Thorough exam, comanagement help facilitate diagnosis of hematologic disorders
Hematologic disorders are a common malady in the general population, and ocular manifestations can be the presenting signs or symptoms in up to 90% of patients (Lang et al.). This paper will review basic hematology concepts and common associated ocular manifestations.
Blood has many important functions. The four main components of blood include: plasma, red blood cells (RBCs), white blood cells and platelets. Each component is highly specialized, serving a variety of life sustaining functions, which include:
- transporting oxygen and nutrients to the lungs and tissues
- forming blood clots to prevent excess blood loss
- carrying cells and antibodies that fight infection
- bringing waste products to the kidneys and liver, which filter and clean the blood
- regulating body temperature
The blood that runs through the veins, arteries and capillaries is known as whole blood – a mixture of 55% plasma and 45% blood cells. Approximately 7% to 8% of total human body weight is blood, with an average-sized man containing 12 pints of blood, and an average-sized woman containing 9 pints of blood (American Society of Hematology, Whitaker, Fauci et al.)
Plasma, one of the four components of blood, comprises 90% water and a mixture of blood cells, salts, glucose and proteins, all of which carry important nutrients to the body’s cells and strengthen the immune system.
There are three types of blood cells that circulate within plasma: RBCs (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes).
Of these cells, erythrocytes are the most abundant. Their biconcave shape and lack of a nucleus enable RBCs to change their shape in order to fit through small vessels. On average, in a healthy person, a RBC survives 90 to 120 days, and about 1% of human RBCs break down each day. The job of removing old and damaged RBCs from the circulation is accomplished by the spleen. The production of RBCs in the bone marrow is matched by the breakdown and removal of RBCs in healthy individuals.
Hemoglobin (Hb), a protein contained in red cells, helps carry oxygen from the lungs to the rest of the body, returning carbon dioxide to the lungs so it can be exhaled. It is composed of heme (the portion containing iron) and globin (a protein made up of amino acid chains) and may be affected when mutations in the globin genes result in changes in the amino acids of the protein.
White blood cells, or leukocytes, are specialized cells of the immune system that defend the body from infection. There are several types of white blood cells: neutrophils, eosinophils, basophils, monocytes, macrophages, dendritic cells and lymphocytes. A distinguishing feature amongst white blood cells is the presence or absence of granules. Leukocytes that contain granules, membrane-bound enzymes that aid in digestion of endocytosed particles, are classified as neutrophils, eosinophils and basophils. Each contains a multi-lobed nucleus and is known as the polymorphonuclear (PMN) leukocytes.
Neutrophil granulocytes are the most abundant of the white blood cells, making up 60% to 70% of the total leukocyte count. They are active in phagocytosis and the most common cell found in the early stages of acute inflammation. Basophil granulocytes are chiefly responsible for allergic and antigen response by releasing histamine. Eosinophils are primarily involved in both allergic reaction and parasitic infection.
Monocytes have two important functions. Aside from being a primary player in phagocytosis, they are antigen-presenting cells that allow for an activated antibody response from T cells. As monocytes leave the bloodstream, they differentiate into tissue macrophages that attack microorganisms and remove dead tissue debris.
Dendritic cells originate in the bone marrow and function as antigen-presenting cells (APCs). They are more efficient APCs than macrophages and are usually found in lymphoid organs, such as the thymus, lymph nodes and spleen, as well as in the bloodstream. Dendritic cells help regulate the adaptive immune response. They have three main functions, which include: antigen presentation, immune maintenance and tolerance and immune memory.
Lymphocytes are a family of cells characterized by a lack of specific granules. This cell type includes two major classes, the T and B lymphocytes. T lymphocytes (also known as thymus-dependent) are further divided into two major subsets: T-helper cells and T-killer/suppressor cells (Parkin et al., Raviola).
T-helper cells (also called CD4+ cells) coordinate immune regulation by secreting specialized factors that activate other white blood cells to ward off infection. T-killer/suppressor cells (also called CD8+ cells) are involved in the direct killing of certain tumor cells, viral-infected cells and parasites. They are also important in the down-regulation of the immune response.
Lymphocytes circulate with blood and lymph and can infiltrate connective and epithelial tissues. To become stimulated, T lymphocytes must interact with histocompatibility molecules (membrane glycoproteins) present on the surface of eukaryotic cells and are coded by a set of genes known as major histocompatibility complex (MHC). Histocompatibility molecules are either expressed on the surface of all cells or exclusively expressed on the cells of the immune system.
B lymphocytes (also known as bursa-dependent lymphocytes) are involved in the production of antibodies that respond to bacteria, viruses and tumor cells. Antibodies, also known as immunoglobulins, are specialized proteins that bind to a foreign substance (antigen) and signal other cells to engulf, kill or remove that substance from the body. Immunoglobulins are subdivided into several classes. Immunoglobulin G (IgG) represents the bulk of the immunoglobulins in human blood. Other types include IgM, IgA, IgE and IgD.
Natural killer (NK) cells are similar to the T-killer cell subset (CD8+ T cells). They directly kill certain tumor (i.e., melanomas, lymphomas) and viral-infected cells (i.e., herpes and cytomegalovirus). NK cells are unique, as they have the ability to recognize stressed cells in the absence of antibodies and MHC allowing for a much faster immune reaction.
Lastly, platelets are small fragments of cells that aid in the coagulation process. These specialized blood cells gather at the site of an injury, attach to the lining of the injured blood vessel and form a platform on which clotting can occur. This results in the formation of a fibrin clot that covers the wound and prevents blood from leaking out. Fibrin also forms the initial scaffolding upon which new tissue forms, thus promoting healing (Rose et al., Steinberg).
The most common hematologic disorders known to cause ocular sequelae include the anemias, sickle cell hemoglobinopathy, polycythemia, blood cancers and platelet disorders.
Anemias: red blood cell disorders
In general, anemia develops when the rate of breakdown of RBCs exceeds the production of RBCs. Classically, and more specifically, it is defined as a reduction in the hemoglobin concentration, the number of circulating RBCs or the hematocrit (Hct), or volume of packed red cells in the blood.
Specifically, anemia is divided into three major categories: hypoproliferative, maturation defect and hemolysis. Causes of anemia may be broadly classified as impaired RBC production, blood loss and fluid overload, and increased RBC destruction. Clinically, these three forms may interplay to cause anemia.
In the U.S., hypoproliferative anemia is the most common and includes iron deficiency, chronic kidney disease (CKD) and the inflammation-associated anemia of chronic disease. The latter can be found in patients with chronic diseases such as rheumatoid arthritis, inflammatory bowel, HIV/AIDS and cancer (Braunwald et al).
Images: DelGiodice M
Hypoproliferative anemia represents absolute or bone marrow failure. In response to acute blood loss, the erythroid marrow fails to effectively proliferate.
Overall, iron deficiency represents the most common type of anemia. Because iron absorption is a highly regulated process, it is highly conserved in the body, with excretion only through blood loss or exfoliation of epidermal cells. When the RBC reaches the end of its lifespan, the iron attached to the heme is released to transferrin (carrier protein) and delivered to the bone marrow to be recycled to young RBCs. Thus, serum ferritin level is a convenient laboratory value that corresponds to iron stores. Clinically, such individuals may be further classified as those with an increased demand, reduced intake or absorption and/or those with increased loss of iron. Thus, management is directed at identifying the cause and treating the appropriate systemic manifestation.
Hemolytic anemia represents approximately 5% of all anemias. This type of anemia is caused by the hemolysis of RBCs either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). Hemolysis is associated with a release of hemoglobin and lactic acid dehydrogenase (LDH). An increase in indirect bilirubin and urobilinogen is derived from released hemoglobin and can lead to jaundice. Hemolytic anemia occurs when the bone marrow is unable to increase production to make up for the premature destruction of red blood cells. If the bone marrow is able to keep up with the early destruction, anemia does not occur (sometimes called compensated hemolysis) (Beutler).
Hemolysis is the final event triggered by a large number of hereditary and acquired disorders. More than 200 causes for hemolysis exist, ranging from relatively harmless to life-threatening. It can be either acquired or inherited, and its treatment depends on the cause and nature of the breakdown.
Ocular manifestations of anemia
While the exact pathophysiology of anemic retinopathy is not completely understood, it seems to be related to retinal hypoxia, venous stasis, angiospasm and increased capillary permeability (Loewenstein). Anemic retinopathy is most likely to occur in patients with severe anemia or when thrombocytopenia, a disorder of low platelets, coexists (Carraro et al.). The ocular changes found in anemic retinopathy are nonspecific and may closely resemble diabetic or hypertensive retinopathy (Weiss).
Patients with anemia may develop both anterior and posterior segment complications. Anterior segment signs may include conjunctival pallor and hemorrhages. Retinal findings may include intraretinal hemorrhages, Roth’s spot hemorrhages, cotton-wool spots, retinal exudates, venous dilation, optic nerve edema and pallor. Patients who show signs of optic neuropathy require neuroimaging. Because ophthalmic manifestations may be nonspecific, it is important to rule out other possible vasculopathic etiologies. Most notably, ocular signs typically resolve upon the resolution of anemia.
Macular hemorrhage caused by anemia is rare. Oner et al. was the first to report a patient with bilateral macular hemorrhage caused by acute onset of autoimmune hemolytic anemia in 2005. A case of bilateral macular hemorrhage secondary to azathioprine-induced aplastic anemia was reported by Sudhir. Haddadin et al. reported a patient with unilateral macular hemorrhage as the only presentation of megaloblastic anemia in pregnancy (Figure 1).
Given the nonspecific ophthalmologic course with regard to funduscopic signs, it is important to take an accurate systemic history to corroborate an appropriate diagnosis. Once the cause is determined, the approach is to implement the appropriate treatment to correct the anemia.
In cases that are mild or appear to be resolving on their own, observation alone may be sufficient. On the contrary, in cases of autoimmune hemolytic disease where there is notable increased red blood cell destruction, systemic corticosteroids are the first line of treatment. A loading dose is given, followed by a gradual reduction of the dose over many weeks or months. If corticosteroid therapy causes intolerable side effects or if patients do not respond to corticosteroid therapy, the next step consists of a splenectomy (Tabbara).
If surgery is contraindicated or if RBCs continue to be destroyed, then immunosuppressive drugs, such as Cytoxan (cyclophosphamide, Bristol-Myers Squibb) or Imuran (azathioprine, Prometheus Laboratories), are used. When RBC destruction continues to take place after all these efforts, blood transfusions may be required.
Other management may include discontinuing systemic medications such as penicillin, sulfa drugs, cephalothin, ampicillin, methicillin, quinine and quinidine, all of which may be responsible for immune hemolysis. In addition, folic acid administration is important because active hemolysis may consume folate and cause megaloblastosis.
Sickle cell hemoglobinopathy
Sickle cell disease (SCD) affects more than 72,000 Americans, primarily of African heritage. Persons of Arabian, Mediterranean, Caribbean, Indian, Asian, and South and Central American descent are also affected. Sickle cell disease occurs in about one in every 500 African-American births and one in every 1,000 to 1,400 Hispanic-American births. About 2 million Americans, or one in 12 African-Americans, carry the sickle cell trait.
SCD and its variants are a result of genetic disorders resulting from the presence of a mutated form of hemoglobin, hemoglobin S (HbS). This protein is unstable as it generates oxidant and induces iron decompartmentalization and cellular dehydration, which results in abnormal membrane defects such as endothelial adhesivity, phospholipid destabilization and protein defects. Both HbS polymerization (RBC sickling) and the aforementioned membrane defects play an important role in the pathophysiology of hemolytic anemia and vaso-occlusion in sickle cell anemia. Normal red cells are soft, smooth and round, enabling them to move easily through blood vessels.
The most common form of SCD found in North America is homozygous HbS disease (HbSS) also known as sickle cell anemia, an autosomal recessive disorder. SCD causes significant morbidity and mortality, particularly in people of African and Mediterranean ancestry.
Carriers of the sickle cell trait (i.e., heterozygotes who carry one HbS allele and one normal adult hemoglobin [HbA] allele) have some resistance to the often-fatal malaria. This property explains the distribution and persistence of this gene in the population in malaria-endemic areas. However, in areas such as the U.S., where malaria is not a problem, the trait no longer provides a survival advantage. Instead, it poses the threat of SCD, which occurs in children of carriers who inherit the sickle cell gene from both parents (i.e., HbSS).
Although carriers of sickle cell trait do not suffer from SCD, individuals with one copy of HbS and one copy of a gene that codes for another abnormal variant of hemoglobin, such as HbC or Hb beta-thalassemia, have a less severe form of the disease. The most common types of sickle cell disease are SS, SC and S beta-thalassemia.
In sickle cell anemia, both hemolytic anemia and vaso-occlusive phenomenon occurs. Occlusion of blood vessels prevents the delivery of oxygen to tissues and organs. Sickled cells die after just 10 to 20 days. Because they cannot be replaced fast enough, the blood is chronically short of RBCs, leading to anemia.
Ocular manifestations of sickle cell hemoglobinopathy
Similar to other forms of anemia, ocular manifestations of sickle cell disease may affect both the anterior and posterior segments. Anterior segment involvement includes: comma-shaped (sickled) conjunctival vessels, rubeosis iridis, hyphema, secondary neovascular glaucoma and focal iris atrophy. Posterior involvement is more common and may be classified as nonproliferative or proliferative disease. Nonproliferative changes include peripheral venous tortuosity, Angioid streaks, salmon-patch hemorrhages, black sunburst spots, dark without pressure and iridescent spots. Proliferative retinopathy consists of five stages (Sugihara):
- Stage 1: peripheral arteriolar occlusion
- Stage 2: peripheral arterio-venous anastomoses
- Stage 3: neovascular and fibrous proliferations (“sea-fan” formation)
- Stage 4: vitreous hemorrhage
- Stage 5: retinal detachment
Polycythemia vera (PV) is a chronic, clonal, myeloproliferative disorder characterized by an absolute increase in the number of red blood cells and in the total blood volume and is usually accompanied by leukocytosis, thrombocytosis and splenomegaly. Polycythemia is characterized by a hypercellular bone marrow. It typically occurs in older men and causes slowing of blood flow as the result of hyperviscosity of the blood.
Secondary disorders that are attributable to polycythemia include diseases of the heart and lungs. A decrease in total arterial oxygen saturation upregulates erythropoietin production, which stimulates erythroid precursors in the bone marrow to produce more RBCs for increased oxygen delivery (Tasman et al.).
Ocular manifestations of polycythemia vera
Ocular manifestations of polycythemia are in tandem with systemic hyperviscosity. Retinal venous engorgement and intraretinal hemorrhages are a common manifestation of this rare condition.
Leukemia: white blood cell disorder
Leukemia is a cancer of the blood or bone marrow and is characterized by an abnormal proliferation of white blood cells (WBCs) or leukocytes. Normal leukocyte count for men and nonpregnant women is 5,000 to 1,000 WBCs per mm3 or 5.0 to 10.0 x 109 WBCs per liter (Nissl).
The major forms of leukemia are divided into four categories. The terms “myelogenous” and “lymphocytic” denote the type of white cell involved. Myelogenous and lymphocytic leukemias each have acute and chronic forms. Leukemia is further divided into acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia (CLL). Approximately 50% or more of all leukemias manifest some form of ocular involvement (Miller et al., Reddy et al.)
CML, also known as chronic granulocytic leukemia (CGL), is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. Basic science has defined the molecular pathogenesis of CML as unregulated signal transduction by a tyrosine kinase. Clinical science has demonstrated that it is curable through immune mediated-elimination of leukemia cells by allogeneic T-lymphocytes (Kantarjian) (See table below).
Ocular manifestations of leukemia
Ocular involvement may be due to leukemic infiltration of various ocular tissues or as a result of one of the secondary complications of the disease. These complications include anemia, thrombocytopenia and leukostasis, all of which may predispose the patient to retinal hemorrhages and ischemia. In those with acute leukemia, ocular manifestations have been described in up to half of patients at the time of diagnosis. Ocular manifestations of leukemia are most common in acute rather than chronic leukemias. Both acute and chronic leukemia can cause ocular signs, either initially or later in the disease process. Also, various chemotherapeutic agents used to treat leukemia may cause ocular toxicity.
On the basis of histologic evidence, leukemic infiltrates most often involve the choroid and have been reported in 50% to 82% of patients (Ren). In contrast, clinically evident leukemic infiltrates are most often seen in the retina and may manifest in a variety of ways.
One of the first changes is that veins become more dilated and tortuous and both arteries and veins become more yellowish, reflecting the decreased red cell count and increased white cell count. Retinal vascular sheathing is often present due to perivascular infiltration by leukemic cells. Hemorrhages may occur at all levels of the retina and may extend into the vitreous. Hemorrhages may be round or flame-shaped and often have a white component. In Roth’s spot hemorrhages, the white area consists of leukemic cells and debris, platelet-fibrin aggregates or septic emboli. Duane et al. confirmed the observation of the fibrin and platelet aggregate in the white center of Roth’s spots in leukemic patients.
Cotton-wool spots are often present with leukemia and are probably due to ischemia from anemia, hyperviscosity or leukemic infiltration. Most infiltrates and hemorrhages are seen in the posterior pole and the peripapillary region. Less common manifestations include microaneurysms, which tend to be peripheral. Peripheral retinal vascular changes, consisting of microaneurysms, ischemia and retinal neovascularization, are more common in the chronic leukemias and are believed to be caused by leukostasis (Duke et al.) (Figures 2 to 5).
Leukemic retinopathy usually is not treated directly. Systemic treatment involves the use of chemotherapy, immunotherapy and radiotherapy. Intraocular leukemic infiltrate is best treated with chemotherapy that is appropriate for the type and stage of leukemia. External-beam radiation may be applied to lesions of the optic nerve or orbit. The presence of leukemic infiltration is usually a poor prognostic indicator (Rosenthal).
Lymphomas are a diverse group of cancers of the lymphatic system that comprise 3% to 4% of cancers diagnosed annually (Steidl). Hodgkin’s disease is the most common form of lymphoma; all other lymphomas are termed non-Hodgkin’s lymphomas. Hodgkin’s lymphoma (HL) follows a more predictable pattern of growth, and its spread is more limited than non-Hodgkin’s lymphomas. The characteristic pathologic abnormality is a polycellular infiltrate made up of giant (Reed-Sternberg) cells that are fibrotic and necrotic in nature.
Presently, 80% to 90% of those with Hodgkin’s disease achieve long-term remission when receiving multi-agent chemotherapy and radiation. The WHO 2008 classification schema recognizes two histological types of HL: the nodular lymphocyte predominant and the “classic” HL. The most common sites of involvement are the cervical, supraclavicular and mediastinal lymph nodes.
The stage of disease is defined according to the Ann Arbor staging system or its Cotswolds variant. Staging work-up includes physical examination, chest X-rays, chest and abdominal CT scan, bone marrow biopsy and (18)fluordeoxyglucose positron emission tomography, or (18)FDG-PET, which also plays a central role in response assessment and prognosis definition (Gobbi et al.).
Non-Hodgkin’s lymphoma consists of many different types. These types can be divided into aggressive and indolent forms, and they can be formed from either B or T lymphocytes. B cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and mantle cell lymphoma. Prognosis and treatment depend on the stage and type of disease (National Cancer Institute). Both Hodgkin’s and non-Hodgkin’s lymphoma are treated with a variety of chemotherapy and radiation.
Ocular manifestations of lymphoma
Orbital involvement is a rare complication of Hodgkin’s disease, whereas non-Hodgkin’s is the most common type of ocular lymphoma. Ocular abnormalities associated with lymphoma have been divided anatomically into a vitreoretinal and uveal form. The vitreoretinal form is associated with primary central nervous system non-Hodgkin’s lymphoma (PCNSL) and is typically a large B-cell tumor (Sbeity).
In contrast, the uveal form is associated with systemic non-Hodgkin’s lymphoma. Involvement of the uveal tract may present as a non-resolving uveitis, diffuse choroidal infiltration or exudative retinal detachment. The characteristic retinal finding is a low-lying, yellow-white mass deep to the sensory retina. They may appear as single, multiple, confluent or discrete punctate lesions that may involve all layers of the retina (Cho et al.). Retinal phlebitis and the presence of cotton-wool spots have been reported as initial clinical findings in Hodgkin’s disease.
Treatment options for lymphoma include observation, involved-field radiation, subtotal lymphoid radiation, chemotherapy with or without radiation, and bone marrow transplant. Newer biologic therapies are also being investigated for the treatment of lymphoma.
The hemostatic system of blood vessels comprises platelets, coagulation factors and endothelial cells. An abnormal function of any component may result in the lack of clot formation and excess bleeding. Platelets play a vital role in the coagulation. As they bind to von Willebrand factor (vWf), adhesive reactions allow the platelets to interact with each other and form an aggregate.
The most common cause of abnormal bleeding, as a result of a subnormal number of platelets, is thrombocytopenia. Four basic processes of thrombocytopenia exist: artifactual thrombocytopenia, deficient platelet production, accelerated platelet destruction and abnormal pooling of platelets. The most common subtype of thrombocytopenia is accelerated platelet destruction, which may be seen in idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC).
ITP and TTP are rare blood disorders that more commonly affect women. ITP is characterized as acute, chronic or secondary to systemic disease. Acute ITP accounts for approximately 90% of all pediatric immunologic thrombocytopenia, whereas chronic ITP and TTP are responsible for affecting those in the third to fourth decade. Both are relapsing disease entities characterized by occlusion of the microcirculation. While they most often present with a low platelet count, micro-angiopathic hemolytic anemia, fever, renal dysfunction and neurologic signs, they may be a precursor to a more ominous prognosis (George). Drug-induced platelet destruction can be observed in patients taking various medications, such as amiodarone, sulfonamides, ibuprofen and tamoxifen. Heparin-induced thrombocytopenia is the most frequent drug-induced cause of decreased platelet production (Aster et al.).
Acute ITP is usually a self-limiting condition, whereas chronic ITP may require both medical and surgical therapy. Those with chronic ITP may be treated as outpatients or inpatients. The traditional approach is to start with prednisone and move onto intravenous gammaglobulin in cases that are initially refractory to therapy. Advanced therapy with high-dose IV gammaglobulin and additional immunosuppressive agents is reserved for patients with severe ITP and/or symptoms of bleeding that require hospitalization; surgical therapy includes splenectomy.
Cases of acute TTP typically present with neurological symptoms. In such cases, infusion or exchange of fresh frozen plasma is the treatment of choice and has dramatically changed the fatality rate. Relapsing episodes of TTP respond best to plasma infusion, with remission of relapsing episodes documented in most cases. Plasma-resistant hemolytic uremic syndrome or TTP invariably has a poor outcome if alternative treatments are not effective (Ruggenenti).
DIC is a common platelet anomaly caused by the release of tissue thromboplastin into the circulation with excessive clotting in blood vessels throughout the body. Anticoagulant drugs such as heparin are often administered to patients with DIC who are also being treated for their underlying disease. All-trans retinoic acid (ATRA), which is used for the treatment of acute promyelocytic leukemia (APL), improves DIC in APL (Aoshima).
Ocular manifestations of platelet disorders
The most common ocular manifestations of TTP include papilledema, extraocular muscle palsies and visual field defects, which are typically secondary to concomitant CNS involvement (Giusti et al.). Retinal findings consist of hemorrhages, retinal vascular occlusions and serous detachments (Stefani et al., Lambert et al.) The cause of the serous detachments appears to be focal occlusion of the choriocapillaris resulting in retinal pigment epithelial damage and blood-retinal barrier disruption.
Findings on fluorescein angiography are characterized by focal areas of nonperfusion of the choriocapillaris associated with late leakage into the subretinal space, which is consistent with histopathologic studies that reveal occlusion of the choriocapillaris and large choroidal vessels, presumably by fibrin, with overlying necrosis of the pigment epithelium. Also, TTP has been linked in one case report with Purtscher retinopathy (Power et al.).
Clinically, the development of serous retinal detachments usually is associated with exacerbations of TTP and acute hypertension. Although serous retinal detachments have been described as a preterminal event, resolution of the detachments may occur when the underlying hypertension and thrombocytopenia are controlled.
The classic ocular finding in DIC is serous retinal detachment (Cogan, Hoines et al.). The pathogenesis involves occlusion of the choriocapillaris resulting in retinal pigment epithelial damage and barrier and pump function. If the underlying DIC can be reversed, the retina may reattach, and vision may return. Other findings associated with DIC include retinal and vitreous hemorrhages (Kaiser et al.).
Plasma cell dyscrasias
Plasma cell dyscrasias are a group of blood disorders that share two characteristics: a proliferation and accumulation of cells found in normal antibody production and the development and secretion of gamma-globulin and its polypeptide subunits. The plasma cell dyscrasias include multiple myeloma (MM), Waldenstrom’s macroglobulinemia (WM), heavy chain diseases, amyloidosis and benign monoclonal hypergammaglobulinemia.
MM, also known as plasma cell myeloma, is a cancer of plasma cells responsible for producing antibodies. In MM, an abnormal accumulation of plasma cells within the bone marrow interferes with normal B lymphocyte production via chromosomal translocation. MM most commonly occurs in African-American men with a median survival of 3 to 7 years and represents the second most common hematological malignancy after non-Hodgkin’s lymphoma. Because the signs and symptoms are often ominous, a common tetrad has been developed. CRAB stands for: calcium (elevated), renal failure, anemia and bone lesions (International Myeloma Working Group). The most common symptom in patients with MM is bone pain, often located in the spine and ribs. Suspected cases of MM should undergo X-rays of the skull, axial system and long bones, protein electrophoresis of the blood and urine, complete metabolic panel with specific attention to calcium levels and creatinine, and bone marrow biopsy (detects the amount of plasma cells in the marrow). A unique characteristic of MM is the presence of Bence Jones proteins, composed of free light chains, via electrophoresis. Treatment of MM depends on the initial age and associated comorbidities. In patients younger than 65 years, high-dose chemotherapy with autologous hematopoietic stem-cell transplantation has become the preferred treatment. For patients older than 65 years who cannot handle stem-cell transplantation, treatment commonly includes chemotherapy and prednisone. New advances have brought forth emerging treatments including protein homeostasis modulation, kinase inhibitors, cytokine inhibitors and immunomodulatory agents (Mahindra et al.).
WM, also known as lymphoplasmacytic lymphoma, is a rare blood cancer affecting B cells and IgM. The average onset of age is 60 years, with some cases occurring in the late teenage years. Due to its slow growth, it is often referred to as “indolent lymphoma” (Cheson). The clinical features include normochromic normocytic anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy and signs of hyperviscosity. Diagnosis of WM often depends on a significant IgM spike in the blood and malignant cells in bone marrow biopsy. Active agents in the treatment of WM include rituximab, chlorambucil, cyclophosphamide, fludarabine, bortezomib, lenalidomide, bendamustine, everolimus and alemtuzumab (Gertz).
The heavy chain diseases are a group of rare B cell proliferative disorders characterized by abnormal constituents of monoclonal (M) protein; a portion of the immunoglobulin heavy is incomplete or truncated and without a bound light chain (Wahner-Roedler et al.). Diagnosis of HCD requires documentation of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine. Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.
Amyloidosis refers to a group of disorders involving abnormal deposition of amyloid proteins in organs and tissues. A protein is considered amyloid when it is in its insoluble form. More than 28 types of amyloid proteins have been described. Suspected cases should undergo monoclonal protein studies with diagnosis dependent on tissue biopsy. Ancillary tests can include Congo red stain, electron microscopy, immunofluorescence and immunohistochemistry to help discriminate between amyloid and other pathologic fibrils. Once amyloid is confirmed, typing should be performed. Genetic mutational analysis is vital for determining hereditary amyloidoses but is unhelpful in nonmutated forms (Leung et al.). Treatment depends on the underlying cause but most commonly involves chemotherapy and stem-cell transplantation (Trinn).
Benign monoclonal hypergammaglobulinemia (MGU) is an immunoproliferative disorder characterized by elevated gamma globulins in blood serum with a life-long average 1% annual risk of developing lymphoproliferative malignancies (Stelmach-Goldys et al.). The prevalence is 3% of people 50 years and older. The majority of hypergammaglobulinemias are caused by an excess of IgM with absence of IgG, IgA and IgE, resulting in susceptibility to bacterial and opportunistic infections.
The current diagnostic criteria for MGUs are concentration of monoclonal protein in serum less than 3.0 g/dL, bone marrow plasmacytosis less than 10% and lack of organ damage including: hypercalcemia, renal impairment, anemia and bone lesions. Currently, there are no methods for classification of patients due to the risk of progression to MM, and there is no therapy to prevent the progression, so the standard treatment for patients with MGUS is observation.
Ocular manifestations of plasma cell dyscrasias
Multiple myeloma is the most common plasma cell dyscrasias. Anterior segment involvement may occur as corneal stromal IgG crystalline deposits and ciliary epithelium cysts. Retinal involvement includes microaneurysms, nerve fiber layer hemorrhages, infarcts and exudative retinal detachments. Macular detachments associated with and without yellow subretinal precipitates have been reported with multiple myeloma and no evidence of systemic hyperviscosity (Ho et al.). Orbital and neuroophthalmic manifestations are caused by the mass effects of plasmacytomas. Proptosis, diplopia, choroidal folds, cranial nerve palsies and optic nerve involvement have been reported (Knapp et al.).
Venous dilation, retinal hemorrhages and retinal edema proliferate with increasing viscosity with severe cases, causing exudative detachments. Macular neurosensory elevation also has been reported in patients with WM with simultaneous increased plasmaviscosity. Changes from hyperviscosity may be reversible with plasmapheresis (Murphy).
Light-chain disease accounts for a small portion of the plasma cell dyscrasias. Ocular involvement consisting of a retinal vasculopathy with capillary nonperfusion, neovascularization and vitreous hemorrhage has been reported (Enzenhaver et al.).
The coagulopathies are a group of clotting disorders that may be genetic or acquired and include coagulation factor deficiencies and thrombophilia. The end product of the hemostatic cascade is the formation of fibrin, the major component of clotted blood. The integrity of the clotting cascade is attainable via particular factors that act as catalysts. The activation of these factors is accomplished via extrinsic and intrinsic pathways. With the activation of the coagulation system, the fibrinolytic system is turned on, which forms plasmin and clears fibrin (Kaiser et al.).
The most common inherited coagulation disorders are X-linked deficiencies of VIII (hemophilia A) and IX (hemophilia B); activated factor X is dependent on these via the intrinsic pathway. Systemic presentation involves pain and swelling in weight-bearing joints secondary to hemarthrosis, and the severity depends on the percentage of activated factors. Severe systemic manifestations are attributable to central nervous system (CNS) bleeding, with a mortality rate of 34% (Eyster et al.).
Thrombophilia is a group of disorders that cause a hypercoagulable state through an abnormal balance between the anticoagulant and procoagulant factors causing a predisposition to venous thrombosis. Genetic causes for thrombophilia include: factor V Leiden abnormality with activated protein C resistance, prothrombin mutations, protein C deficiency, protein S deficiency and antithrombin III deficiency. Acquired causes of thrombophilia include: antiphospholipid antibody syndrome, hyperhomocysteinemia, and abnormal lipoprotein levels.
Factor V Leiden is the most common genetic predisposition to venous thrombosis, occurring in 5% to 7% of Caucasians with a rare occurrence in darker individuals.
Prothrombin mutations represent the second most common inherited abnormality second to factor V Leiden.
Protein C deficiency has been associated with more than 160 mutations and is estimated to occur in 6% of patients with inherited thrombophilia.
Protein S deficiency is inherited as an autosomal-dominant trait that has intrinsic anticoagulant activity. It also serves as a nonenzymatic cofactor necessary for the anticoagulant activity of activated protein C. Unlike protein C deficiency or antithrombin III deficiency, heterozygous protein S deficiency is not as strong a risk factor for thrombosis.
Antithrombin III deficiency is inherited as an autosomal-dominant defect with heterozygosity conferring an increased risk of venous thrombosis. The prevalence of antithrombin III deficiency is increased in patients with inherited thrombophilia. As an endogenous inhibitor of thrombin and other procoagulant factors, it serves as a major coagulation inhibitor. A deficiency results in a hypercoagulable state.
The antiphospholipid antibody syndrome is a clinical syndrome causing venous and arterial thrombotic events. Antiphospholipid antibodies consist of two different antibodies: the lupus anticoagulant and the anticardiolipin antibody; the latter of which is more common. Although the two are similar, there are distinct clinical, laboratory, and biochemical differences. While both of these antibodies are associated with thrombosis in connective tissue diseases such as lupus and autoimmune diseases, malignancy, AIDS, and multiple drugs, some cases are found in otherwise healthy patients. The latter group is generally considered to have primary antiphospholipid antibody syndrome. However, both syndromes may be associated with arterial and venous thrombosis, fetal loss and thrombocytopenia.
Hyperhomocysteinemia describes a variety of disorders that causes plasma levels of homocysteine, homocystine and their metabolitesto be elevated. Mild hyperhomocysteinemia occurs in 5% to 7% of the general population (Biousse et al., Welch et al.). Some studies have estimated that 10% of the risk of coronary artery disease in the general population is attributable to hyperhomocysteinemia. Homocysteine is an amino acid formed during the metabolism of methionine via vitamins B12, B6 and folate. Independently, hyperhomocysteinemia serves as a risk factor for thrombophilia.
Ocular manifestations of coagulopathy
While coagulation factor deficiencies including factors VIII and IX are known to cause ocular manifestation, particularly following trauma or surgery, they most commonly follow intracranial hemorrhaging consisting of: pupillary abnormalities, cranial nerve palsies, visual blurring and papilledema.
Activated protein C deficiency and antithrombin III have been linked to a positive correlation with retinal vascular occlusions (Ciardella et al., Gottlieb et al.). Some reports have also displayed a correlation between factor V Leiden and retinal vein occlusions. Furthermore, patients with central retinal vein occlusions (CRVOs) were found to have a higher prevalence of factor V Leiden mutations compared with that of the general populations (Glueck et al., Albisinni et al., Greiner et al.). Limited ophthalmic sequelae are noted for the prothrombin mutations and protein S deficiency.
The ocular manifestations of antiphospholipid antibodies include retinal venous and arterial occlusions, amaurosis fugax, diplopia and visual field loss (Wiechens et al., Donders et al.). Extensive vasoocclusion, neovascularization and vitreous hemorrhage may occur.
Treatment consists of photocoagulation for the neovascularization and systemic anticoagulation and immunosuppression. The role of systemic treatment of lupus anticoagulant in the management of ocular disease is unclear, although some suggest that systemic anticoagulation be started promptly (Kleiner et al.).
Most notably, the lupus anticoagulant should be suspected in all cases of occlusive retinopathy in young adults without obvious causes. The diagnosis of lupus anticoagulant is best conducted via the Russell viper venom time and the tissue thromboplastin inhibition test; both yield sensitive and relatively specific results. Anticardiolipin antibodies can be measured by enzyme-linked immunosorbent assay, which can be more sensitive (Petri et al., Dunn et al., Levine et al.).
Hyperhomocysteinemia has been shown to be responsible for increased incidence of young adults with retinal artery and vein occlusions. One study found that hyperhomocysteinemia is a risk factor for central retinal vein occlusions and was found in a high percentage of bilateral CRVOs (55%) and ischemic CRVOs (30%) and was associated with severe vision loss (Wenzler et al.).
The patient with ocular manifestations of hematologic disorders can be challenging. A thorough systemic history, detailed ocular examination, appropriate lab work and comanagement with a general physician or hematologist/oncologist will increase the likelihood of accurate diagnosis. Given the vast array of overlapping signs, symptoms and diagnosis, a low threshold should be taken in the absence of typical diabetic and hypertensive manifestations.