Hemolytic Tests Exploring Factor H Functional Activities.

Impairment of the complement regulatory protein Factor H (FH) is implicated in the physiopathological mechanisms of different diseases like atypical hemolytic and uremic syndrome and C3 glomerulopathies. It may be due to genetic abnormalities or acquired with the development of autoantibodies. FH has several ligands; therefore, the exploration of its functions requires to perform different tests. Among them, two hemolytic tests are very useful because they give specific and complementary information about FH functions. The first one is dedicated to explore the FH capacity to dissociate the alternative pathway C3 convertase, whereas the second one is designed to explore the capacity of FH to bind cell surfaces and to protect them from complement attack. This chapter describes the procedures to perform these two hemolytic tests, exploring in a complementary way the FH functionality.

Sheep Erythrocyte Preparation for Hemolytic Tests Exploring Complement Functional Activities.

Sheep erythrocytes (SE) are commonly used in complement functional tests. Non sensitized SE are useful to study the FH activity of cell protection. Indeed, as the cell surface of sheep erythrocytes is rich in sialic acids, Factor H (FH) is able to bind on it and therefore they represent a model of nonactivating surface. Because of their high capacity of complement regulation SE need to be modified to explore other functionality of the complement pathways, like the Complement hemolytic 50 (CH50) or the AP C3 convertase decay assays. For these tests, SE are sensitized with an anti-sheep red blood cell stroma antibody. In presence of serum or plasma complement components, sensitized SE may initiate complement cascade activation via the classic pathway explored in the CH50 assay. Sensitized SE may also be used to prepare C3b-coated SE that, with the use of buffers favoring AP, are suitable for the C3 Nef hemolytic assay and for the hemolytic assay studying the AP decay activity of FH. In this chapter we describe how to prepare SE for these different hemolytic tests.

A predictive model for estimating the number of erythrocytapheresis or phlebotomy treatments for patients with naïve hereditary hemochromatosis.

BACKGROUND AND AIMS: Standard treatment for naïve hereditary hemochromatosis patients consists of phlebotomy or a personalized erythrocytapheresis. Erythrocytapheresis is more efficient, but infrequently used because of perceived costs and specialized equipment being needed. The main aim of our study was to develop a model that predicts the number of initial treatment procedures for both treatment methods. This information may help the clinician to select the optimal treatment modality for the individual patient. METHODS: We analyzed retrospective data of 125 newly diagnosed patients (C282Y homozygous), treated either with phlebotomy (n = 54) or erythrocytapheresis (n = 71) until serum ferritin (SF) reached levels ≤100 µg/L. To estimate the required number of treatment procedures multiple linear regression analysis was used for each treatment method separately. RESULTS: The linear regression model with the best predictive quality (R2  = 0.74 and 0.73 for erythrocytapheresis and phlebotomy respectively) included initial SF, initial hemoglobin (Hb) level, age, and BMI, where initial SF was independently related to the total number of treatment procedures for both treatment methods. The prediction error expressed in RMSPE and RMSDR was lower for erythrocytapheresis than for phlebotomy (3.8 and 4.1 vs 7.0 and 8.0 respectively), CONCLUSIONS: Although the prediction error of the developed model was relatively large, the model may help the clinician to choose the most optimal treatment method for an individual patient. Generally erythrocytapheresis halves the number of treatment procedures for all patients, where the largest reduction (between 55% and 64%) is reached in patients with an initial Hb level ≥ 9 mmol/L (14.5 g/dL). ClinicalTrials.gov number NCT00202436.

Therapeutic Erythrocytapheresis Is Effective in Treating High Altitude Polycythemia on the Qinghai-Tibet Plateau.

INTRODUCTION: High altitude polycythemia (HAPC) is a common chronic disease at high altitudes. It is characterized by excessive erythrocytosis (≥190 g·L-1 in females or ≥210 g·L-1 in males). HAPC severely jeopardizes the health status of plateau dwellers. The Qinghai-Tibet plateau, with an elevation above 4000 m, is the highest plateau in the world. Both Han and Tibetan populations residing there face the threat of HAPC. Therapeutic erythrocytapheresis (TE) was introduced to Tibet as an alternative to phlebotomy in 2015. METHODS: In this study, we retrospectively analyzed 155 patients with HAPC treated with TE in Tibet. Routine blood testing values before and after TE were compared to evaluate treatment efficacy. The efficiency rate, defined as the rate of increase in red blood cell depletion attained by TE compared with 450 mL whole blood phlebotomy, was calculated using whole blood volume and hematocrit before and after treatment and used to identify patients who maintained a normal hemoglobin level in the year after the TE procedure. RESULTS: On average, TE reduced red blood cell levels by 1.5×1012·L-1, hemoglobin concentration by 52 g·L-1, and hematocrit by 14% (P<0.001 for each). Patients who underwent TE with an efficiency rate ≥1.9 were more likely to maintain a normal hemoglobin level in the following year than those who underwent TE with an efficiency rate <1.9 (90 vs 28%, P<0.01). CONCLUSIONS: TE is a feasible therapeutic method to treat HAPC on the Qinghai-Tibet plateau. The efficiency rate is a useful tool to predict the expected interval between TE procedures.

Treatment of Cytokine Storm in COVID-19 Patients With Immunomodulatory Therapy.

Observational evidence suggests that excessive inflammation with cytokine storm may play a critical role in development of acute respiratory distress syndrome (ARDS) in COVID-19. We report the emergency use of immunomodulatory therapy utilizing an extracorporeal selective cytopheretic device (SCD) in two patients with elevated serum interleukin (IL)-6 levels and refractory COVID-19 ARDS requiring extracorporeal membrane oxygenation (ECMO). The two patients were selected based on clinical criteria and elevated levels of IL-6 (>100 pg/ml) as a biomarker of inflammation. Once identified, emergency/expanded use permission for SCD treatment was obtained and patient consented. Six COVID-19 patients (four on ECMO) with severe ARDS were also screened with IL-6 levels less than 100 pg/ml and were not treated with SCD. The two enrolled patients' PaO2/FiO2 ratios increased from 55 and 58 to 200 and 192 at 52 and 50 hours, respectively. Inflammatory indices also declined with IL-6 falling from 231 and 598 pg/ml to 3.32 and 116 pg/ml, respectively. IL-6/IL-10 ratios also decreased from 11.8 and 18 to 0.7 and 0.62, respectively. The two patients were successfully weaned off ECMO after 17 and 16 days of SCD therapy, respectively. The results observed with SCD therapy on these two critically ill COVID-19 patients with severe ARDS and elevated IL-6 is encouraging. A multicenter clinical trial is underway with an FDA-approved investigational device exemption to evaluate the potential of SCD therapy to effectively treat COVID-19 intensive care unit patients.

Eritroaféresis terapéutica: experiencia en pacientes con policitemia vera y eritrocitosis secundaria / Therapeutic erythroapheresis: Experience in patients with polycythemia vera and secondary erythrocytosis

La eritrocitaféresis terapéutica (ET) es una estrategia más eficiente que la flebotomía en la reducción del hematocrito en las eritrocitosis primarias y secundarias. Objetivo: Analizar la tasa de respuesta y seguridad de la ET en policitemia vera (PV) y eritrocitosis secundaria (ES). Pacientes y método: Revisión retrospectiva de los pacientes con PV o ES tratados con ET, ante el fracaso a flebotomías o con comorbilidades que impedían cambios importantes de volemia. Resultados: Se realizaron 127 sesiones de ET (48 PV y 79 ES) en 20 pacientes (12 ES y 8 PV). La respuesta se obtuvo en el 87,5% de PV y en el 50% de ES. La tasa de complicaciones fue del 7,08%. Conclusiones: A pesar del tamaño de nuestra muestra y la heterogeneidad clínica de nuestra serie, podemos postular que la ET reduce de manera segura los valores de hematocrito en menor tiempo que la flebotomía, especialmente en pacientes con PV y en casos seleccionados de ES en quienes se prevé intolerancia hemodinámica a la flebotomía o en quienes falla este método

Therapeutic erythrocytapheresis (TE) is a more efficient strategy compared to phlebotomy to deplete levels of haematocrit in primary and secondary erythrocytosis. Objective: To analyse response rate and safety profile of TE in polycythemia vera (PV) and secondary erythrocytosis (SE). Patients and method: Retrospective review of all patients with PV or SE treated with TE, due to phlebotomy failure, or comorbidities that prevented changes of blood volumen. Results: 217 TE sessions (48 PV and 79 SE) corresponding to 20 patients (12 ES and 8 PV). Response were achieved in 87.5% of PV patients and in 50% of SE patients. Adverse effects related to TE performance occurred in 7.08%. Conclusion: Despite our small sample size and the heterogeneous nature of the patients included, we can postulate that TE is a secure strategy that can achieve haematocrit depletion in a shorter time than phlebotomy, specifically in PV patients and in selected cases of SE with expected haemodynamic intolerance to phlebotomies or in patients who fail to respond to phlebotomies

Therapeutic erythroapheresis: Experience in patients with polycythemia vera and secondary erythrocytosis. / Eritroaféresis terapéutica: experiencia en pacientes con policitemia vera y eritrocitosis secundaria.

Therapeutic erythrocytapheresis (TE) is a more efficient strategy compared to phlebotomy to deplete levels of haematocrit in primary and secondary erythrocytosis. OBJECTIVE: To analyse response rate and safety profile of TE in polycythemia vera (PV) and secondary erythrocytosis (SE). PATIENTS AND METHOD: Retrospective review of all patients with PV or SE treated with TE, due to phlebotomy failure, or comorbidities that prevented changes of blood volumen. RESULTS: 217 TE sessions (48 PV and 79 SE) corresponding to 20 patients (12 ES and 8 PV). Response were achieved in 87.5% of PV patients and in 50% of SE patients. Adverse effects related to TE performance occurred in 7.08%. CONCLUSION: Despite our small sample size and the heterogeneous nature of the patients included, we can postulate that TE is a secure strategy that can achieve haematocrit depletion in a shorter time than phlebotomy, specifically in PV patients and in selected cases of SE with expected haemodynamic intolerance to phlebotomies or in patients who fail to respond to phlebotomies.

Effectiveness of Cytapheresis for Ulcerative Colitis in Special Situations: Delayed Onset of Optimum Efficacy in Elderly Patients.

BACKGROUND: Cytapheresis is a non-pharmacologic treatment option in which depleting elevated/activated leucocytes is known to exacerbate and perpetuate ulcerative colitis (UC) by releasing inflammatory cytokines. Therefore, it is a relevant treatment for elderly patients who wish to avoid pharmacologicals. METHODS: The efficacy of Cytapheresis for remission induction in 72 patients who received Cytapheresis for active UC at our hospital was retrospectively evaluated. Patients included 11 elderly cases, patients on steroids, biologics, calcineurin inhibitor, and 13 with extra-intestinal complications. Lichtiger's UC clinical activity index ≤4 meant remission was assessed at the end of therapy and then 1 month later. The efficacy on extra-intestinal manifestations meant improvement of the main morbidity. RESULTS: At the end of Cytapheresis therapy, the remission rate in the elderly was 36.4%, and 54.2% in the non-elderly patients. One-month post Cytapheresis, the remission rate in the elderly had increased to 72.7% (p = 0.042), but to 58.3% in the non-elderly, suggesting a delayed response phenomenon in the elderly. The efficacy of Cytapheresis in 4 cases with loss of response to biologics was 75%, and 84.6% in the 13 patients with extra-intestinal complications, indicating a dramatic efficacy on dermatitis and arthralgia. CONCLUSIONS: Unlike pharmacologicals, the efficacy of Cytapheresis appears to be time dependent. Accordingly, in the elderly, we observed a delayed response, indicating that elderly patients may respond beyond the end of Cytapheresis therapy. Therefore, patients who do not show efficacy at the end of Cytapheresis therapy should be followed up for delayed response. Further, Cytapheresis is favored by patients for its good safety profile.

The sex parameter in estimation of total blood volume for pediatric erythrocytapheresis.

BACKGROUND AND OBJECTIVES: Estimation of the total blood volume (TBV) is fundamental to the control of automated red cell exchange (RCE). Error in the TBV estimate can produce outcomes that deviate from the prescribed targets, and may endanger the patient. Both the Spectra Optia and the COBE Spectra use the Nadler formulae to estimate TBV. There is a potential for large overestimates of TBV when the Nadler formula for males is applied to prepubertal boys. MATERIALS AND METHODS: This study uses our large clinical experience with RCE to examine procedure outcomes when RCE in prepubertal boys is programed with the female parameter instead of male. We determined the differences between programmed and measured values for three outcomes: (a) Programmed End Hematocrit - Post spun HCT by Hemata Stat II, (b) Programmed End Hematocrit - Post CBC HCT, and (c) Predicted Post Hgb S+C - Measured Post Hgb S+C. We defined the experimental group as Male-Female, where the biological sex was male but programmed sex was female, and two control groups where programmed and biological sex were the same. RESULTS: Small but statistically significant differences were demonstrated between the mean programmed-to-observed deviations of these outcome measures in all but two group and subgroup comparisons; however, the absolute magnitudes of the observed differences were not clinically significant. The suggested weight cutoff to begin programming males as male is 35 kg. CONCLUSION: The study provides experiential validation that performing RCE in prepubertal boys using the female parameter is safe.

Successful granulocyte apheresis using medium molecular weight hydroxyethyl starch.

Granulocyte transfusion (GTX) is a therapeutic option for severe bacterial or fungal infection in patients with sustained neutropenia after chemotherapy or stem cell transplantation. However, high molecular weight hydroxyethyl starch (HES), which has been used for selective sedimentation of red blood cells during apheresis, is not easily available in many countries including Japan. In this study, we evaluated the efficiency of granulocyte collection using medium molecular weight HES (130 kDa) in combination with the Spectra Optia apheresis system. Apheresis was performed for 2 consecutive days from seven donors and the mean total neutrophil yield from the first and second apheresis was 5.27 ± 3.10 × 1010 and 2.91 ± 2.92 × 1010, respectively. Infusion of concentrates from the first apheresis resulted in a significant neutrophil count increase and concentrates from the second apheresis were enough for maintenance of the neutrophil counts in all the recipients. Although the number of cases is limited, our results clearly show that sufficient number of granulocytes can be harvested by using medium molecular weight HES and this strategy is a safe and effective clinical practice in countries where high molecular weight HES is not available.

[Is apheresis still a useful tool in the treatment of nephrological diseases?]

Therapeutic apheresis is by now a century-old extracorporeal procedure, but it is still very much relevant thanks to advances in medical device technology. In addition to the classic plasma exchange, we now have double filtration techniques, plasma absorption, immunoadsorption, leuko and cyto-apheresis, LDL apheresis. The application of these highly selective techniques has opened up new perspectives in the treatment of various nephrological diseases. Unfortunately, renal diseases that can be treated with apheretic techniques are often relatively rare and this prevents us from carrying out extensive studies aimed at demonstrating the real benefits of these methods. Every three years, the American Society of Apheresis provides solid recommendations regarding the diseases that can be treated with apheresis. New immunosuppressants, immuno-modulating substances and monoclonal antibodies are becoming extremely selective and sophisticated weapons against diseases with a clearly identified causal agent. This does not exclude the fact that, due to economic reasons or even to minimize the side effects of these new drugs, apheretic techniques could still retain an important, if ancillary, role.

Solving the calcium gluconate shortage in real-time: Mistakes made and lessons learned.

PURPOSE: During a national shortage of calcium gluconate, we switched to calcium chloride for routine supplementation for peripheral blood stem cell (PBSC) collections. Subsequently, we analyzed the postprocedure ionized calcium level, as we aimed for an equivalent result compared to before the shortage. METHODS: Pharmacy representatives helped us to find an "equivalent" substitute for calcium gluconate at 46.5 mEq in 500 mL normal saline, infused at 100 mL/hour. After instituting a presumably comparable protocol using calcium chloride (40.8 mEq in 250 mL normal saline at a rate of 100 mL/hour), we reviewed ionized calcium results post-PBSC procedures to compare with those obtained with calcium gluconate. Having noticed a difference in the mean values, we adjusted the rate of calcium chloride to reach our desired outcome. RESULTS: Twenty-seven procedures were analyzed on 15 unique patients. We used the Spectra OPTIA with a whole blood: anticoagulant ratio of 13:1. Ionized calcium levels post-PBSC collection with the first calcium chloride protocol were significantly higher (P = 0.003) in nine patients treated. Subsequently, we decreased the calcium chloride infusion rate to 75 mL/hour and achieved similar mean levels to calcium gluconate (P = 0.382). CONCLUSION: Changes in replacement fluids for apheresis procedures can be complex, particularly when dealing with electrolytes that could be clinically significant at critically high or low levels. Once we recognized the need to take into account the amount of elemental calcium infused, we achieved the desired postprocedure ionized calcium results. This study can serve as a lesson for future shortages of infusions used during apheresis procedures.

Improvement of maternal and fetal outcomes in women with sickle cell disease treated with early prophylactic erythrocytapheresis.

BACKGROUND: The desire for pregnancy in sickle cell disease (SCD) women has become a true challenge for hematologists, requiring a multidisciplinary approach. Erythrocytapheresis (ECP) is an important therapeutic tool in SCD, but only limited data on starting time and the effects of ECP during pregnancy are available. STUDY DESIGN AND METHODS: This is a double-center retrospective cross-sectional study on a total of 46 single pregnancies in SCD women from January 2008 to June 2017. ECP was started at 10.7 ± 5.2 weeks of gestation, and prophylactic enoxaparin (4,000 U daily) was introduced due to the reported high prevalence of thromboembolic events in pregnant SCD women. RESULTS: The alloimmunization ratio was 2.1 per 1,000 and the alloimmunization rate was 5.6%. In early ECP-treated SCD women, no severe vaso-occlusive crisis, sepsis or severe infection, or preeclampsia or eclampsia were observed. We found normal umbilical arterial impedance during pregnancy, suggesting an optimal uteroplacental function in early ECP-treated SCD women. This was also supported by the improvement in newborn birthweights compared to previous studies. In our cohort, three SCD women were started later on ECP (20-25 weeks), and gestation ended with late fetal loss. Placenta pathology documented SCD-related damage and erythroblasts in placental vessels, indicating fetal hypoxia. CONCLUSIONS: Collectively, our data generate a rationale to support a larger clinical trial of early ECP program in SCD pregnancy.

The use of cytapheresis in the treatment of infectious diseases.

Cytapheresis (removal of cellular blood components) has been employed for treatment of infectious diseases since the 1960s. Techniques have included thrombocytapheresis (buffy coat apheresis) for loiasis, erythrocytapheresis for malaria and babesiosis, and leukocytapheresis for pertussis-associated lymphocytosis. Published data on these applications is largely limited to case level data and small observational studies; as such, recommendations for or against the use of cytapheresis in the treatment of infections have been extrapolated from these limited (and at times flawed) data sets. Consequently, utilization of cytapheresis in many instances is not uniform between institutions, and typically occurs at the discretion of treating medical teams. This review revisits the existing literature on the use of cytapheresis in the treatment of four infections (loasis, malaria, babesiosis, and pertussis) and examines the rationale underlying current treatment recommendations concerning its use.

Cytapheresis (CAP) with leukocyte removal filter/bead column as one therapeutic option for inflammatory bowel disease.

Inflammatory bowel disease (IBD) like Crohn's disease and ulcerative colitis are chronic inflammatory disorders that affect the bowel. The disease is characterized by periods of clinical remission and relapse due to severe intestinal inflammation. Drug therapy of IBD is associated with unpleasant side effects. Further, efficacies of conventional drugs decrease with chronic use and this can represent a major difficulty in the long term management of IBD. However, in active IBD, leukocytes are elevated in the lesion they may be able to be a factor of IBD aggravation. Membrane filters column and leukocyte adsorbing beads have been developed which are direct blood perfusion systems for removing any desired level of leukocytes. Clinical studies with these two new models have shown good effects for active IBD. Clinical data suggest that leukocytapheresis might be an effective adjunct to therapy of IBD, to promote remission, taper conventional drug dosage and potentially should reduce the number of patients who require colectomy. The results may further understandings of the pathophysiology of IBD and this in turn should contribute to a more effective treatment of this disorder.

Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis.

Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed "long-interval cytapheresis (LI-CAP)", in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (p<0.0001). The rate of clinical remission after LI-CAP was 80%. The rate of steroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC.

Survey on Transfusion-Transmitted Cytomegalovirus and Cytomegalovirus Disease Mitigation.

CONTEXT: - Cytomegalovirus (CMV) can be transmitted by cellular blood products, leading to severe disease in immunosuppressed patients such as neonates and transplant recipients. To mitigate transfusion-transmitted CMV (TT-CMV), "CMV-safe" blood products (leukoreduced and/or CMV-seronegative) are transfused. Attempts to develop practice guidelines for TT-CMV mitigation have been limited by paucity of high-quality clinical trials. OBJECTIVE: - To assess current TT-CMV mitigation strategies across medical institutions for specific at-risk populations. DESIGN: - Supplemental questions regarding TT-CMV and CMV disease mitigation were added to a College of American Pathologists Transfusion Medicine (Comprehensive) Participant Survey in 2015, addressing whether a given institution provided CMV-safe products for 6 at-risk patient populations. RESULTS: - Ninety percent (2712 of 3032) of institutions reported providing universally leukoreduced blood products. Among institutions without universal leukoreduction, 92% (295 of 320) provided leukoreduced products on the basis of clinical criteria. Eighty-three percent (2481 of 3004) of respondents reported having availability of CMV-seronegative products; however, wide variation in policies was reported governing CMV-seronegative product use. Among all respondents, less than 5% reported using CMV prophylaxis and monitoring in high-risk patient groups. Transplant centers reported higher rates of CMV prophylaxis (25% [97 of 394] solid organ) and monitoring (15% [59 of 394] solid organ) for CMV-negative transplant recipients. CONCLUSIONS: - Universal leukoreduction is the primary strategy for mitigating TT-CMV. While most institutions have both CMV-seronegative and leukoreduced blood products available, consensus is lacking on which patients should receive these products. High-quality studies are needed to determine if CMV-seronegative and leukoreduced blood products are needed in high-risk patient populations.

From total blood exchange to erythrocytapheresis and back to treat complications of sickle cell disease.

Erythrocytapheresis is an important procedure in the management of certain complications of sickle cell disease, including acute stroke, stroke prevention, acute chest syndrome, and multiorgan failure. Erythrocytapheresis in sickle cell disease simply entails the removal of the patient's red blood cells containing the abnormal sickle hemoglobin and replacing them with normal red blood cells carrying normal hemoglobin. In these procedures, the patient's plasma is not exchanged but is returned to the patient. Several studies have demonstrated that the plasma of patients with sickle cell disease contains several components that increase blood viscosity and initiate or promote vaso-occlusion. These factors include increased levels of globulins, especially immunoglobulin G, acute-phase reactants, fibrinogen, coagulation factors, inflammatory mediators, and heme in the steady state and increase further during painful crises. This may explain why, in certain complications of sickle cell disease, such as acute chest syndrome, hepatic crisis, and priapism, erythrocytapheresis by itself may not be effective despite repetitive cycles of red blood cell exchange. The use of therapeutic plasma exchange in addition to erythrocytapheresis in these situations seems to be useful in resolving them more efficiently. The role of therapeutic plasma exchange in the management of certain complications of sickle cell disease needs further evaluation. This commentary addresses the role of therapeutic plasma exchange in the management of complications of sickle cell disease.