Page 795 - Williams Hematology ( PDFDrive )

770 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 771

response to increased hypoxic stress, thereby predisposing to ische- for intracranial hemorrhage are as those for non-SCD–related intracra-
mia. 181,182 Stenosis of large vessels, especially of the circle of Willis, nial hemorrhage; role of transfusion is less clear in SCD especially when
without the classic atherosclerotic plaque occurs in conjunction with cause of intracranial hemorrhage is unclear. Patients with moyamoya
a multitude of other factors, including chronic hemolysis, deranged disease who have a particularly poor outcome may benefit from revas-
NO metabolism and impaired vascular autoregulation, and can lead to cularization using encephaloduroarteriosyangiosis. 205,206
stroke. Rare causes of cerebral vascular disease include fat emboliza-
182
tion and venous sinus thrombosis. Moyamoya type fragile collaterals Genitourinary Systems
have been reported in more than one-fifth of patients with prior stroke, Renal Failure Sickling of HbSS erythrocytes in the hypoxic, acidic, and
possibly leading to hemorrhagic stroke in later life. 183–188 hypertonic environment of the renal medulla, oxidative stress, increase
Risk factors for ischemic stroke include transient ischemic attack, in prostaglandins and endothelin-1 in the kidney, and abnormalities of
recent or recurrent ACS, nocturnal hypoxemia, silent infarcts, hyper- the renin angiotensin system contribute to the pathophysiology of renal
207
tension, elevated lactic dehydrogenase, and leukocytosis, whereas ane- disease in SCD. The incidence of renal failure varies between 4 and 20
mia, neutrophilia, the use of glucocorticoids, and recent transfusion percent. 208–211 Dehydration is the most common cause of acute renal fail-
are independent risk factors for hemorrhagic stroke, especially in chil- ure in SCD. Isosthenuria is highly prevalent in SCD, may increase the risk
dren. 175,189–195 Sickle cell genotypes other than HbSS carry a lower risk, as of dehydration, and is irreversible. Glomerular hypertrophy, focal and
212
do patients with HbS–α-thalassemia. 175,196,197 The best predictor of stroke segmental glomerular sclerosis, and hemosiderin deposition in proximal
risk, however, is an increased blood flow velocity in major intracranial renal tubular epithelium have been described; however, no single lesion
197
arteries on TCD ultrasonography. Blood flow velocities less than 170 is pathognomonic of sickle cell nephropathy. Cystatin C is an accurate
cm/s are considered normal. Velocities between 170 and 200 cm/s are marker of glomerular filtration and therefore is preferable to serum cre-
termed conditional, and velocities of greater than 200 cm/s are consid- atinine in estimating renal function. 213,214 Glomerular hyperfiltration,
ered high and are associated with a 10-fold increase in ischemic stroke microalbuminuria, and macroalbuminuria occur sequentially in SCD
in children 2 to 16 years of age. patients starting in infancy and increasing in frequency with age. 122,161,215
There is an increased frequency of stroke among siblings of patients Incidence of microalbuminuria is greater than 60 percent in those over
213
with SCD than would be expected by chance alone, raising the possibil- age 35 years. End-stage renal disease requiring dialysis carries a poor
183
ity of other modifier genes contributing to stroke risk. The TNF (–308) prognosis and is associated with a median survival of 4 years. 216
G/A promoter polymorphism is associated with increased large-vessel Angiotensin-converting enzyme inhibitors decrease proteinuria
stroke risk as is the IL-4–receptor gene 503 S/P variant, although it did and hyperfiltration in SCD; however, large-scale studies are needed to
not reach statistical significance. The clinical features of stroke in SCD characterize the magnitude of the benefit. Treatment of renal disease
encompass the classic findings of stroke in other disorders, including, follows principles used for non-SCD kidney pathology and includes
but not limited to, hemiparesis, seizures, coma, paresthesias, headaches, effective blood pressure control, avoidance of nephrotoxic agents, and
and cranial nerve palsies. Neurocognitive deficits in IQ, memory, lan- treatment of urinary tract infection. A relative decrease in serum ery-
guage, and executive function have been demonstrated. 154,198 thropoietin levels, proportionate to the degree of anemia is observed;
Imaging approaches for acute stroke are the same as those for non however, erythropoietin treatment, with its resultant increase in Hb may
-SCD patients and includes MRI and magnetic resonance angiography. cause an increase in VOEs because of an increase in blood viscosity. 213
Prevention of Primary Stroke Based on the results from the Renal tubular acidosis type IV, secondary to decreased potassium
Stroke Prevention in Sickle Cell Disease (STOP) Study, it is recom- and hydrogen ion in the distal tubule can cause disproportionate acido-
mended that asymptomatic children with HbSS disease older than two sis and hyperkalemia in patients with declining renal function. 213
197
years of age should be screened for stroke risk using TCD. Those with Hematuria is discussed in the section on sickle cell trait.
high TCD velocities should be offered a chronic red cell transfusion Priapism Priapism is prevalent in at least 35 percent of male
program for primary stroke prevention. Repeat TCD screenings should patients with SCD with devastating psychological consequences; true
be done every 3 to 12 months even in patients who have normal or con- prevalence may be higher as it is often underreported. 217–219 The mean
ditional baseline velocities, because they can evolve into a higher-risk age of episodes is 15 years and two-thirds of patients have “stutter-
category. Despite obstacles to TCD screening, clinical practice changes ing priapism” a term used for episodes that last less than 3 hours.
220
based on the STOP study translated into declining stroke rates since Derangements in NO metabolism and adenosine signaling are thought
1991. 199,200 to be the major contributors to priapism in SCD. Greater than 95 per-
94
Prevention of Secondary Stroke Patients with SCD who present cent of priapism is the “low-flow” type resulting from ischemia, is pain-
with a stroke and are not on chronic transfusion should be placed on ful, and is a medical emergency. 221
a transfusion program to prevent secondary strokes. Exchange trans- Aspiration of the corpus cavernosa followed by epinephrine injec-
fusion may be preferable to periodic red cell transfusion, not only to tions, exchange transfusion, and α and β agonists have all been used,
avoid iron overload, but also to further reduce stroke risk. In a retro- but data regarding efficacy are sparse. α-Agonists, etilefrine 50 mg, and
spective study, children who received periodic transfusion had a five- ephedrine 15 to 30 mg per day, seem to reduce the incidence of stut-
222
fold higher relative risk of a recurrent stroke compared to those on an tering priapism. Hormonal therapies, including antiandrogens and
201
exchange transfusion regimen. Despite chronic transfusions, patients luteinizing hormone-releasing hormone, reduce nocturnal erections
221
may have a recurrent stroke, especially in patients with HbS greater but are associated with loss of libido. Transfusion therapy has resulted
than 30 percent. Hydroxyurea was shown to decrease high and con- in neurologic sequelae termed “the ASPEN syndrome” (Association of
202
ditional TCD velocities in more than 90 percent of patients studied. Sickle Cell Disease, Priapism, Exchange Transfusion) and is thought
203
However, a randomized trial comparing transfusions with iron chela- to be secondary to hyperviscosity; care, therefore, must be taken not
223
tion to hydroxyurea with phlebotomy showed a 10 percent stroke rate to increase the hematocrit beyond 30 percent. In recalcitrant cases,
in the hydroxyurea arm, thus establishing transfusion as the preferred a shunt is performed but results in permanent impotence. A penile
222
preventive strategy. 204 prosthesis is used to ameliorate sexual dysfunction.
Anticoagulation therapy has not been studied in patients with SCD Nocturnal Enuresis Nocturnal enuresis is prevalent in 25 to 33
and, therefore, no recommendations can be made. Treatment guidelines percent of the pediatric sickle cell population, which is higher compared

Kaushansky_chapter 49_p0759-0788.indd 770 9/18/15 3:01 PM