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. 

• Splenomegaly

  PNH is associated with abdominal vein thrombosis, which can cause splenomegaly and hypersplenism. [ncbi.nlm.nih.gov]

  […] a an infrequent disorder with insidious onset (usually in the third or fourth decade) and chronic course, characterized by episodes of hemolytic anemia, hemoglobinuria (chiefly at night), pallor, icterus or bronzing of the skin, a moderate degree of splenomegaly [medical-dictionary.thefreedictionary.com]

  Other features include weakness, abdominal and lumbar pain, jaundice with pallor and yellowish discoloration of the skin and mucous membranes, heart murmurs, splenomegaly, and hemosiderinuria. [whonamedit.com]

  Abdominal, chest, and lumbar pain and symptoms of severe anemia may occur; gross hemoglobinuria and splenomegaly are common. [merckmanuals.com]

• Massive Splenomegaly

  We describe a patient under treatment with the anti-complement antibody eculizumab who developed pancytopenia, requiring blood transfusions, due to massive splenomegaly. [ncbi.nlm.nih.gov]

• Easy Bruising

  Symptoms Symptoms may include: Abdominal pain Back pain Blood clots, may form in some people Dark urine, comes and goes Easy bruising or bleeding Headache Shortness of breath Weakness, fatigue Pallor Chest pain Difficulty swallowing Exams and Tests Red [mountsinai.org]

  Symptoms Symptoms may include: Abdominal pain Back pain Blood clots, may form in some people Dark urine, comes and goes Easy bruising or bleeding Headache Shortness of breath Exams and Tests Red and white blood cell counts and platelet counts may be low [huronregional.org]

  bruising Coughing up blood Impotence Seizures Blood clots PNH is not inherited. [medicinenet.com]

• Anemia

  The frequency of PNH clone detected in aplastic anemia and non-aplastic anemia groups was 12.02 and 3.36%, respectively. [ncbi.nlm.nih.gov]

  It may be associated with aplastic anemia, myelodysplastic syndrome, or acute myelogenous leukemia. Risk factors, except for prior aplastic anemia, are not known. [nlm.nih.gov]

• Pain

  Post-procedure pain and fever were common and manageable; only one patient developed a loculated pleural effusion requiring drainage. [ncbi.nlm.nih.gov]

  Resultant symptoms may include the following: Abdominal pain Bloating Back pain Headaches Esophageal spasms Erectile dysfunction Fatigue Progressive chronic renal failure can occur after several years of hemoglobinuria from the acute tubulonecrosis effects [emedicine.medscape.com]

• Fatigue

  Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐Fatigue). [doi.org]

  By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001 [ncbi.nlm.nih.gov]

  […] on the FACIT-Fatigue instrument. [nejm.org]

• Fever

  Thromboses, as observed in our case, may be associated with fever and marked inflammation. [ncbi.nlm.nih.gov]

  Snapshot A 29-year-old woman presents to the emergency room with a high fever and cough. She has been feeling fatigued for a year prior to presentation. Chest radiography reveals a lower lobe pneumonia. [medbullets.com]

  […] symptoms, headache and fever, fever, confusion, and eyes sensitive to light. [news.alexion.com]

• Pallor

  Synonym(s): Marchiafava syndrome Marchiafava-Micheli syndrome - an infrequent disorder with insidious onset and chronic course, characterized by episodes of hemolytic anemia, hemoglobinuria, pallor, icterus or bronzing of the skin, a moderate degree of [medical-dictionary.thefreedictionary.com]

  Other features include weakness, abdominal and lumbar pain, jaundice with pallor and yellowish discoloration of the skin and mucous membranes, heart murmurs, splenomegaly, and hemosiderinuria. [whonamedit.com]

  Pallor, fatigue and stress dyspnea with activity are the usual manifestations. [orpha.net]

  […] activation May cause aplastic anemia myelodysplasia acute leukemia Diagnosis often made during pregnancy Presentation Symptoms/physical exam episodic dark urine with first urine of the day caused by hemoglobin chronic intravascular hemolytic anemia: pallor [medbullets.com]

• Dyspnea

  Symptom of vitamin A deficiency. (27 Sep 1997) nocturnal diarrhoea Diarrhoea that occurs chiefly at night, usually in association with diabetic autonomic neuropathy. (05 Mar 2000) nocturnal dyspnea Dyspnea occurring at night, several hours after assuming [kmle.co.kr]

  The combination of hemolysis and 1 or more of the clinical symptoms such as abdominal pain, chest pain, or dyspnea, resulted in a much greater increased mortality rate when compared with patients with just the individual symptom alone or just hemolysis [ncbi.nlm.nih.gov]

  Pallor, fatigue and stress dyspnea with activity are the usual manifestations. [orpha.net]

  Median age at diagnosis is in the fourth decade 2. anemia profound fatigue stress dyspnea hemoglobinuria dysphagia abdominal pain erectile dysfunction Complications Common thrombosis renal impairment pulmonary hypertension Rare bone marrow failure myelodysplasia [radiopaedia.org]

• Cough

  He presented with cough, fever, and pancytopenia. [ncbi.nlm.nih.gov]

  […] into a paroxysm of grief. bg Направи го както трябва en Pharmaceutical preparations, Including preparations for the prophylaxis of paroxysmal supraventricular tachycardia and ventricular tachycardia bg Тя има дете, има ли някой, който en Paroxysms of coughing [bg.glosbe.com]

  Snapshot A 29-year-old woman presents to the emergency room with a high fever and cough. She has been feeling fatigued for a year prior to presentation. Chest radiography reveals a lower lobe pneumonia. [medbullets.com]

  The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary [soliris.net]

  […] paroxysmal nocturnal hemoglobinuria include one or more the following: Reddish or cola-colored urine especially in the morning Weakness Shortness of breath Headaches Irregular heartbeats Chest pain Abdominal pains Ulcers Pale or yellowish skin Easy bruising Coughing [medicinenet.com]

• Respiratory Distress

  Premature infants may have respiratory distress or other serious complications (eg, necrotizing enterocolitis). [merckmanuals.com]

  It's also common among babies with neonatal respiratory distress syndrome, babies with genetic disorders (such as Down syndrome), and babies whose mothers had rubella (also called German measles) during pregnancy. [kidshealth.org]

  The condition is more common in premature infants and those with neonatal respiratory distress syndrome. Infants with genetic disorders, such as Down syndrome, or babies whose mothers had rubella during pregnancy are at higher risk for PDA. [medlineplus.gov]

  Low birth weight premature infants As many as 20% of neonates with respiratory distress syndrome have patent ductus arteriosus (PDA). [emedicine.medscape.com]

  Successful use of extracorporeal membrane oxygenation in a human immunodeficiency virus infected patient with severe acute respiratory distress sindrome. AIDS Research and Therapy, 11(37):1-6 (2014). Publikacijos santrauka. G. Vaitkevičienė, R. [santa.lt]

• Abdominal Pain

  INTRODUCTION: Abdominal pain in PNH has never been investigated by in-vivo imaging studies. With MRI, we aimed to assess mesenteric vessels flow and small bowel wall perfusion to investigate the ischemic origin of abdominal pain. [ncbi.nlm.nih.gov]

  Venous thrombosis usually manifests as a sudden catastrophic complication, with severe abdominal pain, a rapidly enlarging liver, and ascites ( Budd-Chiari syndrome ). [emedicine.medscape.com]

• Dysphagia

  (see Dysphagia, [[Dysphagia]]) Physiology : due to smooth muscle spasm caused by red blood cell breakdown products Occurs mainly when the hemolysis is rapid Budd-Chiari Syndrome/Hepatic Vein Thrombosis (see Hepatic Vein Thrombosis, [[Hepatic Vein Thrombosis [mdnxs.com]

  Median age at diagnosis is in the fourth decade 2. anemia profound fatigue stress dyspnea hemoglobinuria dysphagia abdominal pain erectile dysfunction Complications Common thrombosis renal impairment pulmonary hypertension Rare bone marrow failure myelodysplasia [radiopaedia.org]

  Researchers defined high disease activity as lactate dehydrogenase ratio at least 1.5 times the upper limit of normal — used as evidence of hemolysis — and history of fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia, major adverse vascular event, dysphagia [healio.com]

  Indications for Testing Laboratory testing for PNH is used to: Diagnose PNH in patients with the following clinical indications : Hemoglobinuria Unexplained hemolysis with iron deficiency, abdominal pain, thrombosis, dysphagia, or granulocytopenia/thrombocytopenia [arupconsult.com]

  Gastrointestinal complaints (episodic abdominal pain and dysphagia/odynophagia, see “Dysphagia, male impotence, abdominal pain”) may be the initial manifestation of the disease in approximately 10% of patients ( Table 4 ). [bloodjournal.hematologylibrary.org]

• Absent Bowel Sounds

  Ischaemia of the gut produces absent bowel sounds. Cerebral vein thrombosis can produce papilloedema and other neurological signs. Red, painful nodules may occur in the skin. [patient.info]

  Other physical examination findings may include the following: Hepatomegaly and ascites in the presence of Budd-Chiari syndrome Splenomegaly in the presence of splenic vein thrombosis Absent bowel sounds in the presence of bowel necrosis Papilledema in [emedicine.medscape.com]

• Thrombosis

  There were 9 patients who presented with thrombosis, and in the remainder the median time to thrombosis was 4.75 years (range, 3 months-15 years). [bloodjournal.org]

  This may explain some of the complexity of the thrombosis in PNH. In this review, the recent changes in our understanding of the pathophysiology of thrombosis in PNH, as well as the treatment of thrombosis, will be discussed. [ncbi.nlm.nih.gov]

• Chest Pain

  A 44-year-old woman, who had been diagnosed with paroxysmal nocturnal hemoglobinuria, presented with chest pain. Angiography revealed critical distal left main stenosis and proximal stenoses of the left anterior descending and circumflex arteries. [ncbi.nlm.nih.gov]

  Symptoms Symptoms may include: Abdominal pain Back pain Blood clots, may form in some people Dark urine, comes and goes Easy bruising or bleeding Headache Shortness of breath Weakness, fatigue Pallor Chest pain Difficulty swallowing Exams and Tests Red [mountsinai.org]

• Palpitations

  Despite this treatment, he continued to have episodes of yellowing of eyes, palpitations, and dark-colored urine at approximately similar intervals (2–4 months). [hindawi.com]

  The symptoms of anaemia include tiredness, palpitations, breathlessness and looking pale. White blood cells are responsible for fighting infections and a low white cell count can mean people are more prone to develop infections. [pnhleeds.co.uk]

  The remainder mainly experience the symptoms of anemia, such as tiredness, shortness of breath, and palpitations. [enerca.org]

  However rare, untreated adult PDA can lead to other medical conditions in adults, such as: shortness of breath or heart palpitations pulmonary hypertension, or raised blood pressure in the lungs, which can damage the lungs endocarditis, or inflammation [healthline.com]

  Symptoms of untreated PDA in an adult include shortness of breath and heart palpitations. [my.clevelandclinic.org]

• Cyanosis

  In patients who do show signs or experience symptoms, these can include: Cyanosis (a blueish hue to the skin) Fatigue Full, bounding pulses Heart palpitations Shortness of breath Diagnosis UT Southwestern heart doctors might perform several tests to determine [utswmed.org]

  However, endocarditis prophylaxis is recommended for PDA patients with a history of endocarditis, for those with prosthetic valve material and for unrepaired PDA with associated pulmonary hypertension and cyanosis. [heart.org]

  These are the most common symptoms of PDA: Skin turns a blue color from not getting enough oxygen (cyanosis) Very tired Fast or hard breathing Trouble feeding, or tiredness while feeding Infections Poor weight gain In older children, trouble doing activities [stanfordchildrens.org]

  Patients with Eisenmenger’s syndrome are cyanotic and may have differential cyanosis (cyanosis and clubbing of the toes but not the fingers because the right-to-left ductal shunting is distal to the subclavian arteries). [ahajournals.org]

• Jaundice

  Although the severe obstructive jaundice requiring endoscopic therapy following cholecystectomy was complicated, critical intravascular hemolysis and thrombosis were not observed. [ncbi.nlm.nih.gov]

  […] anemia myelodysplasia acute leukemia Diagnosis often made during pregnancy Presentation Symptoms/physical exam episodic dark urine with first urine of the day caused by hemoglobin chronic intravascular hemolytic anemia: pallor, fatigue, tachycardia, jaundice [medbullets.com]

  Complimented mediated hemolysis in paroxysmal nocturnal hemoglobinuria, PNH, leads to complement mediated intravascular hemolysis giving rise to hemoglobinuria, jaundice and anemia. [youtube.com]

  Other features include weakness, abdominal and lumbar pain, jaundice with pallor and yellowish discoloration of the skin and mucous membranes, heart murmurs, splenomegaly, and hemosiderinuria. [whonamedit.com]

• Hepatomegaly

  […] with insidious onset (usually in the third or fourth decade) and chronic course, characterized by episodes of hemolytic anemia, hemoglobinuria (chiefly at night), pallor, icterus or bronzing of the skin, a moderate degree of splenomegaly, and sometimes hepatomegaly [medical-dictionary.thefreedictionary.com]

  Pathological findings include systemic venous or portal thrombosis, normoblastic bone marrow hyperplasia, hepatomegaly with necrosis, hemosiderosis, and massive iron deposits in the kidneys. [whonamedit.com]

  Depending on their localization, thromboses (which affect 30-40 % of untreated patients) may manifest as abdominal pain, hepatomegaly, ascites and headaches. [orpha.net]

  […] thrombocytopenia: mucosal bleeding, petechiae, and ecchymoses leukemia: infections thrombosis abdominal pain, fever, and rectal bleeding (mesenteric vein thrombosis) headache, vomiting, and seizures (cerebral venous sinous thrombosis) fever, jaundice, hepatomegaly [medbullets.com]

• Back Pain

  A 41-year-old woman with a Harrington spondylodesis presented with lower back pain. Bone scintigraphy showed diffusely increased parenchymal uptake in both kidneys. She reported 2 previous periods of dark, almost black, urine. [ncbi.nlm.nih.gov]

  Some of the prominent symptoms of PNH include severe anemia, a condition resulting from having too few healthy red blood cells, severe abdominal pain, severe headaches, back pain, excessive weakness, fatigue, and recurrent infections. [rapharma.com]

  Symptoms may include: ● Severe abdominal pain Severe headaches Back pain Fatigue and excessive weakness Recurring infections. [cancer.columbia.edu]

  The most frequently reported adverse events with eculizumab included headache, nasopharyngitis, back pain and nausea. [healio.com]

• Dark Urine

  Two years after disease onset, while pancytopenia remained stable, occurrence of morning dark urine led to found a paroxysmal nocturnal hemoglobinuria clone. [ncbi.nlm.nih.gov]

  Presentation Symptoms/physical exam episodic dark urine with first urine of the day caused by hemoglobin chronic intravascular hemolytic anemia: pallor, fatigue, tachycardia, jaundice, and gross hematuria acute hemolytic episodes from activators of complement [medbullets.com]

  Hemoglobinuria results in the production of classically dark urine during the night and in the morning (about 25 % of patients), and patients may present with renal insufficiency. Jaundice may be present. [orpha.net]

  In reality the condition is present all the time and not everyone experiences dark urine. [pnhleeds.co.uk]

  A 58-year-old patient presented with headache, a history of malaria, and occasionally dark urine. [scielo.conicyt.cl]

• Red Urine

  The classic sign of PNH is dark discoloration of the urine due to the presence of haemoglobin and haemosiderin from the breakdown of red blood cells. As the urine is more concentrated in the morning, this is when the color is most pronounced. [enerca.org]

  The clinical features of PNH are shown in Table 1 .[ 3, 4 ] The most common are fatigue (typically out of proportion to the degree of anemia), shortness of breath, and hemoglobinuria (red urine), especially in the first morning sample ( Figure 1 ). [bcmj.org]

  […] discoloration of the urine due to the presence of hemoglobin and hemosiderin from the breakdown of red blood cells.[10] As the urine is more concentrated in the morning, this is when the color is most pronounced. [en.wikipedia.org]

• Kidney Failure

  failure, high blood pressure in the lungs, abdominal pain, shortness of breath, blood in your urine, problems swallowing, erectile dysfunction, and fatigue.⁶ In addition to controlling anemia, re-establishing control of the complement system can help [youtube.com]

  Mehta RL, Pascual MT, Soroko S, et al: Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int 2004;66:1613-1621. Palevsky PM: Epidemiology of acute renal failure: the tip of the iceberg. [karger.com]

• Headache

  Our case is a 44-year-old woman who presented with a 2 day history of headaches, nausea, and seizures followed by a Todd`s paresis; she had been diagnosed as paroxysmal nocturnal hemoglobinuria for 4 years. [ncbi.nlm.nih.gov]

  Call your doctor or get emergency medical care right away if you get any of these signs and symptoms of a meningococcal infection: headache with nausea or vomiting, headache and fever, headache with a stiff neck or stiff back, fever, fever and a rash, [news.alexion.com]

  Some of the prominent symptoms of PNH include severe anemia, a condition resulting from having too few healthy red blood cells, severe abdominal pain, severe headaches, back pain, excessive weakness, fatigue, and recurrent infections. [rapharma.com]

  The symptoms include: fatigue weakness headaches lightheadedness pale skin shortness of breath Acute Myeloid Leukemia Less commonly, PNH can lead to acute myeloid leukemia. [healthline.com]

  Adverse Reactions The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. [soliris.net]

• Vertigo

  […] nighttime hours, as in the night release of microfilariae of the human filaria Wuchereria bancrofti into the peripheral blood; this type of periodicity is found in regions where the vector mosquito is a night-biting species. (05 Mar 2000) nocturnal vertigo [kmle.co.kr]

  […] до # С en And the only possible cure was hysterical paroxysm. en Soliris (eculizumab) is indicated for the treatment of patients with paroxysmal nocturnal haemoglobinuria (PNH bg От желание да бъда някой, който не съм en Benign paroxysmal positional vertigo [bg.glosbe.com]

• Papilledema

  The sagittal vein is commonly affected, which can give rise to papilledema and pseudotumorcerebri. [emedicine.medscape.com]

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.

• Decreased Platelet Count

  The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies.[4] If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormal white blood cell counts and decreased platelet [en.wikipedia.org]

• Normocytic Anemia

  Paroxysmal nocturnal hemoglobinuria is suspected in patients who have typical symptoms of anemia (eg, pallor, fatigue, dizziness, possible hypotension) or unexplained normocytic anemia with intravascular hemolysis, particularly if leukopenia or thrombocytopenia [merckmanuals.com]

  Flow cytometry Paroxysmal nocturnal hemoglobinuria is suspected in patients who have typical symptoms of anemia (eg, pallor, fatigue, dizziness, possible hypotension) or unexplained normocytic anemia with intravascular hemolysis, particularly if leukopenia [msdmanuals.com]

• Macrocytic Anemia

  CBC showed leukopenia (WBC 2.9 x 103 /µL) with neutropenia (segmented neutrophils 48%), macrocytic anemia (Hgb 6.1 g/dL, hematocrit 20%, MCV,113 fL) and thrombocytopenia (platelet count 59 x 109/L). [ncbi.nlm.nih.gov]

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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5. Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106(12):3699-3709.
6. Clark DA, Butler SA, Braren V, et al. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981;57(1):83-89.
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