Highlights & Basics
- Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia characterized by evidence of intravascular hemolysis such as hemoglobinuria and elevation of plasma lactate dehydrogenase.
- Diagnosis can be made by flow cytometry of granulocytes and red blood cells, looking for the lack of the glycosylphosphatidylinositol anchor or of proteins dependent on it for attachment to the cell membrane.
- Complicated by thrombosis, particularly of hepatic and other intra-abdominal veins, cerebral veins, and other usual and unusual venous sites.
- Treatment includes monoclonal antibodies which inhibit complement protein C5, and pegcetacoplan for patients who may not respond well to C5 complement blockade.
- May arise in patients with or recovering from aplastic anemia. It may also manifest with cytopenias that are the result of marrow hypoproduction.
Quick Reference
History & Exam
Key Factors
hemoglobinuria
Budd-Chiari syndrome
thrombosis
Other Factors
history of aplastic anemia
fatigue
anemia
abdominal pain
dysphagia and odynophagia
erectile dysfunction
dyspnea
infections
bleeding diathesis
neurologic signs and symptoms
Diagnostics Tests
1st Tests to Order
urine dipstick
urine microscopy
CBC
reticulocyte count
serum LDH
unconjugated bilirubin
D-dimer
Other Tests to consider
haptoglobin
flow cytometry for glycosylphosphatidylinositol anchor or anchored proteins
fluorescent aerolysin
immunotyping
antiglobulin (Coombs) test
serum iron, serum ferritin
serum creatinine and BUN
Treatment Options
acute
classic PNH (hemolytic anemia): nonpregnant
classic PNH (hemolytic anemia): nonpregnant
with Hb <8.5 g/dL
with underlying aplastic anemia and/or kidney damage
with iron deficiency
with thrombosis
Definition
Classifications
Proposed classification
- Classic hemolytic PNH: clone size large enough to result in clinical evidence of hemolysis with no evidence of another bone marrow disorder
- PNH in the setting of another specific bone marrow disorder, such as aplastic anemia-PNH (evidence of PNH in the setting of aplastic anemia) and low-risk myelodysplastic syndrome-PNH (evidence of PNH in the setting of myelodysplasia)
- Subclinical PNH: clone size too small to result in evidence of hemolysis
Vignette
Common Vignette 1
Common Vignette 2
Other Presentations
Epidemiology
Etiology
Pathophysiology
Diagnostic Approach
Clinical presentation
- Signs of anemia (pallor, tachycardia, and systolic heart murmur)
- Signs of thrombosis (most commonly deep vein thrombosis, although cerebral or arterial thrombosis may be present)
- Signs of Budd-Chiari syndrome (right upper quadrant tenderness, liver enlargement, and ascites); see Budd-Chiari syndrome
- Signs of elevated intracranial pressure (headache/vomiting, papilledema, coma in severe cases), and/or frank sensorimotor deficits according to the affected site, which may be present and are related to cerebrovascular thrombotic events.[20]
Indications for testing
- Hemoglobinuria or hemosiderinuria
- Unexplained Coombs-negative hemolytic anemia
- Aplastic or hypoplastic anemia (current or in the past)
- Myelodysplasia with evidence of hemolysis (hemoglobinuria or elevated serum lactate dehydrogenase [LDH])
- Thrombosis, especially in unusual sites (e.g., intra-abdominal) with evidence of hemolysis, or in young patients when thromboses are unexplained[21]
- Unexplained iron deficiency
- Dystonic symptoms (esophageal spasm, abdominal pain, erectile dysfunction) with signs of hemolysis
- Renal dysfunction with signs of hemolysis
- Thrombocytopenia and/or granulocytopenia with signs of intravascular hemolysis.[2]
Investigations
Risk Factors
History & Exam
Tests
Differential Diagnosis
Autoimmune hemolytic anemia, warm antibody type
Differentiating Signs/Symptoms
- Splenomegaly is often present.
Differentiating Tests
- The direct antiglobulin (Coombs) test is usually positive.
- Spherocytes may be present on blood film.
Microangiopathic hemolytic anemia
Differentiating Signs/Symptoms
- A reason for microangiopathy (cancer, hypertension, hemangioma, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura) is usually present.
Differentiating Tests
- Blood film shows schistocytes.
- Cells lacking GPI-anchored proteins are not present.
Differentiating Signs/Symptoms
- Hemoglobinuria follows exposure to cold. In children, often occurs 2 weeks after a viral infection or immunization.
Differentiating Tests
- Donath-Landsteiner (bithermic hemolysis) test may be positive.
- Direct Coombs test may be positive with anti-C3d.
- Cells lacking GPI-anchored proteins are not present.
Myoglobinuria
Differentiating Signs/Symptoms
- Evidence of muscle breakdown (pain, history of trauma, relevant drug history, etc.) present.
Differentiating Tests
- Urinary pigment is myoglobin.
- Serum creatine kinase is increased, as is serum alanine aminotransferase and aspartate aminotransferase.
- Cells lacking GPI-anchored proteins are not present.
Differentiating Signs/Symptoms
- From asymptomatic to bouts of abdominal pain, diminished bowel sounds, ascites/varices, bowel perforation, or renal failure. Signs and symptoms depend on the thrombosed vessel.
Differentiating Tests
- Cells lacking GPI-anchored proteins are not present.
- Testing for other sources of thrombosis may be positive
Criteria
Treatment Approach
Hemolytic anemia
Underlying aplastic anemia and/or kidney damage
Iron deficiency anemia
Symptomatic anemia
Thrombosis
Marrow hypofunction
Treatment Options
classic PNH (hemolytic anemia): nonpregnant
hemolysis control
Primary Options
- eculizumab
600 mg intravenously once weekly for 4 weeks, then 900 mg once weekly for 1 week, followed by 900 mg every 2 weeks thereafter
- eculizumab
- ravulizumab
dose depends on patient's body weight; consult specialist for guidance on dose
- ravulizumab
Secondary Options
Comments
- Eculizumab and ravulizumab specifically inhibit intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). They improve anemia in most patients, abolish symptoms due to nitric oxide deprivation, and rapidly relieve fatigue.[25] [26] Eculizumab is given as long as the patient has hemolysis (usually lifelong). The cost of the drug is high, so clear indications for its use (hemolysis, moderate-to-severe anemia, symptoms from dystonias, evidence of renal impairment, thrombosis) should be present.
- Although eculizumab is known for its established efficacy and safety, the dosing regimen may pose a treatment burden and impact patient adherence. Additionally, around 25% of patients may experience breakthrough hemolysis, increasing the risk of thrombotic events and other potentially life-threatening complications related to intravascular hemolysis. Ravulizumab is an alternative treatment option addressing these challenges. Ravulizumab achieves immediate, complete, and sustained inhibition of complement-mediated hemolysis with a longer dosing interval.
- There is a low risk of meningococcal infection with both eculizumab and ravulizumab; all patients must be immunized at least 2 weeks before beginning treatment, according to current immunization recommendations. Immunization should be updated as long as the patient is receiving therapy. Antibacterial prophylaxis may be given in situations where treatment must start within 2 weeks of vaccination. Eculizumab and ravulizumab are only available via restricted distribution programs due to the meningococcal infection risk.
- Pegcetacoplan is an option for patients who may not respond well to C5 complement blockade. It targets complement C3 to control both intravascular and extravascular hemolysis. In the PEGASUS trial, pegcetacoplan demonstrated superiority over eculizumab in improving hemoglobin levels and clinical and hematologic outcomes by providing comprehensive hemolysis control.[32] However, there were reports of breakthrough hemolysis in some patients.
- There is a risk of serious infections with pegcetacoplan. All patients must be immunized against encapsulated bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) at least 2 weeks before beginning treatment, according to current immunization recommendations. Immunization should be updated as long as the patient is receiving therapy. Antibacterial prophylaxis may be given in situations where treatment must start within 2 weeks of vaccination. Pegcetacoplan is only available via restricted distribution programs due to the risk of serious infections.
with Hb <8.5 g/dL
RBC transfusion
Comments
- Patients may require transfusion with red blood cells if Hb falls to a level that is symptomatic (fatigue, shortness of breath, symptoms of heart failure), usually to <8.5 g/dL. This is occasionally accompanied by a bout of hemoglobinuria due to destruction of the abnormal PNH cells. This can be prevented by removing white blood cells from the transfused unit through washing or appropriate filtering. Washing will also remove any residual complement from the cells.[42] Iron overload is not a problem in PNH patients, as chronic losses in urine result in iron deficiency even in heavily transfused patients.
with underlying aplastic anemia and/or kidney damage
erythropoiesis-stimulating agents
Primary Options
- epoetin alfa
40,000 units subcutaneously once weekly initially, increase according to response, maximum 60,000 units/week
- epoetin alfa
- darbepoetin alfa
200 micrograms subcutaneously every 2 weeks, increase according to response, maximum 300 micrograms every 2 weeks
- darbepoetin alfa
Comments
- If Hb has not increased by at least 1 g/dL after 4 weeks at initial dose of epoetin alfa, dose may be increased if iron status is satisfactory.
with iron deficiency
oral or parenteral iron replacement
Primary Options
Secondary Options
- iron dextran
consult specialist for guidance on dose
- iron dextran
- sodium ferric gluconate complex
125 mg intravenously once weekly for 8 weeks, maximum 1000 mg cumulative dose
- sodium ferric gluconate complex
- iron sucrose
consult specialist for guidance on dose
- iron sucrose
- ferric carboxymaltose
consult specialist for guidance on dose
- ferric carboxymaltose
Comments
- Patients with PNH lose up to 20 times as much iron per day as healthy people and may require supplementation with oral or parenteral iron. It is important to note that iron repletion may be followed by a brief episode of hemoglobinuria.[41]
- Oral iron supplementation is an easy way to replace iron and is usually given in its elemental form. If patients cannot tolerate this or have such rapid iron loss that oral iron cannot keep up with the losses, iron can be given parenterally. Parenteral iron is generally safe, although severe cases of anaphylaxis have been reported.
- Treatment is continued so long as iron stores, monitored by serum ferritin, are adequate and not excessive or hemolysis has been blocked by complement inhibitors.
with thrombosis
thrombolysis
Primary Options
- alteplase
100 mg intravenously given over 2 hours
- alteplase
- reteplase
10 units intravenously initially, followed by 10 units 30 minutes later
- reteplase
Comments
- Thrombolytic agents may be used in acute stage of thrombosis, unless platelet count is <50,000/microliter or thrombosis is intracranial.[43]
- For cerebral thrombosis, antiedema therapy (usually dexamethasone or mannitol) and anticoagulation are used, but evidence is limited.
- This should be followed by full anticoagulation with warfarin or heparin (preferably low-molecular-weight heparin).
classic PNH (hemolytic anemia): pregnant
hemolysis control
Primary Options
- eculizumab
600 mg intravenously once weekly for 4 weeks, then 900 mg once weekly for 1 week, followed by 900 mg every 2 weeks thereafter
- eculizumab
Comments
- Eculizumab specifically inhibits intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). It improves anemia in most patients, abolishes symptoms due to nitric oxide deprivation, and rapidly relieves fatigue.[25] [26] Eculizumab is given as long as the patient has hemolysis (usually lifelong). The cost of the drug is high, so that clear indications for its use (hemolysis, moderate to severe anemia, symptoms from dystonias, evidence of renal impairment, thrombosis) should be present. There are no clinical trials evaluating the use of eculizumab in pregnancy.[25] [26] However, several recent reports describe successful outcomes for both mother and child.[33] [34] An analysis of 79 pregnancies involving 61 women receiving eculizumab during pregnancy demonstrated improved outcomes for the mother and fetus. All children achieved age-appropriate milestones. A higher dose of eculizumab was needed in the second and third trimester. Anticoagulation should be given during the pregnancy and continued for at least 3 months postpartum.[36] There is a lack of data on the use of ravulizumab and pegcetacoplan in pregnancy.
- There is a low risk of meningococcal infection with eculizumab; all patients must be immunized at least 2 weeks before beginning the treatment, according to current immunization recommendations. Antibacterial prophylaxis may be given in situations where treatment must start within 2 weeks of vaccination. Eculizumab is only available via restricted distribution programs due to the meningococcal infection risk.
without thrombosis
thromboprophylaxis
Primary Options
- enoxaparin
see local specialist protocol for dosing guidelines
- enoxaparin
- dalteparin
see local specialist protocol for dosing guidelines
- dalteparin
Secondary Options
- heparin
see local specialist protocol for dosing guidelines
- heparin
Comments
- LMWHs are considered optimal, having less risk than unfractionated heparin of heparin-induced thrombocytopenia.
- Warfarin is contraindicated in pregnancy due to its teratogenic effect.[48]
with thrombosis
thrombolysis
Comments
- There are no data to support thrombolytic therapy in pregnant women with PNH. Generally, systemic thrombolysis is considered risky in pregnant women, even though scant reports have shown encouraging outcomes with manageable complications in cases of life-threatening thrombosis.[46] Seek specialist guidance for management.
with Hb <8.5 g/dL
RBC transfusion
Comments
- Patients may require transfusion with red blood cells if Hb falls to a level that is symptomatic (fatigue, shortness of breath, symptoms of heart failure), usually to <8.5 g/dL. This is occasionally accompanied by a bout of hemoglobinuria due to destruction of the abnormal PNH cells. This can be prevented by removing white blood cells from the transfused unit through washing or appropriate filtering. Washing will also remove any residual complement from the cells.[42] Iron overload is not a problem in PNH patients, as chronic losses in urine result in iron deficiency even in heavily transfused patients.
with underlying aplastic anemia and/or kidney damage
erythropoiesis-stimulating agents
Primary Options
- epoetin alfa
40,000 units subcutaneously once weekly initially, increase according to response, maximum 60,000 units/week
- epoetin alfa
- darbepoetin alfa
200 micrograms subcutaneously every 2 weeks, increase according to response, maximum 300 micrograms every 2 weeks
- darbepoetin alfa
Comments
- Although endogenous erythropoietin (EPO) levels are usually high in PNH, supplemental injections of recombinant EPO have been found useful in some patients.[37] [38] EPO is generally considered to be safe in pregnancy, but there are no conclusive data of its use in pregnant PNH patients. The potential benefit must be weighed against the risk of thrombosis related to EPO use.
- If Hb has not increased by at least 1 g/dL after 4 weeks at initial dose of epoetin alfa, dose may be increased if iron status is satisfactory.
with iron deficiency
oral or parenteral iron replacement
Primary Options
Secondary Options
- iron dextran
consult specialist for guidance on dose
- iron dextran
- sodium ferric gluconate complex
125 mg intravenously once weekly for 8 weeks, maximum 1000 mg cumulative dose
- sodium ferric gluconate complex
- iron sucrose
consult specialist for guidance on dose
- iron sucrose
- ferric carboxymaltose
consult specialist for guidance on dose
- ferric carboxymaltose
Comments
- Patients with PNH lose up to 20 times as much iron per day as healthy people and may require supplementation with oral or parenteral iron. It is important to note that iron repletion may be followed by a brief episode of hemoglobinuria.[41]
- Oral iron supplementation is an easy way to replace iron and is usually given in its elemental form. If patients cannot tolerate this or have such rapid iron loss that oral iron cannot keep up with the losses, iron can be given parenterally. Parenteral iron is generally safe, although severe cases of anaphylaxis have been reported.
- Treatment is continued so long as iron stores, monitored by serum ferritin, are adequate and not excessive or hemolysis has been blocked by complement inhibitors.
PNH in the setting of another specific bone marrow disorder: nonpregnant
treatment of underlying disorder
Comments
- Marrow hypofunction in paroxysmal nocturnal hemoglobinuria (PNH) may be treated as in aplastic anemia with immunosuppressants.[49]
- If immunosuppressants are ineffective, hematopoietic stem cell transplantation may be considered, particularly if a suitably matched related donor is available.[50] [51] [52] These measures become necessary if the platelet count and/or particularly the granulocyte count become too low (e.g., absolute neutrophil count <500/microliter).
- Stem cell transplantation cures marrow hypofunction in PNH. When it is successful all manifestations of the disease are eliminated. However, it carries the usual risk of death and chronic morbidity from chronic graft-versus-host disease.
- See Aplastic anemia .
with Hb <8.5 g/dL
RBC transfusion
Comments
- Patients may require transfusion with red blood cells if Hb falls to a level that is symptomatic (fatigue, shortness of breath, symptoms of heart failure), usually to <8.5 g/dL. This is occasionally accompanied by a bout of hemoglobinuria due to destruction of the abnormal PNH cells. This can be prevented by removing white blood cells from the transfused unit through washing or appropriate filtering. Washing will also remove any residual complement from the cells.[42] Iron overload is not a problem in PNH patients, as chronic losses in urine result in iron deficiency even in heavily transfused patients.
with underlying aplastic anemia and/or kidney damage
erythropoiesis-stimulating agents
Primary Options
- epoetin alfa
40,000 units subcutaneously once weekly initially, increase according to response, maximum 60,000 units/week
- epoetin alfa
- darbepoetin alfa
200 micrograms subcutaneously every 2 weeks, increase according to response, maximum 300 micrograms every 2 weeks
- darbepoetin alfa
Comments
- If Hb has not increased by at least 1 g/dL after 4 weeks at initial dose of epoetin alfa, dose may be increased if iron status is satisfactory.
with iron deficiency
oral or parenteral iron replacement
Primary Options
Secondary Options
- iron dextran
consult specialist for guidance on dose
- iron dextran
- sodium ferric gluconate complex
125 mg intravenously once weekly for 8 weeks, maximum 1000 mg cumulative dose
- sodium ferric gluconate complex
- iron sucrose
consult specialist for guidance on dose
- iron sucrose
- ferric carboxymaltose
consult specialist for guidance on dose
- ferric carboxymaltose
Comments
- Patients with PNH lose up to 20 times as much iron per day as healthy people and may require supplementation with oral or parenteral iron. It is important to note that iron repletion may be followed by a brief episode of hemoglobinuria.[41]
- Oral iron supplementation is an easy way to replace iron and is usually given in its elemental form. If patients cannot tolerate this or have such rapid iron loss that oral iron cannot keep up with the losses, iron can be given parenterally. Parenteral iron is generally safe, although severe cases of anaphylaxis have been reported.
- Treatment is continued so long as iron stores, monitored by serum ferritin, are adequate and not excessive.
with thrombosis
thrombolysis
Primary Options
- alteplase
100 mg intravenously given over 2 hours
- alteplase
- reteplase
10 units intravenously initially, followed by 10 units 30 minutes later
- reteplase
Comments
- Thrombolytic agents may be used in the acute stage of thrombosis, unless the platelet count is <50,000/microliter or thrombosis is intracranial.[43]
- For cerebral thrombosis, antiedema therapy (usually dexamethasone or mannitol) and anticoagulation are used, but evidence is limited.
- This should be followed by full anticoagulation with warfarin or heparin (preferably low-molecular-weight heparin).
PNH in the setting of another specific bone marrow disorder: pregnant with thrombosis
thrombolysis
Comments
- There are no data to support thrombolytic therapy in pregnant women with paroxysmal nocturnal hemoglobinuria (PNH). Generally, systemic thrombolysis is considered risky in pregnant women, even though scant reports have shown encouraging outcomes with manageable complications in cases of life-threatening thrombosis.[46] Seek specialist guidance for management.
with Hb <8.5 g/dL
RBC transfusion
Comments
- Patients may require transfusion with red blood cells if Hb falls to a level that is symptomatic (fatigue, shortness of breath, symptoms of heart failure), usually to <8.5 g/dL. This is occasionally accompanied by a bout of hemoglobinuria due to destruction of the abnormal PNH cells. This can be prevented by removing white blood cells from the transfused unit through washing or appropriate filtering. Washing will also remove any residual complement from the cells.[42] Iron overload is not a problem in PNH patients, as chronic losses in urine result in iron deficiency even in heavily transfused patients.
with underlying aplastic anemia and/or kidney damage
erythropoiesis-stimulating agents
Primary Options
- epoetin alfa
40,000 units subcutaneously once weekly initially, increase according to response, maximum 60,000 units/week
- epoetin alfa
- darbepoetin alfa
200 micrograms subcutaneously every 2 weeks, increase according to response, maximum 300 micrograms every 2 weeks
- darbepoetin alfa
Comments
- Although endogenous erythropoietin (EPO) levels are usually high in PNH, supplemental injections of recombinant EPO have been found useful in some patients.[37] [38] EPO is generally considered to be safe in pregnancy, but there are no conclusive data of its use in pregnant PNH patients. The potential benefit must be weighed against the risk of thrombosis related to EPO use.
- If Hb has not increased by at least 1 g/dL after 4 weeks at initial dose of epoetin alfa, dose may be increased if iron status is satisfactory.
with iron deficiency
oral or parenteral iron replacement
Primary Options
Secondary Options
- iron dextran
consult specialist for guidance on dose
- iron dextran
- sodium ferric gluconate complex
125 mg intravenously once weekly for 8 weeks, maximum 1000 mg cumulative dose
- sodium ferric gluconate complex
- iron sucrose
consult specialist for guidance on dose
- iron sucrose
- ferric carboxymaltose
consult specialist for guidance on dose
- ferric carboxymaltose
Comments
- Patients with PNH lose up to 20 times as much iron per day as healthy people and may require supplementation with oral or parenteral iron. It is important to note that iron repletion may be followed by a brief episode of hemoglobinuria.[41]
- Oral iron supplementation is an easy way to replace iron and is usually given in its elemental form. If patients cannot tolerate this or have such rapid iron loss that oral iron cannot keep up with the losses, iron can be given parenterally. Parenteral iron is generally safe, although severe cases of anaphylaxis have been reported.
- Treatment is continued so long as iron stores, monitored by serum ferritin, are adequate and not excessive.
PNH in the setting of another specific bone marrow disorder: pregnant without thrombosis
thromboprophylaxis
Primary Options
- enoxaparin
see local specialist protocol for dosing guidelines
- enoxaparin
- dalteparin
see local specialist protocol for dosing guidelines
- dalteparin
Secondary Options
- heparin
see local specialist protocol for dosing guidelines
- heparin
Comments
- The risk of thrombotic complications during pregnancy is high.[47] For this reason, anticoagulation with a low-molecular-weight heparin (LMWH) has been recommended.
- Patients should be started on a LMWH as soon as pregnancy is documented and continue treatment for at least 3 months postpartum.[36]
- LMWHs are considered optimal, having less risk than unfractionated heparin of heparin-induced thrombocytopenia.
- Warfarin is contraindicated in pregnancy due to its teratogenic effect.[48]
with Hb <8.5 g/dL
RBC transfusion
Comments
- Patients may require transfusion with red blood cells if Hb falls to a level that is symptomatic (fatigue, shortness of breath, symptoms of heart failure), usually to <8.5 g/dL. This is occasionally accompanied by a bout of hemoglobinuria due to destruction of the abnormal PNH cells. This can be prevented by removing white blood cells from the transfused unit through washing or appropriate filtering. Washing will also remove any residual complement from the cells.[42] Iron overload is not a problem in PNH patients, as chronic losses in urine result in iron deficiency even in heavily transfused patients.
with underlying aplastic anemia and/or kidney damage
erythropoiesis-stimulating agents
Primary Options
- epoetin alfa
40,000 units subcutaneously once weekly initially, increase according to response, maximum 60,000 units/week
- epoetin alfa
- darbepoetin alfa
200 micrograms subcutaneously every 2 weeks, increase according to response, maximum 300 micrograms every 2 weeks
- darbepoetin alfa
Comments
- Although endogenous erythropoietin (EPO) levels are usually high in PNH, supplemental injections of recombinant EPO have been found useful in some patients.[37] [38] EPO is generally considered to be safe in pregnancy, but there are no conclusive data of its use in pregnant PNH patients. The potential benefit must be weighed against the risk of thrombosis related to EPO use.
- If Hb has not increased by at least 1 g/dL after 4 weeks at initial dose of epoetin alfa, dose may be increased if iron status is satisfactory.
with iron deficiency
oral or parenteral iron replacement
Primary Options
Secondary Options
- iron dextran
consult specialist for guidance on dose
- iron dextran
- sodium ferric gluconate complex
125 mg intravenously once weekly for 8 weeks, maximum 1000 mg cumulative dose
- sodium ferric gluconate complex
- iron sucrose
consult specialist for guidance on dose
- iron sucrose
- ferric carboxymaltose
consult specialist for guidance on dose
- ferric carboxymaltose
Comments
- Patients with PNH lose up to 20 times as much iron per day as healthy people and may require supplementation with oral or parenteral iron. It is important to note that iron repletion may be followed by a brief episode of hemoglobinuria.[41]
- Oral iron supplementation is an easy way to replace iron and is usually given in its elemental form. If patients cannot tolerate this or have such rapid iron loss that oral iron cannot keep up with the losses, iron can be given parenterally. Parenteral iron is generally safe, although severe cases of anaphylaxis have been reported.
- Treatment is continued so long as iron stores, monitored by serum ferritin, are adequate and not excessive.
subclinical PNH: nonpregnant
monitoring
Comments
- Asymptomatic patients with small paroxysmal nocturnal hemoglobinuria (PNH) clones and no evidence of hemolysis (no anemia) should be in periodic follow-up and be managed in the setting of emerging complications.
subclinical PNH: pregnant
thromboprophylaxis
Primary Options
- enoxaparin
see local specialist protocol for dosing guidelines
- enoxaparin
- dalteparin
see local specialist protocol for dosing guidelines
- dalteparin
Secondary Options
- heparin
see local specialist protocol for dosing guidelines
- heparin
Comments
- There are no solid data on subclinical paroxysmal nocturnal hemoglobinuria (PNH), but it seems prudent to initiate thromboprophylaxis when pregnancy is documented.[48]
- Low-molecular-weight heparins are considered optimal compared to unfractionated heparin, conferring less risk of heparin-induced thrombocytopenia.
following acute clinical PNH with thrombosis: nonpregnant
lifetime anticoagulation
Primary Options
- enoxaparin
see local specialist protocol for dosing guidelines
- enoxaparin
- dalteparin
see local specialist protocol for dosing guidelines
- dalteparin
- heparin
see local specialist protocol for dosing guidelines
- heparin
- warfarin
see local specialist protocol for dosing guidelines
- warfarin
Comments
- Thrombolytic agents used in the acute stage of thrombosis should be followed by full anticoagulation with warfarin or heparin (preferably low-molecular-weight heparin).
- Patients with documented thrombosis should receive lifelong secondary prophylaxis although, for patients on complement C5 inhibitor treatment, there is no clear evidence for the benefit of lifelong anticoagulation. Eculizumab has been shown to markedly reduce the incidence of thrombosis in paroxysmal nocturnal hemoglobinuria (PNH).
- Most authors suggest a target international normalized ratio of 2.0 to 2.5.
- Prophylactic anticoagulation with warfarin or heparin derivatives has been used with variable success.[45]
Emerging Tx
Iptacopan
Crovalimab
Danicopan
Gene therapy
Follow-Up Overview
Prognosis
PNH in the setting of aplastic anemia
Subclinical PNH
Monitoring
Complications
Citations
Parker CJ. Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria. ASH Education Book 2016;2016(1):208-16. [Abstract][Full Text]
National Organization for Rare Disorders. NORD rare disease report: paroxysmal nocturnal hemoglobinuria. January 2023 [internet publication].[Full Text]
Dezern AE, Borowitz MJ. ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 1 - Clinical Utility. Cytometry B Clin Cytom. 2018;94(1):16-22.[Abstract][Full Text]
1. Rosse W. Paroxysmal nocturnal hemoglobinuria as a molecular disease. Medicine (Baltimore). 1997 Mar;76(2):63-93.[Abstract]
2. Parker CJ. Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria. ASH Education Book 2016;2016(1):208-16. [Abstract][Full Text]
3. Cançado RD, Araújo ADS, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021 Jul-Sep;43(3):341-8.[Abstract][Full Text]
4. Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993 May 21;73(4):703-11.[Abstract]
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7. Bat T, Abdelhamid ON, Balasubramanian SK, et al. The evolution of paroxysmal nocturnal haemoglobinuria depends on intensity of immunosuppressive therapy. Br J Haematol. 2018 Sep;182(5):730-3.[Abstract][Full Text]
8. Sugimori C, Mochizuki K, Qi Z, et al. Origin and fate of blood cells deficient in glycosylphosphatidylinositol-anchored protein among patients with bone marrow failure. Br J Haematol. 2009;147(1):102-12. [Abstract][Full Text]
9. Rother R, Bell L, Hillmen P, et al. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005 Apr 6;293(13):1653-62.[Abstract][Full Text]
10. Clark DA, Butler SA, Braren V, et al. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981 Jan;57(1):83-9.[Abstract][Full Text]
11. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal haemoglobinuria. New Engl J Med. 1995 Nov 9;333(19):1253-8.[Abstract][Full Text]
12. Tichelli A, Gratwohl A, Wursch A, et al. Late haematological complications in severe aplastic anemia. Br J Haematol. 1988 Jul;69(3):413-8.[Abstract]
13. Fattizzo B, Ireland R, Dunlop A, et al. Clinical and prognostic significance of small paroxysmal nocturnal hemoglobinuria clones in myelodysplastic syndrome and aplastic anemia. Leukemia. 2021 Nov;35(11):3223-31.[Abstract][Full Text]
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
Information on the investigation and diagnosis of PNH.Published by
National Organization for Rare Disorders
Published
2023
Summary
Primary clinical manifestations of PNH are hemolytic anemia, marrow failure, and thrombophilia.Published by
International PNH Interest Group
Published
2005
Treatment
Summary
Information on treatment of PNH.Published by
National Organization for Rare Disorders
Published
2023
Summary
Consensus guideline reviewing PNH management strategies.Published by
International PNH Interest Group
Published
2005
Summary
Appropriate interpretation of flow cytometry results aids classification, the evaluation of disease progression, and response to therapy.Published by
International Clinical Cytology Society/European Society for Clinical Cell Analysis
Published
2018