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Chapter 42 Sickle Cell Disease 593

Anticoagulation or Antiplatelet Therapy

Although there is clear evidence of activation of the coagulation
system in SCD, the role of thrombogenesis in vasoocclusive crisis
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remains unclear. Similarly, there have been no thorough evaluations
of the role of antiplatelet or antithrombotic agents for the treatment
of SCD. D-dimer levels (a degradation product of cross-linked fibrin)
increase during acute vasoocclusive crisis. 110
Minidose heparin, 5000 to 7500 units every 12 hours, adminis-
tered to four patients for 2–6 years reduced hospitalization and
emergency department time by 75%, and pretreatment pain fre-
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quency recurred after heparin was discontinued. Larger clinical
studies will be required to better understand the risks and benefits of
heparin therapy for acute vasoocclusive crisis in SCD. Heparin has
not been studied for acute arterial stroke in patients with SCD but
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has a role in SCD-associated dural venous sinus thrombosis. The
management of stroke is fully discussed under Specific Complications
and Their Management.
Acenocoumarol was administered in low doses that achieved a
mean international normalized ratio (INR) of 1.64 and reduced the
elevated levels of prothrombin activation fragment (fragment 1+2) to
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50% of pretreatment levels. Clinical endpoints were not measured. Fig. 42.9 Right common carotid arteriogram taken in anteroposterior pro-
In a crossover study, 29 patients were treated with acenocoumarol to jection demonstrating complete occlusion of the origin of the right anterior
target an INR of 1.6–2.0. No effect on crisis frequency was noted, cerebral artery (arrowhead). (From Stockman JA, Nigro MA, Mishkin MM, Oski
although again, there were significant reductions in markers of coagu- FA: Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med 287:846,
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lation system activation. In 37 acutely ill sickle cell patients with 1972.)
elevated D-dimers, the effect of low-dose warfarin therapy (1 mg
without a target INR) in 12 of them was examined. In multivariate
analysis, low-dose warfarin was the only variable associated with a
significant decrease in D-dimer levels, suggesting a warfarin-induced called a “sickle cell crisis” by Diggs, who used the expression “crisis”
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decrease in thrombin activity. Therefore oral anticoagulation, even to refer to any new rapidly developing syndrome in the life of a
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at low doses, is associated with a decrease in laboratory markers of patient with SCD. The basic mechanism is believed to be vasooc-
coagulation pathway activation in SCD; however, further clinical clusion of the bone marrow vasculature causing bone infarction,
trials are required to understand the clinical risks and benefits. which in turn causes release of inflammatory mediators that activate
Aspirin was compared with placebo in 49 pediatric patients with afferent nociceptors. 122
SCD in a double-blind crossover study. The frequency and severity Although a general correlation of vasoocclusive severity and geno-
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of crises were not affected by aspirin therapy. Cerebral thrombosis, type has been posited, there is tremendous variability within geno-
which accounts for 70% to 80% of all CVAs in SCD, results from types and in the same patient over time. In one large study of patients
large-vessel occlusion (Fig. 42.9) rather than the more typical micro- with Hb SS disease, one-third rarely had pain, one-third were hospi-
vascular occlusion of SCD. In the United States, there is an ongoing talized for pain approximately two to six times per year, and one-third
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clinical trial testing the safety and efficacy of aspirin in diminishing had more than six pain-related hospitalizations per year. Over a
the incidence and progression of cognitive defects and overt or silent 5-year period in the National Cooperative Study of SCD, 40% of
stroke in pediatric patients. patients had no painful episodes, and 5% of patients accounted for
The management of stroke risk and stroke is fully discussed under one-third of the emergency department visits. Pain is more frequent
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Specific Complications and Their Management. with the Hb SS genotype, low levels of Hb F, higher Hb levels, and
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sleep apnea. The frequency of pain peaks between ages 19 and 39
years. After the age of 19 years, more frequent pain correlates with a
Experimental Therapies higher mortality rate. Medical personnel who see patients only in
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the emergency department gain a biased view of SCD skewed by a
Experimental approaches in early stages of clinical evaluation include frequently affected minority with severe disease. 126,127
glutamine supplementation, gene correction using zinc finger nucle- Pain may be precipitated by events such as cold, dehydration,
ases or “CRISPR” that exploit physiologic homology-directed DNA infection, stress, menses, and alcohol consumption. Any underlying
repair, agents that inhibit sickle erythrocyte adhesion to endothelium cause should be searched for and corrected, but the majority of
(recombinant P-selectin glycoprotein ligand-1–immunoglobulin G painful episodes have no identifiable cause. Pain can affect any area of
conjugate), agents that increase the production of nitric oxide (NO) the body, most commonly the back, chest, extremities, and abdomen;
[glutamine], and herbal extracts with unknown mechanisms of action may vary from trivial to excruciating; and is usually endured at
(Niprisan). 116–118 home without a visit to the emergency department. There may
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be premonitory symptoms. The duration averages a few days,
with hospital admissions typically lasting between 4 and 10 days.
Specific Complications and Their Management Painful episodes are biopsychosocial events caused by vasoocclusion
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in an area of the body having nociceptors and nerves. Pain is
an effect and, as such, consists of sensory, perceptual, cognitive,
Pain Crisis and emotional components. Frequent pain generates feelings of
despair, depression, and apathy that interfere with everyday life
Acute Pain Episode or Crisis and promote an existence that revolves around pain. This scenario
Acute pain is the first symptom of disease in more than 25% of may lead to a chronic debilitating pain syndrome; fortunately, this
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patients and is the most frequent symptom after age 2 years. Pain is rare.
is the complication for which patients with SCD most commonly There is no specific clinical or laboratory finding pathognomonic
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seek medical attention. An episode of acute pain was originally of pain crisis. The diagnosis is established by history and physical