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Hematologic Diseases and Malignancies


Key Concepts

  • Severe anemia can be detected when discontinuous blood columns are present within the bulbar conjunctival vasculature.

  • β-thalassemia is associated with a decreased tear break-up time and Schirmer testing.

  • Sludging and segmentation of the conjunctival blood vessels (comma sign) is a pathognomic finding of sickle cell disease.

  • Leukemic cells can infiltrate the conjunctiva, iris, and anterior chamber, resulting in glaucoma, spontaneous hyphema, and uveitis.

  • Plasma cell disorders may cause paraprotein depositions in the cornea and conjunctiva, presenting as fine, iridescent, polychromatic crystals.

Knowledge of the various ocular manifestations of hematologic diseases and malignancies may lead to the early diagnosis and treatment of a potentially life-threatening disorder in those patients who have not yet developed overt systemic clinical symptoms. The familiarity of the ophthalmologist with such secondary ocular findings additionally benefits patients with established disorders who are referred for ophthalmic consultation and care.

Basics of Hematology

Blood cell production is initiated in the bone marrow by the pluripotential hematopoietic stem cell, which can differentiate into myeloid or lymphoid progenitors. The myeloid cell line includes erythrocytes, granulocytes (basophil, eosinophil, and neutrophil), monocytes/macrophages, and platelets. Furthermore, the lymphoid cell line is composed of T-lymphocytes, B-lymphocytes, and natural killer cells. Lymphocyte maturation and activation takes place in the thymus and lymph nodes. Of note, plasma cells are differentiated forms of B-lymphocytes that produce antibodies.

Anemia

Anemia is defined as a decrease in the circulating mass of red blood cells (RBCs), which can be detected by RBC count, hemoglobin concentration, or hematocrit. Most patients with mild anemia have no complaints and are unaware of their condition. Symptoms of moderate to severe anemia may include fatigue, weakness, palpitations, malaise, decreased exercise tolerance, headaches, and rarely syncope.

Iron Deficiency Anemia

An estimated 15% of the world’s population has iron deficiency anemia, representing the most common type of anemia. The prevalence in the United States is estimated to be less than 1% in men and 2%–5% in women. The usual causes of iron deficiency in adults include chronic blood loss (e.g., gastrointestinal tract loss and menstruation), malabsorption, and poor dietary intake.

Systemic Manifestations

The clinical manifestations specific to iron deficiency anemia may include brittle hair, spooning of fingernails (koilonychia), dysphagia due to esophageal stricture (Plummer–Vinson syndrome), glossitis, angular stomatitis, and pica. Iron deficiency anemia is diagnosed by laboratory testing, which may be associated with the following abnormal laboratory values: reduced serum iron level, elevated iron-binding capacity, reduced serum ferritin level, and elevated serum transferrin receptor level. In severe cases of iron deficiency, a peripheral blood smear reveals erythrocyte morphologic changes that include microcytosis and hypochromia. Prussian blue staining of a bone marrow aspirate to show decreased iron in macrophages and in erythroid precursors is rarely necessary to establish iron stores.

Ophthalmic Manifestations

There are few specific anterior segment manifestations of iron deficiency anemia, although severe iron deficiency may be associated with blue sclera. While pallor of the inferior palpebral conjunctiva is a known sign to screen for anemia, the sensitivity of the technique is poor (38%). In contrast, discontinuous blood columns within the bulbar conjunctival vasculature are easily viewed with a slit lamp and are a highly sensitive screening tool (83%–94%). With worsening anemia, there is an increasing chance that the blood column will develop a gap between the erythrocytes.

Thalassemia

The thalassemias are a group of inherited hemolytic anemias characterized by defects in the production of the α or β chains of hemoglobin, resulting in an imbalance of the globin chain synthesis and subsequent hemolysis in the spleen or bone marrow. The defect can be found in a single allele of the β gene (β-thalassemia minor), in both alleles of the β gene (β-thalassemia major), or in the α genes (α-thalassemia).

Systemic Manifestations

The clinical manifestations of thalassemia are extremely variable; they range from no symptoms to severe anemia with jaundice, hypogonadal dwarfism, pathologic fractures, and death. Initial evaluation includes blood film interpretation, which may reveal basophilic stippling and abnormally shaped RBCs. These findings warrant further investigation with hemoglobin electrophoresis; however, definite diagnosis is made by identification of the underlying mutation by DNA analysis.

Ophthalmic Manifestations

Gartaganis et al. examined the ocular surface of 52 patients with β-thalassemia and found a significant decrease in tear break-up time and Schirmer testing compared to control subjects. Sixty-four percent of patients had a decrease in the number of goblet cells on conjunctival cytology examination. Other ocular abnormalities in β-thalassemia include lens opacities, angioid streaks, retinal pigment epithelial degeneration, and retinal vascular anomalies. It remains unclear if some of the ocular findings are secondary to the disease itself or from treatment with desferrioxamine.

Sickle Cell Disease

Sickle cell disease is caused by a mutation in the β-globin gene, resulting in production of hemoglobin S (HbS) instead of hemoglobin A. Individuals develop sickle cell disease when they have two HbS genes (homozygous, HbSS) or one HbS gene with another mutant β-globin gene (compound heterozygote, HbSC). They are said to have a sickle cell trait (HbAS) if the second gene is the normal HbA. When HbS is deoxygenated, it polymerizes and becomes rigid crystal-like rods. Significant amounts of HbS polymer within RBCs cause hemolysis and obstruction of microvessels, leading to vaso-occlusive events.

Systemic Manifestations

HbAS patients are generally asymptomatic except during episodes of extreme hypoxia or severe infection. On the other hand, HbSS and HbSC patients often present with acute disease, such as infections, splenic sequestration, vaso-occlusive crises, and acute chest syndrome. These patients can also suffer from chronic organ damage to the kidneys, lungs, and brain. Diagnosis of sickle cell disease is made by hemoglobin electrophoresis; genetic testing may also be performed.

Ophthalmic Manifestations

Ocular findings occur in up to 33% of patients with sickle cell disease. Vision threatening manifestations are more commonly secondary to sickle retinopathy. Sludging and segmentation of the conjunctival blood vessels, also known as the “comma sign,” is considered pathognomonic for sickle cell disease. The vessels appear short, isolated, and darkened. Spontaneous subconjunctival hemorrhage and sectoral iris atrophy secondary to ischemia are also potential anterior segment findings.

Leukemia

The term leukemia defines a group of disorders characterized by the proliferation of a clone of abnormal hematopoietic cells. These abnormal clones are typically immature cells that accumulate and cause a decrease in the production of normal hematopoietic cells. Systemic manifestations include anemia, bleeding, and increased susceptibility to infection.

The leukemias are classified by the cell type involved (myeloid or lymphoid) and by the rapidity of abnormal cell proliferation (acute or chronic). Without appropriate diagnosis and treatment, leukemia is generally fatal.

Overall, the percentage of patients with any type of ocular involvement from leukemia at the time of autopsy ranges from 28% to 80%. The major manifestations of leukemic ophthalmopathy are hemorrhage (primarily retinal) and leukemic tissue infiltration. The avascular cornea is generally spared from these leukemic complications. Should the anterior segment and iris become infiltrated with leukemic cells, associated symptoms and physical findings may include decreased vision, ocular discomfort, headache, photophobia, epiphora, conjunctival injection, abnormal cells in the aqueous, fine keratic precipitates on the endothelium, hypopyon, gray-yellow discoloration of the iris, loss of the normal iris architecture with a gelatinous material filling the iris crypts, spontaneous hyphema, and glaucoma. The eye may be the primary site of recurrence in previously treated leukemia. Anterior chamber paracentesis may be considered for any patient presenting with uveitis and a recent history of leukemia.

Acute Leukemia: Acute Myeloid Leukemia

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