Contraceptive Attitudes and Beliefs of Women With Sickle Cell Disease: A Qualitative Study.

OBJECTIVES: We aimed to qualitatively explore factors influencing contraceptive use in women living with sickle cell disease (SCD). STUDY DESIGN: We conducted a semi-structured qualitative study using data from interviews with reproductive-aged women with SCD. The Theory of Planned Behavior, which describes an individual's attitudes, subjective norms, and perceived behavioral control as drivers of a health behavior, served as a framework for data collection and thematic analysis. RESULTS: We analyzed interviews from 20 participants. Attitudes toward contraception showed skepticism regarding hormonal contraception and concern about adverse effects of contraception related to SCD. The role of subjective norms in contraceptive choice depended on whether participants possessed trusted sources of information, such as health care providers, family, and friends, or whether they relied on themselves alone in their contraceptive decision-making. The influence of health care providers was complicated by inconsistent and sometimes conflicting counseling. Finally, with regard to participants' perceived control in their contraceptive choices, some were motivated to alleviate menstrual pain or prevent SCD-related pregnancy risks, but many reported feeling disempowered in contraceptive decision-making settings because of their demographic characteristics or pressure from health care providers. CONCLUSIONS: Women living with SCD are influenced by many factors similar to those documented for other populations when making decisions about contraception. However, SCD amplifies both the importance and risks of contraception and may also complicate individuals' autonomy and contraceptive access. Hematology and reproductive health providers should recognize the risk of coercion, maximize patients' reproductive agency, and coordinate reproductive health counseling for patients with SCD.

Contemporary Obstetric and Neonatal Outcomes in Sickle Cell Disease: A Retrospective Cohort Study.

OBJECTIVE: Sickle cell disease is associated with adverse perinatal outcomes. Aspects of sickle cell disease in pregnancy, such as health care utilization and neonatal abstinence syndrome, are understudied. We aimed to describe contemporary sickle cell disease outcomes in a U.S. hospital system to improve perinatal counseling. STUDY DESIGN: We conducted a retrospective cohort study of patients with sickle cell disease who delivered at >20 weeks' gestation at two sites within the University of Pennsylvania Health System from May 1, 2017 to August 30, 2020. Descriptive statistics were utilized. RESULTS: Over the study period, 48 patients with sickle cell disease had 52 deliveries of 53 neonates. Sickle cell disease-related morbidity was prevalent prior to pregnancy; 27% had a history of avascular necrosis, and 58% had experienced acute chest syndrome. In the year prior to pregnancy, 52% used daily opioids. During pregnancy, more than half of patients were admitted at least once for sickle cell disease-related complications, spending a median 3 days admitted interquartile range (0-23); >10% spent >70 days of pregnancy admitted. New daily opioids were prescribed during pregnancy for 10% to manage pain crises. Acute chest syndrome was experienced by 23% of patients during pregnancy, and 8% required placement of long-term intravenous access. Preterm delivery <37 weeks occurred in 48%. The primary cesarean rate in nulliparas was 43%. Additionally, 50% experienced a hypertensive disorder of pregnancy, 35% underwent transfusion during delivery admission, and 10% had a perinatal venous thromboembolism. Finally, 53% of neonates were admitted to the intensive care unit. Low birth weight was noted in 34%, severe respiratory distress in 15% of infants, and neonatal abstinence syndrome in 21%. CONCLUSION: Sickle cell disease remains associated with significant perinatal morbidity and need for hospitalization. These data provide contemporary outcomes to target improvements in the care of patients with sickle cell disease. KEY POINTS: · SCD was associated with significant perinatal morbidity and healthcare utilization.. · Most patients with SCD required hospitalization during pregnancy.. · Neonates of patients with SCD experienced preterm birth, NICU admission, and neonatal abstinence syndrome..

Fertility and Pregnancy in Women with Transfusion-Dependent Thalassemia.

Because women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both mother and baby require concerted and collaborative efforts between the hematologist, obstetrician, cardiologist, hepatologist, and genetic counselor among others. Proactive counseling, early fertility evaluation, optimal management of iron overload and organ function, and application of advances in reproductive technology and prenatal screening are important in ensuring a healthy outcome. Many unanswered questions remain requiring further study, including fertility preservation, non-invasive prenatal diagnosis, chelation therapy during pregnancy, and indications and duration of anticoagulation.

Sex as an Independent Risk Factor for Venous Thromboembolism in Sickle Cell Disease: A Cross-Sectional Study.

Venous thromboembolism (VTE) affects up to 25% of individuals with sickle cell disease (SCD), but risk factors are not well characterized. We sought to measure the prevalence of VTE among SCD patients in our health system and to describe the relationship between medical history, biological sex, and VTE. We performed a retrospective chart review of SCD patients who visited an outpatient hematology clinic within Penn Medicine between June 2014 and June 2019. Demographics and medical history were compared across those with and without a history of VTE. We developed a logistic regression model to describe factors independently associated with VTE. Of 597 patients with SCD who were identified, 147 (24.6%) had a history of VTE; 100 were female and 47 were male. In the regression model, female sex was independently associated with history of VTE (odds ratio 1.91, 95% confidence interval 1.26-2.91), as were pulmonary hypertension, hydroxyurea use, and history of stroke. Among females only, 49.7% were parous and 18.8% had used oral contraceptives, and these proportions did not differ by history of VTE. One-quarter of the SCD patients in our health system had a history of VTE, confirming significantly higher rates than in the general population. Females had twice the odds of VTE compared to males, highlighting an important sex disparity in SCD disease outcomes and raising questions regarding optimal pregnancy and contraceptive care for females with SCD.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. MATERIALS AND METHODS: As part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. RESULTS: Here we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. CONCLUSIONS AND RELEVANCE: TTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.

Contraceptive use and preferences among females with sickle cell disease.

OBJECTIVES: Females with sickle cell disease now have a life expectancy that extends well into and beyond their reproductive years. Pregnancy and childbirth are accompanied by high morbidity and mortality in this population, rendering contraception a critical part of their health care. STUDY DESIGN: We approached adult female patients of the Hospital of the University of Pennsylvania hematology clinic who were of reproductive age (ages 18-45) and carried a diagnosis of sickle cell disease. We evaluated contraceptive method uptake and method characteristic preferences, as well as other reproductive history, and compared contraceptive uptake rates to that from female respondent data from the National Survey of Family Growth (2017-2019). RESULTS: Of 95 eligible patients, we completed surveys with 48 participants (response rate of 51%). Over half (n = 27, 56%) of participants were not currently using any form of contraception-double the rate of the general United States population (25%). The most common contraceptives currently used were the depot medroxyprogesterone (DMPA) injection (n = 6, 13%) and the progestin intrauterine device (IUD) (n = 6, 13%). DMPA uptake was significantly higher, and permanent contraceptive and oral contraceptive pill uptake significantly lower, among these participants with sickle cell disease compared to the general United States population. Participants' preferred contraceptive characteristics included effectiveness (n = 39, 81%), control over when to use the contraceptive (n = 39, 81%), and lack of side effects (n = 38, 79%). CONCLUSIONS: Contraceptive uptake was significantly lower and method mix different among females with sickle cell disease compared to the general United States population. Further research is needed on contraceptive safety, non-contraceptive benefits, and contraceptive decision-making for females with sickle cell disease. IMPLICATIONS: This study sheds light on the contraceptive choices and preferences of females with sickle cell disease, who are at disproportionate risk for pregnancy complications. In order to maximize the reproductive health of females with sickle cell disease, we must consider how their disease interacts with contraception and better understand how they approach contraceptive decision-making.

Deferasirox-associated Fanconi syndrome in adult patients with transfusional iron overload.

BACKGROUND AND OBJECTIVES: Deferasirox is an oral chelator approved for iron overload, which has a potential side effect of renal Fanconi syndrome, with proximal tubular dysfunction and tubular acidosis. Monitoring of renal function is recommended, though no standard for monitoring exists. We aim to describe cases of deferasirox-associated Fanconi syndrome in adults and the renal monitoring required to detect these findings. MATERIALS AND METHODS: We present a review of the literature and six cases from our institution of deferasirox-associated partial Fanconi syndrome in adult patients with transfusional iron overload secondary to ß-thalassemia or Diamond Blackfan Anaemia. RESULTS: While prior cases in the literature occurred at high doses of deferasirox, our series included patients on doses as low as deferasirox 10 mg/kg who had been aggressively chelated. All patients had resolution of laboratory abnormalities with drug interruption. CONCLUSION: Rather than chelating to normal iron levels, this series supports prior suggestions that deferasirox dose be reduced if ferritin <500-1000 ng/ml, and also supports dose reduction if liver iron content <3 mg iron per g dry weight or for those undergoing aggressive chelation with rapid decrease in iron. Monitoring with metabolic panel and urinalysis were sufficient to detect clinically significant proximal tubular dysfunction, but should be followed up with additional studies to confirm the diagnosis while deferasirox dose is decreased or held.

Challenges of blood transfusions in ß-thalassemia.

Patients with ß-thalassemia major (BTM) require regular blood transfusions, supported by appropriate iron chelation therapy (ICT), throughout their life. ß-thalassemia is a global disease that is most highly prevalent in Southeast Asia, Africa, and Mediterranean countries. However, the global distribution of patients with ß-thalassemia is changing due to population migration, and Northern European countries now have significant thalassemia populations. Globally, many patients with BTM have limited access to regular and safe blood transfusions. A lack of voluntary nonremunerated blood donors, poor awareness of thalassemia, a lack of national blood policies, and fragmented blood services contribute to a significant gap between the timely supply of, and demand for, safe blood. In many centers, there is inadequate provision of antigen testing, even for common red cell antigens such as CcEe and Kell. Policies to raise awareness and increase the use of red blood cell antigen testing and requesting of compatible blood in transfusion centers are needed to reduce alloimmunization (the development of antibodies to red blood cell antigens), which limits the effectiveness of transfusions and the potential availability of blood. Patients with BTM are also at risk of transfusion-transmitted infections unless appropriate blood screening and safety practices are in place. Hence, many patients are not transfused or are undertransfused, resulting in decreased health and quality-of-life outcomes. Hemovigilance, leukoreduction, and the ability to thoroughly investigate transfusion reactions are often lacking, especially in resource-poor countries. ICT is essential to prevent cardiac failure and other complications due to iron accumulation. Despite the availability of potentially inexpensive oral ICT, a high proportion of patients suffer complications of iron overload and die each year due to a lack of, or inadequate, ICT. Increased awareness, training, and resources are required to improve and standardize adequate blood transfusion services and ICT among the worldwide population of patients with BTM. ICT needs to be available, affordable, and correctly prescribed. Effective, safe, and affordable new treatments that reduce the blood transfusion burden in patients with ß-thalassemia remain an unmet need.

Management of the Dialysis Patient with Sickle Cell Disease.

While patients with sickle cell disease currently constitute a very small minority of the US dialysis population (0.1%), there is anticipated growth of this group as the life expectancy of those with sickle cell disease (SCD) increases. SCD patients suffer a high burden of morbidity, which is enhanced by the presence of end-stage renal disease (ESRD). In this review, we discuss the pathophysiology of SCD and the basic tenets of its management with focus on the dialysis patient with SCD. Anemia in dialysis patients with SCD is a unique challenge. The hemoglobin target in SCD dialysis patients with ESRD should not exceed 10 g/dl. SCD patients, and particularly those on dialysis, are likely to be poorly responsive to erythropoietin-stimulating agent (ESA) therapy and might be at increased risk for vaso-occlusive crisis (VOC) with ESA. Iron chelation and hydroyxurea therapy require special considerations and modifications in dialysis patients with SCD. There are theoretical advantages to both hemodialysis (HD) and peritoneal dialysis (PD) in SCD patients. With HD, there is a secure vascular access available for both standard and exchange blood transfusion in patients who need them. With PD, the absence of an acute rise in hematocrit with ultrafiltration (UF) might offer lower risk of VOC. During VOC, reduction in UF goals should be considered but administration of intravenous fluids should be reserved only for clear cases of volume depletion. Finally, renal transplantation appears to confer a survival advantage to dialysis in SCD patients and should be pursued when possible.

Increasing prevalence of thalassemia in America: Implications for primary care.

Thalassemia, once a rarity in the United States, is increasingly encountered in clinical practice due to shifts in immigration. Early carrier screening in at-risk populations can help clinicians implement genetic counseling and prevent new cases. Chronic transfusions are the mainstay of therapy for patients with severe thalassemia (beta thalassemia major), and are used intermittently in individuals with milder forms of thalassemia (Hb H/H Constant Spring disease and beta thalassemia intermedia). Iron overload is a major source of morbidity and mortality in individuals with transfusion and non-transfusion-dependent thalassemia, necessitating iron chelation therapy. Iron overload contributes to increased risk of cirrhosis, heart failure, and endocrinopathies, while ineffective erythropoiesis and hemolysis contribute to multiple complications, including splenomegaly, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis. An understanding of the importance of carrier screening, complications, monitoring, and management strategies, coupled with collaboration with a hematologist with thalassemia expertise, is essential to reduce the morbidity and mortality in patients with thalassemia.

How I treat refractory thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.

Adult sickle cell disease epidemiology and the potential role of a multidisciplinary comprehensive care center in a city with low prevalence.

The aim of this study was to determine the characteristics of the sickle cell disease population in a city of low prevalence and compare them to those reported in the literature. We performed a retrospective cross-sectional study of all sickle cell disease patients seen in the Calgary Health Region, Calgary, Alberta, Canada from 2006 to 2010. Data on clinical endpoints including emergency department (ED) visits, hospital admissions, transfusions, as well as laboratory parameters were collected. A total of 37 adult sickle cell disease patients were identified. Over 5 years, they were represented by a total of 49.2 ED presentations/year, 29.2 (59.0%) of these requiring admission. Eighty-three percent of these presentations were for acute pain episodes. We concluded that the number of ED visits, hospital admissions and several other parameters in our cohort were similar to those in other centers of higher prevalence. This suggests that guidelines representing regions of high prevalence may be applicable to smaller centers, where patients experience similar clinical outcomes.

Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost and adverse events.

BACKGROUND: Azathioprine (AZA), used to treat inflammatory bowel disease (IBD), is metabolized by thiopurine methyltransferase (TPMT). The accumulation of individual metabolites varies because humans display genetic polymorphism for TPMT expression. Deficiencies in TPMT result in accumulation of toxic metabolites, followed by neutropenia and hepatic inflammation. Concern over acute toxicity frequently leads to under dosing and frequent monitoring tests and visits. OBJECTIVE: To determine whether assessment of TPMT activity before the administration of AZA would predict acute toxicity and, thus, allow for reductions in health care costs related to biochemical screening for, and management of, AZA-induced adverse events. METHODS: Before AZA treatment, 29 patients with IBD were prospectively randomized to one of two groups: group 1, in which no TPMT assay was performed, was started on AZA at 1 mg/kg/day and then titrated every two weeks to a target dose of 2.5 mg/kg/day; and group 2, in which TPMT assays were performed, was started on AZA at the target dose of 2.5 mg/kg/day. For both groups, complete blood count and liver enzymes were monitored weekly for six weeks and at monthly intervals thereafter. Additional tests and health care interventions were undertaken at the discretion of the attending physicians. RESULTS: Of the 29 patients in the study, 15 were randomly assigned to group 1 and 14 to group 2. Demographics and disease activity were similar for both groups. Mean follow-up time was 7.1 months (range 3.5 to 10.7 months). Eight patients from group 1 and six patients from group 2 withdrew as a result of AZA-induced adverse events. There was no correlation between the TPMT activity and the development of AZA-induced adverse events. The direct health care costs for group 1 (300.11 dollars per patient) were lower than in group 2 (348.87 dollars per patient). CONCLUSION: The prospective assessment of TPMT enzyme activity before initiating AZA therapy in IBD patients incurred additional cost and did not predict AZA-induced toxicity.