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paroxysmal nocturnal hemoglobinuria (PNH, Marchiafava-Micheli syndrome)

PNH is an acquired stem cell disorder characterized by production of abnormal erythrocytes, granulocytes & platelets. Lymphocytes are unaffected. Etiology: - may be associated with myelodysplastic syndrome or aplastic anemia - see genetics Epidemiology: - PNH usually occurs in young adults Pathology: 1) bone marrow aplasia - an abnormal clone of stem-cells is postulated to develop within an aplastic or regenerating marrow 2) associated with 10-30% of cases of aplastic anemia 3) hemolysis is caused by the absence of decay-accelerating factor (CD55) & the membrane inhibitor of membrane lysis (CD59) [2] Genetics: - mutation in the PIG-A gene disrupting synthesis of GPI-linked glycoproteins including: a) complement inhibitory proteins - decay accelerating factor (DAF, CD55) - membrane inhibitor of reactive lysis (MIRL, CD59) - C8-binding protein (homologous restriction factor) b) other proteins - CD58 (lymphocyte function-associated antigen-3) - CD14 (endotoxin-binding receptor) - CD24 - CD16 (Fc-gamma receptor) - CD48 Clinical manifestations: 1) chronic episodic intravascular hemolysis 2) thrombotic complications are common (20-30%) a) arterial thrombosis & venous thrombosis - Budd-Chiari syndrome b) may present with neurologic symptoms c) cerebral venous thrombosis or sinus thrombosis d) case of temporal-occipital venous thrombosis associated with headache & loss of peripheral vision [6] 3) anemia, thrombocytopenia, neutropenia, pancytopenia 4) scattered petechiae may be observed 5) nocturnal hemoglobinuria present in <25% of patients 6) patients may present with - direct antiglobulin test negative hemolytic anemia - aplastic anemia [2] - non-specific low back &/or abdominal pain 7) spontaneous fluctuations 8) bouts of hemoglobinuria initiated by: a) infection b) surgery c) whole blood transfusion d) injection of contrast dyes e) intense exercise 9) clinical improvement in 50% of patients with time Laboratory: 1) complete blood count a) pancytopenia b) normocytic anemia d) neutropenia in 65% of patients at some time during the course of the disease d) thrombocytopenia in 67% of patients at some time during the course of the disease 2) reticulocyte count: reticulocytosis 3) direct antiglobulin test is negative 4) serum iron low (through urinary loss) 5) sucrose hemolysis test* 6) acidified serum test (Ham test)* 7) flow cytometry for subpopulation of WBC & RBC lacking CD55 & CD59 - CD55 erythrocytes in blood - CD59 erythrocytes in blood - CD55 + CD59 erythrocytes in blood 8) non-specific serum chemistries a) serum LDH generally elevated b) serum bilirubin unconjugated bilirubin is generally elevated c) serum haptoglobin: low or absent haptoglobin d) serum leukocyte alkaline phosphatase is low 9) urinalysis: a) hemoglobinuria is variable b) hemosiderinuria almost constantly present 10) bone marrow biopsy a) usually hypercellular, but may be hypocellular b) normoblastic 11) peripheral blood smear: shistocytes not a feature 12) see ARUP consult [3] * erythrocytes are more susceptible to complement-mediated intravascular hemolysis. Thus forms the basis for the sucrose hemolysis test & the Ham test. False negatives in transfused patients Complications: 1) thrombosis of major vessels (primarily venous), including cerebral venous thrombosis [6] 2) renal failure 3) infections 4) bleeding 5) PNH may rarely progress to acute myelogenous leukemia Differential diagnosis: - aplastic anemia - hemolytic anemia (direct antiglobulin test negative) Management: 1) largely supportive - do not treat asymptomatic PNH in the absence of hemolysis [2] 2) eculizumab (Soliris) a) one of 3 FDA-approved agents for PNH b) monoclonal Ab to complement C5 [2] c) inhibits terminal complement activation [2] d) reduces hemolysis & hemoglobinuria e) diminishes transfusion requirements f) improves quality of life g) potentionally decreases risk of thrombosis in transfusion-dependent patients [2] 3) other monoclonal Ab to complement C5 - ravulizumab (Ultomiris) [2], crovalimab (Piasky) [10] 4) complement-C3 inhibitors - available only through a restricted program under a risk evaluation & mitigation strategy (REMS) - pegcetacoplan (Empaveli) - iptacopan (Fabhalta) 5) danicopan (Voydeya) is complement factor D inhibitor inhibitor - for use only in combination with ravulizumab or eculizumab - available only through a restricted program under a risk evaluation & mitigation strategy (REMS) 6) anticoagulation a) patients with thrombosis b) consider prophylaxis for deep vein thrombosis if > 50% of cells are CD55 or CD59 deficient 7) supplemental iron & folic acid (all patients) [2] 8) danazol may be helpful [2] 9) allogeneic hematopoietic stem cell transplantation can facilitate long-term survival

Related

acidified serum test (Ham test, acid hemolysin test) phosphatidylinositol N-acetylglucosaminyltransferase subunit A; GlcNAc-PI synthesis protein; phosphatidylinositol-glycan biosynthesis class A protein; PIG-A (PIGA) sucrose hemolysis test

General

hemolytic anemia hemoglobinuria hypercoagulability syndrome

Database Correlations

OMIM 311770

References

  1. Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996, pg 635
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. ARUP Consult: Paroxysmal Nocturnal Hemoglobinuria - PNH The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/paroxysmal-nocturnal-hemoglobinuria - ARUP Consult: Paroxysmal Nocturnal Hemoglobinuria Testing https://arupconsult.com/ati/paroxysmal-nocturnal-hemoglobinuria-testing
  4. Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2009 Jun 25;113(26):6522-7. PMID: 19372253 - Brodsky RA How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021 Mar 11;137(10):1304-1309 PMID: 33512400 PMCID: PMC7955407 Free PMC article
  5. Parker CJ Paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol. 2012 May;19(3):141-8. PMID: 22395662
  6. Sykes DB, Rosovsky RP, Singhal AB, Gonzalez RG, Moy AP. Cae 20-2017 - A 32-Year-Old Woman with Headache, Abdominal Pain, Anemia, and Thrombocytopenia. N Engl J Med 2017; 377:2581-2590. Dec. 28, 2017 PMID: 29281575 http://www.nejm.org/doi/full/10.1056/NEJMcpc1710566
  7. Sutherland DR, Illingworth A, Keeney M, Richards SJ. High-Sensitivity Detection of PNH Red Blood Cells, Red Cell Precursors, and White Blood Cells. Curr Protoc Cytom. 2015 Apr 1;72:6.37.1-30. PMID: 25827482
  8. Devos T, Meers S, Boeckx N et al Diagnosis and management of PNH: Review and recommendations from a Belgian expert panel. Eur J Haematol. 2018 Dec;101(6):737-749. PMID: 30171728 Review.
  9. DeZern AE, Brodsky RA. Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia. Hematol Oncol Clin North Am. 2015 Jun;29(3):479-94. PMID: 26043387 PMCID: PMC4695989 Free PMC article. Review.
  10. Ingram I Subcutaneous C5 Inhibitor Approved for PNH. Longer-acting crovalimab designed for more sustained effect and less treatment burden. MedPage Today June 24, 2024 https://www.medpagetoday.com/hematologyoncology/hematology/110793