PBL Sessions: Hematology Organ System - 2
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Page 10
Final Discussion of Case:
Tasks
Discuss the logic of the stem cell transplant procedure for this patient.
Review the causes for hemolysis and how to distinguish them.
Discuss how the underlying disease process in this patient led to the various findings.
Prepare your group representative for the case wrap up session.
Key Issues
Your patient is a 37-year-old woman who has experienced increasing fatigue over the past 6 months. She has less energy. She finds it difficult to climb more than one flight of stairs. In the past month she has noted pain with swelling of her right leg.
Pathologic / Radiologic Learning Issues
Clinical Learning Issues
Discussion
Pain and Anxiety Management
Pain threshold is different for everybody and not absolute. Pain is always subjective and people respond behaviorally based on an individual genetically determined threshold and prior experience.
Prior experience can set a negative learning paradigm in place: needle stick ----> pain. With repeated trials conditioning takes place.
An anxiety response consists of internal arousal, cognitions (e.g., "this is going to hurt") and outward behavior (tensing of muscles).
What can the physician do?
Direct the patient, before the procedure, to practice progressive muscle relaxation (a physiologist named Jacobson realized that it is not possible for muscles to be tense and relaxed at same time). This is a good intervention to reduce anxiety, and with muscles not being so tense, needles do not hurt as much.
Have the patient practice imagery. Have her imagine that she is doing something relaxing during the procedure. This distraction technique interferes with the negative thoughts and breaks the anxiety cycle.
Have the patient perform slow deep breathing. This is a distractor, as above.
These techniques have plenty of research to back up their effectiveness with both adults and children. One does not need a psychiatric consult. These techniques can be done anywhere. There is an additional benefit in that the health care team is working with the patient, and there is less time spent overall and there is less aversive behavior in the long run.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
PNH is an acquired clonal disease of bone marrow stem cells, and all hematopoietic elements produced in the marrow, including hematopoiesis, myelopoiesis, and megakaryopoiesis, can be affeced. Since normal clones of stem cells do not completely disappear with PNH, the proportion of abnormal cells is variable among patients and can even vary over time in a single patient. PNH occurs when an inactivating somatic mutation in a gene on the X-chromosome occurs. This gene, known as pig-A or PIGA, is required for the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor that attaches many proteins to the external cell membrane surface. A partial or complete absence of PIGA results in the absence of those proteins.
Two such cell surface proteins that have functional significance are PNH decay accelerating factor (DAF), also known as CD55, and CD59. CD55 and CD59 block cell surface complement activation. When these proteins are deficient or absent, then RBCs are much more susceptible to complement-mediated lysis. In addition, platelets are more likely to initiate thrombosis.
The clinical manifestations of PHN relate to involvement of the three major hematopoietic cell lines:
As the name of the disease implies, there can be episodic hemolysis leading to hemoglobinuria, and it can occur at night, but this classic pattern is not seen in most PNH patients. The anemia can be quite variable. The hemoglobinuria can be intermittent to absent. However, hemosiderinuria is present in most patients. Hemolysis can be intermittent because conditions such as infections that increase complement activation occur sporadically. Iron deficiency anemia can occur due to significant iron loss via the urine. Thus, the anemia can be normocytic to microcytic, depending upon the severity of iron deficiency. Aplastic anemia may occur. The degree of intravascular hemolysis is usually not severe, but in some instances hemolysis is marked and may lead to acute renal failure.
Though platelet survival is normal in PNH, complement activation leads to platelet aggregation with thrombosis. Platelet numbers can be reduced. Thrombosis is primarily venous. The intra-abdominal veins are most often affected. Involvement of hepatic and portal veins leads to Budd-Chiari syndrome. Cerebral venous thrombosis can also occur and has a mortality rate of 50%. For a given patient, thrombotic episodes tend to recur at the same site, probably as a consequence of endothelial damage.
Granulopoiesis is altered, resulting in mild granulocytopenia. Though there are reduced numbers of functional leukocytes, there are usually enough normal leukocytes to prevent significant immune deficiency. Some patients with PNH may develop myelodysplastic syndromes or acute leukemia, usually acute myelogenous leukemia.
The traditional screening tests for PNH have been the sucrose hemolysis test ("sugar water" test) and the Ham acid hemolysis test. RBCs incubated in an isotonic solution of sucrose with low ionic strength exhibit increased binding of complement. In PNH the RBCs are abnormally sensitive to complement and will demonstrate lysis after 30 minutes of incubation in this solution. This test suggests, but does not confirm, PNH. The Ham acid hemolysis test is a confirmatory test for PNH. In acidified serum, complement is activated by the alternate pathway and binds to RBCs. The abnormally sensitive PNH cells will rupture.
The most specific confirmatory testing for PNH involves flow cytometry to determine populations of peripheral blood cells with CD55 and CD59 binding. In PNH, there will be increased numbers of cells lacking CD55 and CD59. The proportion of abnormal cells indicates the probable severity of the disease.
The median survival with PNH is about 14 years. A third of persons who survive more than 10 years have a spontaneous remission. Treatment of anemia in PNH can include transfusion of washed RBCs (to lessen hemolysis). Treatment of iron deficiency with iron may actually exacerbate hemolysis, because the sudden increase in marrow RBC production, and the younger RBCs are more sensitive to complement-mediated hemolysis. Glucocorticoid therapy with prednisone has been utilized to reduce complement-mediated lysis. Anticoagulation may be required for thrombotic episodes. Use of stem cell transplants has been highly successful for treating PNH, but must be weighed against the potential complications of this treatment, and the possibility of spontaneous remission.
References
Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253-1258.
Krauss JS. Laboratory diagnosis of paroxysmal nocturnal hemoglobinuria. Ann Clin Lab Sci. 2003;33:401-406.
Rosse WF. Paroxysmal nocturnal hemoglobinuria as a molecular disease. Medicine (Baltimore). 1997;76:63-93.
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