Page 1297 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

904 PART 7: Hematologic and Oncologic Disorders

PATHOPHYSIOLOGY Steady-state sickle cell disease is characterized by intense inflamma-
tion that accelerates during VOC, likely secondary to nearly constant
The single nucleotide mutation in the sixth codon of the β-globin gene tissue ischemia-reperfusion. This is illustrated by frequent fever during
changes the corresponding amino acid in β-globin from valine to glu- VOC and the ACS and by increased leukocyte, platelet, and endothe-
tamic acid. This induces a conformational change in the hemoglobin lial cell activation, with increased circulating mediators and markers
tetramer that renders it susceptible to polymerization with deoxygen- of oxidant stress and inflammation. Examples of these inflammatory
ation in hypoxic, hyperosmolar, or acidic regions of the circulation. markers include elevated levels of C-reactive protein, cytokines (tumor
The rod-like polymer bundles distort the red cell membrane into the necrosis factor α, interleukin 1β, and granulocyte-macrophage colony-
characteristic sickle shape. Intracellular hemoglobin S polymerization stimulating factor), chemokines (interleukin 8), integrins (α β ), selec-
1
4
and “sickling” are associated with a complex combination of pathophysi- tins (E and P), adhesion molecules (VCAM-1 and intracellular adhesion
ologic changes (Table 96-1 and Fig. 96-2). It is likely that adhesion of molecule 1), markers of oxidant stress and inflammation (isoprostanes
erythrocytes and leukocytes to endothelial receptors such as vascular and tyrosine nitration), hemostatic activation (platelets and coagulation
cellular adhesion molecule 1 (VCAM-1) combines with physical rigid- factors), angiogenic factors (placenta growth factor), and vasoconstric-
ity and distortion (“sickling”) of the red blood cells to occlude the tors (endothelin 1). 4,5
microvascular circulation. Additional involved cell adhesion molecules Associated with this inflammation is a state of endothelial dysfunc-
include intercellular adhesion molecule 1, E selectin, and P selectin. tion, with impaired NO bioavailability. Strong evidence points to intra-
The resulting tissue ischemia-reperfusion drives tissue and organ vascular consumption of NO by cell-free plasma hemoglobin liberated
injury, generalized inflammation, and ultimately produces tissue infarc- from red cells by intravascular hemolysis and by radical-radical inactiva-
tion. These pathophysiologic events produce clinical and biochemical tion reactions with superoxide produced by xanthine oxidase, uncoupled
perturbations, such as fever and leukocytosis, which can mimic sepsis. endothelial NO synthase and the NADPH oxidases. Impairment of
8,9
Tissue ischemia and infarction produce severe pain attacks called acute NO signal transduction leads to many adverse consequences, including
pain episode or vaso-occlusive crisis (VOC) and specific end-organ increased inflammation and impaired microcirculatory blood flow. 10,11
pathophysiology, such as the acute chest syndrome (ACS), an acute lung It may also lead to platelet activation and acute and chronic pulmonary
injury syndrome similar to acute respiratory distress syndrome (ARDS), hypertension. 12,13
discussed in greater detail below.

BASELINE PHYSIOLOGY
Sickle cell disease is fundamentally a severe hemolytic anemia. This
TABLE 96-1 Pathogenesis of Sickle Cell Anemia is characterized by a normocytic, normochromic anemia with reticu-
locytosis at baseline. Characteristic laboratory profiles for patients with
Mechanism Modifying Factors
SS and SC without hydroxyurea treatment are presented in Table 96-2.
RBC sickling Hemolysis is mostly but not exclusively extravascular and is due pri-
Hemoglobin polymerization Hemoglobin deoxygenation-degree and duration of hypoxia marily to mechanical injury and destruction of erythrocytes rendered
(crystal-solution equilibrium) Hemoglobin concentration-cellular dehydration rigid by intracellular hemoglobin S polymerization. Baseline leukocy-
tosis is commonly present and should not necessarily be construed as
Inversely proportional to hemoglobin F concentration evidence of infection. Nucleated red blood cells commonly are mis-
Disturbance of Transcriptional induction of endothelial cell genes counted in the complete blood count as white cells, although the overall
vasoregulation encoding endothelin 1, a potent vasoconstrictor, after counting error is usually relatively small. The diminished oxygen-
contact with sickled RBCs carrying capacity due to chronic anemia is compensated by increased
cardiac output (Table 96-3). Cardiomegaly and biventricular chamber
Endothelin 1 levels are elevated during VOC and ACS
dilation due to constantly increased cardiac output are common
Cell-free plasma hemoglobin impairs nitric oxide bioavailability (Table 96-4). Splenic dysfunction due to sub-clinical splenic infarc-
Activation of the coagulation Platelet activation by hemolysis and cell free hemoglobin tion is almost universal by late childhood in patients with homozygous
system Pulmonary in situ thrombosis and thromboemboli from sickle cell disease; on computed tomography, the spleen appears typi-
distant sources cally as a small calcified mass (Fig. 96-3). As discussed below, patients
with SC disease or S-thalassemia may retain their spleens and present
Elevated whole blood tissue factor procoagulant activity with acute splenic sequestration or infarction. While almost 98% of
Increased adhesion of RBCs Increased expression of adhesion molecules results in adult SS patients have functional asplenia, about 50% of patients with
and WBCs to vascular endo- RBC-endothelial cell adhesion and endothelial cell damage SC or S-β -thalassemia have a spleen. Likewise, gradual infarction of
+
thelium Association between clinical severity and in vitro adhesion the renal medulla by adolescence leads to isosthenuria (iso-osmolar
of sickled RBCs to endothelial cells urine), with increased urination because of diminished urinary con-
centrating capacity, mimicking a mild nephrogenic diabetes insipidus
Increased expression of adhesion molecules after activation phenotype. Aside from increasing maintenance fluid requirements,
by inflammatory cytokines (TNF α and IL-1β) these changes mean that urine specific gravity is not closely indicative
Reticulocyte integrin complex, α β , binds to plasma of hydration status. The increased cardiac output and higher plasma
4
1
fibronectin and endothelial cell VCAM-1 content of each milliliter of blood present the renal glomeruli with
Sickle red blood cell CD36 and endothelial cell CD36 bind to a volume of plasma per minute up to twice that of patients without
thrombospondin secreted by activated platelets sickle cell disease. This leads to baseline glomerular hyperfiltration
(up to 200 mL/min) and a low baseline serum creatinine range in adults
Increased numbers of circulating microvascular endothelial of approximately 0.5 to 0.6 mg/dL, and even lower in children (see
cells in sickle cell disease, particularly during VOC
Table 96-2). Serum creatinine levels above this level actually imply
Increased endothelial cell activation as evidenced by renal insufficiency. A serum creatinine level of 1.0 mg/dL may often
increased ICAM-1, VCAM-1, E selectin, P selectin be associated with other consequences of renal insufficiency, such as
ACS, acute chest syndrome; ICAM-1, intercellular adhesion molecule 1; IL-1β, interleukin 1β; RBC, hyperkalemia, hyperuricemia, and increased anemia due to a partial
red blood cell; TNFα, tumor necrosis factor α; VCAM-1, vascular cellular adhesion molecule 1; VOC, defect in erythropoietin secretion. Importantly, these features of renal
vaso-occlusive pain crisis; WBC, white blood cell. insufficiency may arise even when the glomerular filtration rate may

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