Known by their acronym AIHA, they are essential hematological diseases.
They can be classified in severity from a mildly symptomatic disease to a rapidly fatal syndrome. It is estimated that the incidence of AIHA is between 0.6 and 3 cases per 100,000 people.
Antibodies mediate AIHA, and, in most cases, immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is called “hot” because IgG antibodies bind better to body temperature.
The “cold” AIHA is mediated by IgM antibodies, which bind to the maximum at temperatures below 37 ° C. This manual reviews the most common types of AIHA, emphasizing diagnosis and treatment.
In most cases, the final etiology of AIHA is unknown. In warm AIHA, the target epitopes in most patients are Rh2 proteins.
What makes the immune system track these proteins is unknown. Still, one theory is that the initial immune response to a foreign antigen begins to cross-react with the Rh proteins. The immune system fails and suppresses this autoreactive response, leading to hemolysis.
In IgG-mediated (hot) hemolysis, the red cells are coated with IgG molecules, which label the cells for absorption and destruction by splenic macro-phages.
In AIHA “cold,” the IgM molecules attach supplements to the surface of red blood cells.
Rarely, this can lead to the activation of the complete complement cascade, which results in the lysis of red blood cells, but more often stops in stage C3, leading to red blood cells coated with C3, which are connected by the hepatic macrophages.
Diagnosis and Symptoms
In many patients, the symptoms and signs of anemia lead to the suspicion of hemolysis.
Older patients often present earlier in the disease due to a lack of tolerance to anemia, especially if a sudden red blood cell count increases.
Dark or tail-colored urine, which responds to the presence of free hemoglobin, may be benign for some patients.
Patients with rapid onset hemolysis may notice lumbar back pain. Those with cold agglutinins often see symptoms related to the agglutination of red blood cells in the peripheral circulation, such as the development of acrocyanosis in cold weather.
In rare cases, patients have abdominal pain when eating cold foods due to ischemia related to the agglutination of red blood cells in the viscus.
Some patients with cold agglutinins may present an annexation of their hemolysis with exposure to cold. Unlike patients with immune thrombocytopenia (ITP), those with AIHA may have mild on-exam splenomegaly.
Enlarged lymph nodes or massive splenomegaly should raise concerns about the simultaneous presence of lymphoma or chronic lymphocytic leukemia.
Making the diagnosis
The two critical steps in the diagnosis are:
- Demonstrate hemolysis.
- Demonstrate the autoimmune component.
Treatment of autoimmune hemolytic anemia
- First-line Prednisone 1 mg / kg / day Folic acid 1 mg / day.
- Second-line Rituximab 375 mg / m2 weekly for four weeks of splenectomy.
- Third line Azathioprine 125 mg/day Cyclophosphamide 1 g / m2 IV every 28 days Mycophenolate 500-100 mg twice a day Cyclosporine Danazole 200 mg 4 times a day Alemtuzumab.
Laboratory evaluation for hemolysis
Hemolysis is tested by finding evidence of red cell degradation and the compensatory increase in red cell production.
The following sections discuss the laboratory tests that are performed to investigate hemolysis.
When red blood cells undergo hemolysis, they release their contents, mainly composed of hemoglobin, including lactate dehydrogenase (LDH), an enzyme found in a high concentration of red blood cells.
Most patients with hemolysis have an elevated LDH level, making it a sensitive test.
However, this finding is not specific to hemolysis because many other processes, including liver disease and pneumonia, also increase serum LDH levels.
The hemoglobin is rescued by haptoglobin, and the rest of the heme is broken down into the bilirubin and then into the urobilinogen, which is excreted in the urine. The bilirubin produced by the heme decomposition is not conjugated but is administered to the liver, where it is conjugated and excreted in the bile.
In hemolysis, the concentration of unconjugated bilirubin (indirect bilirubin) increases, whereas, in liver disease, the level of conjugated bilirubin (direct bilirubin) increases.
However, if the patient has a concomitant disease with an increase in direct bilirubin, the bilirubin test in the serum is not reliable.
Haptoglobin binds to free serum hemoglobin and is absorbed by the liver. Haptoglobin usually falls to deficient levels in hemolysis. One confusion is that haptoglobin is an acute phase reactant and may arise with a systemic disease or inflammation.
However, patients with advanced liver disease will have low haptoglobin levels due to lack of synthesis, and up to 2% of the population may lack congenitally haptoglobin.
If hemolysis is very rapid, the amount of hemoglobin released will exceed the binding capacity of haptoglobin and will lead to free hemoglobin in the plasma.
This can be quantified grossly by examining the color of the plasma. Even minimal amounts of free hemoglobin will cause the plasma to turn pink. In fulminating hemolysis, the plasma will have a tail color.
In most patients with hemolysis, the destruction of red blood cells is accompanied by an increase in the reticulocyte count.
Reticulocytes are red cells that still contain RNA and are a marker of red cells approximately 24 hours old or less.
Traditionally, reticulocytes were measured by manually staining the blood smear with vital blue and counting the percentage of the age of the cells that absorb the stain; this percentage needs to be adjusted for the hematocrit.
A percentage greater than 1.5% indicates a high cell oocyte count.
Recently, automatic whole blood count machines have taken advantage of the fact that reticulocytes will absorb certain spots; these machines can directly measure the flow cytometry of reticulocyte count, which results in an “absolute” reticulocyte count.
The reticulocyte count obtained with this method does not have to be corrected for the hematocrit, and levels of approximately 90,000 / μL are considered. However, the reticulocyte count may also be elevated in blood loss or patients with other causes of anemia (e.g., iron deficiency) under treatment.
In addition, up to 25% of patients with AIHA will never have increased counts for various reasons, such as nutritional deficiency, autoimmune destruction of red blood cell precursors, or lack of erythropoietin.
The blood smear provides vital information. The laboratory parameter characteristic of the isoferocitos AIHA is seen in the blood smear.
In AIHA, antibodies, and complements bind to red blood cells. When macrophages absorb antibodies or complements in the spleen, part of the membrane of erythrocytes is also removed, decreasing the cell area.
As the surface area of the red blood cell decreases as it passes through the spleen, the shape of the cell changes from a biconcave disk to a sphere before the cell is destroyed, reflecting the fact that a sphere has a surface smaller for a given volume.
The vast majority of patients with AIHA will have spherocytes in their blood. However, spherocytes are not specific to AIHA, as they can be seen in hereditary spherocytosis and clostridial septicemia.
Severe patients with cold agglutinins usually have red cells-gelatinization in the blood smear. In addition, patients with AIHA will often have a high mean corpuscular volume (MCV) for two reasons.
In patients with bristreticulocytosis, the MCV will rise due to the large size of the reticulocyte. In patients with cold agglutinomyosis, MCV can be falsely elevated due to the grouping of red blood cells.
Hot autoimmune hemolytic anemia
In AIHA, hemolysis is mediated by antibodies that bind to the surface of red blood cells. The AIHA in which the IgG antibodies are the offending antibodies is called warm AIHA.
“Warm” refers to the antibody binding better to body temperature (37 ° C). In hot AIHA, tests will show IgG molecules bound to the surface of red blood cells, and 50% of patients will also show C3.
There are cases between 50% and 90% of AIHA cases due to hot antibodies. The incidence of AIHA hot series is approximately 1 case per 100,000 patients per year; this form of hemolysis affects women more often than men.
The goal of therapy in warm AIHA can be challenging to define. However, most would agree that a hematocrit target more significant than 30% (or higher to prevent symptoms) with a minimal increase in reticulocyte count, a reflection of a significantly slower hemolytic process, is a reasonable objective.
The initial treatment of warm AIHA is prednisone at a standard dose of 1 mg/kg per day. Patients with proton pump inhibitors should also be started to prevent ulcers.
Patients may take up to 3 weeks to respond to prednisone therapy. The prednisone narrows slowly once the patient’s hematocrit is above 30%.
Although about 80% of patients respond to steroids, only 30% can take steroids completely. Steroids may be the most appropriate long-term therapy for patients who can keep up with a daily dose of 10 mg or less.
In addition, because active hemolysis leads to increased demand for folic acid, patients with warm AIHA often prescribe folic acid 1 mg per day to prevent megaloblastic anemia due to folic acid deficiency.
There is no standard therapy for patients who can not be treated with steroids or in whom steroid therapy fails.
The two main options are therapy with splenectomy or rituximab (anti-CD20). Splenectomy is the definitive therapy for warm AIHA.
The reported response varies in the literature, ranging from 50% to 80%, with 50% to 60% remaining in remission. The time of the procedure is a balance between allowing steroids to work and the risk of steroid toxicity.
In a patient with low presurgical risk and a refractory disease or who can not be disconnected from high doses of steroids, splenectomy should be performed sooner.
Splenectomy may be delayed or attempted first with another therapy in patients who require lower doses of steroids or medical risk factors for surgery.
Most splenectomies are performed laparoscopically. The small incisions allow faster healing, and the laparoscopic approach provides a better visualization of the abdomen to locate and eliminate the accessory spleens.
When experienced surgeons perform splenectomy, the mortality rate is low (<0.5%).
The most worrisome complication of splenectomy is the overwhelming post-splenectomy infection (OPSI).
The spleen appears to play a minimal role in immunity in adults, except to protect against somatized organisms. In hours, splenectomized patients infected with an encapsulated organism (e.g., pneumococcus) will develop overwhelming sepsis.
These patients often have disseminated intravascular coagulation and progress rapidly to fulminating purpura. Approximately 40% to 50% of patients die of sepsis even when the infection is detected early.
The overall risk of sepsis throughout life can be as high as 1: 500. The organism that causes sepsis most commonly in splenectomized patients is Streptococcus pneumonia, reported in more than 50% of cases.
Neisseria meningitides and Haemophilusinfluenzae have also been implicated in many cases.
Overwhelming sepsis after dog bites has been reported due to infections of Capnocytophaga canimorsus. Patients also have an increased risk of severe malaria and severe babesiosis.
Patients who have undergone a splenectomy should be warned about the risk of OPSI and should report to the emergency department if they have a fever above 101 ° F (38.3 ° C) or tremors.
For patients in remote areas, some doctors will prescribe prophylactic antibiotics while traveling to a health care provider or even recommend doses of antibiotics “on hold” to take while traveling to medical care.
This usually consists of amoxicillin or macrolide for patients allergic to penicillin. Patients who are being planned or considering splenectomy should be vaccinated against pneumococcal, meningococcal, and influenza infections.
If there is a plan to treat with rituximab, patients should first be vaccinated since they will not be able to mount the immune response after being treated with rituximab. Treatment with rituximab is the other option for patients who do not achieve remission with steroid therapy.
The majority of the data for rituximab are case reports, but there seems to be a response rate in the range of 50% to 80%, with 50% of these. These responses seem to be lasting in ITP repeated treatment is effective.
An important consideration is that most patients respond gradually to rituximab for months, so a rapid response should not be expected.
Most studies have used the traditional dose of 375 mg / m2 weekly for four weeks.
A study evaluating a smaller dose of rituximab at 100 mg weekly for four weeks reported an initial response rate of 100% and a two-year response rate of 80%, but more studies are needed for this new dosage.
Drug-induced hemolytic anemia
AIHA caused by a pharmacological reaction is rare, with a lower incidence than ITP related to the drug. The AIHA rate related to brain cutting is estimated at 1: 1,000,000, but less severe cases can be lost.
Most patients will have a positive DAT without signs of hemolysis, but in rare cases, patients will present relentless hemolysis that kills them.
Multiple mechanisms induced by drugs have been proposed for immunoemolysis, including mechanisms of drug absorption (induced by hapten) and immunocomplexes.
The hapten mechanism is frequently associated with high doses of penicillin. High doses of penicillin lead to incorporating the drug in the membrane of red blood cells when binding to proteins.
Patients will manifest a positive DAT with IgG antibody, but they will not complement.
The patient’s plasma will only be reactive with red blood cells coated with penicillin and not with normal cells. As mentioned, very few patients will have hemolysis, and if they have hemolysis, it will resolve within a few days after the interruption of the offensive drug.
The binding of a drug-antibody complex to the red cell membrane can cause hemolysis through the immune system.
Again, the patient will have only a positive DAT most of the time, but in rare cases, patients will present hemolysis that endangers life after exposure or re-exposure to the drug.
The onset of hemolysis is rapid, with signs of acute disease and intravascular hemolysis. Quinine is a paradigmatic drug, but many other drugs have been implicated.
The tests show a positive test of Coombs with anti-complement but not anti-IgG. This pattern is due to the effectiveness of the tertiary complex in the fixation complex.
The patient’s plasma reacts with red cells when the medication is added. A form of immunocomplex hemolysis associated with disseminated intravascular coagulation (DIC) and rapid hemolysis has been recognized.
Patients who receive certain second and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome. The clinical symptoms begin between 7 and 10 days after administering the drug that the patient has only received the antibiotic for surgical prophylaxis.
Immune hemolysis occurs with narrow hematocrit, hypotension, and DIC. It is often believed that patients have sepsis and are often re-exposed to the cephalosporin, which causes a worsening of the clinical state.
The result is often fatal due to massive hemolysis and thrombosis. Finally, 8% to 36% of patients taking methyldopa will develop a positive DAT after six months of treatment, with less than 1% with hemolysis.
According to the notion that methyldopa induces autoimmune hemolytic anemia, lysis in these patients is indistinguishable from warm AHAI. Hemolysis often resolves quickly after discontinuing me-levodopa, but the Coombs test can remain positive for months.
This drug-induced hemolytic anemia has been reported with levodopa, procainamide, and chlorpromazine, but fludarabine is today’s most common cause.
In many patients, the first clue about the presence of the drug AIHA is finding a positive DAT.
Rarely will patients have severe hemolysis, but the hemolytic process is mild in many patients, and it can be mistakenly assumed to be part of the underlying disease.
Finding the offensive drug can be a challenge; unless a patient has recently started a new medication, identifying the problem with the drug is difficult in a patient hospitalized with multiple agents.
Patients who started recently with “suspect drugs,” especially the most common agents cefotetan, ceftriaxone, and piperacillin, should have these agents suspended.