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.

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.

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.

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.

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.

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.