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Paroxysmal Nocturnal Hemoglobinuria

PNH

Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially debilitating nonmalignant blood disorder resulting from a somatic mutation and the subsequent destruction of blood cells by the complement system. Clinical manifestations are variable and range from mild to severe.

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Presentation

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. 

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[huronregional.org]
  • bruising Coughing up blood Impotence Seizures Blood clots PNH is not inherited.[medicinenet.com]
Splenomegaly
  • PNH is associated with abdominal vein thrombosis, which can cause splenomegaly and hypersplenism.[ncbi.nlm.nih.gov]
  • 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]
  • […] 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]
  • There may be splenomegaly too. 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]
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]
Dyspnea
  • In particular, significant improvement of EORTC QLQ-C30 was observed in fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QOL and laboratory values.[ncbi.nlm.nih.gov]
  • 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]
  • 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).[symptoma.com]
  • 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[healio.com]
Cough
  • He presented with cough, fever, and pancytopenia.[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]
  • 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]
  • […] happens: Skin : Red, painful, or swollen area Arm or leg: Sore, warm, and swollen limb Stomach : Pain Ulcers and bleeding Brain : Bad headache with or without vomiting Seizures Trouble moving, talking, or seeing Lungs : Trouble breathing Sharp chest pain Coughing[webmd.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]
  • Anemia work-up revealed a misunderstood association of a hemolytic anemia with a negative direct antiglobulin test and iron deficiency.[ncbi.nlm.nih.gov]
  • Positive rates were: PNH (86.0%), minor-PNH (33.3%), others (5.0%), anemia (13.4%), malignancy (5.3%), infection (3.7%), normal (0.0%); within anemia group, aplastic anemia (40.0%), immune hemolytic anemia (11.1%), iron deficiency anemia (1.6%).[ncbi.nlm.nih.gov]
  • Herein, we review the interaction between the C' and the redox systems in C'-mediated hemolytic anemias, paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia, including acute hemolytic transfusion reaction.[ncbi.nlm.nih.gov]
  • PNH concomitant with inherited hemolytic anemia has been rarely reported. Here, we report an interesting PNH patient who was misdiagnosed with iron deficiency anemia due to concomitant heterozygous β-thalassemia.[ncbi.nlm.nih.gov]
Fatigue
  • 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]
  • Furthermore, the patient showed significant improvements in fatigue scale scores and quality of life.[ncbi.nlm.nih.gov]
  • Pallor, fatigue and stress dyspnea with activity are the usual manifestations.[orpha.net]
  • The patient experienced dizziness, fatigue, and restricted physical activity for the previous 3 years. Thalassemia gene analysis revealed heterozygous β-thalassemia.[ncbi.nlm.nih.gov]
  • In particular, significant improvement of EORTC QLQ-C30 was observed in fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QOL and laboratory values.[ncbi.nlm.nih.gov]
Fever
  • Thromboses, as observed in our case, may be associated with fever and marked inflammation.[ncbi.nlm.nih.gov]
  • He presented with cough, fever, and pancytopenia.[ncbi.nlm.nih.gov]
  • Post-procedure pain and fever were common and manageable; only one patient developed a loculated pleural effusion requiring drainage.[ncbi.nlm.nih.gov]
  • Furthermore, during treatment with eculizumab, intravascular hemolysis occurred due to a viral infection accompanied by a high fever.[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]
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]
  • 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]
  • 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]
  • CD59 Type III – absent levels of CD59 Genetics X-linked inheritance for PIGA Single variant is sufficient to produce PNH phenotype Clinical Presentation Chronic hemolysis and hemoglobinuria Jaundice Dark urine (due to hemoglobinuria) Anemia – fatigue, pallor[arupconsult.com]
Refractory Anemia
  • The presence of a subclinical PNH population in myelodysplastic bone marrow disorders, such as aplastic anemia or refractory anemia, may correlate with a positive immunotherapeutic response ( Blood 2006; 107, 1308-1314).[ltd.aruplab.com]
  • PNH can present as any of the following three syndromes or sets of symptoms: Classic PNH PNH in the setting of another specified bone marrow disorder (eg, PNH/aplastic anemia or PNH/refractory anemia- myelodysplastic syndrome [MDS] ) Subclinical PNH ([emedicine.medscape.com]
  • The second high-risk group consists of patients with bone marrow failure syndromes, including aplastic anemia, myelodysplastic syndrome (MDS; typically the refractory anemia subtype), and unexplained cytopenias.[hematologyandoncology.net]
Abdominal Pain
  • Six PNH patients with (AP) and six without (NOP) abdominal pain underwent MRI.[ncbi.nlm.nih.gov]
  • The clinical manifestation included fatigue (87.1%), hemogolobinuria (44.3%), infection (22.9%), bleeding (37.1%), and abdominal pain (2.9%). FHb (free hemoglobin) in 56 patients (80%) was 50 mg/L.[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]
  • 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]
  • Three of 4 patients had an improvement in their platelet count, and 3 of 3 had major improvement in abdominal pain/discomfort. The one patient whose platelet count did not respond had developed marrow failure, and she did well with an allo-SCT.[ncbi.nlm.nih.gov]
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]
  • 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]
  • Fortunately, even the minority of patients who, in terms of hemoglobin level, have only a limited response to eculizumab usually have improvement in symptoms such as abdominal pain and dysphagia, and the risk of thrombosis is probably decreased considerably[nejm.org]
  • […] associated with overlap syndromes Worsening hemolysis with infection Malignancy risk for acute myeloid leukemia (AML), myelodysplastic syndromes Other signs and symptoms – abdominal pain, iron deficiency anemia, smooth muscle dysfunction, male impotence, dysphagia[arupconsult.com]
  • 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.[symptoma.com]
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
  • PNH treatment should be proposed as soon as possible to avoid recurrent thrombosis.[ncbi.nlm.nih.gov]
  • Thrombosis can occur at any site, but coronary thrombosis is extremely rare.[ncbi.nlm.nih.gov]
  • Cerebral venous sinus thrombosis caused by paroxysmal nocturnal hemoglobinuria is uncommon.[ncbi.nlm.nih.gov]
  • Whereas venous and arterial thrombosis is a very common symptom of the disease, the frequency of PNH clones in patients with unexplained venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has not been studied.[ncbi.nlm.nih.gov]
  • Anticoagulation is only partially effective in preventing thrombosis in PNH; thus, thrombosis is an absolute indication for initiating treatment with Eculizumab.[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]
  • 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]
  • 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).[symptoma.com]
  • 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]
  • Signs and symptoms of 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[medicinenet.com]
Palpitations
  • The remainder mainly experience the symptoms of anemia, such as tiredness, shortness of breath , and palpitations . [4] A small proportion of patients report attacks of abdominal pain , difficulty swallowing and pain during swallowing , as well as erectile[en.wikipedia.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]
  • The authors report a 57-year-old male patient who presented with diarrhea, darkened urine, jaundice and increased blood urea nitrogen and creatinine.[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]
  • Jaundice may be present. Depending on their localization, thromboses (which affect 30-40 % of untreated patients) may manifest as abdominal pain, hepatomegaly, ascites and headaches.[orpha.net]
  • Symptoms of paroxysmal nocturnal hemoglobinuria are variable: Hemolytic anemia – dark cola colored urine, yellow skin color (jaundice) Aplastic anemia – fatigue, lack of energy, or light-headedness when standing up or with exertion, increased infections[childrensmn.org]
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]
  • 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]
  • The Budd-Chiari syndrome will produce hepatomegaly and ascites. There may be splenomegaly too. Ischaemia of the gut produces absent bowel sounds. Cerebral vein thrombosis can produce papilloedema and other neurological signs.[patient.info]
  • : 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]]) Abdominal Pain Ascites Acute Hepatomegaly[mdnxs.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]
  • 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]
  • 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]
  • History The classic manifestation of paroxysmal nocturnal hemoglobinuria (PNH) is dark urine during the night with partial clearing during the day (see image below).[emedicine.medscape.com]
  • 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]
Kidney Failure
  • 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.[symptoma.com]
  • Possible Complications Complications may include: Kidney failure Low platelet count (thrombocytopenia) Low red blood cell count (caused by the premature breakdown of red blood cells) Nervous system problems Severe bleeding (hemorrhage) Stroke When to[mclaren.org]
  • The social and economic implications of CKD are substantial not only due to morbidity and mortality associated with the progression to kidney failure, but also because of its association with accelerated cardiovascular disease [ 35 ].[karger.com]
Red Urine
  • 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]
  • Only a minority of affected people (26%) have the telltale red urine in the morning that originally gave the condition its name. [4] Allogeneic bone marrow transplantation is the only cure, but has significant rates of additional medical problems and[en.wikipedia.org]
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]
  • Depending on their localization, thromboses (which affect 30-40 % of untreated patients) may manifest as abdominal pain, hepatomegaly, ascites and headaches.[orpha.net]
  • 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]
  • 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]
  • 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]
Papilledema
  • The sagittal vein is commonly affected, which can give rise to papilledema and pseudotumorcerebri.[emedicine.medscape.com]

Workup

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.

Haptoglobin Decreased
  • : 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[symptoma.com]
Decreased Platelet Count
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

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

  1. Hemolytic anemiaEculizumab, 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.

Prognosis

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.

Etiology

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.

Epidemiology

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. 

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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

Summary

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].

Patient Information

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.

References

Article

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Last updated: 2018-06-21 17:35