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Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC-030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD. (Blood. 2011;118(12):3376-3383) IntroductionSickle cell disease (SCD) is a major health care and socioeconomic problem that affects millions of people worldwide. In the United States alone, SCD affects Ͼ 80 000 people, the majority of whom are African American. Pain is the hallmark symptom of SCD and the leading cause of emergency department visits, hospitalizations, and daily suffering. 1 Patients suffer unpredictable, incapacitating acute pain episodes that are believed to result from red blood cell (RBC) sickling and "vaso-occlusion." However, many features of this pain are not explained by hemoglobin polymerization and vascular obstruction. Furthermore, individuals with SCD often develop chronic pain syndromes that are poorly understood and ineffectively treated. 1,2 The frequency and severity of pain is associated with increased mortality and profoundly erodes patients' quality of life. 3 Because they are often from minority and lower socioeconomic groups, SCD patients are commonly underserved and suboptimally treated.The pathologic mechanisms leading to the perception of pain during RBC sickling episodes and the transition from acute to chronic pain remain poorly understood. 1,2 Patient descriptors of SCD pain include neuropathic pain attributes such as "aching," "shooting," and "stabbing," as well as nociceptive pain qualities such as "sharp," "throbbing," and "pounding." These descriptors depict spontaneous pain or nonstimulus-evoked pain. 2,4 Furthermore, increased hospital admissions and reports of...

DHTR/H syndrome occurs in pediatric SCD patients, typically 1 week posttransfusion, and presents with back, leg, or abdominal pain; fever; and hemoglobinuria that may mimic pain crisis. Hb is often lower than it was at the time of original transfusion, suggesting the hemolysis of the patient's own RBCs in addition to hemolysis of the transfused RBCs; a negative DAT and reticulocytopenia are often present. Severe complications including acute chest syndrome, congestive heart failure, pancreatitis, and acute renal failure were associated with DHTR/H syndrome in our patients. DHTR/H in the pediatric sickle cell population is a serious and potentially life-threatening complication of RBC transfusion. It is important to avoid additional transfusions in these patients, if possible, because these may exacerbate the hemolysis and worsen the degree of anemia. DHTR/H syndrome must be included in the differential of a patient who has SCD and vaso-occlusive crisis who has recently had a transfusion.

Sickle Cell Disease (SCD) pain is associated with colder temperatures and touch and described as “cold”, “hot” and “shooting” suggesting hypersensitivity to tactile stimuli. Sickle mice exhibit hypersensitivity to thermal (cold, heat) and mechanical stimuli compared to controls. It is unknown whether humans experience this same hypersensitivity. Thus, we quantified thermal and mechanical sensitivity differences between SCD patients and controls. Our primary hypothesis was that SCD patients will exhibit hypersensitivity to thermal and mechanical stimuli compared to race-matched controls. Our secondary hypothesis was this hypersensitivity will be associated with older and female subjects, and with frequent pain and hemolysis in SCD patients. A total of 55 patients and 57 controls ≥7 years completed quantitative sensory testing. SCD patients detected the sensation of cold and warm temperatures sooner as seen in their significantly lower median cold and heat detection thresholds [29.5°C vs. 28.6°C, p=0.012 and 34.5°C vs. 35.3°C, p=0.02] and experienced cold and heat pain sooner as seen in their significantly lower median cold and heat pain thresholds [21.1°C vs. 14.8°C, p=0.01 and 42.7°C vs. 45.2°C, p=0.04]. We found no mechanical threshold differences. Older age was associated with lower cold, heat, and mechanical pain thresholds in both groups. No association with pain, gender, or hemolysis was found. SCD patients exhibit hypersensitivity to thermal stimuli suggesting peripheral or central sensitization may exist and could contribute to SCD pain.

Because Berkeley sickle cell mice are used as an animal model for human sickle cell disease, we investigated the progression of the histopathology in these animals over 6 months and compared these findings to those published in humans with sickle cell disease. The murine study groups were composed of wild-type mixed C57Bl/6-SV129 (control) mice and sickle cell (SS) mice (␣ ؊/؊ , ␤ ؊/؊ , transgene ؉) of both sexes and between 1 and 6 months of age. SS mice were similar to humans with sickle cell disease in having erythrocytic sickling, vascular ectasia, intravascular hemolysis, exuberant hematopoiesis, cardiomegaly, glomerulosclerosis, visceral congestion, hemorrhages, multiorgan infarcts, pyknotic neurons, and progressive siderosis. Cerebral perfusion studies demonstrated increased blood-brain barrier permeability in SS mice. SS mice differed from humans with sickle cell disease in having splenomegaly, splenic hematopoiesis, more severe hepatic infarcts, less severe pulmonary manifestations, no significant vascular intimal hyperplasia, and only a trend toward vascular medial hypertrophy. Early retinal degeneration caused by a homozygous mutation (rd1) independent from that causing sickle hemoglobin was an incidental finding in some Berkeley mice. While our study reinforces the fundamental strength of this model, the notable differences warrant careful consideration when drawing parallels to human sickle cell disease. (Blood. 2006;107: 1651-1658)

The risk for thrombosis is increased in patients with hereditary hydrocytosis, an uncommon variant of hereditary stomatocytosis. Erythrocytes from 2 patients with hydrocytosis were studied to gain insight into the mechanism of thrombosis in this disorder. Erythrocytes demonstrated abnormal osmotic scan ektacytometry and decreased erythrocyte filtration rates. There was also a mild increase in adherence of erythrocytes to endothelial monolayers in a micropipette assay. Adhesion of erythrocytes to the subendothelial matrix proteins thrombospondin and laminin, however, was not significantly increased. Percentages of hydrocytosis erythrocytes and reticulocytes with phosphatidylserine exposed on the outer surfaces were increased in both patients compared with healthy controls, indicating altered membrane phospholipid asymmetry. Increased phosphatidylserine exposure accelerating thrombin-forming processes has been proposed as a mechanism for thrombosis in sickle cell disease and ␤-thalassemia and may play a similar role in hereditary hydrocytosis.

SCD patients with PHT have higher levels of markers of endothelial activation and other inflammatory markers than patients without PHT. A trend towards an increased level of markers of coagulation activation was observed in SCD patients with PHT compared with that in patients without PHT. Markers of hemolysis are associated with coagulation activation and endothelial dysfunction in SCD patients. Clinical trials of anticoagulants and anti-inflammatory agents are warranted in SCD patients with PHT.

Older children with sickle cell disease and VOC have increased hospitalizations and longer LOS. This age effect should be considered when measuring the effect of an intervention on hospital utilization in these children.