Paroxysmal Cold Hemoglobinuria

What is Paroxysmal Cold Hemoglobinuria?

Paroxysmal cold hemoglobinuria is the rarest form of autoimmune hemolytic anemia.

Symptoms of Paroxysmal Cold Hemoglobinuria

The disease is characterized by attacks of chills, fever, nausea, vomiting, severe, often unbearable abdominal pain and the appearance of black urine some time after hypothermia. Sometimes, as well as with cold agglutinin disease, Raynaud’s syndrome is expressed.

During a crisis, the spleen sometimes enlarges, and yellowness appears.

The hemoglobin content in paroxysmal cold hemoglobinuria outside the crisis is normal. In winter, with frequent crises, the hemoglobin content can drop to 70-80 g / l with a rise in the reticulocyte content and irritation of the red sprout of the bone marrow.

During a crisis, the number of leukocytes sometimes decreases, occasionally there is a slight thrombocytopenia, a large amount of protein is found in the urine, a positive Gregersen test for occult blood. After a crisis, hemosiderinuria (hemosiderin in the urine) sometimes remains for a short time.

Diagnostics of the Paroxysmal Cold Hemoglobinuria

Autoimmune hemolytic anemias are a heterogeneous group of diseases characterized by a common symptom (anemia with signs of increased destruction of erythrocytes). Rapidly developing anemia with an increase in temperature to 38–39 ° C, yellowing of the sclera or the appearance of dark urine, an increase in ESR, first of all, makes it possible to exclude autoimmune hemolytic anemia. More often, an increase in the content of bilirubin and reticulocytes is detected. Sometimes an enlargement of the spleen and liver is detected. Often, such patients are mistakenly referred to infectious diseases hospitals with suspected acute hepatitis. There they find severe anemia and leukocytosis with a shift to myelocytes and mistakenly assume acute or chronic leukemia, but no blast cells are found in the bone marrow and irritation of the red germ is found. This clinical picture is not always the case. Sometimes there is no hyperbilirubinemia, splenomegaly. The urine may be red and high in protein, suggesting acute glomerulonephritis. However, the absence of erythrocytes in red urine and a positive reaction of urine to occult blood make one suspect the hemolysin form of autoimmune hemolytic anemia or Markiafava-Micheli disease.

Low-symptom forms of autoimmune hemolytic anemia, which do not give severe hemolytic crises, are possible in the presence of both incomplete heat and complete cold agglutinins. Moderate anemia, a sharp increase in ESR often make the doctor think of an oncological disease. At the same time, the patient is looking for tumors of a wide variety of organs and systems in vain. However, the study of the content of reticulocytes, bilirubin, the detection of an enlarged spleen indicate one of the forms of autoimmune destruction of erythrocytes. The doctor should clarify how the patient tolerates the cold.

The absence of the same disease in relatives, the appearance of hemolytic anemia for the first time in full health, an increase in ESR, a combination of hemolytic anemia with thrombocytopenia make autoimmune hemolytic anemia more likely. This diagnosis can only be confirmed using special methods.

Serological diagnostics. Serological diagnosis of autoimmune hemolytic anemias with incomplete thermal agglutinins. The diagnosis of autoimmune hemolytic anemias is confirmed by a positive direct Coombs’ test, which usually helps to identify incomplete antibodies fixed on the surface of red blood cells.

Previously, it was assumed that incomplete antibodies have the same valence, so they cannot combine two red blood cells. It is now known that incomplete thermal agglutinins fixed on erythrocytes have two valences. The repulsion of negatively charged red blood cells counteracts the slight attraction of red blood cells caused by incomplete antibodies, and in most cases incomplete warm antibodies do not result in autoagglutination. Sometimes, in severe cases, autoagglutination is observed in patients with warm antibodies. This can lead to an error in determining the blood group. The addition of protein (albumin, gelatin) to erythrocytes leads to dispersion of the ion cloud and agglutination of erythrocytes, on which antibodies are fixed, on this basis the determination of Rh-affiliation is based.

Antibodies in autoimmune hemolytic anemia are detected using a direct Coombs ‘test in 65% of patients, in most patients with a negative direct Coombs’ test they can be established using an aggregate hemagglutational test.

A positive direct Coombs’ test, as well as, apparently, an aggregate hemagglutination test, is not a mandatory indicator of autoimmune hemolytic anemia. First of all, this concerns the fixation of proteins that do not belong to the class of immunoglobulins on erythrocytes. This phenomenon is sometimes observed with lead poisoning, as well as with pronounced reticulocytosis due to transferrin fixation.

Diagnosis of autoimmune hemolytic anemia with warm hemolysins is based on the determination of these warm hemolysins in the serum of patients. The direct Coombs test is often negative. The patient’s serum in a weakly acidic environment causes hemolysis of the donor’s erythrocytes in the presence of complement. A positive sucrose test, which is considered characteristic of Markiafava-Mikeli disease, can also be positive in the hemolysin form of autoimmune hemolytic anemia. The sucrose test is based on the destruction of red blood cells by complement. In the classical version of this test, fresh serum from a single-group donor and a sucrose solution in an acidic buffer are added to the patient’s erythrocytes. In Markiafava-Micheli disease, complement in the presence of sucrose destroys erythrocytes with a pathologically altered membrane. In the hemolysin form of autoimmune hemolytic anemia, cell destruction is associated not with a membrane defect, but with the presence of autoantibodies on the surface of erythrocytes.

A sucrose sample can be supplied in two additional versions: the patient’s serum is mixed with the donor’s erythrocytes and it is determined whether this leads to hemolysis in the presence of sucrose (second option). You can also incubate the patient’s serum with their own erythrocytes (third option). In Markiafava-Mikeli disease, the direct, main, variant of the test is positive and the second variant is negative, the third variant of the test is positive, but hemolysis is less pronounced than in the first variant.

Hemolysis is less pronounced when the first, direct, variant of the test is performed and it happens, although not always, in the second (cross) variant of the test. Often, the aggregate hemagglutination test is positive.

Diagnosis of cold hemagglutinin disease is based on the determination of the titer of total cold antibodies in the serum. For this, the patient’s blood is taken into a warm, dry test tube and immediately placed in a thermostat at 37 ° C. After retraction of the clot, the serum is separated and its serial dilutions, divisible by two, are prepared. Then, a suspension of washed donor erythrocytes is added to the samples and incubated at different temperatures (4, 20 and 37 ° C). Normal serum at a temperature of 4 ° C can cause agglutination of donor erythrocytes in a dilution not exceeding 1: 4. In the presence of pathological Cold antibodies in the serum, their titer is very high. Agglutination occurs when the patient’s serum is diluted many thousands of times. Mild forms of the disease cause agglutination in a large titer only at low temperatures, while at a temperature of 20 ° C, and even more so 37 ° C, agglutination does not occur. With the same forms of the disease, but with a more severe clinical picture, agglutination can occur at 20 ° C.

Antibody specificity. In different forms of autoimmune hemolytic anemia, antibodies are directed against different antigens. So, in autoimmune hemolytic anemia with incomplete thermal agglutinins, antibodies are directed in most cases against an antigen related to the Rh system. However, this antigen does not belong to the usual antigens of the Rh system. It is present in almost all people, regardless of their Rh-affiliation and is associated with a section of the erythrocyte membrane, on which the Rh antigens are attached. There are only a few people in the world without this antigen.

Treatment of Paroxysmal Cold Hemoglobinuria

Treatment of autoimmune hemolytic anemias with incomplete thermal agglutinins depends on the form and stage of the process. Often there is a need for urgent therapy, and the patient’s life and ability to work depend on the correctness of the tactics chosen by the doctor.

The most acute course of autoimmune hemolytic anemia with incomplete thermal agglutinins. The prognosis for these forms of anemia was very poor before the use of glucocorticosteroids.

Currently, glucocorticosteroid hormones are the main agents used in the relief of hemolytic crises in thermal forms of autoimmune hemolytic anemia.

The dose of prednisolone at the onset of the disease depends on the severity of the process. In some cases, an acute hemolytic crisis is stopped by the appointment of prednisolone 50-60 mg / day. However, in some cases, this dose is insufficient, and it is increased to 80, 100 and even 150 mg / day. It should be emphasized that if prednisolone is administered intramuscularly, then its dose should be twice, and when administered intravenously, four times more than when taken orally.

The first signs of a sufficient dose of prednisolone are a decrease in temperature, a decrease in general weakness, and an end to the fall in hemoglobin. Only on the 3-4th day from the start of treatment, hemoglobin begins to rise, jaundice decreases.

The dose of prednisolone begins to be reduced immediately after normalization or significant improvement in blood counts, it is reduced slowly, under the control of blood tests. Large doses of prednisone can be reduced more drastically, 2.5-5 mg per day. In the future, when the patient receives small doses (30 mg / day or less), they are reduced much more slowly (2.5 mg per 3-5 days), and at very small doses, even more slowly (1/4 tablets in 10-15 days).

If autoimmune hemolytic anemia is manifested for the first time not by an acute hemolytic crisis, but by moderate anemia (70-80 g / l) with a satisfactory general condition of the patient, then prednisolone at a dose of 25-40 mg / day can be used.

In a small part of patients (3.8%), a single use of prednisolone leads to recovery with complete and stable normalization of blood counts and negative Coombs’ test and aggregate hemagglutination test. In 7.3% of patients, it is possible to obtain remission, in which the condition is good, the hematological parameters are normal.

In almost half of patients, treatment with prednisone gives a temporary effect, reducing the dose or discontinuing the drug leads to a relapse of the disease. In about half of these patients, an exacerbation occurs when the dose of prednisolone is reduced to 15-20 mg, in half, a relapse occurs several weeks after the complete withdrawal of the drug. Reappointment of prednisolone in the same patients in most cases leads to the normalization of hemoglobin levels, but often it is necessary to resort to higher doses of glucocorticosteroid hormones than the first time. These patients are forced to take prednisolone for a long time, and this entails a number of complications (Cushing’s syndrome, steroid diabetes, steroid ulcers, increased blood pressure, etc.).

With severe exacerbations of autoimmune hemolytic anemia, patients often need transfusions of blood-substituting fluids.

It must be remembered that the transfusion of red blood cells is not a direct treatment for autoimmune hemolytic anemia, it is only a necessary measure. After improving the general condition of the patient, transfusion should not be performed.

If steroid therapy gives a temporary or incomplete effect, then the question arises about the removal of the spleen and the use of immunosuppressive drugs.

Removal of the spleen in autoimmune hemolytic anemias was carried out at the beginning of the 20th century.

The effectiveness of this operation in the idiopathic form of autoimmune hemolytic anemia with incomplete thermal agglutinins is very variable and, according to different authors, is 25-86%, which is explained by differences in the patient population.

In 64.6% of patients, a complete improvement was achieved, in which there were no exacerbations, and only positive tests for antibodies did not allow these patients to be considered recovered. 20.9% had a significant improvement, the frequency of crises decreased, and a much lower dose of prednisolone was required to stop crises.

The administration of large doses of prednisolone on the day of surgery and in the immediate period after it contributed to a significant decrease in postoperative mortality and, in fact, to a wider use of spleen removal in autoimmune hemolytic anemia. Indeed, when the destruction of red blood cells occurs predominantly in the spleen, there are many chances of a good result from removing the spleen. However, even when erythrocytes are destroyed in the liver, and even in the vessels with thermal hemolysin forms, one can count on the success of spleen removal, although somewhat less and more delayed. Success in these cases is most likely due to the participation of the spleen in the production of antibodies and in the process of fragmentation of the erythrocyte membrane, their transformation into microspherocytes.

Thrombotic complications pose the greatest danger in the postoperative period.

Thrombotic complications often develop during the period of the maximum increase in the level of platelets, namely on the 8-10th day after surgery. For the prevention of thrombotic complications, heparin is used, which is prescribed immediately after the operation (5000 U in the abdominal skin 2-3 times a day for a week). Then you can apply to-rantil 50 mg 3-4 times a day or trental 100 mg 3 times a day for 1.52 months.

Removal of the spleen is usually recommended for autoimmune hemolytic anemia in patients who, if necessary, have constantly used prednisolone for 4-5 months, or who have had frequent exacerbations during the year, when the intervals in treatment with prednisolone do not exceed 2 months. It is especially important not to delay treatment with glucocorticosteroid hormones in young people. Removal of the spleen is indicated for young people, since it is extremely undesirable for them to use immunosuppressive drugs without special indications.

Removal of the spleen is possible in symptomatic forms of autoimmune hemolytic anemia, in combination with chronic active hepatitis.

The efficiency of spleen removal in hemolysin forms of autoimmune hemolytic anemia is less than in agglutinin ones. Rarely, patients experience complete improvement, but the condition of patients after removal of the spleen improves, hemolytic crises become less severe, more rare. The risk of thrombotic complications in the hemolysin form of the disease is especially great. Especially careful prevention is needed.

Immunosuppressive drugs are used for autoimmune hemolytic anemia. 6-mercaptopurine and azathioprine, which is close to it in structure, inhibit the inductive phase of antibody synthesis, interfere with normal blast transformation and proliferation of lymphocytes, mainly suppress IgG production and have little effect on IgM production. The drug is used at a dose of 100 to 200 mg / day.

In addition to azathioprine, for autoimmune hemolytic anemias with incomplete thermal agglutinins, cyclophosphamide 400 mg every other day, vincristine 2 mg once a week are used.

There are different views on the use of immunosuppressive drugs in autoimmune hemolytic anemia. The effect does not come immediately, therefore it is inappropriate to prescribe drugs in the acute phase of the disease. With their help, you can try to get rid of prednisone, especially if the removal of the spleen is ineffective. Most patients tolerate drugs well. During the admission period, a clear repair is outlined (a special function of cells, which consists in the ability to correct chemical damage and breaks in molecules), due to which it is possible to reduce the dose of prednisolone, but it is very rare to get a lasting improvement.

The use of immunosuppressive drugs, especially in children, is highly inappropriate without serious indications. It is necessary to remember about their mutagenic effect.

Immunosuppressive drugs should only be used in cases of ineffective spleen removal.

The treatment of autoimmune hemolytic anemia with complete Cold agglutinins has some specific features.

There is a greater decrease in the effectiveness of glucocorticosteroid therapy than with thermal forms. It should be noted that in hemolytic crises, glucocorticosteroid hormones are prescribed in a much lower dose than in the thermal forms: 25 mg / day.

Immunosuppressants, especially chlorbutin, have some benefits. Against the background of taking chlorbutin (2.55 mg / day) or cyclophosphamide (400 mg every other day), patients have less cold intolerance and manifestations of increased destruction of erythrocytes. However, after discontinuation of the drug, the same symptoms of the disease reappear. Removal of the spleen in this form of the disease is ineffective.

Currently, plasmapheresis is used for the treatment of autoimmune hemolytic anemia with complete cold agglutinins; at the same time, the extracted blood should be constantly warmed up to prevent the process of adhesion of erythrocytes. Plasmapheresis treatment can be combined with immunosuppressive therapy. The state of health of patients with cold forms is better than with heat, the condition remains satisfactory for many years and in most cases they do not lose their ability to work.

The prognosis for autoimmune hemolytic anemias depends on the form of the disease.

If the disease has an idiopathic form, then in most patients the condition improves from the use of prednisone, however, recovery is observed in no more than 10% of patients. After removal of the spleen, 63% of patients experience an improvement in their condition, and a significant improvement occurs in 15%. A certain proportion of patients with improvement respond to treatment with immunosuppressive drugs. Thus, modern therapy has a good effect in most patients with this form of autoimmune hemolytic anemia (90%).

In the case of a symptomatic form of the disease, the prognosis is primarily due to the disease that caused autoimmune hemolytic anemia. In a number of patients with a symptomatic form of the disease (with cirrhosis of the liver, with chronic lymphocytic leukemia), it is possible to obtain a certain effect from removing the spleen in relation to autoimmune hemolytic anemia.

The ability to work in the majority of patients with autoimmune hemolytic anemia is restored, but in a number of patients all methods of therapy give only a temporary improvement.

In a small number of patients (according to various sources, 3-4%), it is not possible to obtain an effect in the acute period, even from large doses of prednisolone. The cause of death, in addition to the acute destruction of erythrocytes, can be thrombotic complications – thrombosis of cerebral or mesenteric vessels.

Sometimes death is caused by a decrease in corticosteroids that occur during severe injuries, infections, in patients who have been taking large doses of prednisolone for several years, which should be taken into account by the doctor and prescribe a dose of prednisolone at which the patient’s blood pressure does not decrease.

The prognosis for cold forms of autoimmune hemolytic anemia is not bad in relation to life, however, remission is rarely achieved.