P falciparum–infected RBCs through the fast and slow circulatory compartments of the perfused human spleen. Schematic representation of observations in the ex vivo human spleen model challenged with cultured iRBCs, using the circulatory features extracted from in vivo imaging in human volunteers as a framework (Figure 1). Ring- and schizont-iRBCs differed in their main phenotypic characteristics, with ring-iRBCs displaying no cytoadherent properties in vitro and no observable surface modifications (A). In the fast compartment, corresponding to the perifollicular zone on histologic sections, only schizont-iRBCs were retained, whereas both ring- and schizont-iRBcs were retained in the slow compartment, corresponding to the red pulp (B). This resulted in significantly different clearance rates. The similarity between the proportion of blood flowing to the slow compartment (10.2%) and the proportion of retainable ring-iRBCs retained in the same compartment (11%) was striking. The quantitative dimension of the spleen microcirculatory framework is important. Because 5% of the cardiac output goes to the spleen, a given RBC will enter the spleen every 20 minutes. The slow compartment accounts for only 10% of the spleen plasma flow, which corresponds to 10% to 20% of spleen RBC flow (depending on the intensity of plasma skimming effect¹¹ ). Therefore, the quality control of the deformability of a given RBC occurs every 100 to 200 minutes. This fits with the 60-minute half-life of stiff-heated RBCs previously observed in healthy controls.³⁹  The order of magnitude of those previous clinical observations perfectly fits our framework (C). In addition, according to our volume estimates (Figure 1), an average 150-g spleen contains approximately 100 g of red pulp (70% of 150 g). The physiologic daily input of senescent RBCs to the spleen (1% of total RBC biomass ∼ 20 mL/day) thus corresponds to approximately 20% of the red pulp volume. During acute P falciparum malaria, parasitemia more than 5% is not uncommon. The input of ring-iRBCs to the spleen may therefore exceed the red pulp volume, probably saturating the slow circulatory compartment. The risk of saturation probably becomes significant when the ring-iRBC biomass at least equals the physiologic daily input of senescent RBCs, ie, at a peripheral parasitemia of approximately 1%. Saturation is expected to transiently reduce spleen filtering function and to induce abrupt changes in the slow/fast circulation balance. Those mechanisms, along with sequestration of mature iRBCs in the PFZ and red pulp sinus lumens, are potential strong determinants of both splenomegaly and outcome in acute malaria.