In red blood cell (RBC) diseases, the spleen contributes to anemia by clearing the damaged RBCs, but its unique ability to mechanically challenge RBCs also poses the risk of inducing other pathogenic effects. We have analyzed RBCs in hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), two typical examples of blood disorders that result in membrane protein defects in RBCs. We use a two-component protein-scale RBC model to simulate the traversal of the interendothelial slit (IES) in the human spleen, a stringent biomechanical challenge on healthy and diseased RBCs that cannot be directly observed in vivo. In HS, our results confirm that the RBC loses surface due to weakened cohesion between the lipid bilayer and the cytoskeleton and reveal that surface loss may result from vesiculation of the RBC as it crosses IES. In HE, traversing IES induces sustained elongation of the RBC with impaired elasticity and fragmentation in severe disease. Our simulations thus suggest that in inherited RBC disorders, the spleen not only filters out pathological RBCs but also directly contributes to RBC alterations. These results provide a mechanistic rationale for different clinical outcomes documented following splenectomy in HS patients with spectrin-deficient and ankyrin-deficient RBCs and offer insights into the pathogenic role of human spleen in RBC diseases.

在红细胞（RBC）疾病中，脾脏通过清除受损的红细胞而导致贫血，但其机械挑战红细胞的独特能力也带来了诱发其他致病作用的风险。我们分析了遗传性球形红细胞增多症 (HS) 和遗传性椭圆红细胞增多症 (HE) 中的红细胞，这两种血液疾病导致红细胞膜蛋白缺陷的典型例子。我们使用二元蛋白质规模红细胞模型来模拟人脾内皮间缝 (IES) 的穿越，这是对健康和患病红细胞的严格生物力学挑战，无法在体内直接观察到。在 HS 中，我们的结果证实红细胞由于脂质双层和细胞骨架之间的内聚力减弱而失去表面，并揭示表面损失可能是由于红细胞穿过 IES 时的囊泡形成所致。在 HE 中，穿过 IES 会导致红细胞持续伸长，在严重疾病中弹性受损和破碎。因此，我们的模拟表明，在遗传性红细胞疾病中，脾脏不仅过滤掉病理性红细胞，而且还直接导致红细胞改变。这些结果为血影蛋白缺陷和锚蛋白缺陷红细胞的 HS 患者脾切除后记录的不同临床结果提供了机制原理，并为人类脾脏在红细胞疾病中的致病作用提供了见解。