Page 1232 - Hematology_ Basic Principles and Practice ( PDFDrive )

1078 Part VII Hematologic Malignancies

Acetazolamide therapy has been evaluated in two double-blind, Frequently, the PTE resolves with removal of the native kidney.
placebo-controlled, randomized clinical trials of patients with CMS. Plasma EPO levels can be normal or high in patients with PTE
Acetazolamide is an inhibitor of carbonic anhydrase and stimulates The molecular basis of PTE remains unclear; AngII is believed,
ventilation by promoting the development of metabolic acidosis. however, to play an important role in its pathogenesis by sustaining
Furthermore, acetazolamide reduces renal EPO production. Patients the secretion of EPO. Growing evidence indicates that increased
with CMS were randomized to receive placebo or acetazolamide AT1R expression makes erythroid progenitor cells hypersensitive to
therapy at a dose of 250 or 500 mg/day for 21 days. Drug therapy AngII. Furthermore, AngII can modulate release of erythropoietic
at both doses of acetazolamide resulted in reduction of hematocrit stimulatory factors, including EPO and IGF-1. Androgens are
levels by 7% (p < .001) and serum EPO levels by 50–67% (p < .1), thought to play a role in the development of the syndrome. Andro-
with an increase in nocturnal oxygen saturation levels of 5% (p < gens can directly affect erythroid progenitor cells or stimulate EPO
.01). Presently, 250 mg of acetazolamide daily appears to be an production or actually the RAS. Treatment of patients with PTE
inexpensive, nontoxic, and effective therapy for CMS. includes intermittent phlebotomy or administration of drugs. The
ACE inhibitor enalapril suppresses the renin–angiotensin pathway
Smokers’ Polycythemia or Carbon Monoxide- and virtually eliminates the need for therapeutic phlebotomy in these
patients. Maximal reduction of hemoglobin levels is evident 6 months
Induced Polycythemia after starting therapy with either ACE inhibitor or angiotensin recep-
tor blockers. Some patients are exquisitely sensitive to these medica-
Smoking is the most common cause of secondary polycythemia. tions and may become severely anemic. The AT1R antagonist losartan
Those affected have a carboxyhemoglobin-induced increase in RBC has been shown to be as effective in treating PTE as are ACE inhibi-
mass or decrease in plasma volume, either of which is reversible tors. Therapy is usually begun at hematocrit levels above 55% with
with smoking cessation. Excessive carbon monoxide exposure can the hope of maintaining hematocrit levels below 50% to reduce the
also be attributed to exposure to industrial emissions and automo- risk of thrombosis. Furthermore, the ACE inhibitor fosinopril in an
bile exhaust. Carbon monoxide binds to hemoglobin with a more open-label crossover trial with theophylline was shown to produce a
than 200-times greater affinity than oxygen, resulting in not only dramatic reduction in hematocrits in patients with PTE (51.3–43.7%;
occupation of one of the heme groups of hemoglobin but also an p < .005). Low doses of ramipril, another ACE inhibitor, normalized
increase in the O 2 affinity by the remaining heme group. Individuals the hematocrit level in 26 out of 27 patients with PTE after a mean
smoking even one pack of cigarettes a day frequently have elevated of 127 days of therapy.
hematocrit levels. These patients characteristically have normal
blood gases and elevation of carboxyhemoglobin levels, resulting in
a reduction in P 50 o 2 . The elevation of the hematocrit level is reversed Polycythemia Accompanying Kidney and Liver
with interruption of the smoking behavior. Increased hematocrit Diseases and Neoplastic Disorders
levels have been observed in 3–5% of heavy smokers. Although
these patients are not immune to thrombotic complications, the Polycythemia has been reported in association with kidney diseases
number of thromboembolic events is lower than in patients with PV. such as renal cell carcinoma, renal artery stenosis, hydronephrosis,
Polycythemia has also been reported to be associated with hookah Wilms tumor, and polycystic kidney disease, paragangliomas, and
use. A hookah is an oriental pipe containing tobacco often mixed pituitary adenomas. Renal tumors account for approximately one-
with molasses and fruit flavors connected by a long flexible tube third of cases of tumor-associated polycythemias. The tumor tissue
that draws the smoke to the bowl of water. Hookah use exposes has been demonstrated to produce excessive amounts of EPO, and
the user to generous amounts of carbon monoxide, resulting in the erythrocytosis resolves with surgical resections of the tumor. The
erythrocytosis. mechanisms underlying the activation of the EPO gene have been
related to somatic mutations of the VHL gene in clear-cell renal
carcinomas. Clear-cell carcinoma is associated with erythrocytosis
Postrenal Transplantation Erythrocytosis and high serum EPO levels caused by increased expression of EPO
mRNA, HIF-1α, and HIF-2α. These abnormalities were related to
Postrenal transplantation erythrocytosis (PTE) is defined as a persis- a point mutation in the VHL gene that impaired the bindings of
tently elevated hematocrit level greater than 51% after renal trans- HIF-1α to VHL, leading to its accumulation and increased produc-
plantation without an elevation of the WBC count or platelet count. tion of EPO. Polycythemia is also a well-described paraneoplastic
PTE is a potentially dangerous condition found in approximately manifestation of hepatocellular carcinoma in 2.5–10% of patients
10–15% of renal allograft recipients. PTE usually develops within and is again caused by the production of EPO by the tumor. Polycy-
8–24 months after a successful renal transplantation and resolves themia in hepatoma patients is strongly related to tumor burden and
spontaneously within 2 years in about 25% of patients despite per- elevated α-fetoprotein levels. Polycythemia has also been associated
sistently good renal allograft function. PTE is more common in males with cerebellar hemangioblastomas and very large uterine fibromas.
and may recur in the same patient after a second successful renal In tumor-associated erythrocytosis, EPO production has been shown
transplantation. Factors that increase the likelihood of its develop- to be autonomous of hypoxic stimuli. Paragangliomas are tumors
ment are a lack of EPO therapy before transplantation, a history of arising from extraadrenal paragangliar neural crest cells. Most para-
smoking, diabetes mellitus, transplant-related renal artery stenosis, gangliomas arise retroperitoneally or within the peritoneal cavity and
retention of the native kidney, low serum ferritin levels, and normal are associated with high EPO levels and erythrocytosis. After tumor
or high pretransplantation EPO levels. PTE is also more frequent in resection, reduction of the EPO levels and erythrocytosis occurs.
patients who do not experience rejection. There is some evidence that Germ-line mutations involving two Krebs cycle enzymes, fumarate
the use of cyclosporine as an immunosuppressive agent is associated hydratase and succinate dehydrogenase, have been implicated in the
with increased risk of PTE. At higher hematocrit levels (usually hereditary paraganglioma–pheochromocytoma syndrome. In tumors
>60%), thrombotic events may complicate the clinical course of deficient in these enzymes fumarate and succinate accumulate, which
patients with PTE. inhibits PHD, leading to accumulation of HIF-1α and eventually
Approximately 60% of patients with PTE experience malaise, resulting in erythrocytosis. In another patient with a paraganglioma
headache, plethora, lethargy, and dizziness. In addition, from 10% who did not have the inherited syndrome but had extreme erythro-
to 20% develop thromboembolic complications involving either cytosis, a germ-line mutation in PHD2 was demonstrated. In this
arteries or veins. Retention of the native kidney is essential for the patient’s tumor, tumor analysis showed LOH with the mutant allele
development of PTE in most cases. Although the transplanted kidney predominating, which was associated with a loss of function. The
produces EPO under normal regulatory mechanisms, the native degradation of both HIF-1α and HIF-2α was decreased. These data
kidney overproduces EPO despite the development of erythrocytosis. indicate that PHD2 can act as a tumor suppressor gene. The tumor