**Question:** Sickling in 'HbS' disease is primarily caused by

A. Hemoglobin S polymerization
B. Hemoglobin S production
C. Decreased oxygen affinity
D. Hemoglobin S mutation

**Core Concept:** Hemoglobin S (HbS) is a variant of hemoglobin found in individuals with sickle cell anemia or trait. Sickle cell anemia is a genetic disorder characterized by abnormal red blood cells that assume a sickle or crescent shape when deoxygenated, leading to various clinical manifestations. In the context of this question, we focus on the primary cause of the deformed red cells.

**Why the Correct Answer is Right:** In HbS disease, sickling occurs due to Hemoglobin S polymerization. When deoxygenated, the abnormal hemoglobin S molecules tend to form polymers, which cause red blood cells to solidify and lose their flexibility. This leads to red blood cells adopting an abnormal sickle shape, which can cause blockages in blood vessels, reducing blood flow and oxygen delivery to tissues.

**Why Each Wrong Option is Incorrect:**

A. Hemoglobin S production (Option A): Although HbS is the primary cause of sickling, the question specifically asks for the primary cause of the deformed red cells. Hemoglobin S production is relevant but not the main focus in this context.

B. Decreased oxygen affinity (Option C): Although decreased oxygen affinity contributes to the overall pathophysiology of HbS disease, it is not the primary cause of the deformed red cells. The primary cause lies in the abnormal hemoglobin S polymerization.

D. Hemoglobin S mutation (Option D): The correct answer is D, as HbS mutation is the source of the abnormal hemoglobin S, which leads to polymerization and the subsequent sickling process.

**Clinical Pearl:** A thorough understanding of the primary cause (HbS polymerization) is crucial in understanding the pathophysiology of HbS disease and its clinical manifestations. Knowledge of the genetic basis (HbS mutation) is also essential but is less directly relevant to the primary cause of deformed red cells.