The immune system clears the sporozoites from blood circulation within 30 minutes, but a few escape and quickly invade the liver cells where they mature into schizonts. The liver schizonts rupture after 6 to 30 days. About 98% of patients experience liver schizogony by 90 days. It is this event that releases thousands of merozoites into the bloodstream, where they may invade any red blood cell. The merozoites mature successively from ring forms to trophozoites to mature schizonts (asexual forms) over 48 hours.
Within the red blood cells, the parasites digest hemoglobin. As the hemoglobin is digested, the toxic metabolite hemozoin is formed and isolated in the parasite’s food vacuole. The intracellular parasites modify the erythrocyte in several ways. The parasites derive energy from anaerobic glycolysis of glucose to lactic acid which may contribute to clinical manifestations of hypoglycemia and lactic acidosis. The parasites reduce red cell membrane deformability which results in hemolysis and accelerated splenic clearance which may contribute to anemia. The alterations to uninfected red blood cells, such as the addition of P. falciparum glycosylphosphatidylinositol (GPI) to the membrane may play a role in increased clearance of uninfected cells and contribute to anemia.
The new daughter merozoites are released from the schizont stage of infected erythrocytes. The remnants of the cell membrane and the hemozoin crystal are phagocytized by circulating macrophages which is an important stimulus for the activation of the immune cascade. Additionally, free heme is released into the peripheral blood which is an important stimulus for endothelial activation
Red cell lysis stimulates the release of proinflammatory cytokines such as tumor necrosis factor (TNF). TNF suppresses hematopoiesis, which also contributes to anemia. The liver and spleen enlarge over time. Thrombocytopenia is caused by a combination of hypersplenism and the deposition of platelets adjacent to parasite microvascular sequestration and fibrin thrombi.
Merozoites continue the asexual cycle and infect new red cells; A few differentiate into male or female gametocytes (sexual forms), which cause no symptoms. The gametocyte-committed parasites leave the bloodstream and develop in the bone marrow over three to four days. Mature male and female gametocytes then circulate in the bloodstream until they are ingested by a blood-feeding anopheline mosquito.
These sexual forms complete their life cycle within the midgut of the Anopheles mosquito with development into sporozoites, which migrate to the salivary glands of the mosquito; from there, they can infect another human through another bite.
