Rates of Strokes in Californians with Sickle Cell Disease in the Post-STOP Era.

Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke. Using statewide emergency department and hospitalization data from the California Department of Health Care Access and Innovation (1991-2019), we determined the cumulative incidence and rates for primary and recurrent strokes and TIAs in people with SCD pre- and post-STOP. For the 7,636 patients included in our SCD cohort, cumulative incidence for first ischemic stroke was 2.1% (95% CI: 1.8%, 2.4%) by age 20 years and 13.5% (95% CI: 12.3%, 14.7%) by age 60 years. Cumulative incidence for first intracranial hemorrhage (ICH) was 0.5% (95% CI: 0.4%, 0.7%) by age 20 years and 6.8% (95%CI: 5.9%, 7.7%) by age 60 years. Ischemic stroke rates increased in children (age <18 years, 234.9 vs 165.1 per 100,000PY, P=0.012) and adults (ages 31-50 years, 431.1 vs 303.2 per 100,000PY, P=0.031) in 2010-2019, compared to the preceding decade. There was an increase in rates of ICH in ages 18-30 and TIA in children <18 years from 2010-2019 when compared to the prior decade. Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia. These findings underscore the need for prevention of strokes in adults with SCD and suggest an emphasis on the management of modifiable cerebrovascular risk factors that have been demonstrated to be effective in the general population.

Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis.

Low bone mineral density is highly prevalent in sickle cell disease (SCD); whether bisphosphonates can safely preserve or increase bone mass in SCD adults remains unknown. In this study, lumbar spine bone density remained stable with alendronate use, and treatment-related side effects were mostly mild and self-limited. PURPOSE: To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis. METHODS: We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype. RESULTS: Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age ± standard deviation 42.4 ± 10.9 years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm2) at the femoral neck (0.72 vs 0.85, p = < 0.001) and total hip (0.79 vs 0.88, p = 0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357 g/cm2 (p = 0.028) in those on alendronate for > 5 years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4 years. CONCLUSION: In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48 months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for < 5 years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.

Pregnancy outcomes in women with sickle cell disease in California.

Adverse pregnancy outcomes occur frequently in women with sickle cell disease (SCD) across the globe. In the United States, Black women experience disproportionately worse maternal health outcomes than all other racial groups. To better understand how social determinants of health impact SCD maternal morbidity, we used California's Department of Health Care Access and Information data (1991-2019) to estimate the cumulative incidence of pregnancy outcomes in Black women with and without SCD-adjusted for age, insurance status, and Distressed Community Index (DCI) scores. Black pregnant women with SCD were more likely to deliver at a younger age, use government insurance, and live in at-risk or distressed neighborhoods, compared to those without SCD. They also experienced higher stillbirths (26.8, 95% confidence interval [CI]: 17.5-36.1 vs. 12.4 [CI: 12.1-12.7], per 1000 births) and inpatient maternal mortality (344.5 [CI: 337.6-682.2] vs. 6.1 [CI: 2.3-8.4], per 100 000 live births). Multivariate logistic regression models showed Black pregnant women with SCD had significantly higher odds ratios (OR) for sepsis (OR 14.89, CI: 10.81, 20.52), venous thromboembolism (OR 13.60, CI: 9.16, 20.20), and postpartum hemorrhage (OR 2.25, CI 1.79-2.82), with peak onset in the second trimester, third trimester, and six weeks postpartum, respectively. Despite adjusting for sociodemographic factors, Black women with SCD still experienced significantly worse pregnancy outcomes than those without SCD. We need additional studies to determine if early introduction to reproductive health education, continuation of SCD-modifying therapies during pregnancy, and increasing access to multidisciplinary perinatal care can reduce morbidity in pregnant women with SCD.

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 µg/mmol during vaso-occlusive crises to 2.62 µg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood.

BACKGROUND: Previous natural history studies have advanced the understanding of sickle cell disease (SCD), but generally have not included sufficient lifespan data or investigation of the role of genetics in clinical outcomes, and have often occurred before the widespread use of disease-modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To further advance knowledge of SCD, St. Jude Children's Research Hospital established the Sickle Cell Clinical Research and Intervention Program (SCCRIP), to conduct research in a clinically evaluated cohort of individuals with SCD across their lifetime. PROCEDURES: Initiated in 2014, the SCCRIP study prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. Biological samples are banked for future genomics and proteomics studies. The organizational structure of SCCRIP is based upon organ/system-specific working groups and is opened to the research community for partnerships. RESULTS: As of August 2017, 1,044 (92.3% of eligible) patients with SCD have enrolled in the study (860 children and 184 adults), with 11,915 person-years of observation. Population demographics included mean age at last visit of 11.3 years (range 0.7-30.1), 49.8% females, 57.7% treated with hydroxyurea, 8.5% treated with monthly transfusions, and 62.9% hemoglobin (Hb) SS or HbSB0 -thalassemia, 25.7% HbSC, 8.4% HbsB+ -Thalassemia, 1.7% HbS/HPFH, and 1.2% other. CONCLUSIONS: The SCCRIP cohort will provide a rich resource for the conduct of high impact multidisciplinary research in SCD.

Postpartum fevers, a rare presentation of secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease of excessive immune system activation. We report a case of HLH in a 20-year-old primigravid woman who presented with postpartum fevers. She was successfully treated with dexamethasone and anakinra, a deviation from the HLH-94 protocol, to preserve her ability to breastfeed.

Clinical Vignettes, Part II: Eyes, Teeth, and Bone.

Microvascular occlusions caused by sickle cell disease (SCD) can affect all ocular and orbital structures. Sickle cell retinopathy (SCR) is the most common ophthalmic manifestation of SCD. Fortunately, most individuals with SCR are visually asymptomatic. Vision loss in SCD most commonly occurs as a consequence of proliferative sickle cell retinopathy (PSR), in which pathologic retinal neovascularization occurs. To prevent significant vision loss and blindness, which can occur from complications of PSR, regular retinopathy surveillance screening examinations and consistent follow-up with a retina specialist are recommended. Scatter laser photocoagulation is the current gold-standard treatment to prevent vision threatening progression of PSR. Patients with sickle cell disease should have regular checkups with their dental care provider. Patients should be educated on the importance of proper dental care, a healthy diet, and the need for early intervention if they suspect any dental problems or are having dental pain. If any dental procedures that involve surgery or sedation are planned, it is critical to consult with the hematologist before the procedure is started. Prophylactic antibiotics may have to be prescribed before invasive dental procedures, such as extractions or periodontal surgery but is best determined by discussions between the dental care provider and the hematologist. Osteonecrosis is a highly prevalent skeletal complication of sickle cell disease that affects all genotypes. Risk factors for osteonecrosis include older age, HbSS genotype with concomitant alpha-thalassemia trait, frequent vaso-occlusive episodes, history of acute chest syndrome, elevated body mass index, and low white blood cell counts. Osteonecrosis causes progressive joint damage and associates with chronic pain, frequent acute care visits, and overall poor health-related quality of life. Current consensus guidelines recommend analgesics, physical therapy, and early consideration of joint arthroplasty in sickle cell-related osteonecrosis, although surgery may be deferred until late adolescence after growth plates have fused.

The incidence of cancer-associated thrombosis is increasing over time.

Cancer-associated thrombosis (CAT) is an important cause of morbidity and mortality for patients with malignancy and varies by primary cancer type, stage, and therapy. We aimed to characterize the incidence, risk factors, temporal trends, and the effect on mortality of CAT. The California Cancer Registry was linked to the statewide hospitalization database to identify individuals with the 13 most common malignancies diagnosed between 2005 and 2017 and determine the 6- and 12-month cumulative incidence of CAT by venous thromboembolism (VTE) location, tumor type, and stage after adjusting for competing risk of death. Cox proportional hazard regression models were used to determine risk factors associated with CAT and the effect of CAT on all-cause mortality. 942 019 patients with cancer were identified; 62 003 (6.6%) had an incident diagnosis of CAT. Patients with pancreatic, brain, ovarian, and lung cancer had the highest, and patients with breast and prostate cancer had the lowest 12-month cumulative incidence of CAT. For most malignancies, men, those with metastatic disease and more comorbidities, and African Americans (vs non-Hispanic Whites) were at highest risk for CAT. Patients diagnosed with cancer between 2014 and 2017 had a higher risk of CAT compared with those diagnosed between 2005 and 2007. CAT was associated with increased overall mortality for all malignancies (HR ranges 1.89 to 4.79). The incidence of CAT increased over time and was driven by an increase in pulmonary embolism±deep vein thrombosis (PE±DVT). CAT incidence varies based on tumor type and stage and on individual risk factors including gender, race/ethnicity, and comorbidities. For all tumor types, CAT is associated with an increased mortality.

Acute Care Utilization at End of Life in Sickle Cell Disease: Highlighting the Need for a Palliative Approach.

Background: People with sickle cell disease (SCD) have a life expectancy of <50 years, so understanding their end-of-life care is critical. Objective: We aimed to determine where individuals with SCD were dying and their patterns of care in the year preceding death to highlight end-of-life research priorities and possible opportunities for intervention. Design: Using the California SCD Data Collection Program database (containing administrative data, vital records, and Medicaid claims), we examined people with SCD who died between 2006 and 2015 (cases) at age <80 years and examined their hospital and emergency department (ED) utilization in their last year of life. Comparators included living controls with SCD matched 1:1 based on age, analysis year, insurance, and income. Results: We identified 486 people with SCD (cases) who died at a median age of 45 years (SD: 16 years). Most died in the hospital (63%) and ED (15%). In their last year of life, people with SCD were hospitalized for an average of 42 days (SD: 49 days) over five admissions. Inpatient admissions and ED visits were stable throughout the year until the month before death when acute care utilization sharply increased. In their last year of life, cases had more hospitalizations than controls, but similar ED utilization. Conclusions: People with SCD are dying acutely at a young age and most die in the hospital and the ED. Since clinicians caring for people with SCD currently cannot predict which acute events may be life-threatening, a comprehensive palliative approach to people with SCD must extend beyond chronic pain management and psychosocial support to include advance care planning.

Osteonecrosis in sickle cell disease: an update on risk factors, diagnosis, and management.

Osteonecrosis, a form of ischemic bone injury that leads to degenerative joint disease, affects ∼30% of people with sickle cell disease. Although osteonecrosis most commonly affects the femoral head (often bilaterally, with asymmetric clinical and radiographic progression), many people with sickle cell disease also present with multifocal joint involvement. We present the case of a young woman with bilateral osteonecrosis of the femoral head at varying stages of progression; we also highlight other important comorbid complications (eg, chronic pain requiring long-term opioids, debility, and social isolation) and postoperative outcomes. In this review, partly based on recommendations on osteonecrosis management from the 2014 evidence-based report on sickle cell disease from the National Heart, Lung and Blood Institutes, we also discuss early signs or symptoms of osteonecrosis of the femoral head, radiographic diagnosis and staging criteria, hydroxyurea effect on progression to femoral head collapse, and surgical outcomes of total hip arthroplasty in the modern era. In summary, we failed to find an association between hydroxyurea use and femoral head osteonecrosis; we also showed that evidence-based perioperative sickle cell disease management resulted in superior postoperative outcomes after cementless total hip arthroplasty in sickle cell-related osteonecrosis of the femoral head.

Height-corrected low bone density associates with severe outcomes in sickle cell disease: SCCRIP cohort study results.

Low bone mineral density (BMD) disproportionately affects people with sickle cell disease (SCD). Growth faltering is common in SCD, but most BMD studies in pediatric SCD cohorts fail to adjust for short stature. We examined low BMD prevalence in 6- to 18-year-olds enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP), an ongoing multicenter life span SCD cohort study initiated in 2014. We calculated areal BMD for chronological age and height-adjusted areal BMD (Ht-aBMD) z scores for the SCCRIP cohort, using reference data from healthy African American children and adolescents enrolled in the Bone Mineral Density in Childhood Study. We defined low BMD as Ht-aBMD z scores less than or equal to -2 and evaluated its associations with demographic and clinical characteristics by using logistic regression analyses. Of the 306 children and adolescents in our study cohort (mean age, 12.5 years; 50% female; 64% HbSS/Sß0-thalassemia genotype; 99% African American), 31% had low areal BMD for chronological age z scores and 18% had low Ht-aBMD z scores. In multivariate analyses, low Ht-aBMD z scores associated with adolescence (odds ratio [OR], 7.7; 95% confidence interval [CI], 1.94-30.20), hip osteonecrosis (OR, 4.0; 95% CI, 1.02-15.63), chronic pain (OR, 10.4; 95% CI, 1.51-71.24), and hemoglobin (OR, 0.74; 95% CI, 0.57-0.96). Despite adjusting for height, nearly 20% of this pediatric SCD cohort still had very low BMD. As the SCCRIP cohort matures, we plan to prospectively evaluate the longitudinal relationship between Ht-aBMD z scores and markers of SCD severity and morbidity.

Osteonecrosis of the femoral head in sickle cell disease: prevalence, comorbidities, and surgical outcomes in California.

Osteonecrosis of the femoral head (ONFH) is a prevalent complication of sickle cell disease (SCD) that has not been well described in population-based cohort studies. Using California's Office of Statewide Planning and Development discharge databases (1991-2013), we estimated the cumulative incidence of ONFH after accounting for the competing risk of death and used a multivariable Cox proportional hazards regression to identify factors associated with ONFH diagnosis. We also calculated rates of readmissions to the hospital or emergency department within 30 to 90 days of hip replacement surgery. Of the 6237 patients in our SCD cohort, 22% (n = 1356) developed ONFH at a median age of 27 years, and 23% (n = 308) of the patients with ONFH underwent hip replacement surgery at a median age of 36 years. The cumulative incidence of ONFH to age 30 years was higher among SCD patients with more severe disease (24%; vs 8% in less severe) and those with antecedent acute chest syndrome (ACS) (18%; vs 8% without prior history of ACS). From 2003 to 2013, SCD patients with more severe disease (hazard ratio [HR], 2.77; 95% confidence interval [CI], 2.38-3.23) or with antecedent ACS (HR, 1.61; CI, 1.35-1.91) were more likely to develop ONFH. Twenty-seven percent of post-hip surgery patients were readmitted within 30 days, mostly for painful vaso-occlusive crises. ONFH is a common SCD complication that increases with age; ongoing studies into prevention and effective nonsurgical interventions for SCD-induced osteonecrosis must remain a high research priority.