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Review Article Paroxysmal nocturnal hemoglobinuria: Diagnosis and management protocol Abdul Kareem Almomen, Abdul Ghani Al Bakistani1, Ahmad Alsaeed2, Asma Al Olama3, Ayman Hejazi4, Christian Awarji5, Fahed Almhareb6, Faisal Alsayegh5, Hazzaa Alzahrani6, Mahmoud Almarashly3, Mohammad Qari7, Mohammad Aslam1, Rania Seliem8, Salam Al Kindi9, Saud Abuharbesh10, TareK Owaidah6, Wafaa Bassuni2 Department of Hematology and Oncology, King Saud University Medical City, Riyadh, 1Departments of Hematology and Pathology, King Faisal Specialist Hospital and Research Center, 2Departments of Oncology, King Abdulaziz Medical City, Jeddah, 4 King Abdulaziz Medical City, 6Department of Hematology and Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, 7Departments of Hematology, College of Medicine, King Abdulaziz University, Jeddah, 10Security Forces Hospital, Riyadh, Saudi Arabia, 3Dubai Hospital, Dubai, United Arab Emirates, 5Department of Pathology and Hematology, Mubarak Hospital, Kuwait City, Kuwait, 8Department of Pathology, Rashid Hospital, Dubai, United Arab Emirates, 9Department of Hematology, Qabous University Hospital, Mascut, Oman Address for correspondence: MD. Abdul Kareem Almomen, Center of Excellence in Thrombosis and Hemostasis, King Saud University Medical City, P. O. Box: 66533, Riyadh 11586, Saudi Arabia. E‑mail:
[email protected]
ABSTRACT Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, rare clonal blood disorder, characterized by chronic intravascular hemolysis, bone marrow failure, renal failure and pulmonary hypertension, and a heightened risk of thrombotic complications. PNH etiology is an Х‑linked gene somatic mutation of the phosphatidylinositol glycan class А (PIG‑A), that results in deficiency of the glycosylphosphatidylinositol anchor structure responsible for fixing a wide spectrum of proteins on blood cell membranes, absence of these proteins, particularly CD55 and CD59, dysregulates the complement on cell membranes and results in significant chronic complement‑mediated hemolysis. Early diagnosis of PNH is crucial for effective disease management. However, the heterogeneity of clinical symptoms and rarity of this disease usually results in untimely diagnosis, severe disability of patients, and increased risk of fatal complication. These recommendations are formulated by a panel of experts from the gulf cooperation countries. This information reflects their experience and to assist specialists looking after PNH patients, including hematologists, nephrologists, dialysis specialists, gastroenterologists, cardiologists, and surgeons. Key words: Epidemiological studies, paroxysmal, phosphatidylinositol
DEFINITION AND DIAGNOSTICS CRITERIA
epidemiological studies shows that despite up‑to‑date management, 35% of patients with classical PNH die within the first 5‑year of diagnosis, and the 10‑year mortality rate is about 50%.[1,2] The primary causes of death in PNH patients are thrombotic complications, which account for 40-67% of fatal outcomes.[3‑6]
Definition
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, rare, life‑threatening, progressive systemic disorder, characterized by chronic intravascular hemolysis. PNH is associated with a significant increase in mortality, development of arterial and venous thrombosis, visceral organ damage, and rapid deterioration in quality of life. Evidence from major
Other severe complications include renal failure, pulmonar y hypertension, peripheral neuropathy and smooth muscle dystonia, which can manifest as chest pain, abdominal pain, dysphagia, and erectile dysfunction.[6,7]
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The main pathogenetic mechanism that mediates organ damage and mortality is the dysregulation of the complement system. The complement system is part of the innate immune system that has three main activation pathways: Classical, alternative, and lectin‑mediated. All the pathways lead to the key step that consists of cleavage
Website: www.jahjournal.org
DOI: 10.4103/1658-5127.137081
Vol. 5 • Issue 2 • April-June 2014
37
Journal of Applied Hematology
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Almomen: PNH diagnosis and management
of complement C3 to C3a and C3b proteins. C3b participates in the formation of C5 convertase, which results in cleavage of the C5 protein to C5a and C5b. The C5a protein is a pro‑inflammatory and pro‑thrombotic agent, and C5b protein promotes the formation of the membrane attack complex (MAC). The MAC mediates the hemolysis of red blood cell (RBC), the generation of pro‑coagulatory membrane microparticles, and initiates the activation of platelets.[8‑10]
The differentiation of the sub‑clinical form of PNH does not have clinical significance by itself, but is needed to ensure monitoring of patients’ PNH clone size, due to the possibility of progression to a clinical hemolytic form of AA/PNH, which would require appropriate treatment. Classical paroxysmal nocturnal hemoglobinuria
Patients with classical PNH usually demonstrate significant intravascular hemolysis with increases in the serum lactate dehydrogenase (LDH) level, reticulocytosis and decreases in the haptoglobin level.[12] In this PNH variation, there are no definitive morphologic signs of other bone marrow pathology (AA, MDS, myelofibrosis) and usually no karyotype abnormalities.[16]
C5 convertase activation is normally blocked by a glycosylphosphatidylinositol (GPI)‑anchored CD55 (decay‑accelerating factor). CD55 is absent or deficient in PNH cells, resulting in an increased susceptibility of the C5 protein on cell surfaces to cleavage. Overproduction of C5a initiates leukocyte and platelet activation and stimulates inflammation and thrombosis. Normally, generation of the MAC on the cell surface is blocked by another GPI‑anchored complement inhibitor – CD59.[11,12] However, in the absence of CD59, the MAC initiates RBCs lysis. Platelets without CD55 and CD59 are affected by complement‑dependent aggregation and activation.[12,13]
Paroxysmal nocturnal hemoglobinuria with underlying bone marrow failure syndrome (aplastic anemia/PNH, myelodysplastic syndrome/PNH)
In patients with AA/PNH and MDS/PNH clinical and laboratory signs of intravascular hemolysis are diagnosed. The symptoms of bone marrow failure or intravascular hemolysis can predominate in different stages of the disease and often in combinations.[5,13] In spite of usually minimal symptoms and only laboratory signs of intravascular hemolysis in patients with a small PNH clone size, twice‑a‑year monitoring is necessary due to the possibility of clone expansion with severe hemolysis development and high‑risk of thrombotic complications.[17,18]
Flow cytometry measurement allows identification of the cells with GPI‑anchored protein (GPI‑AP) 15 deficiency. It is the “gold standard” in PNH diagnosis.[14] RBCs are classified into three types: (i) Type I RBCs with normal GPI‑AP expression on cell surface, (ii) Type II RBCs with partial GPI‑AP expression and (iii) Type III RBCs with complete GPI‑AP deficiency. More informative is the determination of GPI‑AP deficiency on granulocytes that allows a definitive diagnosis.[15] It is also reasonable to perform this testing also on monocytes in patients with small populations of GPI‑AP deficient cells.[16]
Sub‑clinical form of paroxysmal nocturnal hemoglobinuria (aplastic anemia/serum PNH, myelodysplastic syndrome/sPNH)
Patients with sub‑clinical PNH do not have any clinical or laboratory signs of hemolysis and small populations of GPI‑AP deficient cells can only be identified today by flow cytometry. The sub‑clinical form of PNH can be diagnosed with underlying diseases characterized by bone marrow dysfunction, primarily AA and MDS. It is very important to perform careful monitoring of these patients (twice yearly) for signs of hemolysis and rapid clone expansion, as 15-17% of patients with AA/ sPNH eventually develop the hemolytic form of AA/ PNH.[18,19]
Classification There are three main forms of PNH:
• The classical PNH, characterized by clinical laboratory signs of intravascular hemolysis without evidence of other diseases of bone marrow failure (aplastic anemia [AA], myelodysplastic syndrome [MDS], idiopathic myelofibrosis) • The PNH, diagnosed in patients with AA (AA/PNH), MDS (MDS/PNH) and very rarely myelofibrosis (idiopathic myelofibrosis/PNH), patients of which have clinical and/or laboratory signs of intravascular hemolysis, and a cell clone with PNH phenotype detected in peripheral blood • The sub‑clinical form of the disease (AA/sPNH [serum PNH], MDS/sPNH, idiopathic myelofibrosis/sPNH), identified in patients without clinical or laboratory signs of hemolysis, but having a minor cell clone with PNH phenotype (usually
