Kate Gardner

Delayed haemolytic transfusion reaction in adults with sickle cell disease: a 5‐year experience

Delayed haemolytic transfusion reactions (DHTR) are potentially life‐threatening complications in patients with sickle cell disease (SCD). Between 1 August 2008 and 31 December 2013, 220 of 637 adult patients in our centre had at least one red blood cell (RBC) transfusion in 2158 separate transfusion episodes. Twenty‐three DHTR events occurred in 17 patients (13 female) including 15 HbSS, one HbSC and one HbSβ0 thalassaemia, equating to a DHTR rate of 7·7% of patients transfused. Mean interval from RBC transfusion to DHTR event was 10·1 ± 5·4 d, and typical presenting features were fever, pain and haemoglobinuria. Twenty of the 23 (87·0%) DHTR episodes occurred following transfusion in the acute setting. Notably, 11/23 (47·8%) of DHTRs were not diagnosed at the time of the event, most were misdiagnosed as a vaso‐occlusive crisis. 16/23 DHTRs had ‘relative reticulocytopenia’, which was more common in older patients. Seven of 23 episodes resulted in alloantibody formation, and three caused autoantibody formation. DHTRs are a severe but uncommon complication of RBC transfusion in SCD and remain poorly recognized, possibly because they mimic an acute painful crisis. Most of the DHTRs are triggered by RBC transfusion in the acute setting when patients are in an inflammatory state.

Survival in adults with sickle cell disease in a high-income setting

To the editor: Survival of patients with sickle cell disease (SCD) in high-income countries has improved greatly in the last 60 years. In 1960, it was described as a “disease of childhood”[1][1] whereas 25 years later, the Cooperative Study of Sickle Cell Disease reported that 85% of hemoglobin

Outcome of adults with sickle cell disease admitted to critical care – Experience of a single institution in the UK

Sickle cell disease (SCD) patients are perceived to have a high mortality when admitted to the Critical Care Unit (CCU). We performed a retrospective analysis of all adult sickle admissions to CCU at a single centre over an 8‐year period (1 January 2000 to 31 December 2007). Thirty‐eight patients (14 male) were admitted 46 times to CCU; the commonest reasons for admission were acute chest syndrome (14, 30%), multi‐organ failure (8, 17%) and planned post‐elective surgery (7, 15%). CCU mortality for SCD patients was 19·6%, comparable to a CCU‐wide mortality of 17·6% during the study period in the same institution. Re‐admission to CCU was high (16% over the 8‐year period) but did not increase mortality risk.

Nontraumatic extradural hematoma in sickle cell anemia: A rare neurological complication not to be missed†

A 20-year-old black African-Caribbean male (patient 1), known to have sickle cell anemia (SCA) and on hydroxyurea therapy, presented to our hospital with a one day history of chest and lower back pain. He had a history of multiple previous vaso-occlusive crises requiring simple analgesia. At the time of admission, he was afebrile and hemodynamically stable with no abnormalities detected on physical examination. Laboratory values on admission were: hemoglobin (Hb) 117 g/L (usual baseline Hb 110 g/L), hematocrit 37%, white cell count 14.0 3 10/L, reticulocyte count 216 3 10/L, platelets 303 3 10/L, serum creatinine 49 mmol/L, and total serum bilirubin 75 mmol/L. Sickle cell disease (SCD) results from the recessive inheritance of a mutant beta globin gene in which valine is substituted for glutamic acid at position 6 of the beta-globin chain, resulting in the formation of sickle hemoglobin (HbS). Our patient had sickle cell anemia (SCA), the homozygous form (HbSS) and presented with symptoms suggestive of vaso-occlusion, a hallmark feature of SCD. Vaso-occlusion is caused by the deformed sickle shaped red cells blocking microvasculature leading to tissue infarction and acute inflammation, which results in a painful “crisis” for the patient. At this stage, it appeared that our patient was suffering from a simple unprecipitated vaso-occlusive crisis. Patient 1 was commenced on supportive therapy with simple analgesia, oral fluids, and low molecular weight heparin (LMWH) for prevention of venous thromboembolism. The next day he spiked a fever and was started on intravenous antibiotics because of consolidation on the chest X-ray, consistent with acute chest syndrome. On the same day, he reported a lump on his head over the left parietal area, which was fluctuant and initially measured 2 3 4 cm. The patient denied any headache or trauma. Over the next 24 hr, he deteriorated with ongoing fevers and worsening pain requiring escalation to an opiate based “patient controlled analgesia” pain relief. His laboratory parameters also changed significantly: Hb dropped acutely to 54 g/L with a hematocrit of 17%, and reticulocyte count of 69.9 3 10/L; his platelet count dropped to 75 3 10/L with normal coagulation (PT, APTT, fibrinogen). His C-reactive protein (CRP) level reached a peak of 408 mg/L. The hemolysis markers became markedly elevated: lactate dehydrogenase (LDH) reaching a peak of 3,675 IU/L and bilirubin 200 mmol/L (conjugated bilirubin 29 mmol/L). Three units of packed red blood cells were transfused improving his Hb to 84 g/L. The LMWH was stopped in view of the thrombocytopenia. Twelve hours after the acute fall in Hb, it was noted that his scalp lump had increased in size to 6 3 8 cm and the patient then complained of paraesthesia involving the left side of his chin together with a mild frontal headache. Another hallmark feature of SCD is the hemolytic anemia due to the shortened life-span of the irreversibly sickled RBCs. Patient 1’s findings were consistent with an acute hemolytic episode but the massively elevated LDH combined with an acute drop in the platelet count, were findings not commonly encountered in typical vaso-occlusive crises, where the increase in hemolysis is mild to moderate and mild thrombocytosis, more typical. The drop in platelet count raised the possibility of thrombotic thrombocytopenic purpura but the ADAMTS13 level was normal at 80% (normal range 60–123%). Post transfusion, his Hb remained stable with HbS between 45 and 47%, and his hemolytic parameters improved, reticulocytes returned to baseline at 167 3 10/L. His respiratory problems slowly improved during the admission. The rapidly increasing scalp lump was investigated with an ultrasound scan which demonstrated a hematoma and this unusual finding combined with the facial paraesthesia prompted intracranial imaging. Some of the most devastating complications of sickle cell disease involve the cerebrovascular system. Cerebral lesions of ischemic origin account for up to 75% of the neurological manifestations, the remaining 25% are hemorrhagic, mainly intracerebral and subarachnoid hematomas [1]. There are very few case reports describing the occurrence of spontaneous (nontraumatic) extradural hematomas as a complication of sickle cell disease. Patient 1 underwent an urgent head computed tomography (CT) scan followed by a magnetic resonance imaging (MRI), which demonstrated: (1) an 11 mm deep extradural hematoma overlying the left frontal lobe (see Fig. 1A,B) with deformation of the subjacent brain but without midline shift; (2) the scalp lesion to be a subgaleal hematoma overlying the left frontal and parietal bones; (3) signal changes in the parietal bone (high T1 and T2, with associated increased diffusion weighted signal) considered to represent bone infarction; and (4) further bone infarction within the left mandibular marrow with a hematoma adjacent to the left condylar/subcondylar region and sigmoid notch which was thought to account for the chin paraesthesia. Throughout his inpatient stay, he remained fully conscious (Glasgow Coma Score, GCS, of 15), alert and

Leucocyte telomere length in patients with sickle cell disease

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Intracranial Aneurysms in Sickle-Cell Disease Are Associated With the Hemoglobin SS Genotype But Not With Moyamoya Syndrome

Background and Purpose— Intracranial aneurysms and aneurysmal subarachnoid hemorrhage may occur more frequently in sickle-cell disease (SCD), and this could be related to the sickle genotype and moyamoya syndrome seen in SCD. Methods— Records from a total of 1002 patients with SCD attending 2 specialized adult hematologic services were retrospectively reviewed. We analyzed data of a cohort of 767 patients attending 1 SCD clinic between 2002 and 2013 and of 235 patients from the other clinic who have had neurovascular imaging between 2007 and 2014. Results— We identified 4 patients in the cohort who had an aneurysmal subarachnoid hemorrhage during 9063 patient-years. The highest incidence rate was seen among women in the age group 30 to 39 years with the hemoglobin SS (HbSS) genotype (440 per 100 000 patient-years). Unruptured intracranial aneurysms were found in 20 of the 324 patients, who had imaging data; the prevalence was significantly higher in patients with HbSS genotype compared with other sickle genotypes with the highest prevalence (15%) observed in women in the age group 30 to 39 years. Fifty-one HbSS patients had a moyamoya vasculopathy, but only 3 of these had concomitant intracranial aneurysms. Conclusions— Intracranial aneurysms are common in HbSS SCD. There was also a trend toward more common occurrence of aneurysmal subarachnoid hemorrhage in HbSS; women in the age group 30 to 39 years were most at risk. There was no correlation between the occurrence of intracranial aneurysms and moyamoya syndrome.

Genetic Factors Modifying Sickle Cell Disease Severity

Sickle cell disease (SCD) is a monogenic disorder caused by a single base mutation but despite its apparent genetic simplicity, the clinical phenotype is hugely variable. In addition to environmental factors, family and epidemiological studies indicate that genetic variants co-inherited with the sickle mutation have a key role in modifying the disease course. This article provides an overview of the genetic modifiers of SCD known to date. Co-inheritance of α-thalassemia and persistent fetal hemoglobin (HbF) production are established major genetic modifiers but they do not explain the full spectrum of the phenotypic variability of SCD. While characterization of some of the key variants and pathways involved in HbF regulation have provided new therapeutic targets for HbF reactivation, generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered. Elucidation of new genetic modifiers may also provide an insight into other “druggable” targets for therapeutic intervention.

Super-elevated LDH and thrombocytopenia are markers of a severe subtype of vaso-occlusive crisis in sickle cell disease.

To the Editor: Sickle cell disease (SCD) is characterized by recurrent acute vaso-occlusive crises (VOCs) that can progress to life-threatening complications. Serum lactate dehydrogenase (LDH) is normally elevated in steady-state SCD, then increases further during VOC; the increase being an indication of tissue damage [1,2]. To further understand the role of LDH as a biomarker, we retrospectively reviewed the clinical and laboratory profiles of sickle-related VOCs over a ten-year period (2004–2013 inclusive) involving our cohort of 751 adult patients (4,136 patient-years of observation) attending King’s College Hospital, London, UK. Laboratory data were categorized as “steady state” or “acute.” A patient’s “baseline” steady-state values were defined as the mean of all outpatient clinic results over the study period. “Acute hospital admission” was defined as an emergency admission to a hospital ward for continuing care. Demographic details and laboratory results were collected by interrogating the Electronic Patient Records (EPR). Statistical analyses were performed in Microsoft Excel 2010 using Student’s t test (including comparison of “steady state” and “acute” data, as well as comparing the “cohort” with the “case series”) and Pearson’s correlation coefficient. Non-parametric variables were compared using chi-squared testing. Over the 10 years, 504 of the 751 patients experienced 2,822 hospital admissions. As observed in other studies, our data found a significant increase in LDH levels during VOC (mean of peak LDH 564 6432 IU/L, increase of 56% relative to steady-state (P< 0.00001)). Peak LDH occurred on Day 2.83 (65.10) of admission (Fig. 1). Platelet counts also changed significantly in VOC—initially becoming significantly lower compared to steady-state reaching a nadir (mean minimum of 295 6 151 3 10/L) on Day 3.11 (65.07) of admission, and then increasing to levels significantly higher than steadystate reaching a mean maximum of 424 (6226 3 10/L) on Day 4.55 (66.68) of admission (P< 0.00001, for both minimum and maximum values, compared to steady-state values). The platelet count nadir coincides with the LDH peak (see Fig. 1). Among the 2,822 VOCs, we noted a small but distinct subgroup (18 patients) with very elevated LDH values (>1,500 IU/L— 400% of baseline LDH) accompanied by concomitant thrombocytopenia (<150 3 10/L) (Supporting Information Fig. 1). Details of the 18 cases are in Supporting Information Table I. Average age on admission of the 18 patients was 33.02 years (614.75 years); 12 patients were male, 15 had HbSS, and 3 HbSC. Their clinical histories varied from minimal sickle problems to major comorbidities (Supporting Information Table I). Median number of admissions over 10 years for these patients was nine (IQR 3.25–24.75 admissions) compared to three for the whole 504-admitted cohort. Five of the 18 patients had at least three hospital admissions per year due to VOC. All other hospital admissions for these same patients were accompanied by mild elevations in LDH (Supporting Information Fig. 2 for trajectory of LDH over time for individual patients, and Supporting Information Fig. 3 for LDH values vs. platelet counts). Two patients were on hydroxyurea therapy, two were on regular exchange transfusion programs, and none were on simple transfusion programs. Five of the 18 cases had causes extrinsic to SCD as the primary contributor of the admission: two had a surgical cause for their presentation etiology both resulting in a septic, coagulopathic state; and three patients developed a delayed hemolytic transfusion reaction. The remaining 13 patients were admitted with a seemingly typical VOC accompanied by acute pain and fever, mild hemoglobin decrease, mild LDH increase, and platelets similar to steady state. In the subsequent days, the patients became severely unwell, and hyper-acutely, they developed both a strikingly elevated LDH, and a synchronous drop in platelet count. Peak LDH to mean 2,530 (6775) IU/L) occurred a median 2.5 (IQR 2–3.75) days after admission, with minimum platelet count to mean 74 (640) 3 10/L) at 1 (IQR 0–2) day later (Fig. 1). Of the 18 patients, 15 required red cell transfusion: 10 patients had a simple blood transfusion and five, a red cell exchange transfusion. Separately, two patients were plasma exchanged and three received plasma infusions. LDH swiftly reduced with transfusion (either red cell or plasma) and treatment of the underlying cause (Supporting Information Fig. 2), and hemoglobin rose (with or without transfusion). Subsequently, most had a rebound thrombocytosis with peak platelet count (mean maximum 643 6512 3 10/L) a median of 10.5 (IQR 5.25–13.75) days after the minimum platelet count, i.e. Day 14 of hospital admission. Except for the three patients with hemolytic transfusion reactions, all patients’ direct anti-globulin test tests were negative where tested (6 of 12 patients). The outcome was poor in five of the 18 cases: two patients died, another suffered cauda equina syndrome with residual paraparesis, one now requires home oxygen therapy, and the fifth had a splenic sequestration a week later. The mean length of stay for these 18 patient admissions was 19.8 6 11.8 days, significantly higher than both the mean length of stay for their other hospital admissions (6.3 6 4.7 days) over the 10-year study period (P< 0.001) and for the mean hospital stay of 7.5 6 8.4 days for the overall cohort (P< 0.001). In conclusion, our data suggests that super-elevated LDH levels with thrombocytopenia in sickle VOC represent a distinct, unpredictable but severe acute sickle phenomenon, leading to longer length of hospital stay and high transfusion rate. Severe acute phenomena in SCD have previously been associated with thrombocytopenia. Shome et al. suggested that VOC with markedly elevated LDH and thrombocytopenia represents an acute thrombotic microangiopathy; in this case series, all patients received blood transfusion and plasma exchange successfully (no documented ADAMTS13 level) [3]. Indeed, prior to ADAMTS13 discovery, plasma exchange was considered a therapeutic strategy in multi-organ failure in SCD [4]. Hassell et al. described 17 episodes of typical sickle acute pain that subsequently progressed to multi-organ failure, with most patients developing significant hemolysis and thrombocytopenia [5]. Thrombocytopenia in severe sickle VOC was also noted by the US National Acute Chest Syndrome Study Group [6]. It is not clear whether “super-elevated” LDH and thrombocytopenia marks the “severe” end of the sickle VOC spectrum or represents a micro-angiopathic hemolytic process, but this combination should prompt early intervention such as transfusion.

Interim assessment of liver damage in patients with sickle cell disease using new non-invasive techniques

We explored transient elastography (TE) and enhanced liver fibrosis (ELF™) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSβ0 thalassaemia (sickle cell anaemia, SCA; N = 134), had significantly higher TE results and ELF scores than those with HbSC (N = 49) disease (TE, 6·8 vs. 5·3, P < 0·0001 and ELF, 9·2 vs. 8·6 P < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r = 0·24, P = 0·004; ELF: r = 0·26 P = 0·002), and (weak) negative correlation with haemoglobin (TE: r = −0·25, P = 0·002; ELF: r = −0·25 P = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β = 0·25, P < 0·0001, total blood transfusion units, β = 0·25, P < 0·0001 and LIC β = 0·32, P = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies.

Wandering spleen: A mobile target for radiotherapy

A 65-year-old female was diagnosed with chronic lymphocytic leukemia in 1997. A bone marrow aspirate showed 95% of nucleated cells were lymphocytes, and on immunophenotyping, the CLL score was 5/5. Cytogenetics were normal. She was treated intermittently as her white cell count (WCC) rose; first with 11 courses of chlorambucil from 2003 to 2006, later with six courses of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) from 2006 to 2007. New splenomegaly was noted in June 2009, which progressed through treatment with three courses of fludarabine, a further three courses of R-CVP (2011), and two cycles Figure 1. Contrast-enhanced axial images (panels a, b, d, e) through the upper and lower abdomen, with reformatted coronal images (panels c, f) below. Preradiotherapy images in panels a, b, and c show an enlarged spleen located in the normal position. Postradiotherapy images in panels d, e, and f show the spleen rotated and lying anteriorly within the lower abdomen.