Paroxysmal Nocturnal Hemoglobinuria

The presentation of PNH varies among affected individuals. There are cases with mild and stable symptoms. Other cases have severe progressive symptoms and complications.

The main indicator of hemolysis is hemoglobinuria. Specifically, complement mediated RBC destruction will cause episodic hemoglobinuria and hence the commonly seen dark colored urine. Generally, these episodes are seen in early morning due to the concentrated urine. Since hemolysis is an ongoing process, hemoglobinuria can be present any time whether visible or not [8]. Stressful events may worsen this hemolysis.

Hemolytic anemia is another common sign of premature destruction of red blood cells especially when the hemolysis is in the setting of bone marrow suppression. The clinical manifestations of PNH are attributed to chronic hemolysis. Mild cases cause tachycardia, chest pain, dyspnea with exertion, and headaches. Severe forms cause devastating fatigue, dysphagia, abdominal pain, esophageal spasms, and erectile dysfunction (in males). Chronic hemolysis can result in thrombosis and other complications such as renal diseases.

Thromboembolism is the most common cause of death in PNH. It has been approximated that 15 to 30% of patients will develop thrombosis.

There are varied degrees of bone marrow suppression. Mild forms have little to none symptoms. Severe forms result in pancytopenia. Since anemia is a common clinical sign, the symptoms of anemia such as pallor, tiredness, weakness, dizziness, lightheadedness, dyspnea and chest pain are seen [9]. Leukopenia is associated with an increased risk of bacterial and fungal infections. Thrombocytopenia is associated with bruising, spontaneous bleeding, and excessive bleeding in menstruation (in women).

Aplastic anemia commonly coexists with PNH. While this relationship is unclear, is thought that bone marrow failure is due to autoimmunity [7]. Some patients may have myelodysplasia as well. 

A detailed medical history with family history as well as a physical examination are mandatory. The diagnosis of PNH includes several key labs to clarify the diagnosis in addition to flow cytometry of the patient’s blood:

• Complete blood count (CBC): Usually shows pancytopenia and low hemoglobin
• Reticulocyte count: Elevated
• Lactate dehydrogenase: Elevated
• Serum haptoglobin: Decreased
• Bilirubin: Elevated unconjugated
• Urine: Positive for hemosiderin and hemoglobin

In addition, further hemolysis parameters, renal function, folic acid and vitamin B12 levels, iron status and (pro)BNP for the assessment of right ventricular function should be investigated.

Flow cytometry is used as the gold standard test. Flow cytometry using fluorescence is performed on the patient’s blood to detect the amount of cells deficient in GPI anchored proteins. 1-3% deficiency demonstrates a positive diagnostic test. Furthermore, this can be used to detect abnormal cells [10]. Immunotyping is used to detect missing proteins on cells. Flow cytometry has replaced the outdated tests such as the HAM (acidified serum lysis) and sucrose lysis tests, which are not sensitive or specific [11]. The complement lysis sensitivity test is also outdated.

Sonographic examination of the abdomen and, if necessary, magnetic resonance tomography, pulmonary function tests and electrocardiography (ECG) complete the medical workup of paroxysmal nocturnal hemoglobinuria.

Treatment of PNH depends on the clinical signs and manifestations found in the patient.  

1. Hemolytic anemia: Eculizumab, a monoclonal antibody, targets the CD5 complement protein to inhibit hemolysis. This FDA approved drug alleviates fatigue, improves quality of life and alleviates symptoms secondary to decreased quantity of nitric oxide such as espophageal spasm, abdominal pain, renal dysfunction, pulmonary hypertension, and erectile dysfunction [12]. The cost is expensive and therefore its use should be justified and indicated. Meningococcal vaccines should be updated and maintained while using this drug. Prophylactic use of antibiotics is not recommended at this time. Prednisolone can be used for rapid alleviation of symptoms. One must weigh the benefits and adverse effects with the use of steroids [13]. It should be discontinued after 6 weeks if results are not seen.
2. Aplastic anemia: Erythropoietin can be used along with eculizumab as well for those with kidney dysfunction [14].
3. Iron deficiency anemia: Due to elevated loss of daily iron, supplementation is important and can be done orally. In patients with symptomatic anemia and hemoglobin below <8.5 g/dL, a transfusion may be indicated. Transfusion is done with a packed RBCs (with WBCs filtered out).
4. Thrombophilia: In acute stage of thrombosis, thrombolytic agents like urokinase or tissue plasminogen activator (tPA) are used initially followed by warfarin or low molecular weight heparin. In cases where platelet count is too low (less than 50X10^9/L) or if thrombosis is located intracranially, then thrombolytic agents are not acceptable. Following treatment, patients should be on lifelong secondary prophylaxis with an INR target range of 2-2.5.
   Eculizumab has been shown to have profoundly decrease the risk of thromboembolism. In patients on secondary prophylaxis while on eculizumab, it is recommended they continue the use of anticoagulants until further studies are performed to elucidate if they could be discontinued.
5. Renal dysfunction: Eculizumab has been shown to improve renal complications. 
6. Bone marrow dysfunction: Cyclosporine and antithymocyte globulin may be used [15]. If these medications fail, bone marrow transplant can be performed if an appropriate and suitable match is available. While a successful bone marrow transplant cures PNH, there is risk for graft-versus-host-disease which could be life threatening.

The prognosis of PNH depends on the overall clinical picture. Rarely, there is a reduction in the quantity of defective cells over the patient’s life span. A majority live at least a decade following the diagnosis. Most affected individuals require treatment to manage the manifestations of the disease. Untreated patients have a median survival age of 10 to 20 years [7].

Complications such as thromboembolism and renal failure can lead to fatality especially the former. Patients that develop thrombosis are associated with poor survival rates overall.

The etiology of PNH is due to a somatic mutation in the PIG-A gene in hematopoietic stem cells which is usually in the setting of underlying bone marrow hypoplasia. To understand better, it is pertinent to know the role of this mutation. The PIG-A gene is responsible for synthesizing the GPI anchor which in turn allows key surface proteins, including the complement defence proteins CD55 and CD59, to bind the cell membranes of blood cells. Since the GPI anchor proteins are missing, these surface proteins cannot bind to the cell membrane of blood cells [3]. The somatic mutation is believed to occur due to the natural rate transcriptional errors.

If in the setting of hematopoietic hypofunction such as aplastic anemia, the abnormal hematopoietic cells with the mutated PIG A gene develop into defective blood cells, followed by growth in size of this abnormal clone. Of note, it is important to understand that the relationship between PNH and aplastic anemia is still being investigated.

The global prevalence is 1 to 6 per population of 1,000,000. The prevalence is increased in southeast Asia such as Thailand, where aplastic anemia has higher incidence [4] [5]. PNH is seen equally in both genders. The peak ages in the middle 30s and middle 50s. 

In addition to the results of the PIG-A mutation, the pathophysiology of PNH is also due to the activation of the complement system of these defective blood cells, ie cells lacking CD55 and CD59. Without these regulatory inhibitory proteins, the inhibition is removed and the complement system becomes uncontrolled. Minor activation is constant throughout the day and responsible for low grade hemolysis. Major activation occurs at night time and is responsible for the deposition of lytic terminal complexes on defective cells. Consequently, RBCs lyse intravascularly expelling the hemoglobin into the plasma which is eventually excreted in the urine. Some of the common stressors that activate the complement system are infection, surgery, and trauma. The severity of hemolysis is related to the percentage of abnormal RBCs, their specific abnormality, and the degree of activation.

The abundant amount of released hemoglobin directly binds nitric oxide in tissues causing contraction of smooth muscle. This is responsible for esophageal spasms and abdominal pain. Since nitric oxide is depleted, vascular spasms occur which lead to erectile dysfunction, renal and pulmonary complications [6].

Complement activation of abnormal platelets is thought to be responsible for the thromboembolism, which is seen in deep veins, hepatic and abdominal veins, and cerebral sinuses [7]. Thrombosis can also form in arteries.

Acute and chronic renal dysfunction are complications [6]. This is caused by hemosiderin deposition in renal tubules. Acute failure can be seen during the episodic crises. Renal complications may range from mild and reversible to severe and irreversible. 

Susceptibility to infection, particularly meningococcal, occurs due to defective WBCs. Also contributing to the pathophysiology is hematopoietic suppression, ie aplastic anemia. This allows for the abnormal cells to increase in quantity hence result in clinical manifestations.

There is no prevention of PNH. There are no known risk factors either. 

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder in which a somatic mutation in hematopoietic stem cells results in the production of defective blood cells. This nonmalignant disorder is further characterized by the premature destruction of these abnormal blood cells by the complement system. The somatic mutation is found in the PIG-A (phosphatidylinositol glycan class A) gene which has consequences on blood cells such as red blood cells (RBCs), white blood cells (WBCs), and platelets. Abnormality in each of these cell types has clinical consequences.

One of the main initial presenting features of PNH includes hemoglobinuria, hence dark colored urine is occasionally visible and the reason for the name of the disorder. There are multiple clinical manifestations in PNH including hemolytic anemia, thrombosis, bone marrow hypofunction, renal dysfunction, and susceptibility to infection. PNH manifests differently in patients and varies from one patient to another. Some have mild and benign presentations, while others have severe life threatening complications [1] [2].

Paroxysmal nocturnal hemoglobinuria (PNH) is a blood disorder that is rare and nonmalignant. It caused by a gene mutation that leads to destruction of blood cells and excretion of hemoglobin through urine. Hence, the first clinical sign is dark colored urine. This may be seen at night or in the morning. Not all patients will see dark colored urine. Hemoglobin may be present, but not obvious to the naked eye.

In PNH, different blood cell types are reduced in number because of gene mutation. Therefore, there are many symptoms that patients with PNH can experience. Some patients have mild forms while others have severe life threatening forms. Symptoms may include pale skin, fatigue, bruising easily, shortness of breath, rapid heart rate, chest pain, and headaches. Some of the more severe symptoms include difficulty swallowing, abdominal pain, and erectile dysfunction. Other severe complications are blood clot formation and kidney failure.

Diagnosis of PNH includes a comprehensive history of your symptoms. Important laboratory tests are performed to assess your urine and blood cell counts. Also there are blood tests such as the flow cytometry test, that look for specific findings to determine if there are abnormal blood cells.

Treatment of PNH includes a drug called eculizumab which helps alleviate symptoms and even helps with complications such as blood clots and renal problems. Patients taking this medicine should be up to date on vaccines. Since anemia is common, iron treatment by mouth is important. Severe cases may require blood transfusions. Some patients require bone marrow transplant if a match is found.

Patients should be treated by specialists. If the symptoms are controlled with the available medications, patients have good prognosis.

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