Introduction

Anemia is defined as a decrease in hemoglobin levels relative to an individual's baseline; however, sex- and race-specific reference ranges are often used to diagnose anemia when baseline hemoglobin is unknown. The World Health Organization (WHO) criteria for anemia in men are <13 g/dL, whereas for women, they are <12 g/dL. There are revised criteria for anemia in men and women with chemotherapy-related complications, as well as for age and race. Even "special populations" such as athletes, smokers, older adults, or those living at high altitudes have been reported to have different ranges. 

The critical issue in evaluating any form of anemia is the early recognition of treatable causes. This is crucial because hemoglobin, an iron-rich protein, enables red blood cells (RBCs) to carry oxygen from the lungs to the rest of the body. The biconcave shape of RBCs enables optimal gas exchange. If the body is unable to deliver oxygen, one may experience symptoms such as weakness, lethargy, dizziness, headache, shortness of breath, or arrhythmias. 

Anemia is often subcategorized into microcytic, normocytic, and macrocytic based on mean corpuscular volume (MCV). As there are numerous types of anemia, this laboratory parameter allows clinicians to formulate a practical diagnostic approach. 

Hemolytic anemia is classified as normocytic anemia with an MCV of 80 to 100 fL.  It is a form of low hemoglobin due to red blood cell destruction, increased hemoglobin catabolism, decreased hemoglobin levels, and increased bone marrow efforts to regenerate products. Hemolytic Anemias can be further subdivided into intrinsic and extrinsic causes.[1][2]

Etiology

There are numerous causes of hemolytic anemia, which can be classified in several ways, including acute and chronic disease; immune versus non-immune-mediated; intravascular versus extravascular; inherited versus acquired; and intracorpuscular versus extracorpuscular.

Intracorpuscular causes refer to abnormalities in the red blood cell itself. A red blood cell can be internally damaged when the solubility of hemoglobin is altered (hemoglobinopathy), the structure of the membrane or cytoskeleton is changed (membranopathy), or its metabolic abilities (enzymopathy) are decreased. Examples of hemoglobinopathies include sickle cell disease (SCD) and thalassemias. SCD is caused by a beta-globin gene mutation leading to polymerization of hemoglobin-S, sticking, and, therefore, hemolysis. Thalassemia is the most common cause of hereditary hemolytic anemia and is caused by a partial or complete lack of synthesis of one of the major alpha or beta globin chains of hemoglobin A.[3]

Membranopathies include hereditary spherocytosis (HS) and hereditary elliptocytosis (HE). HS is often autosomal dominant; however, non-dominant and recessive inheritance patterns have been reported. It has been seen in all racial groups. HS has been documented as a rare disease; however, due to limited knowledge, the onset and severity vary considerably, as well as the lack of specific lab tests, making it a difficult disease to study. It is a heterogeneous red cell membrane disorder where the autosomal dominant inheritance can lead to a spectrum of presentations from asymptomatic to life-threatening.[4][5]

Several RBC enzymopathies alter the shape of RBCs and cause nonspherocytic hemolytic anemias.[2] G6PD deficiency and pyruvate kinase deficiency (PKD) both fall into this category. PK is the rate-limiting enzyme in RBC energy production, whereas G6PD is involved in the processing of carbohydrates and plays a protective role from reactive oxygen species in RBCs.[6] G6PD deficiency is an X-linked inherited disorder, almost exclusively seen in males, that causes hemolysis often with certain medications or foods such as fava beans and aspirin.[3]

Alternatively, extracorpuscular causes refer to defects influenced by external factors, including mechanical, immune-mediated, or infectious factors. RBC transfusions can cause both acute and delayed hemolytic reactions. Mechanical trauma to RBCs is seen with microthrombi, fibrin, or valve shearing forces. Pathogens such as malaria and babesiosis are known to destroy RBCs, as well as medications like dapsone, which can be used to treat these diseases, also have deleterious effects as they have oxidant potential.

Epidemiology

Two databases exist that provide a systematic exclusion of the population of people that are not “normal”: the NHANES-III (the third U.S. National Health and Nutrition Examination Survey) database and the Scripps-Kaiser database. 

These databases indicate no difference in hemoglobin values between men aged 20-59 and women aged 20-49. This facilitates the study of patient populations whose values fall outside the ranges considered normative. 

African Americans have been found to have a lower normal hemoglobin concentration, lower serum transferrin saturation, higher serum ferritin levels, lower serum bilirubin levels, and lower leukocyte counts. This is thought to be due to the higher frequency of alpha-thalassemia and G6PD deficiency in the black population. G6PD deficiency is known to affect millions of people worldwide.[7][8][9]

Although it can be seen worldwide, HE is most predominantly seen in malaria-endemic regions of West Africa.[5] Several forms of anemia are seen in these regions, as it is often thought to be protective against malaria.

Overall, hemolytic anemias affect individuals across a broad range of ages, races, and genders, and can be acquired or inherited.

Pathophysiology

Hemolytic anemia is the destruction of RBCs. Normally, red blood cells have a lifespan of 120 days. This process can be chronic or acute and life-threatening. It can be further subdivided as to where the hemolysis is taking place - intravascularly or extravascularly.

When a red blood cell is unable to change shape as it passes through the spleen, it becomes sequestered and undergoes phagocytosis. This is seen in hemoglobinopathies such as sickle cell disease. 

Destruction can also occur with inherited protein deficits (membranopathies, ie, hereditary spherocytosis), fragmentation [microangiopathic hemolytic anemias ie. thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), HELLP], increased oxidative stress or decreased energy production (enzymopathies ie, G6PD Deficiency), antibodies binding with RBC’s resulting in phagocytosis (immune-mediated), drug-induced hemolysis, infections, or direct trauma (conga drums).[10]

Histopathology

A peripheral blood smear should be studied when there is concern for hemolysis. One would look for abnormal red blood cells such as schistocytes, spherocytes, or bite cells.[10] RBC shape is crucial in diagnosis. A distinctive blood smear may even be sufficient for the diagnosis of a type of hemolytic anemia. This is evident in conditions such as hereditary elliptocytosis and Southeast Asian ovalocytosis. However, other hemolytic anemias may have similar features, such as red cell fragmentation, as seen in microangiopathic hemolytic anemia (MAHA) and mechanical hemolytic anemia from leaking prosthetic valves. Oxidant damage produces specific types of red blood cells, thereby aiding diagnosis on a blood smear. Keratocytes or "bite" cells, "blister" cells, and irregularly contracted cells must be differentiated from spherocyte,s as it will alter one's diagnosis.[9]

History and Physical

A patient with anemia may present with shortness of breath, weakness, fatigue, arrhythmias such as tachycardia, or may present asymptomatic. Those with anemia caused by cell destruction or hemolysis may also present with jaundice or hematuria. If symptoms persist for longer periods, lymphadenopathy, hepatosplenomegaly, and cholestasis may also be observed. 

Specific physical exam findings may be able to lead a clinician to a suggested diagnosis. If a patient presents with diarrhea and hemolytic anemia, one may consider hemolytic uremic syndrome. Hematuria, in conjunction with labs supportive of hemolytic anemia, could be a sign of paroxysmal nocturnal hemoglobinuria (PNH).[10] A thorough history must be taken, and a physical exam performed, as these clues can connect the information to form a diagnosis. 

Evaluation

Although a patient may present with physical characteristics that may lead a clinician to suspect hemolytic anemia, laboratory markers are key. Results that will help confirm hemolysis are an elevated reticulocyte count, increased lactate dehydrogenase (LDH), elevated unconjugated bilirubin, and decreased Haptoglobin.

LDH is found intracellularly. When RBCs rupture, this value increases. Haptoglobin binds free hemoglobin. Therefore, because this protein is fully bound to the little hemoglobin that remains, it results in decreased overall Haptoglobin levels. Unconjugated bilirubin is elevated as the body is unable to eliminate it as quickly as it is produced with the destruction of RBCs.

Warm and cold agglutinins can further differentiate whether the cause is immune-mediated. A direct antiglobulin test (DAT) must be performed.[10]

Hemoglobin concentration, or degree of anemia, can be used as an indicator of the extent of hemolysis that occurs in sickle cell disease (SCD). The inverse correlation between low hemoglobin concentration and a high degree of hemolysis has been supported by clinical measures such as LDH, reticulocyte count, and indirect bilirubin.[11]

Treatment / Management

Depending on the severity of illness, immediate interventions, including blood transfusions, plasmapheresis, or diuresis, may be required based on the underlying cause of hemolytic anemia. 

Blood transfusions are always the mainstay of treatment when there is severe anemia, especially when there is active bleeding. Once hemolysis is identified as the cause of anemia, or if no emergent intervention is required, more specific treatment modalities may be implemented. However, the treatment will always vary depending on the cause. 

If the cause is initially unclear, a direct antiglobulin (Coombs) test can be used to distinguish between immune and non-immune causes of hemolysis.  For patients with SCD, blood transfusions, hydroxyurea, erythropoiesis-stimulating agents, and bone marrow transplants are possible options with demonstrated effect.[11]

A blood smear should be obtained, particularly when G6PD deficiency is being excluded, as it can be performed more rapidly than an assay. Additionally, there is a possibility of a false-negative assay, even though the smear remains suggestive of G6PD deficiency.[9] Once the diagnosis is established, patients must avoid medications and foods that exacerbate oxidative stress. 

Because the most feared complication of PNH is thromboembolic events, some recommend initiating prophylactic anticoagulation; however, further studies are needed to develop an appropriate treatment regimen and to identify who would benefit most from this anticoagulation.[3] Splenectomy, steroids, monoclonal antibodies, or immunosuppressants have been used as late treatment options for certain diseases such as autoimmune hemolytic anemias, HS, and SCD.[10][12]

Differential Diagnosis

One of the key laboratory values that aids in the diagnosis of hemolytic anemia is an elevated reticulocyte count, as the bone marrow attempts to produce increased numbers of RBCs. This can be seen in other disease processes such as blood loss anemia; therefore, one must be cautious in taking a thorough history as well as evaluating other lab values that should also be altered, including LDH, haptoglobin, and indirect bilirubin. 

Hemolysis can be seen in many rare conditions, from paroxysmal nocturnal hemoglobinuria to blood transfusions or mechanical circulatory support; therefore, a wide differential must be ruled out.[3] However, to assist one in making this distinction, there have been case reports that help separate intravascular hemolysis from diseases such as PNH, from those like heart valves with mechanical prosthesis, as kidney injury is less seen in the latter unless there is underlying kidney disease.[13]

Prognosis

Overall, the development of anemia increases the risk for mortality in many clinical diseases such as chronic kidney disease, heart failure, and malignancy. This is evident in the publication of landmark trials such as TRICC, TRISS, and TRACS, whose goals were to determine the lowest tolerable level of anemia without increasing mortality. 

The prognosis for hemolytic anemias again varies depending on the cause of the illness, as well as how early it is diagnosed and managed appropriately.  Studies have shown that patients with SCD have poorer outcomes. Specifically, hemoglobin levels of less than 8 g/dL are more likely to have complications during admissions, such as strokes and increased mortality.[11] Patients who are diagnosed with autoimmune hemolytic anemia with marked anemia at onset are at increased risk of multiple relapses and are more often seen to be refractory to multiple lines of treatment.[12] Because the primary treatment for G6PD deficiency is avoidance of oxidative stressors, the disease is rarely fatal. However, these patients are more predisposed to sepsis and complications from infections.[14]

Complications

Complications of hemolytic anemia include:

• Hemolytic anemia can affect multiple organ systems. As RBCs are destroyed, their products cause a chain of reactions that lead to further complications. 
• In SCD, chronic hemolysis reduces the amount of oxygen available for delivery, further leading to tissue hypoxia. As tissues are deprived of blood and, therefore, oxygen, patients can experience fatigue and muscle pain. The worse the degree of anemia, the worse the clinical outcomes in patients with SCD.[11]
• The risk of ischemia and thrombotic complications can be seen in any case of hemolysis as there are more complications being studied from the toxic effects of circulating free hemoglobin and iron. 
• Thromboembolism is the most common cause of death in paroxysmal nocturnal hemoglobinuria (PNH). 15% to 44% of these patients will experience at least one thromboembolic event during the course of their disease. Thalassemia and SCD are both associated with a hypercoagulable state caused by abnormal phospholipid membrane asymmetry, which has been linked to increased hemolysis and thrombosis.[3]
• Excess hemoglobin and iron from hemolysis also cause complications in the kidneys. Iron and hemosiderin deposition in the kidneys, associated with intravascular hemolysis, such as in PNH, has been associated with decreased kidney function.[13]
• Both liver disease and neurological deficits can be seen in Wilson's disease if it is not diagnosed and treated early. Hemolysis is one of the most important presenting symptoms in a child or young adult with Wilson disease.[15]
• Many people with HS are not diagnosed until adulthood when they begin to present with complications. They can often be seen to have recurrent cholelithiasis, and in the most severe cases, which are often found to be recessive, will need regular blood transfusions.[5]

Consultations

While initial laboratory tests and workup for hemolytic anemia can be performed by a primary care provider, a hematology consultation should be obtained for newly diagnosed hemolysis. These patients have the ability to decompensate acutely and may require urgent interventions with the coordination of multiple teams for medications and infusions. 

Deterrence and Patient Education

Hemolytic anemia has many subsets within its disease process. Patients often require a full team of medical professionals and specialists to treat their class of hemolytic anemia. While many have medications that can be taken or a simple deterrence from triggers to avoid any complications, others can have serious consequences. Patients must be educated on the symptoms of worsening clinical status or the beginnings of infections that can lead to further morbidity due to their disease process. 

Enhancing Healthcare Team Outcomes

While the initial evaluation for hemolytic anemia can begin with a general practitioner in a non-urgent setting or even an emergency physician, a thorough diagnosis and ongoing treatment can be challenging. An interprofessional team that incorporates a hematologist is often crucial. Once specific lab markers and blood smears are obtained and reviewed, the cause of hemolytic anemia can be determined. When a patient presents to the emergency department compromised and decompensated, blood transfusions may need to be given when the cause is unknown. However, if a thorough workup can be performed, it is crucial to systematically diagnose the cause of hemolytic anemia, as the treatment for one category may be harmful in another. Furthermore, because the treatments for hemolytic anemias vary widely, morbidity and mortality outcomes vary accordingly.

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Disclosure: Caitlin Baldwin declares no relevant financial relationships with ineligible companies.

Disclosure: Jyotsna Pandey declares no relevant financial relationships with ineligible companies.

Disclosure: Olubunmi Olarewaju declares no relevant financial relationships with ineligible companies.