Stomatocytosis (red blood cells [RBCs] with a transverse slit or stoma across the center) and hypophosphatemia cause RBC membrane abnormalities that can result in hemolytic anemia.
Stomatocytosis
Stomatocytosis is a rare condition of RBCs in which a mouthlike or slitlike pattern replaces the normal central zone of pallor. Stomatocytosis may be:
Congenital
Acquired
Both congenital and acquired stomatocytosis may be asymptomatic or cause hemolysis. Symptoms, if present, result mainly from the anemia.
Congenital stomatocytosis and congenital xerocytosis, which have autosomal dominant inheritance, are rare hemolytic anemias caused by abnormal RBC hydration (either dehydration or overhydration variants). Mutations in PIEZO1 are reported in approximately half of patients with other half having mutations in KCNN4, RHAG, SCL4A1, and ABCB6 (1). They can cause a severe hemolytic anemia that manifests very early in life, although the most common presentation is compensated hemolysis or mild anemia with elevated reticulocyte count and mean corpuscular hemoglobin concentration (MCHC) when there is cellular dehydration. The RBC membrane is hyperpermeable to monovalent cations (sodium and potassium); movement of divalent cations and anions is normal. Iron overload is also common. Splenectomy may ameliorate anemia in severe cases, but careful consideration should be given to the increase in thromboembolic events that follows splenectomy (2) and its less clear therapeutic benefit. Thus, splenectomy is often a last option for patients with severe symptoms.
Acquired stomatocytosis with hemolytic anemia occurs primarily after excessive alcohol ingestion. Stomatocytes in the peripheral blood and hemolysis disappear within 2 weeks of alcohol withdrawal.
Sitosterolemia is a rare autosomal recessive genetic disorder that can present with hemolytic anemia characterized by stomatocytes and macrothrombocytopenia. It is due to increased absorption and decreased biliary excretion of plant sterols in the diet with excessive incorporation of the sterols into RBC membranes. Management includes dietary modification, such as avoiding foods high in plant sterols, and ezetimibe or cholestyramine (is a rare autosomal recessive genetic disorder that can present with hemolytic anemia characterized by stomatocytes and macrothrombocytopenia. It is due to increased absorption and decreased biliary excretion of plant sterols in the diet with excessive incorporation of the sterols into RBC membranes. Management includes dietary modification, such as avoiding foods high in plant sterols, and ezetimibe or cholestyramine (3).
Anemia caused by hypophosphatemia
RBC pliability varies in relation to intracellular ATP levels. Because the serum phosphate concentration affects RBC ATP levels, a low serum phosphate level (< 0.5 mg/dL [< 0.16 mmol/L]) depletes ATP levels in RBCs. The complex metabolic sequelae of hypophosphatemia also include 2,3-diphosphoglyceric acid depletion, a shift to the left in the oxygen dissociation curve, decreased glucose utilization, and increased lactate production. The resultant rigid, nonyielding RBCs are susceptible to injury in the capillary circulatory bed, leading to hemolysis and spherocytosis.
Severe hypophosphatemia may occur in:
Refeeding after starvation
The recovery (diuretic) phase after severe burns
Hyperalimentation
Severe respiratory alkalosis
Patients with uremia receiving dialysis who are taking antacids
Phosphate supplements prevent or reverse the anemia and are considered for patients at risk of or who have hypophosphatemia.
References
1. Andolfo I, Iolascon A, Russo R. The evolving landscape of hereditary stomatocytosis. Blood. 2025;145(26):3089-3100. doi:10.1182/blood.2024024294
2. Stewart GW, Amess JA, Eber SW, et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol. 1996;93(2):303-310. doi:10.1046/j.1365-2141.1996.4881033.x
3. Rees DC, Iolascon A, Carella M, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol. 2005;130(2):297-309. doi:10.1111/j.1365-2141.2005.05599.x
