Substitution at position 6 of the hydrophobic valine for hydrophilic glutamic acid causes an abnormal hemoglobin (HbS) which crystallizes when oxygen tension is low, and the RBC's change shape to long, thin sickle forms that “sludge” in capillaries, further decreasing blood flow and oxygen tension. Sickled cells are prone to stick together, plugging smaller vessels and leading to decreased blood flow with ischemia.