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Patients with chronic haemolysis due to sickle cell anaemia and its sickling variants with high haemoglobin (Hb) S levels, such as sickle cell/β thalassaemia, may develop accelerated haemolysis in several circumstances. These include the appearance of warm autoantibodies and the sickle cell transfusion reaction syndrome1, which is sometimes related to the development of new alloantibodies. In each of these situations, enhanced destruction of the patient’s own red cells, as well as transfused cells, may result in haemoglobin levels that are less than at baseline.
We describe two patients with sickle cell/β thalassaemia who presented with sustained bone pain crises despite maximal hydration, oxygenation, and narcotic analgesia associated with continued red cell transfusions to meet the needs related to sickling and warm autoantibodies. In each case, a combination of brisk reticulocyte response and shortened survival of the transfused red cells resulted in lack of significant clinical benefit, only transient elevation of haemoglobin level or percentage of HbA, and rapid rebound of HbS in response to simple red cell transfusions or even red cell exchange (RCE). Addition of immunosuppressive therapy – in the form of prednisone or intravenous immune globulin (IVIG) - eventually led to stabilisation, with an increase in haemoglobin levels and improvement in the clinical condition.
We have not seen previous reports in the literature addressing, in detail, the course of response to RCE and its lack of effectiveness in the described clinical setting.
A 34-year old African-American female with HbSßo thalassaemia and asthma was admitted to the University of Chicago Medical Center complaining of generalised bone pain. Her medications on admission were: fluticasone propionate inhalation, albuterol inhalation, folic acid, acetaminophen and codeine phosphate (60 mg), and extended release morphine sulphate. She had been transfused with 11 units of red cells in the last 4 years before the admission. Haemoglobin electrophoresis 29 months prior to admission showed: HbS 85.8%, HbA2 5.2%, HbF 7%, HbA <2%. Her blood type was group O, Rh positive with documented antibodies to C, E, Fya, Jkb, and S antigens. On one occasion 4 years earlier, a positive IgG direct Coombs’ test (direct antiglobulin test, DAT) was noted after a Caesarean section. The spleen was enlarged on ultrasound at that time. A repeat DAT 2 years later was negative.
Physical examination showed mild scleral icterus, diffuse bone tenderness, and right upper quadrant abdominal pain and tenderness on deep palpation. The spleen was not palpable. Admission laboratory results were: Hb 7.5 g/dL, absolute reticulocyte count 267 x 103/μL (normal value, n.v. 25–75 x 103/μL), total serum bilirubin 4.3 mg/dL (n.v. 0.1–1.0 mg/dL), unconjugated bilirubin 3.4 mg/dL (n.v. 0.1–1.0 mg/dL), serum lactate dehydrogenase (LDH) 955 IU/L (n.v. 116–245 IU/L), SGOT 81 U/L (n.v. 8–37 U/L), SGPT 28 U/L (n.v. 8–35 U/L), and urine urobilinogen 4 g/dL (n.v. 0.1–1 g/dL). Howell-Jolly bodies were seen on a peripheral blood smear.
Oxygen saturation was maintained in the normal range throughout the period in hospital by delivering 2–3 L/min supplemental oxygen via nasal prongs. Pain management included patient-controlled analgesia (morphine sulphate), oxycodone 90 mg twice daily per os, and supplemental oral and intravenous morphine sulphate. Pain scores were initially 6–7 (on a scale of 10) and subsequently 9–10. On day 6 it was noted that the pain medication was sedating the patient.
On day 4 of the hospital admission the patient’s haemoglobin fell to 5.1 g/dL and total bilirubin reached 11 mg/dL. The patient had no blood loss, but had ongoing pain and intermittent fever. Urine urobilinogen rose to 8 g/dL. On day 5 abdominal ultrasound revealed gallbladder sludge without other secondary signs of acute cholecystitis. Cholecystectomy was considered. Liver function tests were: total bilirubin 9.1 mg/dL, alkaline phosphatase 73 U/L (n.v. 30–120 U/L), SGOT 85 U/L, SGPT 70 U/L. The concentration of LDH was 1,415 IU/L.
Between days 5 and 8 the patient received eight units of red cells. All units transfused during the patient’s time in hospital were compatible or least incompatible and were negative for the antigens against which the patient had known antibodies (see above). The DAT was negative during this period. The absolute reticulocyte count on day 7 was 578 x 103/μL. The haemoglobin concentration reached 6.3 g/dL on day 9 (Figure 1). Haemoglobin electrophoresis on the morning of day 9 (Figure 1A) showed: HbS 79.3%, HbA 14%, HbA2 4.4%, HbF 2.7%.
Because of persistent severe pain (10 on a scale of 10), fever, ongoing transfusion needs and hyperbilirubinaemia (total bilirubin 9.4 mg/dL), despite aggressive hydration, normal oxygen saturation, and maximal pain medication, and in anticipation of possible cholecystectomy, a partial RCE (5 units, with use of the COBE Spectra™ Apheresis System) was performed late on day 9 (Figure 1). The target haematocrit was 24%. The patient’s pre-exchange weight was 102 kg. Her haemoglobin concentration was 5.7 g/dL. On day 10 the HbS level was 60.6%, HbA was 33% (with Hb of 5.1 g/dL), but on day 12 the HbS level rose to 68.5% and HbA fell to 24.8%. The haemoglobin concentration was 5.7 g/dL. The absolute reticulocyte count on day 12 was 854 x 103/μL. The total bilirubin was 3.9 mg/dL (3.6 mg/dL unconjugated).
On day 13 a warm autoantibody (IgG and C3) was detected. Because of a possible infectious cause of the persistent fever, corticosteroid therapy was not instituted. IVIG was administered on days 16–18 (48 g/dose). The haemoglobin concentration remained stable in the range of 5.4 g/dL and rose to 5.7 g/dL following transfusion of red cells on day 20. The bone and abdominal pain improved, but low grade fever persisted and was finally attributed to a dental infection that was treated. The patient was discharged on day 21. When seen in the clinic 2 weeks later, her haemoglobin concentration was 8 g/dL, total bilirubin was 3 mg/dL, and the absolute reticulocyte count was 690 x 103/μL.
A 36-year old African-American female with HbSß+ thalassaemia was admitted to the University of Chicago Medical Center with complaints of fever, chills, and increasing right hip pain as well as generalised bone pain. She had a complicated past history, including avascular necrosis of the right hip, two right hip replacements, cholecystectomy, chronic osteomyelitis of the right hip, hepatitis C, acute chest syndrome, and chronic pancreatitis with fat malabsorption and had undergone RCE several times. Three years previously a diagnosis of warm autoantibody haemolytic anaemia (C3) had been made. She had received intermittent treatment with prednisone, IVIG, rituximab, and mycophenolate mofetil with varying degrees of response. The DAT (IgG) was positive 14 months before admission, but negative 3 months before the current admission. Her blood type was group B, Rh positive. Multiple red cell alloantibodies had been documented (anti-K, C, E, Fya, S, Jkb, M). Baseline haemoglobin electrophoresis (7 years prior to admission) showed: HbS 75.6%; HbA 3.9%; HbA2 6.3%; HbF 11.5%. The last transfusion of red cells (2 units) had been 4 months prior to the current admission.
Medications on admission were: ciprofloxacin, prednisone (5 mg daily), lansoprazole, calcium carbonate, folic acid, zolpidem tartrate, propoxyphene napsylate/acetaminophen, fentanyl transdermal (100 μg applied every 72h), and pancrelipase delayed release capsules for the chronic pancreatic insufficiency. Physical examination was remarkable for diffuse bone pain and right hip pain on rotation. The spleen was not palpable. The patient’s oxygen saturation was maintained within the normal range with 2–3 L/min oxygen delivered via nasal prongs. Her pain scores were 8–10 on a scale of 10 (level 10 at the time of RCE). Pain was managed with patient-controlled analgesia (hydromorphone), but she required additional intravenous boluses in addition to transdermal fentanyl (150 μg every 72 hours). Prior to discharge she was comfortable on oral hydromorphone 4 mg every 4 to 6 hours, as needed.
The patient’s haemoglobin concentration on admission was 6.8 g/dL. Other laboratory results were: total bilirubin 2.7 mg/dL, absolute reticulocyte count 694 x 103/μL. Howell-Jolly bodies were seen on a peripheral blood smear. Initial work-up confirmed the previously noted alloantibodies. Haemoglobin electrophoresis on day 7 (after the transfusion of 3 units of red cells) showed: HbS 73.4%, HbA 10%, HbA2 5.5%; HbF 7.9%, and HbC 3.9%. The DAT was negative on day 8. On day 9 the absolute reticulocyte count was 870 x 103/μL. On day 12, the haemoglobin concentration was 7.4 g/dL, LDH 735 IU/L, and total bilirubin 2.9 mg/dL. The patient had persistent, generalised bone pain. A course of IVIG (total 2 g/kg body weight) was begun, and the prednisone dose was increased to 100 mg daily.
On day 13 HbS was 61.9% and HbA 26.9% (Figure 1B). The haemoglobin concentration was 8.2 g/dL. Her weight was 58.2 kg. Despite aggressive hydration, normal oxygen saturation, and maximal analgesia, the patient was writhing in pain (10 of 10). Partial RCE with four units was performed using a COBE Spectra™ Apheresis System, with a target haematocrit of 28.5%. Cross-matched compatible red cells which were negative for antigens to which the patient had antibodies were used. On day 14 the HbS level was 40.5% and HbA 50.9%, but the next day the HbS rose to 52.8% and HbA level fell to 38.8%. The absolute reticulocyte count was 843 x 103/μL and the haemoglobin concentration was 6.3 g/dL.
Over the next 6 days the patient’s haemoglobin level stabilised at approximately 8 g/dL without further red cell transfusions. The peak absolute reticulocyte count of 954 x 103/μL with an LDH of 600 IU/L was reached on day 20. On day 21 a positive DAT (C3 only) was noted. Splenic autoinfarction was reported on a computed tomography scan. The patient felt better and was discharged on day 24 on prednisone (50 mg daily). Follow-up 27 days later revealed a haemoglobin concentration of 7.1 g/dL, total bilirubin of 2.1 mg/dL, and absolute reticulocyte count of 429 x 103/μL. Eighty-three days after discharge, while the patient was maintained on a prednisone dose of 10 mg daily, her haemoglobin concentration was 10.3 g/dL and her absolute reticulocyte count was 134 x 103/μL. No transfusions had been given since discharge.
The time course of HbA and HbS percentages are detailed in Figure 1. Both of our patients had warm autoantibodies in addition to multiple alloantibodies, but no new alloantibodies were detected. Further, both patients had very high reticulocyte counts without evidence of bleeding. Unlike the usual expected response to RCE with HbA cells, the HbS level dipped only transiently. In both cases there was only a brief rise in HbA level after RCE.
We present two patients with sickle cell/β thalassaemia who underwent automated RCE in the clinical setting of brisk haemolysis and refractory bone pain. Although RCE is not routinely indicated in the management of acute sickling pain crises, in each of our patients RCE was attempted after failure of vigorous standard management with hydration and maximal parenteral narcotics. In Case 1, there was the added indication for RCE before possible cholecystectomy in a patient not responding to simple transfusions. The lack of improvement with RCE can be attributed to two features in these patients: (i) high reticulocyte counts, leading to rapid replacement of removed cells by new HbS-containing cells, and (ii) lack of expected prolonged survival of the exchanged HbA cells because both the HbS- and HbA-containing cells were subject to autoimmune haemolysis.
The coexistence of sickling and autoimmune haemolysis has been well described by prior investigators and the effectiveness of immunosuppressive therapy has been documented2,3. However, it takes time for the immune haemolysis to be controlled, and thus patients remain at risk of severe anaemia and its consequences until the immunosuppressive therapy has a beneficial effect. A somewhat similar situation occurs in the sickle cell transfusion reaction syndrome1,4 which is in the differential diagnosis of brisk haemolysis in patients with sickle haemoglobinopathies. This syndrome is often triggered by a delayed haemolytic transfusion reaction in patients with multiple pre-existing red cell alloantibodies. The exact mechanism of destruction of the patient’s own red cells (beyond that expected from ongoing sickling) in addition to the transfused cells against which alloantibodies may have been formed is not clear, but the problem of sustaining the patient’s haematocrit is the same. Lack of efficacy of RCE in this situation, too, has been documented5. Our patients had very high reticulocyte counts, a feature that differs from the typical reticulocytopenia occurring in the sickle cell transfusion syndrome4. The high reticulocyte counts (HbS cells) would be expected to have sustained the sickling processes.
In summary, coexistence of sickling and autoimmune haemolysis presents major management issues. RCE is unlikely to be effective in these circumstances because of the susceptibility of the transfused HbA cells to rapid removal by the warm autoantibodies. Limiting red cell transfusion, as much as possible, to reduce the risk of development of the sickle cell transfusion syndrome and further alloimmunisation, and using immunosuppressive therapy (e.g., prednisone, IVIG) appear to offer the best chance of controlling the combined haemolytic state.
We thank S. Maaskant and G. Musa for their expert secretarial assistance.