Outcomes of a preoperative risk-based transfusion assignment protocol in sickle cell disease patients: a single-center retrospective study from Saudi Arabia

Abstract

Many patients with sickle cell disease (SCD) need surgical management during their lifetime. The best approach for preoperative transfusion in SCD is still to be determined. In this single-center retrospective study, we included HBSS/HBS-Beta⁰-thalassemia patients younger than 16?years of age who underwent surgery between January 2008 and July 2019. Preoperative transfusion assignment (PTA) was based on SCD severity and surgical risk. Patients were assigned to no transfusion, simple transfusion, or exchange transfusion. A total of 284 patients were identified and 66 (23%) underwent 78 procedures. Mean age at the time of procedure was 8 (5–11) years, mean baseline hemoglobin was 8.5 (7.8–9.3) g/dl, and mean hemoglobin F was 18.4?±?8.2%. SCD severity was low-risk in 57 (73%) and high-risk in 21 (27%) patients. Surgical risk was low-risk in 20 (25.6%) and medium-risk in 58 (74.4%) procedures. PTA was no transfusion in 17 (22%), simple transfusion in 40 (51%), and exchange transfusion in 21 (27%) procedures. Postoperative complications occurred in five (6.4%) of procedures only in the simple transfusion group (three acute chest syndrome, one hemolytic anemia, one pain crisis) undergoing medium-risk surgery. Preoperative risk-based transfusion assignment is feasible. Despite a high baseline hemoglobin level in the no transfusion group, none of the patients developed postoperative complications. It is possible that the high baseline hemoglobin F phenotype was protective and indicates the need to study the risk/benefit of interventions used in this phenotype.     

Tonsillectomy, adenoidectomy, and myringotomy in sickle cell disease: perioperative morbidity. Preoperative Transfusion in Sickle Cell Disease Study Group

PURPOSE: To compare the rates of perioperative morbidity of patients with sickle cell anemia who were randomly assigned to 2 preoperative transfusion regimens and to identify predisposing factors for perioperative complications. PATIENTS AND METHODS: Investigators at 36 centers enrolled 118 patients who were scheduled to have elective surgery and agreed to randomization between 2 preoperative transfusion regimens. Forty-seven subjects were enrolled but not randomized, including 20 who were not transfused before surgery. Perioperative management was based on a prescribed care plan. RESULTS: Tonsillectomy and/or adenoidectomy (TA) were performed on 136 persons, and 29 had myringotomy as their primary procedure. There were no differences in the frequency of complications between the randomized groups. The serious, non-transfusion complication rates for randomized patients were 32% (34 of 107) for TA and 36% (4 of 11) for myringotomy. A history of pulmonary disease was a predictor of postoperative sickle cell-related events for patients undergoing TA surgery. CONCLUSIONS: The more intensive transfusion regimen did not result in fewer perioperative complications. The high frequency of complications emphasizes the need for anticipatory management of persons undergoing TA. A history of pulmonary disease identifies patients at increased risk for sickle cell-related events after TA surgery. Patients undergoing myringotomy have a low frequency of sickle cell-related events but a significant frequency of other serious perioperative complications.     

Minor elective surgical procedures using general anesthesia in children with sickle cell anemia without pre-operative blood transfusion

BACKGROUND: Pre-operative red blood cell (RBC) transfusions are often recommended for patients with sickle cell disease (SCD) who require elective surgery under general anesthesia. However, definitive randomized studies demonstrating the benefit of transfusions in this setting have not been conducted. In particular, the merits of transfusion prior to minor or low-risk surgical procedures in children with SCD have not been demonstrated. PROCEDURE: We hypothesized that children with sickle cell anemia (Hb SS) who have minor elective surgical procedures develop few complications even without pre-operative transfusion. We accessed our Comprehensive Sickle Cell Program's Database to identify all such procedures performed during a 13-year period. Medical records were reviewed to characterize the surgical procedure, the use of transfusions, and perioperative complications. RESULTS: Twenty-eight children with Hb SS had a total of 38 minor surgical procedures. No perioperative transfusions were given in 34 of the cases (85%). Five of these 34 surgeries (15%) were associated with minor post-operative complications (fever or transient pain). No post-operative acute chest syndrome was encountered. CONCLUSIONS: Minor or low-risk elective surgical procedures in children with Hb SS may not routinely require pre-operative transfusion. A randomized clinical trial to compare transfusion with no transfusion for minor surgical procedures is needed.     

Splenic complications of the sickling syndromes and the role of splenectomy.

PURPOSE: To analyze the authors' experience with splenectomy for sickling disorders and evaluate the indications, complications, and outcome. PATIENTS AND METHODS: Over a period of 10 years (1987-1997), 113 patients with sickling disorders (100 with sickle cell disease and 13 with sickle-beta-thalassemia) had splenectomy at the authors' hospital as part of their management. The indications for splenectomy were hypersplenism (26 patients), major splenic sequestration crisis (MSSC) (23 patients), minor recurrent splenic sequestration crisis (MRSSC) (50 patients), splenic abscess (12 patients), and massive splenic infarction (2 patients). RESULTS: Splenectomy in patients with sickle cell disease (SCD) and sickle-beta-thalassemia (S-beta-Thal) was beneficial in reducing their transfusion requirements and its attendant risks, eliminating the discomfort from mechanical pressure of the enlarged spleen, and avoiding the risks of acute splenic sequestration crisis. It also was curative for patients with splenic abscess and massive splenic infarction. Twenty-four patients with SCD (24%) had splenectomy and cholecystectomy caused by concomitant gallstones. There was no mortality, and the postoperative morbidity was 7%. CONCLUSIONS: With careful perioperative management, splenectomy is both safe and beneficial in a select group of patients with SCD and S-beta-Thal.     

Characterizing complication risk from multisite,intermittent transfusions for the treatment of sickle cell disease

Blood transfusions are indicated for some acute complications of sickle cell disease (SCD). To characterize the SCD population at increased risk of transfusion‐associated complications, Georgia hospital discharge data were used to estimate the frequency of intermittent transfusions and the proportion of patients receiving them at multiple institutions. Ten years of data (2007‐2016) showed almost 19% of patients with SCD (1585/8529) received transfusions at more than one hospital. The likelihood of multisite transfusions increased from ages 18 through 40 and with the number of transfusions received. The results support the need to track and share transfusion histories in order to reduce complication risks.     

Less intensive long-term transfusion therapy for sickle cell anemia and cerebrovascular accident.

To determine the efficacy of a less intensive transfusion regimen in preventing recurrent cerebrovascular accidents and reducing transfusion requirements in patients with sickle cell anemia, we offered to 14 patients who had been undergoing aggressive transfusion therapy (sickle hemoglobin concentration kept less than 30% of total) for a mean of 9 years the option of either diminishing or stopping transfusion therapy. Thirteen patients chose to continue a modified transfusion regimen to maintain sickle hemoglobin concentration less than 60%; 10 of these patients have now been followed for 1 year or more (12 to 27 months, mean 15.5 months). There have been no recurrent neurologic events, although two patients have died of complications of hemochromatosis. All patients had a reduction in donor exposure, and there was a mean reduction in net transfusion requirement of 31.4% during the first year after modification. The greatest reduction was achieved in the single patient managed by small-volume (5 ml/kg) simple transfusion rather than partial packed cell exchange. We conclude that although long-term consequences of less aggressive transfusion therapy are unknown, the use of such a regimen may be reasonable, particularly in patients with significant transfusional hemochromatosis.     

Changes of hemostatic factors in patients with hemoglobinopathies

In this study, protein C (PC), protein S (PS), heparin cofactor II (HCFII), prothrombin fragment 1+2(PF1,2), thrombin-antithrombin III complex (TAT), von Willebrand factor (vWF) and thrombomodulin (TM) were investigated in 13 patients with beta thalassemia intermedia (TI) not requiring transfusion, six patients with sickle cell disease (SCD), and seven patients with HbS-beta thalassemia (S-BT) who were not in crisis. These hemostatic parameters were also studied in 12 healthy children assigned as a control group. Protein C and Protein S (PC-PS) were found to be decreased in TI patients and normal in S-BT patients. PC was decreased in SCD patients. In the patients with TI and SCD, the mean PF1,2 level was elevated, whereas the TAT level was not statistically different from that of the control group. These results suggested that in patients with hemoglobinopathies: a) decreased natural anticoagulants and b) enhanced procoagulant activation have been encountered. Other unexpected and interesting results of this study are the decreased vWF and elevated HCFII levels in all three patient groups.     

Life threatening parvovirus B19 and herpes simplex virus associated acute myocardial dysfunction in a child with homozygous sickle cell disease

Human parvovirus (HPV) B19, a common infection, frequently causes transient red cell aplasia in children with hemolytic anemia, such as sickle cell disease (SCD). It was considered to be a self-limited condition, easily treated with blood transfusion. However, acute splenic sequestration, acute chest syndrome, nephrotic syndrome, and stroke have been reported in SCD patients following HPV B19 infection. We report a 3-year-old child with SCD who developed fulminant myocarditis following HPV B19-related aplastic crisis. The diagnosis of myocarditis should be considered in a patient with hemolytic anemia with an infection with HPV B19 who develops signs of cardiopulmonary failure despite correction of anemia.     

Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease

OBJECTIVES: Glomerular disease and renal failure cause substantial morbidity for patients with sickle cell disease (SCD). Proteinuria is an early manifestation of sickle nephropathy, but the prevalence of proteinuria and its clinical correlations in children with SCD are unknown. STUDY DESIGN: Data were collected prospectively on children with SCD for 10 years including physical measurements, laboratory test results, and clinical complications. Persistent proteinuria was defined as > or =1+ protein on urinalysis for at least 6 months. The glomerular filtration rate was estimated with serum creatinine concentration and height. Proteinuria was correlated with other variables by chi(2) analysis. RESULTS: Proteinuria occurred in 20 of 442 pediatric patients including 15 (6.2%) with sickle cell anemia. Proteinuria increased with age, affecting 12% of older teenagers with sickle cell anemia. Proteinuria was significantly associated with lower hemoglobin concentration, higher mean corpuscular volume, and higher leukocyte count. For children of some ages, proteinuria was associated with complications including stroke, acute chest syndrome, cholelithiasis, and hospitalizations. Glomerular filtration rate hyperfiltration occurred early in life, followed by normalization. CONCLUSIONS: Sickle nephropathy, manifested as persistent proteinuria, begins early in life, occurs in all forms of SCD, and is associated with severity of disease. Early detection of proteinuria may allow therapy to prevent progressive renal insufficiency.     

Chronically Transfused Pediatric Sickle Cell Patients are Protected from Cardiac Iron Overload

Iron overload is a major toxicity of chronic transfusions. Myocardial iron overload is associated with cardiac dysfunction. Cardiac and liver magnetic resonance imaging (MRI) was performed on 14 chronically transfused sickle cell disease (SCD) and non-sickle cell disease (non-SCD) patients seen at Vanderbilt Children's Hospital from 1 January 2000 to 10 March 2010. Retrospective review was conducted to assess cardiac T2*, liver T2*, ventricular dimensions and function, echocardiogram, length of transfusion, hemoglobin, and ferritin measurements. Ten patients had SCD and 4 had non-SCD, including α-thalassemia, β-thalassemia, and Diamond-Blackfan anemia. Cardiac T2* was normal in all SCD patients (mean 39 ± 12 ms), but abnormal in 3 of 4 non-SCD patients (mean 11.8 ± 2.4 ms). Liver T2* was similar between SCD (mean 6.2 ± 1.6 ms) and non-SCD patients (mean 5.9 ± 1.9 ms), and did not correlate with serum ferritin. Comparing SCD and non-SCD patients with similar transfusion duration, SCD patients had normal cardiac T2* and non-SCD patients had abnormal cardiac T2*. No patients had cardiomyopathy, but ventricular dilatation was common among SCD patients. Chronically transfused pediatric SCD patients are relatively spared of myocardial iron overload, which is unlikely to be due to lower total body iron burden in SCD patients than non-SCD patients.     

Chronically transfused pediatric sickle cell patients are protected from cardiac iron overload

Iron overload is a major toxicity of chronic transfusions. Myocardial iron overload is associated with cardiac dysfunction. Cardiac and liver magnetic resonance imaging (MRI) was performed on 14 chronically transfused sickle cell disease (SCD) and non-sickle cell disease (non-SCD) patients seen at Vanderbilt Children's Hospital from 1 January 2000 to 10 March 2010. Retrospective review was conducted to assess cardiac T2*, liver T2*, ventricular dimensions and function, echocardiogram, length of transfusion, hemoglobin, and ferritin measurements. Ten patients had SCD and 4 had non-SCD, including α-thalassemia, β-thalassemia, and Diamond-Blackfan anemia. Cardiac T2* was normal in all SCD patients (mean 39 ± 12 ms), but abnormal in 3 of 4 non-SCD patients (mean 11.8 ± 2.4 ms). Liver T2* was similar between SCD (mean 6.2 ± 1.6 ms) and non-SCD patients (mean 5.9 ± 1.9 ms), and did not correlate with serum ferritin. Comparing SCD and non-SCD patients with similar transfusion duration, SCD patients had normal cardiac T2* and non-SCD patients had abnormal cardiac T2*. No patients had cardiomyopathy, but ventricular dilatation was common among SCD patients. Chronically transfused pediatric SCD patients are relatively spared of myocardial iron overload, which is unlikely to be due to lower total body iron burden in SCD patients than non-SCD patients.     

Long-term follow-up of pediatric sickle cell disease patients with abnormal high velocities on transcranial Doppler

Cerebral arteriopathy can be detected in children with sickle cell disease (SCD) by transcranial Doppler (TCD). Abnormally high velocities are predictive of high stroke risk, which can be reduced by transfusion therapy. We report the results of the screening of 291 SCD children followed in our center, including the clinical and imaging follow-up of 35 children with abnormal TCDs who were placed on transfusion therapy. We postulated that patients with normal MRA findings and abnormal TCD velocities that normalized on a transfusion program could be safely treated with hydroxyurea (HU). We report their outcome (median follow-up of 4.4 years). Of 13 patients with normalized velocities on transfusion, 10 had normal MRAs, and transfusion therapy was stopped and HU begun. Four of these ten patients redeveloped high velocities off transfusion, so currently only six remain transfusion-free. Six other transplanted patients remain transfusion-free. Abnormal TCD velocities detect a high-risk group, justifying the research for suitable transplant donors. Multicenter studies comparing HU therapy to long-term transfusion might help identify which patients can avoid transfusion and its complications while avoiding vasculopathy.     

Hodgkin lymphoma in a child with sickle cell anemia

There are reports of patients with sickle cell disease who developed hematological malignancies but the relationship between these malignancies and sickle cell disease (SCD) is not yet defined. The co-existence of a hematological malignancy with SCD poses certain challenges for the management of each condition. We describe a 7-year-old boy with sickle cell anemia who developed Hodgkin's lymphoma and the challenges of management. He presented with a 4-year history of bilateral neck swelling and a 2-month history of weight loss and high-grade fever. Histology of a lymph node biopsy was consistent with mixed cellularity Hodgkin's lymphoma. He was treated with five cycles of Cyclophosphamide, Vincristine, Procarbazine and Prednisolone (COPP) and had complete clinical response. Chemotherapy was associated with an increase in frequency of painful crises and complicated by septicaemia. Blood transfusion needs were minimal; apart from the transfusion preceding the first cycle of chemotherapy, there was no need for further transfusion. Myelosuppression was not a problem in the patient; he responded well to antibiotics during the two episodes of septicemia without the use of hemopoetic growth factor. Patients with sickle cell anaemia who develop Hodgkin's lymphoma can be successfully treated with chemotherapy along with supportive management for crises and infections.     

Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia.

OBJECTIVE: The Stroke Prevention Trial (STOP) demonstrated that chronic transfusion is highly effective in reducing the risk of stroke in children with sickle-cell disease and an abnormal transcranial Doppler ultrasonography examination result. Our objective was to determine whether chronic transfusion therapy reduces the incidence of pain and acute chest syndrome. METHODS: During STOP, 130 children with sickle-cell anemia or sickle beta(0)-thalassemia and abnormal transcranial Doppler ultrasonography examination result were randomly assigned to chronic transfusion (n = 63) or observation (n = 67). In addition to monitoring for stroke, nonneurologic sickle-cell complications were identified and recorded. RESULTS: Mean age at STOP study entry was 8.3 +/- 3.3 years, and mean follow-up was 19.6 +/- 6.5 months. Hospitalization rates (based on intent-to-treat analysis) for acute chest syndrome were 4.8 and 15.3 per 100 patient-years (P =.0027) and for pain were 16.2 and 27.6 per 100 patient-years (P =.13) in the chronic transfusion and observed groups, respectively. If analyzed according to treatment actually received, the difference in pain rate becomes significant (9.7 vs 27.1 events per 100 patient-years, P =.014), and transfusion remains protective from acute chest syndrome (2.2 vs 15.7 events per 100 patient-years, P =.0001). CONCLUSIONS: Compliance with aggressive chronic transfusion reduces the frequency of acute chest syndrome and pain episodes.     

Splenectomy and acute splenic sequestration crises in sickle cell disease

Acute splenic sequestration crises (ASSC) is one of the complications of sickle cell disease (SCD) that can be life-threatening due to loss of blood volume. Over a 5-year period, we have treated 19 patients ranging in age from 4 to 32 years with ASSC. There were 14 males and 5 females; 17 had homozygous SCD and the other 2 had sickle thalassemia. Two patients presented with severe anemia and acute circulatory collapse; 1 of them developed residual weakness of his limbs and decreased visual acuity. Nine patients underwent splenectomy after major episodes of sequestration while the remaining 10 had recurrent minor episodes of sequestration. The clinical features and the role of splenectomy are discussed.     

Higher executive abilities following a blood transfusion in children and young adults with sickle cell disease

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non‐SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3‐7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ²(1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.     

Iron deposition in cranial bone marrow with sickle cell disease: MR assessment using a fat suppression technique

Thirteen patients with sickle cell disease (SCD) undergoing transfusion therapy and 8 control patients were examined by magnetic resonance imaging to discriminate bone marrow change due to iron deposition from hematologic marrow hyperplasia. Using T1-weighted spin echo images, only two subjects showed extremely low signal intensity marrow compatible with iron deposition. However, using T2-weighted fast spin echo images with fat suppression, cranial bone marrow in SCD patients with transfusion therapy showed considerably lower signal than that of controls. The main cause of marrow signal decrease in SCD patients with transfusion therapy was considered to be iron deposition due to repeated transfusion therapy rather than red marrow hyperplasia.     

Procalcitonin is more useful than C-reactive protein in differentiation of fever in patients with sickle cell disease

This study aimed at evaluating the value of C-reactive protein (CRP) and procalcitonin (PCT) levels in the differential diagnosis of fever in patients with sickle cell disease (SCD). The study included 86 children with SCD (group 1) and 49 controls (group 2). During the study, the patients had 114 acute episodes or routine visits to the units. They were classified as having vasoocclusive crisis with fever (group 1A), vasoocclusive crisis without fever (group 1B), and no crisis or fever (steady state, group 1C). Only patients with crises were admitted to the hospital. Patients admitted to the hospital with various clinical signs and symptoms each and every time were included in groups 1A, 1B, and 1C. Thus, a total of 114 clinical episodes were analyzed. The mean CRP levels in the 3 patient groups were significantly higher than that in the group 2, and among the patient groups, the mean CRP was significantly higher in group 1A than the other groups. The mean CRP level in group 1A and group 1B was significantly higher than that in group 1C. There were no significant differences among the 3 SCD groups in terms of the median serum PCT level; however, the median PCT level in group 1A, group 1B, and group 1C patients was significantly higher than that in group 2 patients. These data indicate that vasoocclusive disease with or without fever apparently does not significantly increase PCT levels in relation to the baseline status of children with SCD, which in turn are clearly more elevated than PCT levels of control children.     

Impact of hydroxyurea on perioperative management and outcomes in children with sickle cell anemia

Hydroxyurea has enhanced the treatment for children with sickle cell anemia. The objectives of this study were to compare perioperative transfusions and outcomes for children taking hydroxyurea versus those not taking hydroxyurea. We retrospectively reviewed perioperative management and outcomes for 51 children with sickle cell anemia (HbSS genotype) who underwent surgery in our center between January 2003 and April 2008. Of the 51 patients, 30 (59%) were taking hydroxyurea and 21 (41%) were not taking hydroxyurea. Eight of 30 (27%) in the hydroxyurea group were not transfused preoperatively, 12 of 30 (40%) received a single transfusion and 10 of 30 (33%) received serial transfusions, compared with 1 of 21 (5%) children in the nonhydroxyurea group who was not transfused, 2 of 21 (10%) who received a single transfusion and 18 of 21 (85%) who received serial transfusions or pheresis (P=0.004; for comparison across groups). One patient not taking hydroxyurea developed a delayed hyperhemolytic transfusion reaction, and 2 children taking hydroxyurea developed acute chest syndrome. Overall, children taking hydroxyurea had substantially fewer transfusions compared with children not taking hydroxyurea. Both groups of children had a low complication rate. Further research should be done to optimize perioperative management of children taking hydroxyurea.