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Phenotype submission - Hemolytic Anemia

Hemolytic Anemia

Authoritative source

Summary from authoritative source:

Overview

  • Anemia, like a fever, is not a diagnosis but a presentation of an underlying disease. Multiple diseases can present as anemia due to various mechanisms – and not limited to hemolysis. Anemia can be defined as a reduction in hemoglobin or hematocrit or red blood cell (RBC) count. Acute anemia is predominantly due to acute blood loss or acute hemolysis.

  • Hemolytic anemia is classified as normocytic anemia with an MCV of 80 to 100 fL. It is a form of low hemoglobin due to the destruction of red blood cells, increased hemoglobin catabolism, decreased levels of hemoglobin, and an increase in efforts of bone marrow to regenerate products. There are numerous causes of hemolytic anemia, which have several ways that can be broken down to include acute and chronic disease, immune vs. non-immune mediated, intravascular or extravascular, inherited or acquired, and intracorpuscular or extracorpuscular.

  • Intracorpuscular causes for hemolytic anemia refers 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) is decreased. Membranopathies include hereditary spherocytosis (HS) and hereditary elliptocytosis (HE). Several RBC enzymopathies alter the shape of RBCs and cause nonspherocytic hemolytic anemias. G6PD deficiency and pyruvate kinase deficiency (PKD) both fall into this category.

  • Extracorpuscular causes refer to defects that were influenced by external factors, including mechanical, immune-mediated, or infectious. 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, that can be used to treat these diseases, also have deleterious effects as it has oxidant potential.

  • Autoimmune Hemolytic Anemia (AIHA) are rare, hemolytic anemia defined as hemolytic anemia caused by the destruction of RBCs through autoantibodies directed against antigens on their surface. It is usually classified as warm antibody (wAIHA) and cold antibody (cAIHA) – with unclear incidence. Its more prevalent in persons with autoimmune diseases like systemic lupus erythematosus (SLE, 10%) and in patients with hematological malignancy like non-hodgkins lymphoma (NHL)/chronic lymphocytic leukemia (CLL, 5-10%). AIHA may be acute, chronic or transient. wAIHA is characterized by binding of immunoglobulin to RBCs with completement activation. AIHA is considered primary in the absence of an associated disorder and secondary when one is present. Drug-induced immune hemolytic anemia is a distinct category of secondary immune hemolysis.

Presentation

  • Varies based on underlying cause and degree/duration of anemia. A patient with anemia may present with shortness of breath, weakness, fatigue, arrhythmias such as tachycardia, or can present asymptomatic. Those with anemia caused by cell destruction or hemolysis may also present with jaundice or hematuria. If symptoms have been going on for longer periods, lymphadenopathy, hepatosplenomegaly, cholestasis may even be seen. 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).

  • AIHA, especially the chronic forms, are often associated with compensated hemolysis or mild anemia with no symptoms. Splenomegaly may be present.

Assessments

  • 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, therefore when RBCs rupture, this value increases. Haptoglobin binds free hemoglobin. Therefore, as this protein is fully bound with what little hemoglobin is left, it results in decreased levels of overall Haptoglobin. Unconjugated bilirubin is elevated as the body is unable to eliminate it as quickly as it is produced with the destruction of RBCs.
  • AIHA diagnostic criteria is the evidence for hemolysis accompanied by a positive direct antiglobulin test (DAT) and exclusion of alternative causes, such as a delayed hemolytic transfusion reaction.

Plan

  • Depending on the severity of illness, immediate interventions, including blood transfusions, plasmapheresis, or diuresis, may need to be performed depending on the 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 the known cause of anemia, or if no emergent intervention is required, more specific treatment modalities may be followed.
  • If the cause is initially unclear, performing a direct antiglobulin (Coombs) test can be used to differentiate between an immune or non-immune cause of hemolysis.

Prognosis

  • Hemolytic anemia can affect multiple organ systems throughout the body. As RBCs are destroyed, their products cause a chain of reactions that lead to further complications.

Strengtheners

Signs/Symptoms of anemia, hemolysis. Treatments like blood transfusion, immune tests (Coombs)

Phenotype development:

How to identify persons with hemolytic anemia:

  • Persons may enter a cohort by either a diagnosis of hemolytic anemia, or presence of hemolysis and anemia temporally together.

  • Definition of Anemia: Anemia maybe identified by lab results or by diagnosis. Lab definition of Anemia (< 11g/dl or hematocrit < 30%).

  • Definition of Hemolysis: presence of diagnosis of hemolytic disorder (i.e. without need for anemia). We defined normal hemoglobin as any value > 11g/dl.

  • Intra corpuscular vs extra corpuscular: We decided to differentiate between Hemolytic anemia that is associated with intracorpuscular congenital or genetic defects such as membrane defect (spherocytosis, elliptocytosis, acanthocytosis), enzyme deficiency (G-6-PD deficiency), abnormal hemoglobin (sickle cell disease, thalassemia) and hemolytic anemia that did not include such conditions (i.e., mutually exclusive on the date of hemolytic anemia). We also decided to treat persons with hemolytic anemia with G-6P-D deficiency as a special case – because persons may be living without being aware of G-6-PD deficiency and on exposure to an inciting agent (e.g., a new drug exposure) may develop over hemolytic anemia.

  • Autoimmune Hemolytic Anemia: For person with no evidence of intra corpuscular defects, we then divided persons into those that autoimmune hemolytic anemia (further divided into warm and cold) vs those that did not have autoimmune hemolytic anemia.

Cohort Submission:

270 [P] Hemolytic Anemia (7Pe, 0Era, 365W) all events of hemolytic anemia, indexed on anemia or hemolysis.

210 [P] Hemolytic Anemia Extra corpuscular ex hgpathy, memb defect (7Pe, 0Era, 365W)
all events of hemolytic anemia, indexed on anemia or hemolysis, without congenital or hereditary causes of hemolytic anemia of membrane, or RBC structure. Persons with enzyme disorder (e.g. G-6-PD deficiency) are not excluded.

209 [P] Hemolytic Anemia Extra corpuscular ex hgpathy, memb defect, g6pd (7Pe, 0Era, 365W)
all events of hemolytic anemia, indexed on anemia or hemolysis, without congenital or hereditary causes of hemolytic anemia of membrane, enzyme or RBC structure.

271 [P] Hemolytic Anemia Intra corpuscular (FP)
all events of hemolytic anemia, indexed on anemia or hemolysis, without congenital or hereditary causes of hemolytic anemia of membrane, enzyme or RBC structure.

on data.ohdsi.org/PhenotypeLibrary

Potential problems with this phenotype:

Miss rate/False negative rate/Sensitivity - persons with anemia and hemolysis may not have a code for hemolysis
Index date misclassification - if hemolysis is not acute (e.g. chronic hemolysis) the exact onset may not be known
Specificity - non hemolytic anemia may be considered hemolytic anemia.

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