Paroxysmal nocturnal hemoglobinuria

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Paroxysmal nocturnal hemoglobinuria is a rare, acquired, potentially life-threatening disease of the blood characterised by hemolytic anemia, thrombosis and red urine due to breakdown of red blood cells. PNH is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane.

Paroxysmal nocturnal hemoglobinuria was first described by the European physicians in the 19th century. The hypothesis of hemolysis of red blood cells due to the increased plasma acidity in the night time was described by Dr. Strübing in 1815. From 1911 to 1950, more studies were conducted in order to establish the full description of PNH.

Paroxysmal nocturnal hemoglobinuria may be classified according to the diagnosis results into three subtypes. The subtypes of PNH include classic PNH, secondary PNH, or subclinical PNH.

Paroxysmal nocturnal hemoglobinuria is believed to be caused by a genetic mutation and complement mediated hemolysis. A mutation in PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is considered the main pathogenic factor in development of PNH because PIGA gene is responsible for the GPI anchor synthesis. The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes. Other genetic mutation may also cause PNH like TET2, SUZ12, U2AF1, and JAK2. The anemia in PNH is due to complement mediated hemolysis of RBCs which are defective in the CD59//CD55 markers which are important in inactivating the complement system and protecting the RBCs. Paroxysmal nocturnal hemoglobinuria may be associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.

Common causes of paroxysmal nocturnal hemoglobinuria include a somatic mutation in the PIGA gene. Other causes include mutations in genes of TET2, SUZ12, U2AF1, and JAK2.

Paroxysmal nocturnal hemoglobinuria must be differentiated from other causes of anemia which include iron deficiency anemia, thalassemia, anemia of chronic disease, lead poisoning, and blood loss.

The incidence of paroxysmal nocturnal hemoglobinuria is approximately 0.13 per 100,000 individuals worldwide. Paroxysmal nocturnal hemoglobinuria commonly affects adults. However, some cases of PNH in the childhood have been reported.

There are no established risk factors for paroxysmal nocturnal hemoglobinuria. However, PNH is usually associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.

According to the American society of hematology, screening for paroxysmal nocturnal hemolglobinuria is recommended among patients with hemoglobinuria, cytopenia, suspected myelodysplasia, negative direct coombs test intravascular hemolytic anemia, refractory anemia, and aplastic anemia with no apparent sign of intravascular hemolysis.

If left untreated, patients with paroxysmal nocturnal hemoglobinuria may progress to develop thrombosis which is a main cause of death in PNH. Common complications include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis. Prognosis of paroxysmal nocturnal hemoglobinuria is good as long as anti-complemant therapy eculizumab is taken regularly.

Diagnosis of paroxysmal nocturnal hemoglobinuria has a minimal essential diagnostic criteria. The diagnostic test of choice is flow cytometry. The flow cytometry is used in order to reveal the GPI deficient RBCs.

Common symptoms of paroxysmal nocturnal hemoglobinuria include fatigue, dyspnea, headaches, abdominal pain, dysphagia and chest pain. Less common symptoms may include necrotic skin lesions.

Patients with paroxysmal nocturnal hemoglobinuria usually appear tired. Physical examination of patients with PNH is usually remarkable for fever, skin pallor, skin ecchymosesand skin nodules. Physical examination may show abdominal distension if PNH is associated with budd chiari syndrome.

Laboratory findings consistent with the diagnosis of paroxysmal nocturnal hemoglobinuria include low hemoglobin level, low RBCs count, and negative coombs test. Flow cytometry is the diagnostic test of choice where it shows GPI deficient RBCs.

There are no ECG findings associated with paroxysmal nocturnal hemoglobinuria.

There are no x-ray findings associated with paroxysmal nocturnal hemoglobinuria.

There are no CT scan findings associated with paroxysmal nocturnal hemoglobinuria. However, a CT scan may be helpful in the diagnosis of complications of PNH, which include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis.

There are no MRI findings associated with PNH. However, MRI may be helpful in the diagnosis of complications of PNH which include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis.

There are no other imaging findings associated with PNH.

There are no other diagnostic studies associated with PNH.

The mainstay of treatment for paroxysmal nocturnal hemoglobinuria is medical therapy. Treatment includes anticomplement therapy which includes Eculizumab which acts on reducing the hemolysis and possible complications of PNH. Other treatment regimens include hematopoietic cell transplantation and treatment of the anemia.

Surgical intervention is not recommended for the management of paroxysmal nocturnal hemoglobinuria.

There are no established measures for the primary prevention of paroxysmal nocturnal hemoglobinuria.

There are no established measures for the secondary prevention of paroxysmal nocturnal hemoglobinuria.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Paroxysmal nocturnal hemoglobinuria was first described by the European physicians in the 19th century. The hypothesis of hemolysis of red blood cells due to the increased plasma acidity in the night time was described by Dr. Strübing in 1815. From 1911 to 1950, more studies were conducted in order to establish the full description of PNH.

• In the 19th century, the European physicians conducted observational studies which resulted in the establishment of Paroxysmal Nocturnal Hemoglobinuria (PNH) as a separate disease from paroxysmal cold hemoglobinuria and march hemoglobinuria.
• In 1815, Dr. Paul Strübing, a German physician, was the first to put the hypothesis of PNH. The hypothesis mentioned the abnormal hemolysis of the red blood cells due to increased plasma acidity in the night time.^[1][2]
• Dr. Paul returned the abnormal hemolysis of the RBCs due to increased carbon dioxide gas as a result of the slow circulation nocturnally.
• In 1911, Dr. Ettore Marchiafava and Dr. Alessio Nazari added a more description about PNH.^[3]
• In 1939, Dr. Thomas Hale Ham also reported an evidence about the complement induced hemolysis in PNH. These landmark leads to development of diagnostic test named on Dr. Ham and called the acidified serum lysis test or the Ham test.^[4]
• In 1950, as a result of the discovery of PNH, Dr. Louis Pillemer described the alternative complement pathway.
• In 1951, Dr. Crosby reported a review of history of PNH. The review was built on the obsevations of Dr. Paul Strübing. Dr. Crosby described the natural history of PNH and how thrombosis may develop as a complication of the disease.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Paroxysmal nocturnal hemoglobinuria may be classified according to the diagnosis results into three subtypes. The subtypes of PNH include classic PNH, secondary PNH, or subclinical PNH.

Paroxysmal nocturnal hemoglobinuria may be classified according to diagnosis results into three subtypes:^[1][2]

• Classic PNH: Other bone marrow disorders with a confirmed diagnosis of PNH.
• Secondary PNH: When PNH is due to other bone marrow disorder as aplastic anemia or myelodysplastic syndrome.
• Subclinical PNH: No signs or symptoms of PNH, however, flow cytometry shows results of PNH.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Paroxysmal nocturnal hemoglobinuria is believed to be caused by a genetic mutation and complement mediated hemolysis. A mutation in PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is considered the main pathogenic factor in development of PNH because PIGA gene is responsible for the GPI anchor synthesis. The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes. Other genetic mutation may also cause PNH like TET2, SUZ12, U2AF1, and JAK2. The anemia in PNH is due to complement mediated hemolysis of RBCs which are defective in the CD59//CD55 markers which are important in inactivating the complement system and protecting the RBCs. Paroxysmal nocturnal hemoglobinuria may be associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.

• Normally, Red Blood Cells (RBCs), alike other cells in the body, have surface proteins that acts as a communicating signal between the cells and the environment.
• The signaling proteins are most commonly attached to the surface of the RBCs by glycolipids. The most common glycolipid is the glycosyl phosphatidylinositols (GPI).
• The attached proteins are also protective to the cells against destruction by the complement system.^[1]
• The RBCs are mainly protected by proteins called decay accelerating factor (DAF/CD55). The DAF or CD55 proteins prevent the formation of C3-convertase enzyme, the protectin (CD59), and the C9 which are components of the complement inflammatory system.^[2]

• It is understood that paroxysmal nocturnal hemoglobinuria is caused by genetic mutation and complement mediated hemolysis.

• The acquired gene mutation of PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is the main pathogenic factor in developing PNH. The PIGA gene is responible for the GPI anchor synthesis.^[3][4]
• The PIGA gene is found on the X chromosome and that concludes the affection of all males who have the mutation in one allele. However, the females will be carrier if one allele affected and a second genetic “hit” must take place to develop the disease.^[5]
• The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes.
• It is believed the mutation mechanism is caused by exposure to radiation, chemotherapy, or DNA repair defects.
• Other mutations:
  • Lack of the CD59 on the RBCs surface membrane is strongly related to the clinical signs of PNH. It is related to the intravascular hemolysis and peripheral neuropathy.

• The anemia in PNH is mainly due to complement induced hemolysis. However, other defects can cause anemia in the setting of paroxysmal nocturnal hemoglobinuria. These causes include bone marrow failure and iron deficiency.
• Different mechanisms of anemia in PNH include the following:
  • Complement mediated anemia:^[6]
    • The main cause of anemia in the patients of PNH and it can cause both intravascular and extravascular hemolysis. This type of hemolysis is non immune so, the patients with PNH will have a negative Coombs test.
    • Intravascular hemolysis: This type of hemolytic anemia in PNH is due to lack of CD59 marker as this marker is the main inhibitor of intravascular hemolysis normally.
    • Extravascular hemolysis occurs due to reduced expression of CD55 marker.
  • Aplastic anemia:^[7]
    • Aplastic anemia is defined as pancytopenia due to stem cell defect.
    • It may occur in already diagnosed PNH or before established diagnosis.

Genes involved in the pathogenesis of paroxysmal nocturnal hemoglobinuria include:^[8]

• PIGA gene
• TET2
• SUZ12
• U2AF1
• JAK2

• However, paroxysmal nocturnal hemoglobinuria is usually associated with the following diseases:^[9]
  • Aplastic anemia
  • Myelodysplastic syndrome
  • Acute myelogenous leukemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common causes of paroxysmal nocturnal hemoglobinuria include a somatic mutation in the PIGA gene. Other causes include mutations in genes of TET2, SUZ12, U2AF1, and JAK2.

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of paroxysmal nocturnal hemoglobinuria, however complications resulting from untreated disease name is common.

• Paroxysmal nocturnal hemoglobinuria is caused by a somatic mutation in the PIGA gene. The PIGA gene normally encodes phosphatidylinositol glycan class A.^[1]
• Other gene mutations associated with paroxysmal nocturnal hemoglobinuria include the following genes:^[2]
  • TET2
  • SUZ12
  • U2AF1
  • JAK2

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nazia Fuad M.D., Ahmed Elsaiey, MBBCH [2]

Paroxysmal nocturnal hemoglobinuria must be differentiated from other causes of anemia which include iron deficiency anemia, thalassemia, anemia of chronic disease, lead poisoning, and blood loss.

Paroxysmal nocturnal hemoglobinuria must be differentiated from other causes of anemia which include iron deficiency anemia, thalassemia, anemia of chronic disease, lead poisoning, and blood loss.^[1][2]

Anemia must be differentiated based on different laboratory findings including mean cell volume (MCV), reticulocytosis, and hemolysis.

To review the differential diagnosis of anemia, see below table.

To review the differential diagnosis of microcytic anemia, click here.

To review the differential diagnosis of normocytic anemia, click here.

To review the differential diagnosis of macrocytic anemia, click here.

To review the differential diagnosis of hypochromic anemia, click here.

To review the differential diagnosis of normochromic anemia, click here.

To review the differential diagnosis of anisochromic anemia, click here.

To review the differential diagnosis of hemolytic anemia, click here.

To review the differential diagnosis of anemia with intrinsic hemolysis, click here.

To review the differential diagnosis of anemia with extrinsic hemolysis, click here.

To review the differential diagnosis of anemia with low reticulocytosis, click here.

To review the differential diagnosis of anemia with normal reticulocytosis, click here.

To review the differential diagnosis of anemia with high reticulocytosis, click here.

Disease	Genetics	Clinical manifestation					Lab findings
		History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Iron studies					Specific finding on blood smear
													Serum iron	Serum Tfr level	Transferrin or TIBC	Ferritin	Transferrin saturation
Iron deficiency anemia[3]	−	Menorrhagia GI loss GI surgery Pregnancy	Koilonychia Pica	Glossitis Cheilosis Dysphagia	−	−	Hypochromic	Microcytic	↑	Nl or ↓	Nl	Nl	↓	↑	↑	↓	↓↓↓	Central pallor
Iron deficiency anemia (early phase)[4]	−	Pica Glossitis Cheilosis	Fatigue Headache	Koilonychia Conjunctival pallor Dry skin	−	−	Normochromic	Normocytic	↑	↓	Nl	Nl	↓	↑	↑	↓	↓	Pencil cells Elliptocytosis Hypochromasia
Lead poisoning[5]	−	House painted with chipped paint	Burtonian lines Basophilic stippling Wrist drop Foot drop	Wrist drop Foot drop Burtonian lines	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	Nl	Nl to ↓	Nl	Nl	Nl to ↓	−	RBCs retain aggregates of rRNA Basophilic stippling
Sideroblastic anemia[6]	Defect in ALA synthase gene Autosomal dominant Autosomal recessive X-linked	Alcohol abuse Isoniazid use Chloramphenicol use Idiopathic	Seborrheic dermatitis Glossy Tongue Tingling	Patient present with symptoms of Vitamin B6, copper deficiency symptoms	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	Nl	↑	Nl	Nl to ↓	↑	−	Ringed sideroblasts
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Anemia of chronic disease[7]	−	Rheumatoid arthritis SLE Neoplasm Chronic kidney disease	Headache Shortness of breath	−	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	↑	↓	Nl	↓	↑	−	NA
Thalassemia[8]	α-thalassemia α– globin gene deletions Cis deletions Trans deletions β-thalassemia Point mutation in splice sites and promoter sequences	Associated with parvovirus B19	α-thalassemia Hydrops fetalis β-thalassemia Skeletal deformities Chipmunk facies	Hepatomegaly Splenomegaly	−	−	Hypochromic	Microcytic	Nl	Thalassemia trait: Nl or ↓ Thalassemia Syndromes: ↑	Nl	Nl	Nl to ↑	Nl	Nl	↑	Nl to ↑	Target cells Anisopoikilocytosis
G6pd deficiency[9]	Defect in G6PD enzyme X-Linked recessive	History of using Sulfa drugs Antimalarials Fava Beans Infections	Back pain Hemoglobinuria	Back pain	+	Intrinsic	Normochromic	Normocytic	↑	↑ but usually causes resolution within 4-7 days	↓	↓	Nl to ↑	Nl	↑	↑	↑	RBC with Heinz bodies Bite cells Blister cells
Pyruvate kinase deficiency[10]	Mutation in the PKLR and PKM gene Autosomal recessive	Gallstones	Hydrops fetalis Neonatal hyperbilirubinemia Iron overload Perinatal complications	Skin ulcers Splenomegaly	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↑	Nl	Nl	↑	−	Prickle cells Polychromatophilic erythrocytes
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Sickle cell anemia[11]	Hbs point mutation causes a single amino acid replacement in β chain	High altitude Low Oxygen Acidosis African-American race Parvovirus B19 infection	Painful crisis Dactylitis Priapism Acute chest syndrome Avascular Necrosis Stroke Autosplenectomy Salmonella osteomyelitis	Dactylitis Priapism	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl or moderately ↑	Nl	Nl	Nl or moderately ↑	↓	Nl	Increased erythropoiesis Howell-Jolly bodies Anisocytosis
HbC disease[12]	Glutamic acid–to-lysine mutation in β-globin	Gallstone	Joint pains Increased risk of infections	Splenomegaly Cholelithiasis Avascular necrosis of the femoral head	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	Nl	Nl	Nl	↓	−	Hemoglobin crystals inside RBCs Target cells
Paroxysmal nocturnal hemoglobinuria[13][14]	PIGA gene mutations Impaired synthesis of GPI anchor for decay-accelerating factor	Associated with aplastic anemia Thrombosis	Fatigue Chest pain Dyspnea on exertion Headache	Chronic hemolysis Hepatomegaly Ascites Papilledema Skin nodules	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	↑	↓	−	NA
Hereditary spherocytosis[15]	Mutations in Ankyrin, Band 3, Protein 4.2, and spectrin	Associated with parvovirus B19 Cholelithiasis Megaloblastic crisis	Aplastic crisis	Splenomegaly	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	↑	Nl	−	Small, round RBCs with less surface area and no central pallor
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Microangiopathic hemolytic anemia[16][17]	−	Associated with DIC TTP HUS SLE HELLP syndrome Hypertensive emergency	Purpura Confusion Aphasia Diplopia	Numbness of an arm or hand Jaundice Pale conjunctiva	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	↑	−	Helmet cells
Macroangiopathic hemolytic anemia[18]	Autoimmune	Associated with Prosthetic heart valves Aortic stenosis	Pallor Fatigue	Signs of anemia Complications of hemolysis Decreased vascular volume	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	−	−	Spherocytes or schistocytes
Autoimmune hemolytic anemia[19]	−	Associated with: SLE CLL Mycoplasma pneumonia	Painful blue fingers and toes on exposure to cold temperature Chest pain Chills Dizziness Tachycardia Headache Fatigue	Painful, blue fingers and toes with cold weather	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	−	−	RBC agglutination
Aplastic anemia[20]	Constitutive expression of Tbet Mutations in the perforin gene Mutations in SAP gene	Exposure to Radiation Drugs like Benzene, chloramphenicol, alkylating agents Viral infections like EBV, HIV, Hepatitis Fanconi anemia Idiopathic like Immune mediated, primary stem cell defect	Symptoms based on underlying condition	Short stature Cafe-au-lait spots Thumb defects Radial defects	−	−	Normochromic	Normocytic	↑	↓	Nl	Nl	↓	↓	Nl	↑	↓	Pancytopenia Fatty infiltration
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Folate deficiency[21]	Impaired DNA synthesis	Alcohol consumption History of using drugs like methotrexate, trimethoprim, and phenytoin Low socioeconomic groups with poor nutrition Older people Pregnant and lactating women	No neurological symptoms vs B12 deficiency Odynophagia Angular stomatitis	Glossitis Signs of heart failure Anencephaly and spina bifida	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	RBC macrocytosis Hypersegmented neutrophils Pancytopenia in severe cases
Vitamin B12 deficiency[22]	Impaired DNA synthesis	Pernicious anemia Crohn’s disease Gastrectomy Veganism Diphyllobothrium latum infection	Psychosis Insomnia Depression Cognitive slowing Restless leg syndrome	Neurological deficit Myelopathy Memory loss with reduced attention span Nystagmus Positive romberg sign Positive Lhermitte’s sign	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Senile neutrophil Anisocytosis Ovalocytes
Orotic aciduria[23]	Autosomal recessive Deficiency of enzyme UMPS	Episodic vomiting Rhabdomyolysis	Coma Gastrointestinal manifestation	Neurological manifestation	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Fanconi anemia[24]	Autosomal recessive X-linked recessive	History of anemia at age 16	Hypopigmentation Cafe-au-lait patches Radial ray anomaly	Significant for bilateral short thumbs	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Nl appearing WBC, RBC and Platelets But the number is greatly reduced
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Diamond-Blackfan anemia[25]	Mutations in: RPL5 RPL11 RPL35A RPS7 RPS10 RPS17 RPS19 RPS24 RPS26	Associated with myelodysplastic syndrome Increased risk of AML	Pale skin Sleepiness Heart murmurs	Triphalangeal thumbs Short stature Microcephaly Hypertelorism Ptosis Micrognathia	−	−	Anisochromic	Macrocytic	Nl	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Infections[26]	−	Associated with Malaria Babesia	Fever	Fever Signs of shock Headache	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	Nl	Nl	−	−	−	Trophozoite Maltese crosses
Chronic kidney disease[27]	−	Pericarditis Encephalopathy Rectal incontinence Decreased libido Restless leg syndrome	Polyuria Hematuria Edema	Hypertension	−	−	Normochromic	Normocytic	↑	Nl/↑	Nl	↑	↓	−	↓	↑	↓	Nl
Liver disease[28]	−	Hepatitis Binge drinking Gall bladder disease	Jaundice Abdominal pain Itchy skin	Ascites Right upper quadrant pain Hepatomegaly Swelling in the legs Ankle swelling	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Round macrocytes Target macrocytes
Alcoholism[29]	−	History of increased alcohol intake Folic acid deficiency	Memory impairment Nausea Sweating	Truncal obesity Asterixis Encephalopathy Spider angiomas Hematemesis Gynecomastia	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Oval macrocytes Hypersegmented neutrophils
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

The incidence of paroxysmal nocturnal hemoglobinuria is approximately 0.13 per 100,000 individuals worldwide. Paroxysmal nocturnal hemoglobinuria commonly affects adults. However, some cases of PNH in the childhood have been reported.

• The incidence of paroxysmal nocturnal hemoglobinuria is approximately 0.13 per 100,000 individuals worldwide.^[1]

• Paroxysmal nocturnal hemoglobinuria commonly affects adults. However, some cases of PNH in the childhood have been reported.^[2]

• There is no racial predilection to [disease name].

• Paroxysmal nocturnal hemoglobinuria affects men and women equally.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

There are no established risk factors for paroxysmal nocturnal hemoglobinuria. However, PNH is usually associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.

• Common risk factors of paroxysmal nocturnal hemoglobinuria are not establised.
• However, paroxysmal nocturnal hemoglobinuria is usually associated with the following diseases:^[1]
  • Aplastic anemia
  • Myelodysplastic syndrome
  • Acute myelogenous leukemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

According to the American society of hematology, screening for paroxysmal nocturnal hemolglobinuria is recommended among patients with hemoglobinuria, cytopenia, suspected myelodysplasia, negative direct coombs test intravascular hemolytic anemia, refractory anemia, and aplastic anemia with no apparent sign of intravascular hemolysis.

• According to the American society of hematology, screening for paroxysmal nocturnal hemolglobinuria is recommended among patients with:^[1]
  • Hemoglobinuria
  • Cytopenia
  • Suspected Myelodysplasia
  • Negative direct coombs test intravascular hemolytic anemia
  • Refractory anemia
  • Aplastic anemia with no apparent sign of intravascular hemolysis
  • Unexplained thrombosis especially in unusual sites as:
    • Budd-Chiari syndrome
    • Other intra-abdominal sites (eg, mesenteric or portal veins)
    • Cerebral veins
    • Dermal veins

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

If left untreated, patients with paroxysmal nocturnal hemoglobinuria may progress to develop thrombosis which is a main cause of death in PNH. Common complications include intracranial thrombosis, splenic vein thrombosis, and portal vein thrombosis. Prognosis of paroxysmal nocturnal hemoglobinuria is good as long as anti-complemant therapy eculizumab is taken regularly.

• If left untreated, patients with paroxysmal nocturnal hemoglobinuria may progress to develop thrombosis which is a main cause of death in PNH.
• PNH is associated with high morbidity and mortality rate if appropriate treatment is not administrated regularly.

• Common complications of paroxysmal nocturnal hemoglobinuria include:
  • Intracranial thrombosis
  • Splenic vein thrombosis
  • Portal vein thrombosis

• Prognosis of paroxysmal nocturnal hemoglobinuria is good as long as anti-complemant therapy eculizumab is taken regularly.
• Eculizumab has shown decrease in the risk of thrombosis which is a main cause of death in patients with PNH.

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