The Anemic Patient

Case Report: 

Patient is a 17-year-old girl with no significant medical history who presents to the emergency  department complaining of five days of general fatigue, dyspnea on exertion, and palpitations. The patient’s mother also has noticed that she has looked more pale than usual over the past couple of days. Patient denies fevers, chest pain, cough, nausea, vomiting, rash, sick contacts, tick exposure, recent travel, sore  throat, ear pain, or headache. She denies any dark tarry stools, blood in her stool or any heavy vaginal bleeding. Patient’s family history includes a cousin with sickle cell disease but no other family history of sickle cell, autoimmune diseases, or other blood disorders. Vital signs show a blood pressure of 137/83, and a heart rate of 145, but normal temperature and respirations. Physical exam was remarkable for scleral icterus, pale appearing and slightly jaundiced skin, delayed cap refill. The rest of the physical exam was  unremarkable. In the emergency department her initial labs showed lab work notable for a hemoglobin of 5.9 g/dl, a reticulocyte count of 43.1%, a haptoglobin of <8 mg/dl, a total bilirubin of 5 mg/dl and a lactate dehydrogenase (LDH) of 392 U/L, positive direct antiglobulin test (DAT) 3+, positive antibody identified as IgG.  

Diagnosis:

New Onset Autoimmune Hemolytic Anemia 

Discussion: 

The patient’s history of fatigue, dyspnea on exertion, palpitations, and pale coloring can be vague when taken separately but when put together with her pale coloring and tachycardia, anemia should be high on the differential diagnosis.

Anemia in general can be caused by several factors including blood loss, genetic causes,  hemolysis, acquired disease, drug reaction and more. Breaking down this differential can be a daunting task. It is important to figure out and treat the underlying cause as quickly as possible, especially in a young person with extremely low hemoglobin as there are dangerous causes which must be ruled out. This discussion will take us through the differentiation of her illness and focus on some of the finer details of hemolytic anemia itself.  

When initially differentiating anemia, you can first look at the reticulocyte count. A high reticulocyte indicates increased bone marrow response to a loss of red blood cells (RBCs) from either blood loss or RBC destruction (hemolysis). In contrast a normal or decreased reticulocyte count indicates inadequate RBC production. Culprits of decreased production include deficiencies in iron, B12, or folate, or other disorders such as aplastic anemia, bone marrow fibrosis, anemia of chronic disease or renal failure. This patient had a reticulocyte count of 43.1% which is significantly elevated (reference range 0.5%-2.2%) which essentially rules out decreased production as the cause. When you consider her jaundiced appearance and that this patient had no history of trauma, bloody or dark tarry stools, heavy vaginal bleeding, or hematemesis, her presentation was more likely due to a hemolysis (hemolytic anemia) rather than blood loss.

Hemolytic Anemia is the premature destruction of erythrocytes which is characterized by increased unconjugated bilirubin, increased lactate dehydrogenase, and decreased haptoglobin levels all of which this patient was found to have on later blood draws in the emergency department.  

Hemolytic anemia can then be broken down into two categories, acquired or hereditary.  Hereditary types include enzymopathies such as G6PD or pyruvate kinase deficiency,  membranopathies such as hereditary spherocytosis, hereditary elliptocytosis, and paroxysmal nocturnal hemoglobinuria and hemoglobinopathies such as sickle cell and thalassemia. Acquired disorders include immune mediated in which antibodies attach to RBC surface antigen causing immune mediated destruction of the cell, microangiopathic anemias such as TTP, HUS, DIC, HELLP, and drug induced thrombotic microangiopathy and infection induced from diseases such as Malaria, Babesia, Bartonella, Clostridia, Rickettsia, H.flu, and HIV. There are a lot of clues and objective data that can help narrow this differential, and a big part of that is the peripheral blood smear. The chart below from The American Family Physician Journal helps delineate this. This patient’s lab work showed abnormal morphology and did not further typify, but she did have other clues to help determine her diagnosis. She was a teenager, and this was the first time she was experiencing these symptoms, which leads us to believe that she most likely had an acquired subtype. She was also found to have a DAT + for IgG antibodies *, therefore, autoimmune hemolytic anemia was most likely the diagnosis.  

Phillips, James, and Adam C. Henderson. “Hemolytic Anemia: Evaluation and Differential Diagnosis.” American Family Physician, 15 Sept.  2018, www.aafp.org/afp/2018/0915/p354.html. 

*DAT is used to detect antibodies that are directly attached to a patient’s RBCs

Although this patient most likely had autoimmune hemolytic anemia, other forms of immune hemolytic anemia include alloimmune hemolytic anemia and drug induced hemolytic anemia. Alloimmune hemolytic anemia requires exposure to allogenic RBCs, most commonly through pregnancy, blood or platelet transfusions, causing alloantibodies to attack these RBCs. These are mainly manifested as hemolytic transfusion reactions or hemolytic disease of the newborn. Drug induced immune hemolytic anemia in which antibodies attack drug bound RBCs leading to hemolysis.  

Auto Immune Hemolytic Anemia: 

Autoimmune hemolytic anemia (AIHA) is characterized by autoantibodies that are directed against and attack self RBCs.  

Warm AIHA 

Warm AIHA is IgG mediated, where the antibodies will bind strongly at temperatures higher than 37 degrees Celsius. This is often associated with lymphoproliferative disorders suggesting a possible generalized immune disfunction. They may also present secondary to autoimmune or immunodeficiency disorders such as SLE, RA, AIDS, etc. Children peak in incident around 4 years old and there is an increase in incidence around 40 years of age. Clinical presentations include fatigue, dizziness, may have hepatomegaly or lymphadenopathy (if associated with lymphoproliferative disorder). The treatment is mainly steroids and folate. If patients have a good response to steroids then it often leads to remission. If there is poor steroid response then patients may need splenectomy or cytotoxic drugs, such as cyclophosphamide, may be indicated 

Cold AIHA

There are two main forms of Cold AIHA. The first is Cold Agglutinin syndrome (CAS) which is IgM antibody mediated with clumping occurring from cold agglutinins reacting strongly at 0-4 degrees Celsius. The peak incidence occurs around 70 years of age. Clinical presentation is a mild chronic anemia causing pallor and fatigue and can be exacerbated by the cold (more common in the winter) and may be associated with Raynaud’s. The transient form usually starts 2-3 weeks after infection and resolved 2-3 weeks after that, it can rarely result in transient renal failure. It is typically caused by infection (mycoplasma pneumonia or viral illnesses) and lymphoproliferative disorders (CLL, lymphomas). Treatment includes avoidance of cold exposure (this may mean moving to a warmer climate). If severe, may consider immunosuppressive drugs such as chlorambucil or cyclophosphamide or plasmapheresis. If Cold AIHA is secondary to another cause then treatment of that cause will also be helpful. Unlike Warm AIHA, steroids are not helpful. The second form of Cold AIHA is Paroxysmal cold hemoglobinuria (PCH) which is a rare form of AIHA. This is mediated by biphasic IgG antibody (Donath Landsteiner antibody) and will have a negative IgG test unless at cold temperature 0-4 degrees Celsius. PCH may be idiopathic or be secondary to late stage or congenital syphilis or other infection such as measles, EBV, CMV, zoster, influenza, pneumonia, H. flu. The disease mainly affects children. Clinical presentation is usually an acute attack, high fever, body aches, abdominal cramping, N/V/D, dark urine often preceded by cold exposure. Hemolysis can be severe, and life threatening and may lead to chronic PCH that is exacerbated by cold. Treatment involves keeping patients warm, consider plasmapheresis and treat underlying cause if possible. 

Case Outcome: 

After the Emergency Department, our patient was admitted to pediatric hematology and oncology service where she was started on steroids the next day. Her infectious work up including testing for COVID, viral panel including Epstein-Barr, hepatitis panel, human immunodeficiency virus, parasite smear, and mycoplasma IgM was entirely negative. Her hemoglobin started to slowly improve with steroids and after a week in the hospital she was discharged with a hemoglobin of 9 and with resolution of her tachycardia, fatigue, and pallor. She was discharged on oral steroids until her follow up appointment.  

AUTHOR: Giovanna Deluca, MD

FACULTY REVIEWER: Meghan Beucher, MD

ReferenceS

Dhaliwal, Gurpreet, et al. “Hemolytic Anemia.” American Family Physician, 1 June 2004, www.aafp.org/afp/2004/0601/p2599.html. 

Phillips, James, and Adam C. Henderson. “Hemolytic Anemia: Evaluation and Differential Diagnosis.” American Family Physician, 15 Sept. 2018, www.aafp.org/afp/2018/0915/p354.html. Tefferi, Ayalew. “Anemia in Adults: A Contemporary Approach to Diagnosis.” Mayo Clinic Proceedings,  vol. 78, no. 10, 2003, pp. 1274–1280., doi:10.4065/78.10.1274. 

Theis, Samuel R. “Coombs Test.” StatPearls [Internet]., U.S. National Library of Medicine, 29 Aug. 2020,  www.ncbi.nlm.nih.gov/books/NBK547707/.