In HS, the erythrocytes fail to pass through fenestrations, and this is where resident splenic macrophages sample, or "bite," part of the stuck spherocytes plasma membranes. The macrophages recognize that the spherocyte is not normal, and the macrophage is "programmed" to destroy irregularities filtered at the spleen from the blood. The resident splenic macrophages therefore phagocytose the spherocytes, causing extravascular hemolysis. This leads to both splenomegaly and anemia. Should this process continue unchecked chronically, inappropriate regulation of erythropoeisis leads to extramedullary hematopoiesis. Clinical Presentation
HS patients present in a vast array of presentations from being asymptomatic, to the extreme situations of splenic rupture and/or hemolytic crisis, or in-utero demise. Asymptomatic HS (mild): 20-30% of patients. Infantile-Onset HS (moderate): 60-75% of patients. Neonatal or In-Utero Onset HS (severe): <5% of patients.The most common presentation will demonstrate jaundice (due to increased unconjugated bilirubin), anemia (with secondary pallor), and a palpable spleen sometimes with concomitant tenderness (due to splenic congestion and splenomegaly). Its worth noting that a subsection of HS patients will also have incidental black pigmented gallstones (made of calcium bilirubinate consequence of the extravascular hemolysis), and some of these patients will develop cholelithiasis and/or the potential complex sequelae of this condition, i.e. cholecystisis, choledocholithiasis, etc. Diagnostics
Laboratory Testing
Available lab testing that may aid in the diagnosis of HS is as follows:

Coombs Test
Osmotic Fragility Test
Acidified Glycerol Lysis Test
Supportive blood work: mean cell volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), red blood cell count (RBC), reticulocytes, unconjugated bilirubin, haptoglobin, lactate dehydrogenase (LDH).
Peripheral Blood Smear
Eosin-5-maleimide Binding Test

Common Laboratory Findings
The common findings of lab testing in setting of a patient with hereditary spherocytosis:

Coombs Test: Negative (rules-out autoimmune hemolytic anemia)
Osmotic Fragility Test: Positive (Spherocytes will rupture in liquid solutions less concentrated than the inside of the red blood cell. This is due to increased permeability of the spherocyte membrane to salt and water, which enters the concentrated inner environment of the RBC and leads to its rupture. Although the osmotic fragility test is no longer considered the gold standard for diagnosing hereditary spherocytosis, as it misses ~25% of cases). Acidified Glycerol Lysis Test: Positive (A newer version of the osmotic fragility test that adds glycerol to a hypotonic solution. This produces lysis, a positive test, quicker that the traditional saline version). Supportive blood work:
Mean Cell Volume (MCV): Normocytic (normal range: 80-100fL), or slightly lower. Spherocytes are slightly smaller than normal biconcave red blood cells. Mean Corpuscular Hemoglobin Concentration (MCHC): Increased (normal range: 31-36% Hb/cell). This is secondary to less water being in the cell. Red Blood Cell Distribution Width (RDW): Increased (normal range: 11-15%). The spherocytes create variation in the size of the red blood cells on average, thus expanding the distribution. Red Blood Cell Count (RBC): Sometimes Increased Early (normal range males: 4.3-5.9 million/mm3; normal range females: 3.5-5.5million/mm3). The loss of surface area per cells cause the body to mass produce red blood cells. The spleen will filter spherocytes out and change this value. Reticulocytes: Increased (normal range: 0.5%-1.5% of the RBC listed above).