The current paradigm in Plasmodium falciparum malaria pathogenesis states that young, ring-infected erythrocytes (rings) circulate in peripheral blood and that mature stages are sequestered in the vasculature, avoiding clearance by the spleen. Through ex vivo perfusion of human spleens, we examined the interaction of this unique blood-filtering organ with P falciparum-infected erythrocytes. As predicted, mature stages were retained. However, more than 50% of rings were also retained and accumulated upstream from endothelial sinus wall slits of the open, slow red pulp microcirculation. Ten percent of rings were retained at each spleen passage, a rate matching the proportion of blood flowing through the slow circulatory compartment established in parallel using spleen contrast-enhanced ultrasonography in healthy volunteers. Rings displayed a mildly but significantly reduced elongation index, consistent with a retention process, due to their altered mechanical properties. This raises the new paradigm of a heterogeneous ring population, the less deformable subset being retained in the spleen, thereby reducing the parasite biomass that will sequester in vital organs, influencing the risk of severe complications, such as cerebral malaria or severe anemia. Cryptic ring retention uncovers a new role for the spleen in the control of parasite density, opening novel intervention opportunities. (Blood. 2008;112:2520-2528) IntroductionThe pathogenesis of malaria involves multiple parasite and host factors. 1 Spleen filtering and immune functions have a major impact on the course of plasmodial infection in experimental models. 2,3 In malaria-endemic countries, splenectomy predisposes to fever, to more frequent and higher parasitemia (including circulating mature forms), and may reactivate latent plasmodial infections. 4,5 Despite relatively few published data (reviewed by Bach et al 5 ), clinicians include malaria in the list of infectious diseases justifying increased awareness in splenectomized nonimmune patients. 6 Because key features may differ between animal and human plasmodial infection and because detailed exploration of the human spleen is limited by ethical and technical constraints, 7 the fine interactions between Plasmodium falciparum-infected red blood cells (iRBCs) and the human spleen microcirculatory structures have been explored only indirectly 8,9 or postmortem. 10 Therefore, the mechanisms underlying the putative spleen protective or pathogenic effects during human malaria remain essentially speculative.The architecture of the spleen red pulp (RP) permits intimate scrutiny of red blood cells (RBCs), leading to selective retention of abnormal or senescent RBCs within the RP. 11 To reenter the venous system, RBCs leaving the reticular meshwork of the RP must cross the narrow interendothelial slits in walls of the venous sinuses. This process requires RBCs to undergo considerable deformation: if cells are not sufficiently deformable, they are retained upstream from the venous sinus wall. 11 Such RBC-processin...

Right PVL and PVE result in a comparable hypertrophy of the left liver. During the first laparotomy of a two-step liver resection, PVL can be efficiently and safely performed.