells infected with trophozoites was also increased considerably by brief heating. The factor responsible for heat induced adherence was shown to be the parasite derived variant surface protein PfEMP-1. RNA analysis showed that levels of var mRNA did not differ between heated and unheated ring-stage parasites. Thus fever-induced adherence appeared to involve increased trafficking of PfEMP-1 to the erythrocyte membrane. Fever induced cytoadherence is likely to have important pathological consequences and may explain both clinical deterioration with fever in severe malaria and the effects of antipyretics on parasite clearance.     

Uninfected erythrocytes form "rosettes" around Plasmodium falciparum infected erythrocytes

The human malaria parasite, P. falciparum, exhibits cytoadherence properties whereby infected erythrocytes containing mature parasite stages bind to endothelial cells both in vivo and in vitro. Another property of cytoadherence, "rosetting," or the binding of uninfected erythrocytes around an infected erythrocyte, has been demonstrated with a simian malaria parasite P. fragile which is sequestered in vivo in its natural host, Macaca sinica. In the present study we demonstrate that rosetting occurs in P. falciparum. Rosetting in P. falciparum is abolished by protease treatment and reappears on further parasite growth indicating that, as in P. fragile, it is mediated by parasite induced molecules which are protein in nature. P. vivax and P. cynomolgi, which are not sequestered in the host, did not exhibit rosetting. Rosetting thus appears to be a specific property of cytoadherence in malaria parasites.     

Multiple human serum components act as bridging molecules in rosette formation by Plasmodium falciparum-infected erythrocytes

Rosetting, the binding of parasitized erythrocytes to 2 or more uninfected erythrocytes, is an in vitro correlate of disease severity in Plasmodium falciparum malaria. Although cell ligands and receptors have been identified and a role for immunoglobulin M has been suggested, the molecular mechanisms of rosette formation are unknown. The authors demonstrate unequivocally that rosette formation by P falciparum-infected erythrocytes is specifically dependent on human serum, and they propose that serum components act as bridging molecules between the cell populations. Using heparin treatment and Percoll density gradient centrifugation, they have developed an assay in which parasitized erythrocytes grown in serum-containing medium and optimally forming rosettes are stripped of serum components. These infected cells were no longer able to form rosettes when mixed with erythrocytes and incubated in serum-free medium. Rosette formation was restored by the addition of serum or certain serum fractions obtained by concanavalin A (conA) affinity, anti-IgM affinity, anion exchange, and gel filtration chromatography. The authors clearly demonstrate that multiple serum components-IgM and at least 2 others-are involved in rosette formation. Those others consist of 1 or more acidic components of high-molecular mass that binds to conA (but that is not thrombospondin, fibronectin, or von Willebrand's factor) and of at least 1 more basic, smaller component that does not bind to conA. Data on the size and number of rosettes formed support the authors' hypothesis that multiple bridges are involved in this complex cellular interaction. These findings have important implications for the understanding of pathogenic adhesive interactions of P falciparum and host susceptibility to severe malaria. (Blood. 2000;95:674-682)     

Modulation of malaria virulence by determinants of Plasmodium falciparum erythrocyte membrane protein-1 display

PURPOSE OF REVIEW: Plasmodium falciparum malaria parasites carry approximately 60 var genes that encode variable adhesins termed P. falciparum erythrocyte membrane protein-1. Clonal expression of a single P. falciparum erythrocyte membrane protein-1 variant on the surface of the parasitized host erythrocyte promotes binding of the cell to blood elements (including noninfected erythrocytes, leukocytes) and walls of microvessels. These binding events enable parasitized erythrocytes to sequester and avoid clearance by the spleen, and they also contribute to disease by causing microvascular inflammation and obstruction. RECENT FINDINGS: Steps by which P. falciparum erythrocyte membrane protein-1 is exported to the parasitized erythrocyte surface have recently been elucidated. The ability of parasites to cytoadhere and cause disease depends on the variant of P. falciparum erythrocyte membrane protein-1 as well as its amount and distribution at the erythrocyte surface. An example of a host polymorphism that affects P. falciparum erythrocyte membrane protein-1 display is hemoglobin C, which may protect against malaria by impairing the parasite's ability to adhere to microvessels and induce inflammation. Interference with P. falciparum erythrocyte membrane protein-1-mediated phenomena appears to diminish cytoadherence in vivo and to protect against disease in animal models. SUMMARY: Plasmodium falciparum erythrocyte membrane protein-1-mediated sequestration of parasitized erythrocytes plays a central role in malaria pathogenesis. Clinical interventions aimed at reducing cytoadherence and microvascular inflammation may improve disease outcome.     

Absence of knobs on parasitized red blood cells in a splenectomized patient in fatal falciparum malaria.

We present a case report of fatal falciparum malaria of a splenectomized adult Thai patient. The patient developed high peripheral parasitemia and showed signs of severe malaria with multiorgans involvement. Ultrastructure of Plasmodium falciparum-infected red blood cells in a fatal splenectomized patient and pathological features are reported for the first time with special emphasis on the role of the spleen as a modulating cytoadherence phenotype of parasitized red blood cells (PRBC). In this patient, adherence of the PRBC to the vascular endothelium of brain, kidney and lung including blood circulating cells, was noted, despite the absence of knob on the surface of the PRBC.