Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and serious disease of blood-forming cells that is genetic but acquired later in life. Since it is a somatic mutation, the germ cells are not affected. If left untreated, the disease can be fatal, mainly due to the formation of multiple thromboses.
What is paroxysmal nocturnal hemoglobinuria?
Paroxysmal nocturnal hemoglobinuria is an often severe disease of the blood-forming cells. It is characterized by hemolysis, thrombus formation and a reduced formation of blood cells. Individual or all bloodline cells can be affected. See ezhoushan for What does APV Stand for.
While all patients with PNH show the symptoms of hemolysis, the other symptoms are very variable. In about 35 percent of cases, it can be fatal, which is mainly caused by the large number of thromboses that occur. Due to the constant hemolysis, there is chronic anemia, which is accompanied by severe states of exhaustion.
Although the disease cannot be cured, it can be controlled well with therapy. With consistent treatment throughout life, a good quality of life is achieved with a normal life expectancy. PNH has an estimated prevalence of approximately 16 per 1 million inhabitants and is therefore one of the very rare diseases.
Causes
Paroxysmal nocturnal hemoglobinuria is caused by a somatic mutation of the PIG-A gene. This gene is located on the X chromosome and is responsible for encoding the enzyme N-acetylglucosaminyltransferase. N-acetylglucosaminyltransferase catalyzes the formation of the so-called glucosylphosphatidylinositol anchor (GPI anchor), which anchors protective proteins on the cell surface of blood cells.
These include the proteins CD55 and CD59. With their anchoring on the cell membrane of the blood-forming cells, they serve to protect them from attacks by the part of the immune system known as the complement system. In the absence of these anchor proteins, hematopoietic stem cells and blood cells are destroyed
In addition to increased hemolysis, fewer blood cells are also formed. Pronounced chronic anemia develops. At the same time, thrombosis develops in many parts of the body, which can be dangerous. PNH is an acquired disease that first appears between the ages of 25 and 45.
The underlying gene mutation is not present at birth. It arises as part of a somatic mutation of the PIG-A gene within the multipotent hematopoietic stem cells. No other cases of PNH are found in the family and relatives. Since the germ cells are not affected, the disease cannot be passed on to offspring.
Symptoms, Ailments & Signs
The main symptom of paroxysmal nocturnal hemoglobinuria is chronic hemolysis. Somatic mutations result in so-called mosaics. There are both healthy and defective blood cells. All mutated blood cells have lost protection from the complement system due to the missing anchor and are destroyed.
The diseased erythrocytes are particularly affected. But the most dangerous symptom is the tendency to form thrombosis in both the venous and arterial systems. This is the case in about 50 percent of patients with PNH. The thrombosis is also responsible for most of the deaths, affecting a third of those affected.
Other symptoms are severe exhaustion (fatigue), abdominal cramps, headaches, swallowing disorders, nausea, chest pain, back pain or erectile dysfunction. The pain is caused by small thrombi. They can be mild but also so strong that even opiates have to be administered as painkillers.
The pain is also explained by the lack of nitric oxide (NO), which binds to released hemoglobin. Since NO is responsible for the relaxation of smooth muscles, the lack of NO leads to increased states of tension there. The severity of the disease also depends on how many bloodlines are affected by the mutation. If the immune cells in the blood are mutated at the same time, the immune system is also severely weakened.
Diagnosis & course of disease
During diagnostics, the blood cells are examined for the presence of the protective proteins using flow cytometry. This method can be used to identify the cells that lack protection from the complement system. There is a clear diagnosis when at least two cell lines such as erythrocytes or granulocytes do not have a protective factor.
Complications
In the worst case, this disease can lead to the death of the person concerned. As a rule, however, this only occurs when the person concerned suffers from several thromboses that were not prevented. The risk of developing thrombosis is significantly increased in patients. In most cases, these are also responsible for the death of the patient.
Those affected suffer from pain that occurs in different places. There is pain in the head or in the abdomen. In many cases, there is also chest pain that can spread to the back. Men can also suffer from erectile dysfunction as a result of the disease. There is also permanent nausea or difficulty swallowing. In many cases, ordinary painkillers are no longer sufficient to relieve the pain.
The patient’s quality of life is significantly reduced by the disease. The treatment takes place without complications. The symptoms can be reduced with the help of blood transfusions or a stem cell transplant. However, the life expectancy of the patient is usually reduced due to illness.
When should you go to the doctor?
This disease must always be examined and treated by a doctor. Without treatment, death usually occurs because the disease leads to the formation of thrombosis. Those affected suffer from various complaints, which do not always directly indicate the disease. This can cause pain in the head or abdomen, accompanied by nausea or back pain. Erectile dysfunction can often be a sign of this disease. If the symptoms occur permanently and do not go away on their own, a visit to a doctor is definitely necessary.
The pain can also be so extreme that the person concerned loses consciousness. A weakened immune system can also indicate this disease. If you have frequent colds or other infections, you should also consult a doctor. The first diagnosis of the disease can be made by the general practitioner. However, a specialist doctor is required for further treatments. It cannot generally be predicted whether the disease will lead to a reduced life expectancy.
Treatment & Therapy
PNH is not curable. However, there are some supportive treatments that can improve quality of life. Initially, regular blood transfusions or transfusions of erythrocyte concentrates are necessary due to the chronic anemia. Folic acid or vitamin B12 are recommended to promote blood formation.
Infections must be recognized early and treated with antibiotics because they can trigger haemolytic crises. Short-term administration of steroids can alleviate a hemolytic crisis. However, steroids must not be administered continuously. Severe pain requires treatment with painkillers.
If a thrombosis has occurred, coumarins are continuously administered as anticoagulants. The only real possibility of curing paroxysmal nocturnal hemoglobinuria is stem cell transplantation. However, it is associated with considerable risks, so this therapy is only considered in very severe cases.
Good experiences have been made with the drug eculizumab. These are genetically engineered monoclonal antibodies that inactivate the complement factor C5 of the complement system. This prevents the attack on the unprotected blood cells.
Outlook & Forecast
Prognosis for paroxysmal nocturnal hemoglobinuria is difficult. The clinical picture of this acquired hematological disease can vary greatly. In milder forms, the prognosis is more positive. In the case of severe stem cell damage, stem cell transplantation is often the only way to prolong life. Since the disease is based on a genetic mutation in the bone marrow, it cannot be cured.
Paroxysmal nocturnal hemoglobinuria can only be treated symptomatically. A distinction is made between treatment for symptomatic and asymptomatic courses. Patients with asymptomatic paroxysmal nocturnal hemoglobinuria receive prophylactic anticoagulants. In symptomatic patients, therapy with an antibody called eculizmab, along with other supportive measures, can reduce symptoms.
Bone marrow transplantation is another treatment option. However, it is associated with high risks because the immune system has to be switched off before the transplantation. Ultimately, the severity of the stem cell changes determines how good or bad the prognosis is. Half of those affected survive the diagnosis by only 15 years.
In the past, the prognosis for paroxysmal nocturnal hemoglobinuria was worse than it is today. Modern treatment methods have significantly improved the prognosis for the symptomatic type of disease. However, it cannot be called good. However, the survival time and quality of life of those affected are better today than they used to be.
Prevention
It is not possible to prevent paroxysmal nocturnal hemoglobinuria. However, people who are already ill should protect themselves from infections in order not to trigger a hemolytic crisis. Long-term therapy with eculizumab prevents the symptoms of PNH and allows a normal life expectancy.
Aftercare
Since paroxysmal nocturnal hemoglobinuria is a genetic disease, there are currently no causal therapy options. If the affected patients are asymptomatic, you should wait and see or refrain from therapy. Only oral anticoagulation can be considered prophylactically.
It is important to ensure that the coagulation parameters are constantly monitored. Follow-up care therefore refers to the control and monitoring of supportive therapies against the multiple symptoms of the disease. Long-term control of the blood values for VitB12 and folic acid are indicated to prevent changes in the blood components and the resulting symptoms. These deficiencies in VitB12 or folic acid can then be substituted with medication.
Regular blood count checks are necessary in order to detect infections at an early stage. If glucocorticoids are administered, multiple measures should be taken to monitor treatment. Since long-term use of cortisone can lead to decalcification of the bones, this promotes the development of osteoporosis. Calcium and VitD should be administered prophylactically.
Since blood sugar levels and blood pressure increases can also occur during the course of therapy, these parameters are also checked regularly. In the case of treatment with oral anticoagulation, regular coagulation parameter checks will take place. When taking coumarin, it is essential to pay attention to pharmacokinetic interactions with other drugs. Even with therapy with monoclonal antibodies, it is always important to be aware of the occurrence of side effects in order to intervene with medication if necessary.
You can do that yourself
Since the disease is based on a genetic defect, the relatives of a patient should initiate a check of their genetic predisposition on their own responsibility and on their own initiative.
Since the probability of a thrombosis occurring is increased when people are in a rigid posture for too long, the examination of the musculoskeletal system is necessary. Avoid standing, squatting or sitting for long periods of time. In addition, the circulatory system should be supported in everyday life through various loosening-up exercises. In this way, blood congestion can be avoided and vessels in the organism are not pinched.
The intake of harmful substances such as nicotine or drugs that have side effects on the blood system should be avoided. In the case of an existing illness, the preparations taken should be checked for their risks and the doctor treating you should be consulted. In some cases, a change in the treatment plan is necessary. If states of exhaustion, tiredness or an increased need for sleep occur, the person concerned should react adequately to the signals from his body. The organism should not be overly stressed, as there is a risk of sequelae or complications.
Changes in health perception or an increase in symptoms must be discussed with a doctor immediately. Paroxysmal nocturnal hemoglobinuria can lead to a life-threatening condition if left untreated. Therefore, if self-help measures are not sufficient, consultation with a doctor is essential.
