Paroxysmal nocturnal hemoglobinuria
I. What every physician needs to know.
Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia due to an acquired mutation that results in red blood cells prone to intravascular complement-mediated destruction. Its key features include hemolytic anemia, hemoglobinuria, thromboembolic disease including Budd-Chiari syndrome, and aplastic anemia.
II. Diagnostic Confirmation: Are you sure your patient has Paroxysmal Nocturnal Hemoglobinuria?
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A. History Part I: Pattern Recognition:
The most prominent feature of PNH is hemolytic anemia. However, patients frequently present with venous thromboembolic disease or aplastic anemia. Anyone with aplastic anemia or venous thrombosis in unusual sites such as the hepatic vein (Budd-Chiari syndrome) or cerebral veins should be tested for PNH.
Other symptoms include discolored urine from hemoglobinuria, particularly in the morning, fatigue, and abdominal pain.
Besides transforming to aplastic anemia, PNH less often can transform to myelodysplastic syndrome (MDS) or acute leukemia.
B. History Part 2: Prevalence:
All ethnic groups can develop PNH, but Southeast Asians have a higher predisposition. Overall, the disease is rare.
C. History Part 3: Competing diagnoses that can mimic Paroxysmal Nocturnal Hemoglobinuria.
Other diseases that have overlapping presentations include disseminated intravascular coagulopathy (DIC), drug-induced hemolytic anemia, paroxysmal cold hemoglobinuria, and Wilson’s disease.
D. Physical Examination Findings:
There are no specific physical features to PNH. Exam findings include signs of anemia (pallor, pale conjunctivae, pale palmar creases) and signs of deep vein thrombosis (DVT), such as unilateral swelling, erythema, tenderness, and in the case of abdominal vessels, abdominal pain and distension from ascites. Patients with PNH do not typically have splenomegaly, unless caused by intraabdominal thrombosis.
E. What diagnostic tests should be performed?
The gold standard for diagnostic confirmation in recent years has become flow cytometry of peripheral blood for CD55 and CD59. In PNH, flow cytometry will demonstrate deficiency of these markers in some of the blood cells. When ordering this test, you will need to specify to the lab that markers CD55 and CD59 need to be tested, as these are not routinely run with flow cytometry.
Additional helpful diagnostic tests include the following:
1. Tests for intravascular hemolysis: Complete blood count (CBC) showing anemia, reticulocytosis, elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated urinary hemosiderin.
2. Coombs test (direct antiglobulin test, DAT) is usually negative, unlike autoimmune hemolytic anemia. However, a combination of the typical intravascular hemolysis associated with PNH plus extravascular hemolysis associated with autoimmune hemolytic anemia (positive DAT) can occur in a subset of patients, though usually the extravascular hemolytic component is clinically insignificant. This extravascular hemolysis occurs while on eculizumab (a humanized monoclonal antibody that decreases complement-mediated intravascular hemolysis), which is used for chronic treatment of PNH, since the drug leads to a buildup of complement component C3.
3. Bone marrow biopsy will usually show the physiologic compensatory mechanism of anemia – erythroid hyperplasia – unless aplastic anemia has developed. Therefore, unless neutropenia or thrombocytopenia are present or anemia has not responded to eculizumab, a bone marrow biopsy is not necessary.
Once aplastic anemia has developed:
1. The CBC will usually show cytopenias in more than one cell lineage, e.g., combinations of leukopenia, anemia, and thrombocytopenia.
2. The bone marrow biopsy will show a paucity of blood precursors – aplastic/hypoplastic/hypocellular. The precursors are often replaced by fat globules.
For historical purposes, prior to the advent of flow cytometry, the Ham test and sucrose or sugar water test were used for confirmation of PNH. In the Ham test, red cells from a PNH clone placed in an acid buffer undergo complement-mediated lysis. In the sucrose test, red cells from a PNH clone would also lyse when placed into sugar water. Flow cytometry has eliminated these tests from the laboratory because of its superior sensitivity and specificity.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
a. Complete blood count and peripheral blood smear.
b. Hemolysis labs: lactate dehydrogenase, reticulocyte count, haptoglobin, and urinary hemosiderin.
c. Then if hemolyzing and suspicious for PNH, check peripheral blood flow cytometry for CD55 and CD59.
d. If multiple cytopenias exist or the patient does not respond to treatment, bone marrow biopsy should be done.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Doppler ultrasound should be obtained for a suspected DVT. Abdominal ultrasound with Dopplers can be helpful twofold, first to assess the patency of the abdominal vessels in a patient with suspected intra-abdominal thrombosis. Second, ultrasound can be used to measure spleen size. Patients with PNH usually have normal spleen sizes unless caused by intraabdominal thrombosis whereas other hemolytic anemias may be associated with splenomegaly.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
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III. Default Management.
Immediate management rests with supportive care, while a targeted therapy, eculizumab, a humanized monoclonal antibody to complement 3 (C3), has recently become the mainstay for chronic treatment. Still, stem-cell transplant remains the only cure. Life-long anticoagulation is also commonly necessary.
A. Immediate management.
Severe or symptomatic anemia requires urgent supportive care with packed red blood cell transfusions and intravenous hydration.
B. Physical Examination Tips to Guide Management.
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C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
CBC and hemolysis labs, particularly reticulocyte count and LDH, should be regularly followed.
Flow cytometry has recently become important for monitoring response to therapy, especially with eculizumab or stem-cell transplant. The percentage of granulocytes harboring the abnormal clone (CD55 and CD59 deficiency) is inversely proportional to disease control (see Long-term Management). For example, if the percentage of abnormal (PNH) granulocytes increase, this suggests a higher dose of eculizumab may be needed or perhaps the patient is relapsing after transplant.
Bone marrow biopsy should be repeated at any time if cytopenias develop or worsen.
D. Long-term management.
1. Anticoagulation: Indications for life-long anticoagulation include recurrent or life-threatening thromboembolic disease or if the neutrophil clone is greater than 50% of cells (as measured by flow cytometry).
2. Folic acid supplementation (0.4-1.0 mg daily) is beneficial to replace lost folate from red cell turnover in hemolysis. With effective long-term management, supplements may lose their necessity. Continue to follow these levels.
3. Eculizumab (Soliris) is an anti-complement-5 (C5) monoclonal antibody that prevents complement activation and thus red-cell destruction. Despite its high cost, this treatment has emerged as the primary means of controlling PNH’s hemolytic anemia and thromboembolic manifestations. Its benefit for preventing recurrent blood clots is likely greater than that of anticoagulation and should be used in addition to anticoagulation when clots are severe or recurrent. Eculizumab is not helpful in treating aplastic anemia associated with PNH. Patients must be vaccinated against Neisseria meningitidis at least 2 weeks prior to starting eculizumab. Although data is scarce, eculizumab seems to be safe and effective in pregnancy, which was previously very high risk.
4. Allogeneic stem-cell transplant should be considered in severe cases, such as refractory anemia, recurrent or life-threatening thromboembolism, and aplastic anemia.
5. Treatment for aplastic anemia is discussed elsewhere, but includes stem-cell transplant if severe.
E. Common Pitfalls and Side-Effects of Management.
Side effects of blood transfusions are discussed elsewhere, but include fever, transfusion reactions, and infections.
Side effects of eculizumab include headache, infusion reactions, and as previously mentioned the increased risk of severe infections, particularly from Neisseria species.
Stem-cell transplantation carries a high risk of infection and graft versus host disease. Engraftment failure is also a potentially lethal complication.
IV. Management with Co-Morbidities.
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A. Renal Insufficiency.
For patients with chronic kidney disease, therapeutic anticoagulation with enoxaparin can be verified by checking a factor Xa level 4-6 hours after a dose is injected. This test should be repeated whenever kidney function changes.
B. Liver Insufficiency.
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C. Systolic and Diastolic Heart Failure.
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D. Coronary Artery Disease or Peripheral Vascular Disease.
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E. Diabetes or other Endocrine issues.
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F. Malignancy.
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G. Immunosuppression (HIV, chronic steroids, etc).
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H. Primary Lung Disease (COPD, Asthma, ILD).
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I. Gastrointestinal or Nutrition Issues.
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J. Hematologic or Coagulation Issues.
Anticoagulation for thromboembolic disease in PNH can be problematic in the aplastic patient with thrombocytopenia. The risks of bleeding must be weighed against that of clotting. Although each patient’s care must be individualized, holding anticoagulation when platelets are less than 50,000 per microliter of blood is typically prudent.
K. Dementia or Psychiatric Illness/Treatment.
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V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
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B. Anticipated Length of Stay.
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C. When is the Patient Ready for Discharge.
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D. Arranging for Clinic Follow-up.
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1. When should clinic follow up be arranged and with whom.
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2. What tests should be conducted prior to discharge to enable best clinic first visit.
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3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
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E. Placement Considerations.
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F. Prognosis and Patient Counseling.
Median survival is 14.6 years. Prognosis is worse in those age >55, with history of thrombosis, pancytopenia, myelodysplastic syndrome, or transformation to acute leukemia. Thrombosis occurs in 28% over 8 years, aplastic anemia 15% over 8 years, and MDS in 5% over 8 years. Fifteen percent have a spontaneous remission.
VI. Patient Safety and Quality Measures.
A. Core Indicator Standards and Documentation.
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B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Ensure therapeutic anticoagulation. Warfarin is most commonly used. However, enoxaparin should be used during pregnancy or if planning for pregnancy.
VII. What’s the evidence?
Brodsky, RA. “Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria”. Blood. vol. 111. 2008. pp. 1840-1847.
Hillmen, P. “Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria”. Blood. vol. 110. 2007. pp. 4123-4128.
Hillmen, P. “The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria”. N Engl J Med. vol. 355. 2006. pp. 1233-1243.
Hall, C, Richards, S, Hillmen, P. “Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH)”. Blood. vol. 102. 2003. pp. 3587-3591.
Hillmen, P, Lewis, SM, Bessler, M, Luzzatto, L, Dacie, JV. “Natural history of paroxysmal nocturnal hemoglobinuria”. N Engl J Med. vol. 333. 1995. pp. 1253-1259.
Kelly, RJ. “Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria”. N Engl J Med. vol. 373. 2015. pp. 1032-9.
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