Page 658 - Hematology_ Basic Principles and Practice ( PDFDrive )

560 Part V Red Blood Cells

percent of genotype 1 patients had sustained viral response as well as deferoxamine. 133,223 Deferiprone seems to remove iron from the heart
25% of genotype 2 and 3 patients; median transfusion requirements effectively despite its relative inefficiency in controlling hepatic iron
increased by 44% after 24 weeks of treatment, and LIC increase of content. 133,223,307 Deferasirox treatment for 1 to 2 years has also been
more than 5 mg/g dry weight occurred in 29% of patients, but overall shown to reduce cardiac iron and improve cardiac MRI T2* in
LIC remained stable over the course of the study. In addition, neu- patients with transfusional iron overload. 308,309 Additional studies are
300
tropenia occurred in 52% of patients. New oral therapies that do needed to confirm these observations and to establish the relative
not contain ribavirin or interferon are available to treat hepatitis C, roles of deferiprone, deferasirox, and deferoxamine or a combination
although there is minimal experience in thalassemia to date. thereof in the management of patients with established iron-related
310
Pigmentary gallstones caused by high levels of bilirubin produc- heart disease. In patients who have undergone BMT, improve-
tion are found in an increasing number of patients older than 4-years ments in left ventricular contractility and diastolic function accom-
311
of age. Two-thirds of patients have multiple calcified bilirubinate pany the removal of excess iron by phlebotomy. Heart transplantation
302
calculi after the age of 15 years. Gallbladder surgery is not usually and combined heart–liver transplantation have been performed suc-
indicated unless biliary colic or obstructive jaundice has occurred. cessfully in patients with end-stage cardiac disease. 312–314
Sterile pericarditis occurs in some patients with massive iron
315
overload. Although pericarditis is most often attributed to hemo-
Heart siderosis, an association with β-hemolytic streptococcal infection and
316
other infectious agents has also been suggested. Therapy usually
Cardiac abnormalities are important causes of morbidity and mortal- consists of bed rest, treatment of infection, management of superim-
ity in patients with thalassemia major. Cardiac enlargement secondary posed congestive heart failure, and the use of salicylates or cortico-
to anemia is almost always present in untransfused children. Before steroids. Occasionally, pericardectomy may be indicated.
the availability of chelation therapy, myocardial hemosiderosis and
serious iron-induced cardiac diseases were inevitable during the
second decade. These problems still occur often in older patients with Lungs
thalassemia who are poorly compliant with chelation therapy, and
heart disease, usually in the form of cardiac failure or serious arrhyth- Mild abnormalities of pulmonary function are common in patients
mias, remains the most common cause of death in patients with with thalassemia but rarely cause clinical problems. Some patients
thalassemia major. 189,191 exhibit primarily restrictive defects 317,318 ; others experience mild to
Left-sided heart failure predominates in patients with thalassemia moderate small airway obstruction and hyperinflation. 319–321 Most
303
major and is characterized by dyspnea and orthopnea. Right-sided patients have a decreased maximal oxygen uptake and anaerobic
322
heart failure is less common but may be the presenting cardiac finding threshold; these do not normalize after transfusion. Postsplenectomy
in older patients with more severe iron overload. Symptoms include thrombocytosis and other prothrombotic changes can predispose to
hepatic pain, abdominal discomfort, and peripheral edema. Acute pulmonary vascular occlusion and pulmonary hypertension. 323–326
myocarditis, which occurs in approximately 5% of patients with Treatment with high doses of the iron chelator deferoxamine
thalassemia, is frequently followed by acute or chronic heart failure. 304 may also be associated with acute deterioration of pulmonary
Early electrocardiographic abnormalities include a prolonged P–R function. 176,177
interval, first-degree heart block, and premature atrial contractions.
Later, ST-segment depression and ventricular ectopic beats constitute
ominous indicators of myocardial damage. Periodic evaluation of Kidneys
cardiac function is essential to detect iron-induced heart disease and
to identify patients who will benefit from more intensive chelation The kidneys are frequently enlarged, partly because of extramedullary
therapy (see later discussion). Unfortunately, by the time cardiac hematopoiesis and partly because of marked dilation of the renal
327
results of studies such as echocardiography and 24-hour rhythm tubules. The urine is often dark brown, reflecting the excretion of
328
monitoring become abnormal, clinical heart disease is imminent. products of heme catabolism. The urine also contains large amounts
Whether assessment of cardiac iron by MRI using T2* or other of urates and uric acid.
measures can better anticipate the development of clinical heart The Thalassemia Clinical Research Network studied the preva-
disease is currently under investigation. lence of renal abnormalities in patients with thalassemia major and
In the absence of intensified chelation therapy, ventricular dys- thalassemia intermedia receiving deferoxamine chelation. One-third
function progresses rapidly to chronic refractory congestive heart of thalassemia patients who were not regularly transfused had abnor-
failure, and arrhythmias become increasingly difficult to control. In mally high creatinine clearance. Regular transfusions were associated
the past, death usually occurred within 1 year of onset of heart failure. with a decrease in clearance (p = .004). Almost one-third of patients
303
More recent data demonstrate a survival rate of 48% at 5 years. with thalassemia had hypercalciuria, and regular transfusions were
Survival is notably poorer in patients with heart failure after myocar- associated with an increase in the frequency and degree of hypercal-
ditis or with heart failure accompanied by arrhythmias. 304 ciuria (p < .0001). Albuminuria was found in more than half of
In addition to standard therapy for heart failure and arrhythmias, patients but was not consistently associated with transfusion therapy.
including angiotensin-converting enzyme inhibitors, β-blockers, In summary, renal hyperfiltration, hypercalciuria, and albuminuria
diuretics, and antiarrhythmic agents, the pretransfusion Hb level are common in patients with thalassemia. Higher transfusion inten-
should be maintained between 10 and 12 g/dL. The volume of sity is associated with lower creatinine clearance but more frequent
transfused RBCs should be reduced as needed to prevent acute fluid hypercalciuria. 329
overload. Because the iron-overloaded myocardium has little capacity
to improve its performance unless excess iron is removed, intensive
chelation therapy is a critical part of the management of heart disease Spleen and Splenectomy
in patients with thalassemia. Several studies have shown that heart
failure can be reversed in many patients with the use of continuous Massive splenomegaly is unusual in regularly transfused patients, but
treatment with deferoxamine. 181,305,306 The benefits of this approach even mild or moderate splenomegaly may be associated with findings
may derive from the reduction in cardiac iron stores, the prevention of hypersplenism, including thrombocytopenia, neutropenia, and
of acute toxicity from nontransferrin-bound iron, or a combination increasing anemia. The usual indication for splenectomy is a progres-
of these two mechanisms. Recent data suggest that deferiprone sive increase in transfusion requirements caused by hypersplenism.
may be more effective than deferoxamine in reducing the cardiac The transfusion requirements, and therefore the rates of iron loading,
iron load and treating iron-induced cardiac disease, perhaps because of splenectomized patients are often considerably less than those
of deferiprone’s ability to enter cardiac cells more rapidly than of patients whose spleens are intact. 247,307,330,331 A transfusion