§ Disorders extrinsic to the red blood cells
It is caused by factors outside the red blood cell, such as antibodies from an autoimmune disorder, burns, or medications. In these conditions, red blood cells are usually healthy when they are produced by the bone marrow, but later they are destroyed directly in the bloodstream or get prematurely trapped and recycled in the spleen.
o Autoimmunehemolytic anemia (AIHA)
Autoimmune hemolytic anemia (AIHA) is a collection of disorders characterized by the presence of autoantibodies (warm or cold antibodies) that bind to the patient’s own erythrocytes, leading to premature red cell destruction (ie, hemolysis) and, when the rate of hemolysis exceeds the ability of the bone marrow to replace the destroyed red cells, to anemia and its attendant signs and symptoms. Hemolysis is usually extravascular.
ü Cold agglutinin disease
Cold agglutinin disease is relatively uncommon in children, amounting to approximately 10 percent of cases, most commonly occurring after Mycoplasma pneumoniae or Epstein-Barr virus (EBV) infection. In this disorder, immunoglobulin M (IgM) autoantibodies bind erythrocyte I/i antigens at colder temperatures and fix complement, which leads to anemia, either due to complement-mediated intravascular hemolysis or immune-mediated extravascular clearance, mainly by hepatic macrophages.
ü Warm – reactive AIHA
The most common form of primary AIHA in children, accounting for 60 to 90 percent of cases, involves warm-reactive autoantibodies, usually immunoglobulin G (IgG), that bind preferentially to the red cells at 37°C, leading to extravascular hemolysis mainly in the spleen, with resulting anemia, jaundice and, occasionally, splenomegaly. In some cases, IgG is present in sufficient quantity and proximity to fix complement, resulting in features of concomitant intravascular hemolysis.
ü Paroxysmal cold hemoglobinuria
Paroxysmal cold hemoglobinuria (PCH) is an AIHA seen almost exclusively in children, most commonly after a viral-like illness. PCH is characterized by IgG autoantibodies that bind preferentially at colder temperatures, fix complement efficiently, and cause intravascular hemolysis with hemoglobinemia, hemoglobinuria, and anemia. PCH is discussed in greater detail separately.
ü Drug and toxin-induced
Although not common in children, erythrocyte autoantibodies and hemolysis in association with drug exposure may cause secondary AIHA. This process was described classically after therapy with methyldopa, but red cell autoantibodies have been reported in association with many different pharmaceutical agents. Medications that are particularly important in causing AIHA in children include penicillins, cephalosporins, tetracycline, erythromycin, probenecid, acetaminophen, and ibuprofen. The mechanism of drug-induced hemolytic anemia typically results from generation of autoantibodies, although the drug may be required to form a hapten or even a ternary complex with the erythrocyte.
Toxins which can induced hemolytic anemia are: Lead, cooper (Wilson disease), Interferon alfa, insect, spider and snake bites.
ü Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. It is characterized by small-vessel platelet-rich thrombi that cause thrombocytopenia and microangiopathic hemolytic anemia (MAHA). Some patients may have neurologic abnormalities, mild renal insufficiency, and low-grade fever. Most cases of TTP are acquired, caused by autoantibody inhibition of ADAMTS13 activity. Hereditary TTP, caused by ADAMTS13 gene mutations, is much less common.
ü Hemolytic uremic syndrome
The hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. It is one of the main causes of acute kidney injury in children. Although all pediatric cases exhibit the classic triad of findings that define HUS, there are a number of various etiologies of HUS that result in differences in presentation, management, and outcome
Lab tests:
CBC and Automated Differential
Blood Smear with Interpretation
Reticulocyte count
LDH (lactate dehydrogenase)
Indirect and direct bilirubin level
Haptoglobin
Free hemoglobin in plasma, serum or urine
Urinalysis (hemosiderin)
Evaluation of G6PD
Direct and indirect antiglobulin test (coombs)
§ Hemolytic disease of the fetus and newborn
Hemolytic disease of the fetus and newborn (HDFN), also known as alloimmune HDFN or erythroblastosis fetalis, is caused by the destruction of red blood cells (RBCs) of the neonate or fetus by maternal immunoglobulin G (IgG) antibodies. These antibodies are produced when fetal erythrocytes, which express an RBC antigen not expressed in the mother, gain access to the maternal circulation.
Lab tests:
CBC and Automated Differential
Blood Smear with Interpretation
Reticulocyte count
Coombs test (Direct and indirect antiglobulin test)
Evaluation of G6PD
Indirect and direct bilirubin level
Urinalysis
References:
- Oski FA, Brugnara C, Nathan DG. A diagnostic approach to the anemic patient. In: Nathan and Oski’s Hematology of Infancy and Childhood, 6th, Nathan DG, Orkin SH, Ginsberg D, Look AT (Eds), WB Saunders, Philadelphia 2003. p.409.
- Bottomley SS. Sideroblastic anemias. In: Wintrobe’s Clinical Hematology, 13th ed, Greer JP, Arber DA, Glader B, et al. (Eds), Lippincott, Williams and Wilkins, Philadelphia 2014. p.643.
