Interviews with the Experts: Hemolysis in PNH and Beyond | Aplastic Anemia and MDS International Foundation

Interviews with the Experts: Hemolysis in PNH and Beyond

 

Dr. Shammo is an associate professor of medicine and pathology, Section of Hematology and Stem Cell Transplantation, Division of Hematology/Oncology, at Rush University Medical Center in Chicago where she spearheads the MDS/MPN/bone marrow failure program. She is also director of education in the Division of Hematology/Oncology. Dr. Shammo has designed and is involved as principal investigator for many clinical trials related to chronic myelogenous leukemia, MPN’s, PNH, and myelodysplastic syndromes. This is the second part of a series of interviews about PNH. Read the first and third parts.

What is hemolysis and what its relationship to PNH?

Hemolysis is a term we use to describe destruction and/or rupture of red blood cells.  In paroxysmal nocturnal hemoglobinuria (PNH), hemolysis occurs within the blood vessels and is typically induced by the complement system, which is an integral part of the immune system. The purpose of the complement system is to eliminate ‘non-self’ elements, including infectious organisms, foreign bodies, etc. PNH cells tend to be prone for destruction by the complement system, because they do not have complement shielding proteins. 

What happens in PNH is that an acquired mutation in a gene (PIG-A gene) in hematopoietic stem cells results in their inability to form a specific structure (GPI anchor) that carries a variety of cell surface proteins and, included in them, a variety of complement shielding proteins. Because of the loss of the GPI anchor, blood elements lose their cell surface proteins and that makes them more likely to be recognized by the complement system as if they were a foreign body that merit destruction.

Is hemolysis associated with any other conditions besides PNH?

PNH is a very rare cause of hemolysis.  Hemolytic anemia is broadly divided by the presence or absence of certain antibodies attached to the red cell, which are detected by a test known as Coombs’ test.  PNH tends to be Coombs test negative, meaning there are no specific antibodies attached to the red cell outer membrane which leads to their elimination by the spleen. PNH is a rare cause of Coombs' negative hemolytic anemia but there are many other causes such as hemoglobinopathies, hereditary red cell membrane defects, certain infections or drugs. After a physician identifies a Coombs negative hemolytic anemia, a diagnostic workup needs to be performed to exclude other causes of hemolysis before arriving at a diagnosis of PNH.

Are there degrees of hemolysis or hemolytic activity?

Yes, because the alternate pathway (one of the three known arms of the complement system) is always turned on – and that is why there can be ongoing, but low-level hemolysis In PNH. However, the complement level of activity and capacity to cell-destruct can be intensified by a variety of events, such as infections, surgery or pregnancy. These properties explain pronounced episodes of hemolysis to coincide with significant complement activation and resultant symptoms of anemia, hemoglobinuria and jaundice.

What are the symptoms of hemolysis? How does it make PNH patients feel?

Symptoms of PNH depend on the severity of disease, associated hemolysis, and whether the patient has other features of bone marrow failure such as low platelet or neutrophil count. Most patients with PNH develop anemia and some can have classic associated symptoms such as fatigue, and shortness of breath, depending on their level of anemia. There may be jaundice – yellowness of the eyes and skin --because of bilirubin, which is a byproduct of red cell destruction. Some patients describe dark urine, which is the result of hemolysis, and the presence of free hemoglobin in the urine (hemoglobinuria). Other symptoms include abdominal pain, dysphagia (difficulty swallowing) and clotting. If the hemolytic episode is severe, it can lead to kidney dysfunction.

How is hemolysis treated?

Since hemolysis in PNH is induced by complement activation, one way to control this process is by blocking the action of complement.  Eculizumab (Soliris®) is an antibody to a component of the complement (C5). It works by blocking the action of that part of the complement and prevents complement-induced red cells destruction.  Eculizumab has been studied in several clinical trials and is approved by the FDA for the control of hemolysis associated with PNH.

It should be stated that treatment for patients with PNH should be individualized.  Patients need to discuss the specifics of their disease and therapeutic options with their providers.
Interviewee: 

Jamile Shammo, MD, FACP, FASCP

Lead Photo
Position / Title: 
Associate Professor of Medicine
Institution: 
Rush University Medical Center

Dr. Shammo is an associate professor of medicine and pathology, Section of Hematology and Stem Cell Transplantation, Division of Hematology/Oncology, at Rush University Medical Center in Chicago where she spearheads the MDS/MPN/Bone marrow failure program. She is also director of the Hematology/Oncology Fellowship Program and CME Course Director in the Division of Hematology/Oncology.  After earning a medical degree with honors from Aleppo Medical School in Syria, Dr. Shammo completed internships and residencies in the departments of pathology and internal medicine at McGaw Medical Center of Northwestern University, in Evanston, and a 3-year fellowship in the Division of Hematology/Oncology at University of Chicago.  She is board certified in anatomic and clinical pathology, internal medicine, and hematology, and board eligible in oncology.  She is also a fellow of the American Society of Clinical Pathologists and American College of Physicians, and is a member of the American Society of Hematology, the American Society of Clinical Oncologists, and the American College of Physicians.  Dr. Shammo received the Department of Medicine Service and Teaching Award from Rush University Medical Center in 2003.  She has authored or co-authored over 40 publications, including abstracts, posters, book chapters, and online CME activities, as well as articles published in Blood, JCO, Clinical Lymphoma, Journal of Heart and Lung Transplantation, Cytotherapy, and American Journal of Clinical Pathology, among others. Additionally, she functions as a reviewer for several medical journals and as an editor for the Journal of Clinical Oncology.  She has designed and was involved as principal investigator for many clinical trials related to chronic myelogenous leukemia, MPN’s, PNH, and myelodysplastic syndromes.  As an invited speaker, Dr. Shammo has presented her research at national and international meetings and conferences.