Paroxysmal nocturnal hemoglobinuria: what is it, symptoms, treatment, prognosis

What is paroxysmal nocturnal hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria (abbr. APG) Is a rare disease in which red blood cells break down prematurely. PNH is an acquired disease of hematopoietic stem cells. Hematopoietic stem cells are created in the bone marrow, the spongy center of the long bones of the body. These cells grow and eventually turn into red blood cells, white blood cells, and platelets. Some hematopoietic stem cells in people with PNH are defective and therefore produce defective blood cells. These defective PNH red blood cells are extremely susceptible to premature destruction by a part of a person's own immune system called the complement system.

The destruction of red blood cells (hemolysis) by complement leads to the appearance of hemoglobin in the urine (hemoglobinuria). Hemoglobin is a red, iron-rich, oxygen-containing pigment in the blood. In people with hemoglobinuria, urine may be dark or bloody in color. This is most noticeable in the morning, after the urine has been concentrated during the night while sleeping. However, hemolysis in people with PNH is an ongoing process (i.e., it does not occur only at night). Hemoglobin in urine may not always be visible to the eye.

In addition to hemolysis, people with paroxysmal nocturnal hemoglobinuria also develop recurring, potentially life-threatening blood clots (thrombosis). Patients also have some degree of bone marrow dysfunction. Severe bone marrow dysfunction leads to low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly from one person to another, and patients usually do not show all of the symptoms associated with this disorder.

Signs and symptoms

Symptoms of paroxysmal nocturnal hemoglobinuria are due to the formation of defective blood cells and because the bone marrow does not produce enough blood cells. The specific symptoms and progression of the disorder vary greatly from one person to another. Some people may have mild symptoms that remain stable for many years; others may have severe symptoms that can progress and cause life-threatening complications.

It is important to notethat patients may not have all of the symptoms described below. Sufferers should talk to their doctor about their specific case, associated symptoms, and overall prognosis.

Premature destruction of red blood cells (hemolysis) is the primary clinical sign associated with PNH. Hemolysis can lead to the formation of hemoglobin in the urine, although many people with hemolysis have no visible hemoglobin in their urine. When hemolysis occurs, the outer wall (membrane) of the red blood cell breaks down (lysis) with the release of hemoglobin. Hemoglobin is excreted in the urine, causing the urine to become dark or bloody in color (hemoglobinuria). Hemolysis continues and may worsen (for example, a person may have a hemolytic episode) during periods of infection, trauma, or stress. Premature destruction of red blood cells can lead to low circulating red blood cells (hemolytic anemia), which is exacerbated by underlying bone marrow dysfunction.

Chronic hemolysis is central to all symptoms and physical manifestations associated with PNH. Mild hemolysis can cause:

• fatigue;
• cardiopalmus (tachycardia);
• headaches;
• chest pain;
• shortness of breath when doing physical exercise.

If hemolysis is severe, additional symptoms may develop, including fatigue, daytime sleepiness, difficulty swallowing (dysphagia), painful contractions that affect the abdomen, esophagus (esophageal spasms) and in men can cause erectile dysfunction and impotence. Chronic hemolysis can also lead to blood clots, and some patients may develop acute and chronic kidney disease.

About 15-30 percent of people with paroxysmal nocturnal hemoglobinuria develop blood clots, especially in the veins (venous thrombosis). The exact cause of blood clots in people with PNH is not fully understood. In addition to red blood cells, defective hematopoietic stem cells can also produce defective platelets. Some researchers believe that these defective platelets are prone to blood clots. Chronic hemolysis can also contribute to the formation of blood clots (blood clots).

Blood clots can be carried through the bloodstream to various parts of the body, which can lead to life-threatening complications. Blood clots can reduce or cut off blood flow to various organs, especially the stomach, liver, and brain. The specific symptoms associated with venous thrombosis depend on the specific area of ​​the body affected. For example, blood clots that affect livercan cause:

• jaundice;
• abdominal pain;
• Budd-Chiari syndrome.

Blood clots that affect the stomach and intestines can also cause severe abdominal pain, bloating or a feeling of overflow. Blood clots in the veins of the brain cause symptoms such as headaches or problems with thinking. Blood clots in the lungs can cause shortness of breathdifficulty breathing and heart palpitations. In rare cases, blood clots can form in arteries. Blood clots can potentially cause life-threatening complications by blocking blood flow to vital organs.

All PNH patients have some degree of bone marrow dysfunction. Individuals with mild bone marrow dysfunction may have no symptoms or only mild symptoms. People with severe bone marrow dysfunction may have low levels of red and white blood cells and platelets (pancytopenia). Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets allow the body to form clots that stop bleeding. A low level of circulating red blood cells (erythrocytes) is called anemic. A low level of white blood cells (leukocytes) is called leukopenia, and a low level of platelets is called thrombocytopenia.

People with anemia may experience fatigue, increased need for sleep, weakness, dizziness, irritability, headaches, pale skin, shortness of breath (shortness of breath) and heart symptoms, including chest pain. People with leukopenia have an increased risk of contracting bacterial and fungal infections. People with thrombocytopenia are more susceptible to excessive bruising after minimal trauma and spontaneous bleeding from the mucous membranes, especially the gums and nose. Women with thrombocytopenia may develop increased menstrual blood loss (menorrhagia).

Many people with paroxysmal nocturnal hemoglobinuria may simultaneously have another closely related condition known as acquired aplastic anemia. To a lesser extent, some people may have myelodysplasia. Although the exact relationship between these disorders is unknown, researchers now believe PNH results from autoimmune bone marrow failure, which is the cause of most cases of acquired aplastic anemia and some cases myelodysplasia. In rare cases, PNH can develop into acute leukemia over time. The reason for this conversion is unknown.

Causes and risk factors

For APG development, two factors are required:

1. acquired somatic gene mutation PIGAwhich affects one or more hematopoietic stem cells, creating defective "PNG" blood cells,
2. and the process that leads to the proliferation and proliferation of these defective stem cells.

Most likely, paroxysmal nocturnal hemoglobinuria occurs against the background of autoimmune bone marrow failure, as in most cases of acquired aplastic anemia. The researchers believe that defective PNH stem cells survive a mistaken attack by the immune system and multiply, while healthy stem cells are destroyed, leading to the development of PNH. The reason why defective cells survive and healthy ones are destroyed is unknown.

Gene mutation PIGA is a somatic mutation, which means that it occurs after conception; it is not hereditary and cannot be passed on to children. This mutation occurs by chance, for no apparent reason (sporadically). In PNH, this mutation occurs in one hematopoietic stem cell (clonal disorder), which then multiplies and grows. The reason why PNH cells expand and multiply is not fully understood. Scientists believe that other factors, such as secondary gene mutations or immune factors, are required for PNH cells to grow and multiply. Hence, although the mutation PIGA is necessary for the development of PNH, its presence is insufficient to cause the disorder. In some cases, this additional factor has been shown to be a second somatic mutation (in addition to PIGA), which endows the mutant cell with a growth advantage.

Gene PIGA produces the protein that is necessary for the creation (biosynthesis) of glycosylphosphatidylinositol (GPI) anchors. These anchors allow certain proteins to attach to the cell membrane. These proteins are called GPI-anchored proteins. In cells with mutation gene PIGA GPI-anchors are not formed and, therefore, GPI-anchored proteins cannot attach to cell membranes. Some of these GPI-anchored proteins serve to protect cells from the immune system. Consequently, the lack of these surface proteins makes PNH blood cells extremely susceptible to destruction by a part of the immune system known as the complement system. PNH red blood cells are particularly susceptible to premature destruction by the complement system.

The complement system is a complex group of proteins that work together to fight infections in the body. These proteins react to bacteria, viruses, and other foreign substances in the body. They work with white blood cells to destroy foreign material in the body. In people with PNH, the complement system mistakenly destroys the "PNH" blood cells due to the lack of GPI-anchored proteins that normally protect blood cells from the activity of the complement system.

Affected populations

PNH is believed to affect males and females in equal proportions, although some studies show a slight predominance of females. The prevalence is estimated at 0.5-1.5 per million in the general population. The disease has been described in many racial groups and has been identified in all regions of the world. The disorder may occur more frequently in people from Southeast Asia or the Far East, who are more likely to have aplastic anemia. The disorder can affect any age group. The average age at diagnosis is 30 years.

For the first time, paroxysmal nocturnal hemoglobinuria was reported in the medical literature in the second half of the 19th century. This disorder has been termed paroxysmal nocturnal hemoglobinuria due to the mistaken belief that hemolysis and subsequent hemoglobinuria occurs only in intermittent episodes (paroxysmal) and more frequently at night (at night). However, although hemoglobinuria can manifest itself paroxysmally, hemolysis continues both day and night.

Symptomatic disorders

Symptoms of the following conditions may be similar to those of paroxysmal nocturnal hemoglobinuria (PNH). Comparisons can be useful for differential diagnosis.

PNH with acquired aplastic anemia are closely related diseases, while PNH can also occur in association with some forms of myelodysplasia, such as refractory anemia. People with PNH may develop aplastic anemia or myelodysplasia at the same time. Researchers believe PNH may be due to autoimmune deficiency in the bone marrow, which causes most cases of acquired aplastic anemia and some cases myelodysplasia.

• Acquired aplastic anemia - a rare disease caused by a deep, almost complete bone marrow failure. Bone marrow is a spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually become red blood cells, white blood cells, and platelets. In acquired aplastic anemia, the almost complete absence of hematopoietic stem cells ultimately leads to low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, recurring infections, dizziness, weakness, headaches, and episodes of profuse bleeding. Most cases of acquired aplastic anemia occur for unknown reasons (idiopathic), although researchers now believe that most of these cases are a result of the immune system mistakenly targeting the bone marrow (autoimmunity).
• Myelodysplastic syndrome (MDS, myelodysplasia) is a rare group of blood disorders that result from abnormal development of blood cells in the bone marrow. Three main types of blood cells (i.e. red blood cells, white blood cells, and platelets) are affected. Red blood cells (erythrocytes) deliver oxygen to the body, white blood cells (white blood cells) help fight infections, and platelets help in clotting to stop loss of blood. These malformed blood cells cannot develop normally and enter the bloodstream. As a result, people with MDS have abnormally low blood cell counts (low blood counts). Common symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS can progress to life-threatening bone marrow failure or acute leukemia. The exact cause of MDS is unknown, but in about 90 percent of patients, acquired (somatic) genetic abnormalities can be identified in bone marrow cells. There are no specific environmental risk factors.
• Rarely, people with paroxysmal nocturnal hemoglobinuria may develop leukemia, which is a form of cancer that affects the bone marrow and bloodstream. It is characterized by an uncontrolled accumulation of immature blood cells. Acute forms of leukemia can lead to low red blood cells and white blood cells and platelets (pancytopenia) or high white blood cell count (leukocytosis) with low red blood cells and platelets.
• Paroxysmal cold hemoglobinuria - a rare autoimmune hemolytic disease characterized by the premature destruction of healthy red blood cells (hemolysis) from several minutes to several hours after exposure to cold. Autoimmune diseases occur when the body's natural defenses against invading organisms, for unknown reasons, mistakenly destroy healthy tissue. Typically, the lifespan of red blood cells is about 120 days. In a person with paroxysmal cold hemoglobinuria, red blood cells are destroyed prematurely and suddenly as a result of an antibody-mediated process when exposed to temperatures of 10 to 15 degrees Celsius and below.

The following disorders may be associated with PNH as secondary characteristics. They are not needed for differential diagnosis:

• Budd-Chiari Syndrome - a rare disease characterized by narrowing and blockage of the veins of the liver. In people with PNH, blood clots (thrombi) block the hepatic veins. Symptoms associated with Budd Chiari Syndrome include pain in the upper right side of the abdomen, an abnormally large liver (hepatomegaly) and / or fluid accumulation (ascites) in the space between the two layers of the membrane lining the stomach (abdominal cavity). Additional signs that may be associated with the disease include nausea, vomiting, and / or enlargement of the spleen (splenomegaly). The severity of the disease varies from person to person, depending on the location and number of veins affected. In some cases, if the major hepatic veins are affected, high blood pressure in the veins may develop, through which blood from the gastrointestinal tract (GIT) returns to the heart through the liver (portal hypertension).

Diagnostics

The diagnosis of paroxysmal nocturnal hemoglobinuria can be suspected in people who have symptoms intravascular hemolysis (eg, hemoglobinuria, abnormally high serum LDH) without known reason. Diagnosis can be made based on careful clinical evaluation, detailed patient history, and various specialized tests. The main diagnostic test for people with suspected PNH is flow cytometry, analysis blood, which can identify PNH cells (blood cells that lack GPI-anchored proteins).

Standard treatments

Treatment for paroxysmal nocturnal hemoglobinuria targets the specific symptoms present in each individual and includes many different therapeutic options.

In 2007, the US Food and Drug Administration (FDA) approved the orphan drug Soliris (eculizumab) for the treatment of PNH. It is the first drug approved for the treatment of this disorder. Soliris does not treat PNH, but it stops red blood cell breakdown and may reduce the risk of thrombosis and improve overall quality of life. Soliris works by blocking the body's complement system, which inadvertently destroys PNH red blood cells. Because Soliris blocks part of the body's natural immune system, it increases the risk of meningococcal infections. Therefore, patients should be vaccinated with meningococcal vaccine at least two weeks before receiving the first dose of Soliris.

In 2018, the FDA approved Ultomiris (ravulizumab) for the treatment of PNH hemolysis. Ravulizumab acts similarly to eculizumab and has been shown to be clinically comparable to eculizumab. Ravulizumab is given every eight weeks and eculizumab is given every two weeks.

Adjunctive PNH treatment is symptomatic and supportive and varies with age of the patient, general health, the presence of comorbidities, the severity of PNH and the degree of deficiency bone marrow.

Some people with PNH get folic acid supplements (vitamin B9) to provide adequate folate, as the need for it increases when the bone marrow attempts to compensate for PNH hemolytic anemia by increasing the production of red blood cells (erythropoiesis) in the bone brain. Additionally, people with iron deficiency, which can result from destruction of red blood cells and subsequent loss of iron in the urine, should be given iron supplements.

Some doctors suggest that people with hemolysis symptoms should be treated with steroids such as like prednisone, because it is believed to slow down the rate of destruction of red blood cells Taurus. However, treatment with steroids such as prednisone is controversial because steroid therapy is not beneficial for all and can cause serious side effects, especially if therapy is continued for a long time time.

Drugs that block blood clots (anticoagulant therapy) may be prescribed. Some people may be prescribed long-term anticoagulant therapy. The use of blood thinners should be closely monitored due to the risk of excessive bleeding due to low platelet counts in some people.

People with Budd-Chiari Syndrome with paroxysmal nocturnal hemoglobinuria can be treated thrombolytic therapy, in which certain drugs are used to destroy or dissolve blood clots. Such treatment requires experience in managing the potential side effects of these drugs, since the risk of side effects (especially bleeding) is high.

The only curative therapy for people with PNH - bone marrow transplantation. However, due to the risk of morbidity and mortality, it is intended for individuals with serious complications, such as severe bone marrow failure or repetitive, life-threatening growth thrombus. The specific form of bone marrow transplantation most commonly used in the treatment of paroxysmal nocturnal hemoglobinuria is allogeneic bone marrow transplantation. During allogeneic bone marrow transplant the affected person's bone marrow is usually destroyed by chemotherapy, radiation, or both, and replaced with healthy bone marrow from a donor. The donated bone marrow is transplanted into the body intravenously, where it enters the bone marrow and eventually begins to produce new blood cells. The best option for a bone marrow transplant is an identical twin or sibling with an identical type of HLA. However, in some cases it is necessary to find an unrelated, suitable donor. Bone marrow transplantation can treat underlying bone marrow dysfunction and eliminate defective PNH stem cells.

Soliris and Ultomiris do not affect the underlying bone marrow dysfunction that many people with PNH suffer from. People with severe bone marrow insufficiency may be given immunosuppressive therapy. Individuals with acquired aplastic anemia have responded positively to this form of treatment, which uses certain medications to suppress the activity of the immune system. This form of treatment may be useful in PNH cases in which bone marrow insufficiency predominates. Although immunosuppressive therapy can restore bone marrow function, it does not eliminate the PNH clone. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG) and cyclosporin.

Some people with PNH and low blood cell counts may be given blood transfusion. This treatment consists of red blood cell transfusion to correct anemia, platelet transfusion to treating or preventing severe bleeding and antibiotics for treatment or prevention infections. Affected people who are eligible for a bone marrow transplant should not receive a blood transfusion whenever possible, as a blood transfusion reduces the chances of a successful transplant.

Some people with PNH may get treatment with artificial (synthetic) growth factors. Growth factors are proteins commonly found in the body that stimulate the bone marrow to produce blood cells. Erythropoietin (EPO) is a growth factor produced by the kidneys that stimulates the bone marrow to form red blood cells. Epogen®, Prokrit® and Aranesp® are forms of erythropoietin. Red blood cell growth factor therapy can reduce the need for blood transfusions. Individuals with paroxysmal nocturnal hemoglobinuria with low white blood cell counts may receive growth factors such as granulocyte colony-stimulating factor (G-CSF), which stimulates the bone marrow to produce granulocytes (a type of white blood cell that fights with bacterial infections).

Some people with PNH may get androgen treatment, male hormones that stimulate the bone marrow to produce red blood cells. Danazol androgen therapy may help improve symptoms of anemia.

Forecast

PNH disease is insidious and chronic, with an average survival rate of about 10.3 years. The incidence depends on various manifestations of hemolysis, bone marrow failure and thrombophilia, which determine the severity and clinical course of the disease.

A study of the first 1610 patients included in the International PNH Registry showed that overall, 16% of patients had a history of thrombotic events, and 14% had renal dysfunction. Commonly reported symptoms included the following:

• fatigue (80%);
• shortness of breath (64%);
• hemoglobinuria (62%);
• abdominal pain (44%);
• chest pain (33%).

Patients also reported a deterioration in quality of life due to their illness, with 17% saying they did not work or worked less due to paroxysmal nocturnal hemoglobinuria.

In several large studies, the leading cause of death in patients with paroxysmal nocturnal hemoglobinuria was venous thrombosis, followed by complications from bone marrow failure; however, spontaneous long-term remission or leukemic transformation of the PNH clone has been reported and well documented.

Median survival after diagnosis was 10 years in a series of 80 consecutive patients seen at Hammersmith Hospital in London who received supportive measures such as oral anticoagulant therapy after an established thrombosis and transfusion blood. 60 patients died; of 48 patients whose cause of death was known, 28 died of venous thrombosis or bleeding. 31 people (39%) had one or more episodes of venous thrombosis during their illness. No leukemic transformations occurred in this series.

22 out of 80 patients (28%) survived for 25 years. Of 35 patients who lived for 10 years or more, 12 experienced spontaneous clinical recovery; PNH-infected cells were not detected among erythrocytes or neutrophils during their long-term remission, but several PNH-affected lymphocytes were detected in 3 out of 4 patients examined.