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New Treatments for Neutropenia 

Neutrophilia. The nature of the neutrophil mass and where it resides allows for the neutrophil counts to be extremely variable and very rapidly so. That there can be acute pool shifts that are reflected in sudden neutrophilias that are caused by two sources; principally a mobilization of cells that are hidden in the intravascular space in the marginated pool, and are released into the circulation, rapidly increasing absolute neutrophil counts. Adrenergic cholinergic stimuli, for example, that are associated with stress or exercise will do this. In fact I can take any of you and have you run up and down stairs for a little bit and double your neutrophil count.

These different types of neutropenias are associated with different syndromes. We are talking in all cases here about severe neutropenias. That which I talked about second, acutely developing neutropenias, are associated with prostration, high fever and sepsis and these are the ones that

Most of the associated conditions that we have talked about relate to immune or based upon a pathogenesis in which immune mechanisms are involved. There have been a variety of immune mechanisms that have been described in these conditions; cell-mediated suppression of progenitor cell growth, particularly in lymphoproliferative disorders and other types of idiopathic neutropenias. The most well-studied, however, immune phenomenon that may be associated with idiopathic neutropenia has to do with the presence of anti-neutrophil autoantibodies. The presence of these antibodies, which are detected in a variety of ways, in no way is a direct reflection of neutropenia or indeed predictive of the severity or consequences of the neutropenia,

I want to touch very briefly, before we end, on certain congenital syndromes of neutropenia which are generally not within the bailiwick of an adult hematologist. The most common of these, Kostmann’s syndrome; this is a congenital severe infantile agranulocytosis syndrome, often runs in families. One of the important insights in recent years is the recognition that GCSF can, in many of these infants, be life saving in reversing the agranulocytosis in these patients. There is another phenomenon which commonly occurs as a congenital or heritable syndrome, cyclic neutropenia, which is depicted here. This is a very unusual but distinctive pattern of neutropenia, which occurs in cyclic intervals of approximately three weeks, which are very regular in patients.

Another syndrome which I want to touch on briefly, Chediak-Higashi syndrome. This is a congenital syndrome which is associated with neutropenia which may come to your attention in this way; the cardinal feature of Chediak-Higashi syndrome is related to an inability of cells in general - neuronal cells, mesenchymal cells, blood cells - to form cytoplasmic granules normally. And they make large cytoplasmic granule formations. It’s particularly distinctive in the neutrophils where these large granules are formed. So in addition to this neutropenia they have this unusual morphologic abnormality. Again, this diagnosis is rare. It’s made in children primarily. I would like to point out, however, that the same morphologic abnormality can rarely be seen as a dysplastic feature of neutrophil development in acute leukemia, myeloid leukemia, or in myelodysplastic syndrome that’s evolving into leukemia. A very similar, sort of pseudo Chediak-Higashi syndrome morphology can be observed.

I want to finish now, and the Chediak-Higashi syndrome permits this, with a discussion of intrinsic abnormalities in neutrophil function. There are a series of syndromes which are heritable and congenital which hematologists in general should be aware of. I already mentioned Chediak-Higashi syndrome, which is associated with a variety of different functional abnormalities which are listed here. There are two other syndromes however that have been worked out on a molecular basis, and perhaps because of this reason, are judged to be important as a knowledge base for hematologists in general. The first of these is chronic granulomatous disease. The second, which I’ll discuss, is something called the LAD or leukocyte adhesion deficiency. Both of these are congenital, heritable diseases. Chronic granulomatous disease results from an abnormality in a very important bactericidal function of phagocytes in

The other disease that I want to mention is leukocyte adhesion deficiency. This is also a pediatric disease. It is a disease in which the principle neutrophil integrin, the CD11BCD18 adhesion proteins, are missing. Usually because of an inability to make this. However there are other forms in which this is the missing component. This disease has actually revealed the important functional implications of this particular adhesion protein complex on

I want to finish with a final slide, merely to emphasize that in considering abnormalities of neutrophil function, the most common are those which are acquired. They can occur in all steps of neutrophil function; release from the marrow, their ability to circulate normally, the ability to aggregate, to undergo adhesion to the endothelial surface prior to emigration, and then finally the ability to de-granulate and to undergo phagocytosis and killing. All of these may be affected by acquired conditions. Particularly by neoplastic conditions that affect the