Page 861 - Hematology_ Basic Principles and Practice ( PDFDrive )

744 Part VI Non-Malignant Leukocytes

synthase, the enzyme that catalyzes the first step in the biosynthesis Some patients with type 1 Gaucher disease have excessive bleeding
of glucosylceramide and other glycosphingolipids. Miglustat is an that is disproportionate to their platelet counts and coagulation
orally administered compound that has been shown to effectively profiles. Abnormal platelet function has been described in patients
36
decrease organ volume and improve hematologic parameters in with type 1 Gaucher disease with abnormal bleeding tendencies.
34
patients with type 1 Gaucher disease. However, gastrointestinal side These defects have been attributed to defects in platelet adhesion as
effects are fairly common with oral treatment, so the use of Miglustat well as aggregation. Coagulation deficiencies, particularly low factor
37
has been limited to Gaucher disease patients for whom ERT is not levels of factor XI, have also been described. Because both factor XI
suitable. Miglustat is also used in patients with type C NPD, which deficiency and type 1 Gaucher disease are relatively common in the
12
causes progressive and severe neurologic disease. Most patients with Ashkenazi Jewish population, this finding may reflect concurrence of
type C NPD have mutations in an integral membrane protein the two disorders. However, a report describing Egyptian type 1
involved in cholesterol transport (NPC1). However, because NPC1 Gaucher disease patients with deficiencies in factors II, V, VII, VIII,
is a nonsoluble transporter, protein-replacement therapy is not a X, XI, and XII supports the concept that the coagulopathy is not
therapeutic option at the present time. Using animal models, inves- limited to Ashkenazi Jewish patients and may have a distinct patho-
38
tigators showed that the neurologic pathology in type C NPD was physiology. In fact, many patients with Gaucher disease have sig-
37
associated with the secondary accumulation of a particular glycolipid, nificant deficiencies (less than 50%) of multiple coagulation factors.
GM 2 ganglioside. Based on this finding, studies were carried out This is associated with elevations of coagulation activators, suggesting
using Miglustat to inhibit glycolipid biosynthesis, resulting in reduc- ongoing activation of the coagulation cascade with a resultant con-
tion of GM 2 storage and partial neurologic improvements. Clinical sumption of coagulation factors. 38
trials of Miglustat in type C NPD patients revealed stabilization or Anemia in patients with Gaucher disease is usually mild but
improvement of some clinical markers. occasionally may be severe and can be associated with leukopenia.
Another small-molecule approach under development for the These findings are also probably attributable to sequestration of cells
LSDs is based on the use of enzyme-specific inhibitors that can act in the spleen, as well as dysfunctional bone marrow production of
as “chaperones” of the corresponding mutant proteins, thereby facili- cells as the disease progresses. The mainstay of treatment for the
tating their delivery to lysosomes and enhancing their residual hematologic abnormalities in Gaucher disease is ERT. ERT typically
enzymatic activities. Such “chaperone” therapy is currently being produces a remarkable improvement in the platelet count, hemoglo-
24
evaluated in clinical trials for several LSDs. Numerous other bin, and white blood cell count, as well as a reduction in spleen size.
approaches also have been or are being evaluated in the various LSD ERT may also partially improve the coagulation profile. 38
animal models, including targeting of inflammatory pathways and In patients with massive splenomegaly, splenectomy is often
stem cell-based therapies, and in the future patients should have approached as a treatment option with the expectation that it will
access to various therapeutic choices. As with ERT, the effects of these improve the platelet count and reduce the risk of splenic rupture.
individual therapies are likely to be disease and organ specific, and it However, the spleen is an important reservoir for storage material,
is expected that in the future effective treatment of LSD patients will and its removal can displace lipid deposition to other organs, accel-
require a combination of these approaches. erating the rate and severity of disease.
HEMATOLOGIC MANIFESTATIONS OF LYSOSOMAL Types A and B Niemann–Pick Disease: Acid
STORAGE DISEASES Sphingomyelinase Deficiency

Hematologic findings are associated with several LSDs, but in two, The hematologic findings in types A and B NPD are similar to those
Gaucher disease and NPD (types A and B), hematologic abnor- in Gaucher disease and may include thrombocytopenia and anemia.
malities are among the common presenting features. Hematologic Splenic enlargement is also a common presenting feature of this
findings should be considered in the differential diagnosis of both disorder, and sequestration of cells in the spleen is thought to be the
disorders, and patients with Gaucher disease or NPD may be seen underlying cause of the low platelets, low hemoglobin, or leukopenia
by hematologists to manage their symptoms. In the next section (Fig. 53.1A and B). Some patients with type B NPD have excessive
the hematologic features of these disorders are discussed, as well as bleeding without significant thrombocytopenia or coagulopathy.
several other relevant issues related to hematologic manifestations Frequent and prolonged epistaxis can be particularly problematic and
and LSDs. in some extreme cases may require cauterization, packing, and blood
transfusions.
As with Gaucher disease, a primary cellular site of pathology in
Gaucher Disease: β-Glucosidase Deficiency types A and B NPD is the monocyte-macrophage system, and the
characteristic pathological cells are referred to as Niemann–Pick cells.
Cells of the monocyte–macrophage system are the primary sites of These can be distinguished from Gaucher cells by an experienced
pathology in this disorder. In general, these cells are enriched for pathologist, but are frequently misclassified or not recognized, result-
lysosomes and highly active in phagocytosis. As such, disruption of ing in misdiagnosis. They are also readily evident in blood smears,
lysosomes may have a profound effect on their function. An impor- bone marrow, and other organs, and increase as the disease progresses.
tant diagnostic hallmark of Gaucher disease is the presence in a As noted above, there is another form of NPD (type C) that is caused
variety of tissues of lipid-filled cells derived from the monocyte– by primary defects in cholesterol transport. These patients may also
macrophage system, referred to as Gaucher cells. These cells are readily present with mild hematologic findings and an enlarged spleen,
evident in the bone marrow, but can also be seen in blood smears although in general the hematologic findings are less severe than in
and histologically in other tissues, including liver, spleen, lung, and patients with types A and B NPD (see Fig. 53.1C and D)
others. As the disease progresses, the deposition of Gaucher cells in
these organs increases.
Bleeding is a common presenting symptom of patients with Fabry Disease: α-Galactosidase Deficiency
Gaucher disease and is primarily caused by thrombocytopenia. The
major sites of bleeding are mucocutaneous, including epistaxis, easy Unlike Gaucher and NPD diseases, in Fabry disease the monocyte–
bruising, and gingival hemorrhage. Thrombocytopenia in Gaucher macrophage system is not primarily affected. In this disorder, the
disease is generally thought to be caused by splenic sequestration of primary site of accumulation of glycolipids occurs in the vascular
platelets. Spleen enlargement is present in all symptomatic patients endothelial and smooth muscle cells that surround blood vessels. As
and is a common presenting sign of the disease. Splenic enlargement such, constriction of blood vessels occurs, leading to skin lesions,
in Gaucher disease may be massive, up to 75-fold normal. 35 strokes, and kidney dysfunction. It is noteworthy that several of the