**Core Concept**
Sickle cell anemia is a genetic disorder caused by a mutation in the hemoglobin gene, leading to the production of abnormal hemoglobin (HbS) that can polymerize under low oxygen conditions, causing red blood cells to take on a sickle shape. This abnormal shape can lead to vaso-occlusion, hemolysis, and various clinical manifestations.

**Why the Correct Answer is Right**
The commonest presentation of sickle cell anemia is often a painful episode known as a vaso-occlusive crisis, which occurs when sickled red blood cells obstruct blood flow in small vessels. This can lead to severe pain, inflammation, and tissue damage. The pathophysiology involves the polymerization of HbS, which causes red blood cells to become rigid and sticky, leading to their adherence to endothelial surfaces and subsequent vaso-occlusion.

**Why Each Wrong Option is Incorrect**
**Option A:** While anemia is a characteristic feature of sickle cell anemia, it is not the most common presentation.
**Option B:** Infections are a significant complication of sickle cell anemia, but they are not the most common presentation.
**Option C:** Splenic sequestration or infarction can occur in sickle cell anemia, but it is not the most common initial presentation.

**Clinical Pearl / High-Yield Fact**
The "sickle cell crisis" is often precipitated by infections, dehydration, or other stressors that lead to hypoxia and increased HbS polymerization. This is a key clinical correlation to remember when managing patients with sickle cell anemia.

**Correct Answer: D. Vaso-occlusive crisis**