Extracorpuscular hemolytic anemia

The causes of extracorpuscular hemolytic anemia are listed in Table 8.1 ; they may be immune or nonimmune.

Table 8.1

Causes of hemolytic anemia due to extracorpuscular defects.

Immune	Isoimmune Hemolytic disease of the newborn Incompatible blood transfusion
	Autoimmune IgG only Complement only Mixed IgG and complement Other antibody-mediated mechanisms
	Idiopathic Warm antibody Cold antibody Cold–warm hemolysis (Donath–Landsteiner antibody)
	Secondary Viral infections with EBV, CMV, hepatitis, herpes simplex, measles, varicella, influenza A, coxsackie virus B, HIV, and the novel SARS-CoV-2 Bacterial infections: streptococcal, typhoid fever, Escherichia coli septicemia, Mycoplasma pneumoniae (atypical pneumonia) Drugs and chemicals: quinine, quinidine, phenacetin, p-aminosalicylic acid, sodium cephalothin (Keflin), ceftriaxone, penicillin, tetracycline, rifampin, sulfonamides, chlorpromazine, pyridone, dipyrone, insulin, and lead Hematologic disorders: leukemias, lymphomas, lymphoproliferative syndrome, paroxysmal cold hemoglobinuria, PNH Immunopathic disorders: systemic lupus erythematosus, periarteritis nodosa, scleroderma, dermatomyositis, rheumatoid arthritis, ulcerative colitis, agammaglobulinemia, Wiskott–Aldrich syndrome, dysgammaglobulinemia, IgA deficiency, thyroid disorders, giant cell hepatitis, Evans syndrome (immune-mediated anemia associated with immune thrombocytopenia), ALPS, and common variable immune deficiency Tumors: ovarian teratomata, dermoids, thymoma, and lymphomas
Nonimmune	Idiopathic
	Infection, viral: infectious mononucleosis, viral hepatitis; bacterial: streptococcal, E. coli septicemia, Clostridium perfringens , Bartonella bacilliformis ; parasites: malaria, histoplasmosis
	Drugs and chemicals: phenylhydrazine, vitamin K, benzene, nitrobenzene, sulfones, phenacetin, acetanilide, and lead
	Hematologic disorders: leukemia, aplastic anemia, megaloblastic anemia, hypersplenism, and pyknocytosis
	Microangiopathic hemolytic anemia: TTP, HUS, chronic relapsing schistocytic hemolytic anemia, burns, postcardiac surgery, and march hemoglobinuria
	Miscellaneous: Wilson disease, erythropoietic porphyria, osteopetrosis, hypersplenism, posthematopoietic stem cell transplantation

Abbreviations: ALPS , autoimmune lymphoproliferative syndrome; CMV , cytomegalovirus; EBV , Epstein–Barr virus; HIV , human immunodeficiency virus; HUS , hemolytic–uremic syndrome; SARS-CoV-2 , severe acute respiratory syndrome coronavirus 2.

Immune hemolytic anemia

Immune hemolytic anemia can be isoimmune or autoimmune. Isoimmune hemolytic anemia results from a mismatched blood transfusion or from hemolytic disease of the newborn. In autoimmune hemolytic anemia (AIHA), shortened red cell survival is caused by the action of autoantibodies with or without the participation of complement on the red cell membrane. The red cell autoantibodies may be of the warm type [usually immunoglobulin G (IgG)], the cold type [usually complement-mediated hemolysis by immunoglobulin M (IgM)], mixed with both the types present, or the cold Donath–Landsteiner type (cold IgG).

Immune hemolytic anemia is confirmed by a positive direct antiglobulin test (DAT) (previously referred to as a Coombs’ test) that demonstrates an immunoglobulin and/or complement on the red blood cell (RBC) surface. A DAT is considered positive in the presence of agglutination of antibody (Ab)-coated red cells. Most commercial laboratories use a polyspecific AHG reagent that will be positive in both IgG and C3. Later, monospecific IgG and complement reagents are used. Most laboratories do not test for other autoantibodies leading to a false-negative result in about 3–11% of AIHA cases. If AIHA is strongly suspected despite a negative DAT, consider testing for Donath–Landsteiner Ab or further testing in reference laboratories for unusual autoantibodies that may not appear in conventional testing, either due to low numbers of attached antibodies or failure of the reagent to detect [e.g., immunoglobulin A (IgA) because the reagent is anti-IgG]. Complement participation is usually confined to the IgM type of antibody; only rarely is it associated with IgG (see Section 8.1.4 ). AIHA may be idiopathic or secondary to several conditions listed in Table 8.1 .

Warm AIHA

Antibodies of the IgG class are most commonly responsible for AIHA in children (responsible for about 48–70% of cases). The IgG autoantibody is directed against one of the Rh erythrocyte antigens in over 70% of cases. This antibody usually has its maximal activity at 37°C, and the resultant hemolysis is called warm antibody-induced hemolytic anemia.

Rarely, warm reacting IgA and IgM antibodies may be responsible for hemolytic anemia. As in all patients with AIHA, erythrocyte survival is proportional to the amount of antibody on the erythrocyte surface, although rarely hemolysis can occur in patients with too few antibodies on the surface of the red cell to cause a positive DAT (DAT-negative hemolytic anemia).

Clinical features

Severe, life-threatening condition
Sudden onset of pallor, jaundice, and dark urine
Splenomegaly

Laboratory findings

A hemoglobin level can be very low in fulminant disease or normal in indolent disease.
Reticulocytosis is common, although often the reticulocytes are destroyed by the antibody as well and reticulocytopenia may occur.
Mean corpuscular hemoglobin concentration may be elevated.
Smear shows prominent spherocytes (due to antibody-mediated membrane loss), polychromasia, macrocytes, autoagglutination (IgM), nucleated RBCs, and erythrophagocytosis.
Neutropenia and thrombocytopenia (occasionally).
Increased osmotic fragility and autohemolysis proportional to spherocytes.
DAT positivity establishes the diagnosis of AIHA.
Hyperbilirubinemia and increased serum lactate dehydrogenase.
Haptoglobin level is markedly decreased.
Hemoglobinuria, usually only at first presentation, increased urinary urobilinogen.

Initial management

Warm AIHA is potentially life-threatening and the following must be monitored carefully:

Hemoglobin level (every 4 hours)
Reticulocyte count (daily)
Spleen size (daily)
Hemoglobinuria (daily)
Haptoglobin level (weekly)
DAT (weekly)

Close attention should always be paid to supportive care issues such as folic acid supplementation, hydration status, urine output, and cardiac status.

Blood transfusion

Transfusion should be avoided when possible, because there will be no truly compatible blood available and the survival of transfused cells in this situation is quite limited and may fail to elevate the hemoglobin level significantly. Nonetheless, using the “least incompatible” blood by crossmatching may be required in properly selected situations in order to avoid cardiopulmonary compromise. The guidelines listed below should be followed:

If a specific antibody is identified, a compatible donor may be selected. The antibody usually behaves as a pan agglutinin, and totally compatible blood cannot be found.
Washed packed red cells should be used from donors whose erythrocytes show the least agglutination in the patient’s serum. Despite the autoantibody the absence of an alloantibody should be confirmed prior to transfusion.
The volume of transfused blood should only be of sufficient quantity to relieve any cardiopulmonary embarrassment from the anemia. Aliquots of 5 mL/kg are taken from a single unit and transfused at a rate of 2 mL/kg/h.
The use of such incompletely matched blood is made relatively safe by biologic crossmatching, transfusing of relatively small volumes of blood, and concomitant use of high-dose corticosteroid therapy.

Corticosteroid therapy

Prednisone 2–10 mg/kg/day orally or methylprednisolone 4–8 mg/kg/day IV (both given over four doses each day) for 3 days followed by oral prednisone.
High-dose corticosteroid therapy should be maintained for several days. Thereafter, corticosteroid therapy in the form of prednisone should be slowly tapered over 3–4 weeks.
The dose of prednisone should be tailored to maintain the hemoglobin at a reasonable level; when the hemoglobin stabilizes, the corticosteroids should be discontinued. The presence of a continued positive DAT does not prevent continuing to taper steroids as long as the hemoglobin is stable or rising, and reticulocytosis continues to decrease or remain normal.

70–85% of patients respond within 4–7 days to corticosteroids, but some patients experience ongoing profound hemolysis for the first week after initiation. For these patients and patients who appear dependent on steroids, alternative treatment should be considered.

Rituximab

In patients with a severe disease not responding early on or in patients exhibiting steroid dependence, rituximab (a manufactured monoclonal antibody targeting CD20) should be used in doses of 375 mg/m ² once a week for 4 weeks. It has a very high rate of remission induction in AIHA in children. Immunoglobulin levels should be measured prior to the use of rituximab to rule out common variable immunodeficiency and also to assess for the possibility of autoimmune lymphoproliferative syndrome (ALPS) (see Chapter 16 : Lymphoproliferative Disorders) or other immunological diseases prior to starting rituximab therapy when possible. The short-term side effects include:

Itching
Hives
Hypotension
Chest pain

These can be prevented through premedication with acetaminophen 15 mg/kg, diphenhydramine 1 mg/kg, and, if necessary, corticosteroids. Patients should be monitored carefully during each infusion. Although rituximab eliminates the B-cell compartment, there have not been increased rates of infection, and intravenous gamma globulin has been administered to offset the loss of B-cell function.

If steroids and rituximab fail to induce a remission, alternative therapies listed later can be used. If remission is induced followed by a relapse, the patient can be treated with another course of rituximab or one of the following therapies.

Intravenous gamma globulin

Doses between 1 and 5 g/kg have been employed but the response in children is poor (about 54%). It should be considered in patients with severe hemolysis who are requiring transfusion and are having poor responses to transfusion.

Plasmapheresis

In IgG warm immune hemolytic anemia, plasmapheresis should always be combined with moderate immunosuppression (e.g., rituximab). This ensures that both antibody production and antibody titer reduction are employed concomitantly.

Plasmapheresis has been successful in slowing the rate of hemolysis in patients with severe IgG-induced immune hemolytic anemia. The effect is short-lived if antibody production is ongoing and success is limited. The limited efficacy of plasmapheresis is likely because:

More than half of the IgG is extravascular
Most of the antibodies are on the red cell surface with little remaining free in the plasma

Chronic management

There are several agents available for chronic management of warm AIHA after the initial treatment with steroids and/or rituximab. These agents often require 4–12 weeks to exert their effect and are usually started as steroids are being tapered.

Immunomodulating agents

Mycophenolate mofetil (MMF)

This drug is showing promise in the treatment of several autoimmune diseases, including AIHA. It is also effective in Evans syndrome [autoimmune bicytopenia (immune thrombocytopenia with AIHA)].

Dose: 15 mg/kg twice daily (max 2000 mg/day) given in combination with rituximab.

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