Case: 48 year old female with shortness of breath symptoms
Throughout this case study, we reference relevant medical algorithms that can help physicians more quickly and thoroughly diagnose, assess, and manage health conditions for their patients.
Jackie is a 48-year old female who presented to the Emergency Department with shortness of breath that was present at rest and which severely limited activity.
Her past medical history was only significant for asthma and a 30 pack-year smoking history. There was a family history of colon cancer. She had no recent infections and denied any exposure to chemicals.
Review of systems identified heavy menstrual bleeding for the past year and recent abdominal discomfort. The physical exam identified severe pallor and petechiae.
The complete blood count (CBC) showed RBC 0.8 M per microliter with an MCV 127 fL. The platelet count was 6,000 per microliter without clumps. The white blood cell count was WBC 1,900 per microliter with an absolute neutropenia (800 per microliter). The testing was repeated to exclude dilutional artifact but showed the same results.
The patient felt much better after transfusion of red blood cells and platelets.
Because of the pancytopenia, a hematology consult was requested and a bone marrow biopsy performed. This showed a markedly hypocellular bone marrow without infiltrative processes, consistent with aplastic anemia.
Testing on the bone marrow included cytogenetics and FISH testing for myelodysplasia. Flow cytometry for paroxysmal nocturnal hemoglobinuira (PNH) was requested. Because of the recent transfusion the sample from the ED was sent to avoid a false negative result.
Flow cytometry showed 1.3% of granulocytes and 1.4% of monocytes to be negative for FLAER binding. Red blood cells showed a normal expression of CD59 (Type I). The patient was re-evaluated in light of these findings and a diagnosis of aplastic anemia PNH (AA-PNH) was made. She was started on immunotherapy with the possibility of allogeneic bone marrow transplant if unresponsive.
The initial presentation raised the possibility of pulmonary disease, but the pancytopenia and bone marrow identified the patient’s problem. Aplastic anemia involves production failure in bone marrow precursors. Production failure may range from mild to severe.
Aplastic anemia can occur in a large number of conditions, including:
- Infection (EBV, viral hepatitis, HIV, other)
Identifying a possible cause can be important in planning a management strategy.
Diagnosis of Paroxysmal Nocturnal Hemoglobinuria (PNH)
Paroxysmal Nocturnal Hemoglobinuria (PNH) is an uncommon disorder that is encountered with some frequency in patients with aplastic anemia. Categories include classic PNH and hypoplastic/aplastic forms.
While PNH is a clinical diagnosis, flow cytometry can be helpful in making the diagnosis. Cells affected by PNH lack glycophosphatidylinositol (GPI) anchoring proteins in the plasma membranes. Flow cytometry can detect an absence or deficiency of these proteins. GPI proteins bind aerolysin, a virulence factor of Aeromonas hydrophila. Fluorescein-labeled proaerolysin (termed FLAER) is a marker used in flow cytometry that binds to normal granulocytes and monocytes but not to PNH clones.
Thrombosis in PNH
Thrombosis can be a serious problem and is the most common cause of death in patients with classic PNH. Thrombosis can involve many sites, including hepatic vein thrombosis, deep vein thrombosis, and pulmonary emboli. It is more common when the PNH clone is elevated.
While the cause of thrombophilia in PNH is believed to be multifactorial, it is unclear which mechanisms contribute most to the prothrombotic state of PNH. Current treatment focus on complement inhibition with eculizumab to stop thrombosis, along with anticoagulation.
The prognosis of PNH is highly variable. Some cases are transient, some respond to immunosuppression and some require bone marrow transplant. Terminal complement inhibition with drugs such as eculizumab is also used and has been shown to improve quality of life and decrease thrombotic events.
- Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disease characterized by the expansion of hematopoietic stem cells (HSCs) and progeny mature cells, whose surfaces lack all the proteins linked through the GPI anchor. The disease is characterized by complement-mediated chronic intravascular hemolysis, resulting in hemolytic anemia and hemosiderinuria.
- PNH can also cause bone marrow failure and an intrinsic propensity to thromboembolic events.
- Early identification of PNH can be assisted with the use of medical algorithms.
- Treatment with biological agents, such as eculizumab, can improve quality of life.
- Combining medical training with powerful, evidence-based algorithms can help physicians diagnose, assess, and manage diseases.
About the Authors
Adam Vohra is a Health Innovation Fellow at Apervita. He is currently a dual-degree MD/MBA student in his final year at The University of Chicago Pritzker School of Medicine and Booth School of Business. He plans to pursue a residency in internal medicine next year. Adam is interested in issues related to health care quality and delivery and has published research on predictors of intensive care unit admission for pneumonia. He is currently working on research to create analytics to predict heart failure readmissions. Adam is also involved heavily in health care policy and currently serves on the Board of Trustees of the Illinois State Medical Society as the sole medical student member. In the past, Adam has also represented medical students in the American Medical Association House of Delegates. Prior to coming to The University of Chicago, Adam completed his undergraduate studies at Northwestern University where he studied biology and political science.
Dr. Chad Rudnick, MD, FAAP is a board-certified pediatrician in Boca Raton, FL. He is the Medical Director of The Medical Algorithms Company. A proponent of incorporating medical technology into his practice, Dr. Rudnick uses telemedicine and medical algorithms from The Medical Algorithms Company in his daily practice to better serve his patients and their families. An accomplished medical writer, he maintains a popular pediatric blog, All Things Pediatric, and has written for numerous online and print publications including KevinMD.com.
John Svirbely, MD is a founder and Chief Medical Officer of The Medical Algorithms Company and the primary author of its medical algorithms. John is a co-founder of the Medical Algorithms Project and has developed its medical content for nearly 20 years. He has a BA degree from the Johns Hopkins University and his MD from the University of Maryland. He is a board-certified pathologist with a fellowship in medical microbiology and biomedical computing at Ohio State University. Currently he is in private practice in Cincinnati, Ohio. He has authored multiple books and articles on medical algorithms.