Page 689 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 41 Pathobiology of Sickle Cell Disease 581

23
chronic activation of coagulation, fibrinolysis, and platelets. This is Thrombosis
accompanied by increased whole blood tissue factor (TF) and its
increased expression on endothelial cells and blood monocytes. Such The hypercoagulable state suggested by blood biochemistries is
23
abnormalities can follow signaling via heme/TLR4 or TNF or various accompanied by a thrombotic diathesis. Arterial thrombosis occurs
other perturbing factors. Presence of PS on released microparticles in areas of vasculopathy in the circle of Willis in association with
and on some sickle RBC promotes accelerated thrombin generation. childhood ischemic stroke, and in lungs exhibiting pulmonary
Oxidation appears to create resistance to cleavage of ultra-large forms hypertension. Incidence of venous thromboembolism is increased,
of von Willebrand factor by ADAMTS13. There is excessive con- and sickle cell anemia is a complicating condition for pregnancy.
sumption of antithrombotic proteins. The extant biodeficiency of Downstream consequences of the coagulation system activation may
NO would contribute to TF expression and augmented platelet play a greater role than is currently appreciated.
activation because it normally inhibits these. Products of platelet and
coagulation activation undoubtedly exert signaling and perturbing
effects on endothelium. Stroke and Cerebrovascular Disease

Several stroke syndromes occur in sickle disease and may have differ-
Genesis of Clinical Disease ing pathogeneses. Ischemic stroke with clinical deficit develops in 5%
to 10% of children with sickle cell anemia, with arterial wall changes
For the individual patient, evident clinical disease may not parallel that narrow vascular luminal diameter within the circle of Willis
or accurately predict the extent of underlying overall disease burden. being the strongest risk factor and presumptive cause. Completion of
It has been argued that some clinical complications (pulmonary the actual stroke tends to involve thrombosis at the site of vessel wall
hypertension, leg ulcers, priapism, stroke) are caused by hemolysis, disease. Despite this, most clinical research has focused upon stroke
while others (acute chest syndrome, acute painful episodes) are caused events per se rather than upon separate risks for the apparent funda-
17
by vasoocclusion. That different processes underlie different clinical mental underlying processes, arterial wall disease and thrombotic
complications is entirely possible, but evidence for there being such diathesis. Concurrent α-thalassemia or HbSC disease lowers the risk
12
dramatic dichotomy of phenotype pathogenesis is very indirect. It of this stroke type, and HbF level is not protective. It can be suspected
is important to recall that effects of the proximate inputs (hemolysis that elevated growth factors are participants in arterial wall disease
and vasoocclusion) are undoubtedly modulated by the complex sickle and the sometimes-associated Moyamoya. In a seemingly separate
milieu, and that multiple biologic systems are concurrently activated. syndrome, “silent” strokes (but associated with time-dependent
Also, the vessel wall is exposed lifelong to the great variety of stressors degradation of neuropsychologic function) accumulate throughout
and perturbing substances of the complex sickle milieu. Few data in childhood and are believed to derive from inadequate microvascular
the research literature, whether from general medicine or study of blood flow eventuating in multifocal microinfarcts. Yet another
sickle disease, can be extrapolated with any confidence whatsoever to syndrome, hemorrhagic stroke, can complicate the vessel fragility of
chronicity of this magnitude and complexity. Moyamoya and sometimes aneurysm; otherwise, risk factors and root
causes of hemorrhagic stroke are unknown.
Pain Syndromes
Pulmonary Disease
In adults, a higher frequency of acute painful episodes is associated
10
with increased mortality, presumably reflecting derivation of both The spectrum of sickle pulmonary complications includes chronic
from severity of underlying disease activity. The immense further restrictive lung disease, pulmonary hypertension, asthma, infection,
disturbance of multiple biologic processes during such episodes in situ and embolic thrombosis, and acute chest syndrome (ACS).
augments risk for complications like acute chest syndrome and The acute inflammatory syndrome of ACS is associated especially
sudden death. Pain frequency is higher in association with higher with infection in children and fat embolism (probably from marrow
hematocrit and lower HbF level, consistent with the concept that infarction) in adults, but other presumptive triggers are similarly
acute painful episodes involve ischemic pain from vasoocclusion. implicated. Risk factors include leukocytosis, lower levels of hemo-
However, pain in sickle disease appears to be multimodal and globin and HbF, and a history of asthma. The nature of ACS and its
complex. There probably is a substantial inflammatory contribu- occurrence and timing during acute vasoocclusive episodes raise the
tion to both acute and chronic sickle pain, involving many factors question whether it might be an event of remote organ injury com-
18
24
including inflammatory neuropeptides and mast cells. It probably plicating I/R physiology. Regardless of specific proximate trigger, in
involves a state of nociceptive hypersensitization. The chronic, daily this syndrome it is likely that inflammation, adhesion biology, NO
pain affecting many patients seems to be both inflammatory and deficiency, and endothelial permeability conspire to augment the
neuropathic in origin. deleterious effects of hypoxia on the lung. Mast cell activation,
another consequence of I/R, may contribute to pulmonary suscepti-
bility generally and to pathobiology of ACS and asthma specifically.
Chronic Vasculopathy Pulmonary hypertension occurs in about 6% of adults with sickle
25
cell anemia, in half from pulmonary venous disease, in half from
The macrovascular component of sickle vascular disease is a chronic pulmonary arterial disease. Genesis is almost certainly multifactorial,
inflammatory vasculopathy. Histopathology from the large and as the sickle context involves multiple features associated with pul-
medium vessels at the circle of Willis, where some sickle children monary hypertension in the general population: absence of splenic
develop occlusive disease, is characterized by intimal hyperplasia, function and presence of activated platelets, an inflammatory state,
fibrotic and proliferative changes, and damage to internal elastic and endothelial dysfunction. It is difficult, however, to distinguish
lamina. Pathology of arterial lesions at other sites is described simi- between causes and consequences of this pathobiology. Further, the
larly. This typical arterial wall response to inflammation occurs, in pulmonary arterial wall in sickle cell anemia is awash with suspect
the sickle case, without the fatty streak and foam cells of atheroscle- mediators, and the biodeficiency of NO emasculates a normal braking
rosis, probably reflecting the absence of hyperlipidemia plus the mechanism on inflammation, proliferation, and vasoconstriction.
different spectrum of proximate inflammatory inputs. It is quite Notably, both children and adults with sickle cell anemia not infre-
possible that the specific generative stressors for vasculopathy could quently exhibit sleep-disordered breathing with nocturnal hypoxia,
vary somewhat from organ to organ, but it seems likely that universal the major pulmonary vasoconstrictor. This justifies suspicion that
contributors include inflammation, endothelial dysfunction, growth long-term, repeated exposure to this major stressor plays a role in
factor excess, and aberrant wall shear stress. development of pulmonary hypertension in sickle disease. There may