Splenic Sequestration Research Articles

Anti-glycoprotein antibodies and sequestration pattern of indium-labeled platelets in immune thrombocytopenia

AbstractAntiglycoprotein (anti-GP) antibodies play an important role in the pathophysiology of immune thrombocytopenia (ITP). The sequestration pattern of platelets in the spleen and liver can be studied with 111In-labeled autologous platelet scans. No studies have investigated the role of anti-GP antibodies in sequestration patterns in ITP patients. In this study, we examined the association between antibodies and (1) platelet sequestration site and (2) clearance rate of platelets. All ITP patients receiving an 111In-labeled autologous platelet study between 2014 and 2018 were included. Antibodies were measured using the direct MAIPA method to determine the presence and titer of anti-GPIIb/IIIa, anti-GPIb/IX, and anti-GPV antibodies. Multivariate regression models were used to study the association between anti-GP antibodies, sequestration site, and clearance rate. Seventy-four patients were included, with a mean age of 36 years. Forty-seven percent of the patients showed a predominantly splenic sequestration pattern, 29% mixed, and 25% a hepatic pattern. In 53% of the patients, anti-GP antibodies were detected. Regression models showed a significant association between splenic sequestration and GPV autoantibodies. Furthermore, in patients where antibodies were present, the clearance rate was higher in patients with a splenic sequestration. Anti-GPV antibodies are associated with a splenic sequestration pattern in ITP patients. These associations provide insight into the possible pathophysiological mechanisms of ITP, which may lead to better detection and treatment of this partly idiopathic and prevalent disease.

Manejo clínico de las complicaciones agudas de la anemia falciforme: 11 años de experiencia en un hospital terciario

IntroductionSickle cell disease is an emerging anemia in Europe leading to high morbidity with severe acute complications requiring hospital admission and chronic consequences. The management of these patients is complex and needs interdisciplinary care. The objective is to analyze clinical characteristics and management of patients with sickle cell disease admitted for acute complications. MethodsRetrospective descriptive study of admissions for acute complications of patients with sickle cell disease under 16 years of age in a tertiary hospital between 2010 and 2020. Clinical, laboratory and radiological data were reviewed. ResultsWe included 71 admissions corresponding to 25 patients, 40% diagnosed by neonatal screening. Admissions increased during this period. The most frequent diagnoses were vaso-occlusive crisis (35.2%), febrile syndrome (33.8%) and acute chest syndrome (32.3%). Nine patients required critical care at PICU. Positive microbiological results were confirmed in 20 cases, bacterial in 60%. Antibiotic therapy was administered in 86% of cases and the vaccination schedule of asplenia was adequately fulfilled by 89%. Opioid analgesia was required in 28%. Chronic therapy with hydroxyurea prior to admission was used in 41%. ConclusionsAcute complications requiring hospital admission are frequent in patients with sickle cell disease, being vaso-occlusive crisis and febrile syndrome the most common. These patients need a high use of antibiotics and opioid analgesia. Prior diagnosis facilitates the recognition of life-threatening complications such as acute chest syndrome and splenic sequestration. Despite the prophylactic and therapeutic measures currently provided to these patients, many patients suffer acute complications that require hospital management.

A case of severe multi-system disease in a sickle cell SC patient caused by parvovirus B19 infection

Sickle Cell Disease (SCD) is an inherited hemoglobinopathy, which results in production of abnormal hemoglobin S. HbSC disease is a variant of SCD, which shares a similar clinical complication profile to HbSS disease, but often thought to be a milder condition. In patients with SCD, Hb S in deoxygenated state undergoes polymerization, leading to hemolysis, vaso-occlusive events, and eventually end-organ damage. Among other complications in patients with SCD is increased risk of complications caused by parvovirus B19. We present a case of a 14-year-old female with HbSC disease who presented to the emergency room with complaint of abdominal pain and found to have splenic sequestration. Splenic sequestration progressed rapidly, Hemoglobin (hb) dropped to 4.6 g/dl and acute chest syndrome (ACS) developed. She was treated following the ACS protocol, received 4 units of Packed Red Blood Cells (PRBC) and subsequently underwent a single volume PRBC exchange transfusion. Considering her unusual presentation, with severe ARDS from alveolar hemorrhage requiring mechanical ventilation and multi-organ injury, several autoimmune and infectious conditions with a cytokine storm component including COVID-19 disease, were considered. Results of viral testing revealed parvovirus B19 IgM antibodies signifying an acute infection. She fully recovered with supportive care and was discharged home. Multisystem involvement simulating connective tissue disorders or malignancies with acute parvovirus B19 infection has been reported and is considered extremely rare. To our knowledge, there were no reports of pediatric patients with SC disease presenting with splenic sequestration and ACS in the setting of parvovirus B19 multisystem disease. Keywords: sickle cell disease; acute respiratory distress syndrome; acute chest syndrome; parvovirus B19.

Morbidity Pattern in Sickle Cell Disease in Central Gujarat, India — Single Centre Perspective

INTRODUCTIONSickle cell disease (SCD) poses a considerable health burden in India. About 20 per cent of children with SCD die by the age of two and 30 per cent children with SCD among the tribal community die before they reach adulthood is reported in one ICMR survey. As they are vulnerable to mortality, require regular clinical follow up. This retrospective analysis study was, undertaken to evaluate the morbidity pattern in SCD patients observed in patients followed up at our centre METHODSSCD patients registered and followed up at HOCC between Jan 2011 to June 2017 were included in this study. At first visit to HOCC baseline CBC, PLT, RBC indices, LFT, Creatinine, S.Ferritin,Urine R/M,HPLC pattern,USG abdomen were noted. All 342 patients registered at HOCC were advised to take Hydroxyurea (dose adjusted according to CBC), Folic acid, B12, Multivitamin and Calcium. Vaccination given to selected patients. Out of these 342 patients, 57(16%) patients had 79 hospitalization events, 11 patients (3.2%) had recurrent hospitalizations. All patients were hospitalized in Sterling Hospital Vadodara.CBC PLT,RBC indices,LFT, RFT done on admission in all patients, Blood and urine culture, PS for MP, Dengue NS1,IgG,IgM, in all febrile patients, Viral markers ,CXR,USG Abdomen, MRI pelvis with HIP done in selected patients. All hospitalized patients received adequate hydration by IV fluids.Paracetamol, Contramol, Buprenorphine transdermal patch for pain relief. PCV transfusion to keep HB 8 to 10 gm%.Antibiotics if any evidence of infection, pre-emptive or based on culture report.Oxygen by nasal prongs or NRBM,NIV or Invasive Ventilator support to maintain SPO2 more than 95%.Exchange transfusion if no pain relief in vasoocclusive crisis in 48 hrs or has Acute Chest Syndrome, Splenic Sequestration or Hepatic cell crisis RESULTSSeventy nine hospitalization events of 57 SCD patients during study period were evaluated to analyse morbidity pattern. Out of 57 patients 47 (82%)patients were not taking regular treatment,10 patients (17%)inspite of regular treatment and follow up developed morbid events .Age range 7 yrs to 57 years, M:F ratio 2:1(Male 38,Female 19),5(8%) patients were pregnant ,Vaso-occlusive crisis was most common morbid event 46(58% ) followed by LRTI,ARDS,Acute chest syndrome 9(11%),Hepatic cell crisis 8(10%),Septicemia 6(7.5%),Splenic sequestration 3(3.7%), Aplastic crisis 2(2.5%),Dengue 2(2.5%),Vivax Malaria 2(2.5%),AVN 2(2.5%).Septic arthritis 1(1.2%),Majority of hospitalization observed in month of July and Aug followed by in September ,October, least admissions in the month of April and December,HB F level was more than 20% in 16 patients(28%) and between 10 to 20 % in remaining patients(72%).Duration of hospitalization less than 10 days in majority 69(87%),14 days in 10(12%),Ventilator support was required for 7(8.8%) ,O2 by NRBM in 2(2.5%) ,O2 by nasal prongs 1(1.2%),Blood and Urine Culture for gram negative bacterial growth detected in 6(7.5%),none of the patient had gram positive growth, Exchange transfusion was required for 19 patients(24%) Outcome was favourable in 75(94%),whereas 4 patients(5%) who were not on regular follow up and they reached hospital almost 72 hrs after initial symptoms of crisis succumbed ,Major cause of mortality was Hypoxia, Septicemia with multiorgan failure on day1 of admission in hospital with rapid deterioration within 24 hrs. CONCLUSIONSCD patients on Hydroxyurea and supportive therapy have significantly lower incidence of morbid events requiring hospitalization.Vaso-occlusive crisis is a major reason of hospitalization. Gram negative septicaemia is the leading cause of infective morbidity. Hepatic cell crisis observed predominantly in ethanol addicted patients, Mortality is highest with delayed treatment of ARDS, Acute chest syndrome. Four strong predictors of good outcome are adequate hydration, early control on infection, maintaining adequate oxygenation and early initiation of treatment before organ failure sets in. DisclosuresNo relevant conflicts of interest to declare.

Supplemental Oxygen during Air Travel in Sickle Cell Disease -Common Clinical Practices

Introduction: Air travel may expose patients with sickle cell disease (SCD) to an increased risk of disease related complications. Several factors are felt to contribute, including prolonged hypoxia, dehydration, temperature changes and stress. The Canadian Pediatric Society position statement recommends that SCD patients use supplemental oxygen on flights. While other notable guidelines including the National Heart, Lung and Blood Institute (NHLBI), the National Center for Biotechnology Information (NCBI), the Canadian Haemoglobinopathy Association (CanHaem) and the British Thoracic Society do not make specific recommendations. Since available guidelines and evidence lack consensus, it is unclear what recommendations healthcare practitioners (HCPs) should counsel to their SCD patients.Objectives:1.Determine the recommendations North American hematology HCPs make to SCD patients regarding air travel.2.Determine the proportion of HCPs recommending supplemental oxygen to SCD patients.3.Among HCPs that recommend supplemental oxygen, determine which patient factors influence their decision.4.Evaluate patient experiences regarding supplemental oxygen recommendations prior to air travel.Methods: First, a literature review using PubMed, TRIP database, Medline (Ovid) search engines was completed. Two investigators independently reviewed abstracts and references. Second, a cross-sectional online survey was circulated through CanHaem (186 members) and the American Society of Pediatric Hematology/ Oncology (ASPHO, 1991 members) listservs. North American hematology HCPs were asked to share their air travel recommendations. The survey was peer-reviewed by 7 practitioners prior to distribution for content and face validity. Similarly, a patient survey regarding experiences with air travel was distributed through the Sickle Cell Disease Association of Canada (SCDAC) listserv. University of Alberta ethics research board approved.Results: A review of the literature is summarized in Table 1. A total of 81 surveys were returned with 79 evaluable for analysis. Demographic data reveals that most survey respondents are physicians (90%), pediatric providers (77%), and practice at an altitude <100m above sea level (59%). Sixty-five percent practice in USA, and 35% in Canada. Eighty-two percent of HCPs do not recommend the use of supplemental oxygen for flights under any circumstance. Among those recommending oxygen, 9% recommend it for all patients, and 6% for HbSS/SB0 patients only. While most HCPs did not recommend oxygen, they did advise patients to increase hydration (94%), carry analgesics (94%), and wear warm clothes (83%). A few HCPs discouraged air travel altogether (12%). Air travel is considered a risk factor for vaso-occlusive crises (VOC) and acute chest syndrome (ACS) by 67% ad 37% of HCPs, respectively. Among HCPs recommending oxygen, most indicate that a previous history of VOC, stroke, silent infarct, ACS, splenic sequestration, or a history of altitude related complications increase the likelihood of recommending oxygen. Length of flight is an important consideration for HCPs recommending oxygen; 46% recommend oxygen for flights >6 hours, 31% for flights >10 hours and the remainder for all flight lengths. In a small sample of patients (n=5) the majority have experienced a sickle cell crisis during or shortly after air travel. Only one patient participant has used oxygen in the past.Conclusion: Most HCPs surveyed do not routinely recommend supplemental oxygen to their SCD patients as a prophylactic measure. Among HCPs that recommend oxygen both patient and flight factors influence their recommendations. Although oxygen is not a routine recommendation, most indicate that air travel is a likely risk factor for VOC. In fact, there are numerous published cases of air travel related complications, most commonly splenic complications and VOC, in the SCD population (Table 1). There is a lack of consensus among North American HCPs regarding supplemental oxygen recommendations. Further investigation is needed to delineate the need for supplemental oxygen to prevent complications during air travel for SCD patients. [Display omitted] DisclosuresBruce:Bristol-Meyers-Squibb - consultant 2016-2017: Consultancy; ovartis consult and ad board 2015-2016: Consultancy; Apopharma 2015: Consultancy.

Rationale and Design of a Phase II Open-Label, Multicenter Study to Assess the Pharmacokinetics and Pharmacodynamics of Crizanlizumab in Adult Patients with Sickle Cell Disease

Rationale and Design of a Phase II Open-Label, Multicenter Study to Assess the Pharmacokinetics and Pharmacodynamics of Crizanlizumab in Adult Patients with Sickle Cell Disease

Erythrocyte-Specific Antibodies As a Potential New Therapeutic Modality in Autoimmune and Inflammatory Disorders Beyond Immune Thrombocytopenia (ITP)

ITP is an autoimmune bleeding disorder characterized by platelet destruction and suppression of platelet production. In the majority of patients, platelet destruction due to IgG antibodies reactive with platelet GPIIbIIIa results in platelet phagocytosis by phagocytic cells in the mononuclear phagocytic system. Anti-D is an effective first-line therapy for patients with ITP and was originally brought into practice based on the ability of anti-D to competitively inhibit opsonized-platelet clearance by phagocytic cells. Similar to anti-D, an RBC-specific monoclonal antibody (TER-119) is also able to inhibit platelet clearance in a murine model of passive ITP, also ostensibly due to RBC clearance and competitive inhibition of phagocytic cells. Here, we show that TER-119 only caused measurable anemia after 3 hours post-injection while its ability to ameliorate thrombocytopenia in the passive-murine ITP model was clearly evident by 30 minutes post-injection. Further, TER-119 mediated maximal anemia 4 days after its injection, yet displayed no measurable ameliorative effects in passive-ITP at this time point. Based on these observations, we hypothesized that anti-inflammatory activity, rather than simple competitive inhibition of opsonized-platelet clearance, might be involved in this mechanism. To test this hypothesis, the ability of TER-119 to successfully treat inflammatory diseases not involving antibody-mediated splenic cellular sequestration were examined. In the K/BxN serum-transfer model of arthritis, recipient C57BL/6 mice are injected with K/BxN serum and a rapidly progressing arthritis occurs due to antibodies specific to the self-protein glucose-6-phosphate isomerase. Using this model, the same dose of TER-119 (50 μg/mouse) which was effective in murine ITP could significantly prevent the induction of inflammatory arthritis. In separate experiments, mice were allowed to develop significant arthritis for 5 days and then injected with TER-119. These arthritic mice underwent a reversal in disease severity with significant and substantial decreases in joint swelling and clinical score evident 24 hours after injection of TER-119. In fact three days after injection with TER-119, clinical scores and ankle width measurements returned to baseline. The function of the Fc region was important in the anti-inflammatory activity of TER-119 as deglycosylation of the Fc region of the antibody (known to inhibit IgG Fc region effector functions) dramatically reduced anti-inflammatory function in the arthritis model. To determine if TER-119 could also ameliorate disease activity in an unrelated (non-autoimmune) inflammatory disease model, TER-119 was also examined in a murine model of transfusion-related acute lung injury (TRALI). TRALI is a syndrome of respiratory distress primarily triggered by leukocyte-reactive antibodies from blood product transfusions and is the leading cause of transfusion-related mortality. TRALI was induced by injecting mice with the anti-MHC class I antibody (34-1-2s) which induced a rapid decrease in body temperature and induced significant lung damage, assessed by the presence of pulmonary edema. Mice pretreated with TER-119 (50 μg) underwent a rescue from hypothermia and exhibited an almost complete inhibition of lung edema. We conclude that TER-119 has significant anti-inflammatory activity and suggest that RBC specific antibodies such as anti-D may have significant therapeutic potential in inflammatory disorders beyond just ITP. DisclosuresSemple:Novartis: Consultancy; Rigel: Consultancy; Amgen: Consultancy; UCB: Consultancy. Lazarus:CSL pharmaceuticals: Research Funding; Momenta pharmaceuticals: Honoraria; Rigel pharmaceuticals: Research Funding; St.Michael's Hosp/The Canadian Blood Services: Other: Patents on monoclonal antibodies as IVIg and anti-D replacements.

Sequestration Pattern in ITP Liver/Spleen Scan Correlates with the Presence of Anti-Glycoprotein V Antibodies in ITP Patients

Introduction Immune thrombocytopenia (ITP) is characterized by low platelet counts due to high clearance and low production. Better insight in the pathophysiology of ITP is needed to personalize management regimes, especially in patients with persisting and chronic ITP. In the Haga Teaching Hospital, we reproduced and validated the ITP liver/spleen scan from St Bartholomew's Hospital in London. With this scan the in vivo sequestration patterns of platelets in either spleen, liver or a combination of both (mixed sequestration) can be assessed, by using Indium-111 labelled autologous platelets . The ITP liver/spleen scan may provide better insights in autoantibody-mediated platelet destruction in ITP patients. Autoantibodies directed against glycoprotein (GP) IIb/IIIa, Ib/IX and V namely are found in a majority of ITP patients and can be detected using specific assays, like platelet immunofluorescence test (PIFT) and Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA). To the best of our knowledge no studies have investigated the possible association between sequestration patterns and glycoproteins. In this study we investigated associations between the sequestration patterns from the ITP liver/spleen scan and the presence of different anti-GP platelet antibodies.Methods All ITP patients receiving an ITP liver/spleen scan between 2014 and 2016 in the Haga Teaching Hospital, a large tertiary referral centre in the Netherlands, are collected from our electronic patient files. We retrospectively collected demographic and clinical characteristics, including duration of ITP, previous management of ITP (corticosteroids, rituximab, thrombopoietin receptor agonists (TPO-RA)), antibody assays (PIFT, direct and indirect MAIPA) and the results from the ITP liver/spleen scan. MAIPA is used as a continuous variable. To investigate the association between anti-GP antibodies and the sequestration pattern from the ITP liver/spleen scan we used linear regression models for the continuous variables and logistic regression models for the binary data. Observational data and scatter plots aid in the interpretation of the possible associations. Both univariate and multivariate regression models including age and sex will be performed.Results 55 ITP patients with a median age of 41 years (IQR 29-57) and 67% females underwent an liver/spleen scan in the study period. The median age of the cohort at diagnosis of ITP was 32 (IQR 22-54) years. Treatment history consisted of corticosteroid therapy in 96% of cases, 44% IVIG, 48% TPO-RA and 21% rituximab. 10% of patients received only 1 treatment line, 23% received 2 lines, 33% received 3 lines, 21% 4 lines, 10% 5 lines and 1 patient received 7 lines (2%). Clinical significant bleedings (WHO bleeding grade ≥2) were reported by 53%, and 8% of the patients received a transfusion in the past. Sequestration pattern of the ITP liver/spleen was in 51% of cases a splenic pattern vs. 49% a mixed/hepatic pattern. A significantly higher prevalence of a splenic pattern was present in patients under 30 years at diagnosis while patients older than 30 years showed a more mixed/hepatic pattern. Anti-glycoprotein antibodies were found in 54% of the patients. Interestingly, linear regression models showed no association between either anti-GPIIb/IIIa or anti-GPIb/IX antibody detection and sequestration pattern. However a significant association was observed between the presence of anti-GPV antibodies and sequestration pattern. A higher anti-GPV antibody level and/or affinity was associated with a higher level of splenic sequestration.Conclusions This study has shown that the presence of anti-GPV antibodies is associated with a splenic sequestration pattern in the ITP liver/spleen scan in patients suffering from persistent and chronic ITP. GPV is usually found as a complex with GPIb/IX in several other bleeding disorders. Surprisingly no association was found in our data between a splenic sequestration pattern and the presence of anti-GPIIb/IIIa and especially anti-GPIb/IX. Further studies are needed to clarify the possible role of anti-GPV antibodies in thrombocyte clearance by the spleen in ITP patients. DisclosuresAmini:AMGEN: Research Funding. Schutgens:Baxalta/Shire: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Uniqure BV: Research Funding. Schipperus:AMGEN: Research Funding; Novartis: Research Funding.

Platelet Function in Thrombocytopenic Patients with Chronic Liver Disease

Background: Thrombocytopenia, the most common hematologic abnormality encountered in patients with chronic liver disease (CLD), results from multiple factors including splenic sequestration, relatively reduced production of thrombopoietin for the degree of thrombocytopenia, consumption of platelets secondary to autoantibodies directed against platelets, and bone marrow suppression. Elevated plasma levels of von Willebrand factor (VWF) in CLD patients may partly compensate for the reduced platelet count via interaction of VWF with the platelet receptors glycoprotein (GP) Ib-IX-V and GPIIb-IIIa (integrin αIIβ3), to promote platelet adhesion and aggregation following vessel injury. Platelets in patients with CLD are reported to have reduced function as measured by light transmission platelet aggregation (LTA) and other assays. However, LTA and most other platelet function tests are unreliable in thrombocytopenic samples. In contrast, platelet function evaluated by whole blood flow cytometry is accurate in samples with low platelet counts. Therefore, in the present study we used whole blood flow cytometry to determine whether platelet function as measured by platelet surface P-selectin, activated GPIIb-IIIa and GPIb on in vivo -circulating and in vitro -stimulated platelets is altered in thrombocytopenic CLD patients compared to healthy controls.Methods: Platelet function end points were evaluated in untreated CLD patients with thrombocytopenia (n = 21) participating at U.S. sites in the Phase 3 E5501-G000-310 or E5501-G000-311 studies of a novel thrombopoietin receptor agonist, avatrombopag, compared to healthy controls (n=10). IRB approval was obtained at each study site and written informed consent was obtained from each subject. CLD patient samples analyzed in the present study were collected prior to the administration of any study drug. No patient received a platelet transfusion within 10 days of the blood draw for this study. Platelet surface P-selectin, activated GPIIb-IIIa and GPIb, without or with in vitro stimulation (0.5 μM adenosine diphosphate [ADP], 20 μM ADP, 1.5 μM thrombin receptor activating peptide [TRAP] or 20 μM TRAP) were measured by whole blood flow cytometry. To explore whether the differences in these markers between CLD patients and healthy subjects were related to the difference in platelet count rather than to differences in platelet activation or reactivity, whole blood from healthy controls was diluted with platelet-poor plasma to adjust the platelet counts to those of the thrombocytopenic CLD patients.Results: Circulating platelets (i.e., no in vitro stimulation) from thrombocytopenic CLD patients showed low levels of platelet surface P-selectin and activated GPIIb-IIIa, similar to the healthy subject controls, demonstrating minimal in vivo platelet activation in thrombocytopenic CLD patients. However, the platelets of thrombocytopenic CLD patients had higher platelet surface GPIb mean fluorescence intensity (MFI) than either diluted or undiluted circulating platelets from healthy controls (Figure). In vitro stimulation of CLD patient platelets by ADP or TRAP resulted in lower levels of platelet surface P-selectin and activated GPIIb-IIIa compared to healthy controls, except for the levels of surface P-selectin after stimulation with 20 μM TRAP. The results for the diluted healthy subject controls were unaffected by the platelet count, except for the samples activated with 1.5 μM TRAP in which dilution resulted in reduced platelet surface P-selectin and activated GPIIb-IIIa.Conclusions: 1) Circulating platelets in thrombocytopenic CLD patients are not activated. 2) Agonist-stimulated platelet surface expression of P-selectin and activated GPIIb-IIIa is reduced in thrombocytopenic CLD patients compared to healthy controls with the same degree of thrombocytopenia, which likely contributes to the excessive bleeding in thrombocytopenic CLD patients. 3) Thrombocytopenic CLD patients have a higher expression of GPIb on circulating platelets compared with healthy controls with the same degree of thrombocytopenia. This finding is consistent with the presence of an increased proportion of large immature platelets. The high levels of platelet surface GPIb, together with the previously reported high levels of circulating VWF in these patients, may contribute to vascular integrity at lower platelet counts. [Display omitted] DisclosuresFrelinger:Sysmex: Research Funding; Pfizer: Research Funding; Ironwood: Research Funding; Baxalta: Research Funding; GLSynthesis: Research Funding; Ionis: Research Funding. Michelson:GLSynthesis: Research Funding; Eisai: Research Funding; Ironwood: Research Funding; Sysmex: Research Funding; Ionis: Research Funding; Pfizer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Elsevier: Patents & Royalties; Baxalta: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Instrumentation Laboratory: Consultancy.

Hydroxyurea: Clinical and Hematological Effects in Omani Patients with Sickle Cell Disease

Background and Aim:•It is well known that hydroxyurea impacts on clinical and hematologic indices in sickle cell disease (SCD), we aimed to evaluate the effect of hydoxyurea on clinical and hematological improvement of Omani sickle cell disease pateints.Methods and Materials•In this retrospective single-center study, we selected 18 Omani sickle cell disease patients aged above 18 years, who were started on Hydroxyurea 5-10mg/kg/day as per their standard of care and in whom the inclusion criteria fulfilled.•Inclusion criteria were history of more than three admissions with vaso-occlusive crises /year, history of acute chest syndrome, history of priapism, history of splenic sequestration crises.•Patients were excluded if they had follow-up of Less than six months, blood transfusion during the study, pregnant ladies.•In our study, we looked at the SCD patients who were followed in Haematology clinic in AFH every three months. As per the routine follow up of these patients in this hospital, patients were assessed in each visit for the number of crises, HPEL, CBC, LFT, UEG, and any reported side effects.•Our aim was specifically to observe the number of ER crises, number of hospital admissions, HBF, HB, MCV, WBC over six months post HU treatment .•The data collected based on the doctors notes & lab results from the Hospital information system. Side effects of the drug if any were observed from the prescription history.•The study was approved by the ethical committee in Armed Force Hospital in Muscat, Oman.•Data has been stored and analyzed in the SPSS program.Results•In this study, we looked at 18 patients with SCD who were treated with HU 5-10mg/kg/day .•These patients consisted of 6 females and 12 males.•We found that in patients with sickle cell disease Hu significantly increased the HBF (P=0.008) and MCV (p=0.011) after six months.•There was no statistically significant difference between the baseline and after six months in HB (p=0 .131) and WBC (P=0.078 ).•There was statistically decrease in the number of ER between baseline and six months (p = 0.011) .•There was statistically significant decrease in the number of Hospitalizations between the baseline and the six months (p= 0.026).•Our study showed HU therapy was well tolerated by our patients and remarkable adverse effects were not reported in patients after six months treatment with HU.Conclusion:•The results showed that the use of hydroxyurea 5-10 mg/kg/day for 6 months duration on patients with SCD significantly improve the HBF and MCV and decreased the number of ER crises and hospital admissions without any remarkable adverse effects. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Utilization of a Pediatric Sickle Cell Day Hospital By Patients with Sickle Cell Disease and Pain Events Is Associated with a Lower Rate of Inpatient Hospital Admission Compared to Utilization of the Pediatric Emergency Department

Introduction:Vaso-occlusive crisis (VOC) is a leading cause of morbidity in children with sickle cell disease (SCD) and is the most common reason for hospitalization. Frequent and prolonged hospitalization is a risk factor for development of acute chest syndrome and increased mortality, and also leads to decreases in school attendance and quality of life measures. Furthermore, inpatient care accounts for a large proportion of total disease-related costs.A sickle cell day hospital (DH) is an outpatient facility with several beds, staffed by hematology/oncology trained attending physicians, fellows, nurse practitioners and bedside nurses, all with expertise in caring for patients with SCD. The concept of the DH as an alternative to the emergency department (ED) for treatment of VOC has been explored in adults, with evidence for reduced hospitalization rate, superior pain relief and significant cost-savings. In pediatrics, there is limited data on the utility of a DH for VOC management.We hypothesize that pediatric patients with SCD presenting to our institution with acute VOC who are managed in the DH will have a lower rate of inpatient admission than those managed in the ED.Methods:We performed a retrospective chart review of children aged 4 to 21 years with HbSS, HbSC, HbSβ0- or β+- thalassemia who received initial treatment for uncomplicated VOC with IV opioids in the DH or ED at the Children's Hospital at Montefiore during three consecutive calendar years. Patients were excluded if they had any of the following at the time of presentation: pain score < 7, temperature > 38.0°C, decrease in oxygen saturation >2% below baseline or <92% on room air, new chest x-ray infiltrate, headache or other neurological symptoms, or evidence of splenic sequestration. Patients selected for the ED cohort were limited to those who presented during the hours when the DH was open. Additionally, patients transferred from the DH to the ED or vice versa at any time during the visit were excluded. We abstracted data from the charts of 60 unique patients for each site to allow for assessment of our primary outcome of need for inpatient admission at the time of initial visit, as well as secondary outcomes including time to initial and rescue doses of opioid analgesic. The study was approved by the Institutional Review Board at Montefiore Medical Center.Results:Data from 56 DH and 55 ED patients have been analyzed to date. In general, the cohorts had similar demographics, sickle cell disease status, and pain scores (Table 1), except for younger age in the DH cohort (median 12 years vs 13 years, p = 0.012). Patients who presented to the DH were significantly less likely to be admitted than patients who presented to the ED, with admission rates of 41.1% and 67.3%, respectively (p= 0.008) (Fig 1A). Admitted patients from each setting were further stratified by pain score at presentation (Fig 1B) and by hydroxyurea (HU) status as a surrogate marker of disease severity (Fig 1C). In patients with an initial pain score of 10, there was no significant difference in admission rate based on treatment location (DH 56% vs ED 72.7%, p= 0.362). In contrast, patients with an initial pain score of 7-9 were significantly less likely to be admitted from the DH than from the ED (29% vs 63.6%, p= 0.007). DH-managed patients were significantly less likely to be admitted regardless of HU status compared to ED-managed patients (on HU: 44.8% vs 77.8%, p= 0.036; not on HU: 37% vs 78.4%, p= 0.002).Secondary analyses showed a significant difference between the DH and ED in the median time to initial (Fig 2A) and rescue (Fig 2C) opioid doses (initial: 65 mins vs 76 mins, p= 0.044; rescue: 45 mins vs 123 mins, p < 0.001). This comparison was further stratified based on pain score at presentation, and demonstrated significantly longer median time to initial dose of opioid in the ED for those patients with initial pain score of 7-9 (78 mins vs 93 mins, p= 0.032 - Fig 2B), but no significant difference for those with initial pain score of 10. Time to rescue dose of opioid was significantly longer for patients seen in the ED, regardless of pain score (pain 7-9: median 43 mins vs 125 mins, p < 0.001; pain 10: median 65 mins vs 120 mins p= 0.006 - Fig 2D).Conclusions:A dedicated pediatric sickle cell day hospital is an effective setting for the management of uncomplicated acute VOC. Treatment in this setting is associated with decreased rates of inpatient admission and faster administration of appropriate analgesics. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Case of Rare Autoimmune Pancytopenia Due to Graves’ Disease

Introduction: Graves’ disease has been associated with cytopenias, most commonly anemia. Pancytopenia is a rare complication and is not often encountered.Case Presentation: A 54-year-old woman with history of multiple sclerosis on alemtuzumab was referred for abnormal thyroid function tests. At the initial visit, the patient reported a 20-pound unintentional weight loss, tremors, sweating and heat intolerance. She was 3 years post-menopausal and had no history of recent viral illness, contrast exposure or family history of thyroid disease. Physical exam revealed an anxious appearing woman with fine tremors in both hands, hyperreflexia but no lid lag or exophthalmos. Labs included TSH <0.005 uIU/mL (0.400-4.2), free T4 2.89 ng/dL (0.80-1.50), TSH receptor binding antibody 8.24 IU/L (< 2.00), TSI 7.27 IU/L (<0.56), WBC 2900/uL (4500-11000), ANC 1746/uL (1900 - 8000), hemoglobin 11.4 g/dL (11.7-15.0) and platelet 207,000/uL (150,000-450,000). Thyroid ultrasound noted sub-centimeter hypoechoic/cystic nodules and 24-hour thyroid uptake showed 56.4% symmetric uptake (upper limit of normal 30%). Due to leukopenia, the patient was started on propranolol and underwent radioiodine ablation with 14.8 mCI. Two weeks later, she reported easily bruising and gum bleeding and her blood work was significant for pancytopenia. The patient was referred to hematology and two bone marrow samples were obtained. Though MDS/MPN was initially suspected based on atypia in both specimens, there were no immunophenotypic, cytogenetic or molecular abnormalities suggesting a neoplastic process. Instead the patient was thought to have autoimmune pancytopenia secondary to Graves’ and the atypia was believed to be secondary to peripheral consumption. She was started on prednisone 1 mg/kg/day with resolution of her cytopenias.Discussion: Graves’ disease has been associated with hematological abnormalities including isolated anemia (the most common), thrombocytopenia or leukopenia. Pancytopenia is an uncommon complication and is rarely described in the literature. The exact mechanism remains unclear, but may be related to either reduced production of hematopoietic cells from the bone marrow or increased destruction of mature hematopoietic cells due to autoantibodies. Since thyroid hormones are known to increase erythropoietin, this leads to an exaggerated consumption of iron, folic acid and vitamin B12 and can cause various forms of anemias. Leukopenia may be secondary to immunologic destruction whereas thrombocytopenia may be due to antiplatelet antibodies or increased splenic sequestration. Pancytopenia is rare. Our patient was treated with high dose prednisone with resolution of her pancytopenia, which suggests an autoimmune process as the mechanism. Our case showcases a rare complication of Graves’ disease and highlights that high dose steroid therapy may improve cytopenias associated with this condition.

Scalp Swelling and Headache in a 12-year-old Boy

1. Kathryn Westphal, MD* 2. Respicius Bakalemwa, MD† 3. Elizabeth Groothuis, MD, MPH* 1. *Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2. †Department of Pediatrics, Bugando Medical Centre, Mwanza, Tanzania A 12-year-old boy with sickle cell disease (SCD) is admitted to a hospital in Mwanza, Tanzania, with acute onset of periorbital and scalp swelling. Associated symptoms include fever, headache, difficulty breathing, and back pain. Because resources in sub-Saharan Africa are limited, access to comprehensive care for patients with SCD is variable. The general principles of management focus on early diagnosis, parental education, prevention of infection with vaccinations and prophylactic medications, prompt treatment of infection and pain, the use of hydroxyurea for stroke prevention, and blood transfusions for life-threatening anemia. This patient has a known diagnosis of SCD but has infrequent pain episodes and no previous transfusions. He is not receiving hydroxyurea or prophylaxis against bacterial infections or malaria. He has no history of stroke and no known head trauma. On presentation he is afebrile and his heart rate is 120 beats/min, respiratory rate is 40 breaths/min, and blood pressure is 105/75 mm Hg. His oxygen saturation is 92% in room air. Physical examination is significant for pallor, periorbital edema, scalp edema, dyspnea without adventitious lung sounds, and splenomegaly with diffuse abdominal tenderness. His scalp edema is fluctuant and extends posteriorly from the periorbital region, encompassing the entire scalp. Swelling is most prominent in the frontal and parietal areas. The overlying skin is nonerythematous and nontender but is warm to the touch. His neurologic examination has no focal findings, although generally he appears tired. Initial laboratory results demonstrate a white blood cell count of 84,000/μL (84×109/L) with a lymphocytic predominance (57%), a hemoglobin level of …

The impact of Parvovirus B19 on hereditary haemolytic anaemias.

The impact of Parvovirus B19 on hereditary haemolytic anaemias.

Thrombocytopenia and Hemostatic Changes in Acute and Chronic Liver Disease: Pathophysiology, Clinical and Laboratory Features, and Management.

Thrombocytopenia, defined as a platelet count <150,000/μL, is the most common complication of advanced liver disease or cirrhosis with an incidence of up to 75%. A decrease in platelet count can be the first presenting sign and tends to be proportionally related to the severity of hepatic failure. The pathophysiology of thrombocytopenia in liver disease is multifactorial, including (i) splenomegaly and subsequently increased splenic sequestration of circulating platelets, (ii) reduced hepatic synthesis of thrombopoietin with missing stimulation both of megakaryocytopoiesis and thrombocytopoiesis, resulting in diminished platelet production and release from the bone marrow, and (iii) increased platelet destruction or consumption. Among these pathologies, the decrease in thrombopoietin synthesis has been identified as a central mechanism. Two newly licensed oral thrombopoietin mimetics/receptor agonists, avatrombopag and lusutrombopag, are now available for targeted treatment of thrombocytopenia in patients with advanced liver disease, who are undergoing invasive procedures. This review summarizes recent advances in the understanding of defective but at low level rebalanced hemostasis in stable cirrhosis, discusses clinical consequences and persistent controversial issues related to the inherent bleeding risk, and is focused on a risk-adapted management of thrombocytopenia in patients with chronic liver disease, including a restrictive transfusion regimen.

Red cell transfusion and alloimmunization in sickle cell disease.

Red cell transfusion remains a critical component of care for acute and chronic complications of sickle cell disease. Randomized clinical trials demonstrated the benefits of transfusion therapy for prevention of primary and secondary strokes and postoperative acute chest syndrome. Transfusion for splenic sequestration, acute chest syndrome, and acute stroke are guided by expert consensus recommendations. Despite overall improvements in blood inventory safety, adverse effects of transfusion are prevalent among patients with sickle cell disease and include alloimmunization, acute and delayed hemolytic transfusion reactions, and iron overload. Judicious use of red cell transfusions, optimization of red cell antigen matching, and the use of erythrocytapheresis and iron chelation can minimize adverse effects. Early recognition and management of hemolytic transfusion reactions can avert poor clinical outcomes. In this review, we discuss transfusion methods, indications, and complications in sickle cell disease with an emphasis on alloimmunization.

Laparoscopic splenectomy and proximal splenorenal shunt for portal hypertension due to portal vein thrombosis in a patient with protein S deficiency

Portal vein thrombosis (PVT) is a rare condition in the general population that develops serious complications if left untreated for long time. We present a case of a 29-year-old woman who developed PVT due to protein S deficiency versus neonatal funiculitis. Over time, the patient developed upper gastrointestinal bleeding due to esophageal varices and hypersplenism with splenic sequestration that caused minor bleeding episodes. Laparoscopic splenectomy and proximal splenorenal shunt with distal pancreatectomy due to aneurysmal dilatations of the splenic artery were successfully performed to avoid mayor progression of portal hypertension. Patient was discharged with indefinite anticoagulation and after surgery platelets raised 3 3 ectomy and proximal splenorenal shunt for portal hypertension due to portal vein ombosis is an adequate surgery procedure which should be applied in these medical cases.

Transjugular intrahepatic portosystemic shunt creation may be associated with hyperplastic hepatic nodular lesions in the long term: an analysis of 18 pediatric and young adult patients.

Retrospective studies have demonstrated the efficacy and safety of pediatric and adolescent transjugular intrahepatic portosystemic shunt (TIPS), but long-term outcomes warrant further investigation. To report on the development of hyperplastic hepatic nodular lesion development in children and young adults (<21 years) with TIPS patency >3years. Eighteen children and young adults, including 10 (55.6%) females and 8 (44.4%) males, underwent TIPS creation with >3years' patency and follow-up evaluation at a tertiary children's hospital. The mean age at the time of TIPS creation was 12.5±5.1 years (range: 1.5-20.0years). The mean model for end-stage liver disease (MELD) at the time of TIPS creation was 8.1±1.6 (range: 6-11). Indications for TIPS creation included acute variceal bleeding (8/18, 44.4%), primary (1/18, 5.6%) or secondary (7/18, 38.9%) prevention of varices, portal vein thrombosis (1/18, 5.6%), and splenic sequestration (1/18, 5.6%). Technical successes, intra-procedural parameters, hemodynamic and clinical successes, TIPS patencies, adverse events, imaging evaluations, and follow-ups were recorded. All (100%) TIPS placements were successful; however, a direct intrahepatic portosystemic shunt was created in one (5.6%) patient. Mean reduction of the portosystemic shunt gradient was 9.1±3.3mmHg (range: 4-16 mmHg). Seventeen (94.4%) patients demonstrated clinical success with resolution of their initial clinical indication for TIPS placement. The 3-year TIPS primary, primary-assisted, and secondary patencies were 83.3% (15/18), 94.4% (17/18), and 100% (18/18), respectively. Two (11.1%) patients developed mild, medically controlled hepatic encephalopathy. One (5.6%) patient developed hepatopulmonary syndrome. Nine (50%) patients developed single or multiple hepatic nodules at a mean imaging surveillance time after TIPS of 4.4±3.0years (range: 1.5-10.2years). Six (33.3%) patients developed nodules >1 cm with imaging features most consistent with focal nodular hyperplasia or focal nodular hyperplasia-like nodules. The mean follow-up duration was 5.7±2.9years (range: 3.0-13.1 years). Long-term (>3years) portosystemic shunting via TIPS is associated with the development of hepatic nodular lesions in children. Consequently, children with TIPS may need gray-scale assessment of hepatic parenchyma as part of routine ultrasound exams and extended imaging surveillance until more is understood regarding the natural history of induced nodularity.

Impact of COVID-19 on vasooclusive crisis in patients with sickle cell anaemia

ObjectivesThe study aimed to assess COVID-19 impact on the morbidity and mortality of vasooclusive crisis (VOC) in sickle cell anaemia (SCA) patients. MethodsA prospective cohort study of 100 SCA patients; 50 with COVID-19 (COVID group) and 50 without (non-COVID group). All patients signed written informed consent. ResultsThe COVID group had a significantly higher VOC episode median per year; 3 (IQR,1-6) vs 2 (IQR,2-12) (P < 0.05). The need for hospitalisation was similar in both groups. The non-COVID group had more history of culture-proven infection (P = 0.05). The COVID-group had more osteonecrosis (P < 0.05), splenic sequestration, splenomegaly and hepatic crisis (P = 0.05, 0.006, 0.02; respectively) and significantly higher (P < 0.05) symptoms of fever, cough, fatigue, abdominal pain and anosmia. Mean haemoglobin, lymphocyte subset, platelets, and reticulocytes were reduced in both groups, while lactate dehydrogenase and ferritin levels were significantly elevated. In the COVID group, the rise in white blood cell count, reticulocyte percentage, platelets and ferritin was subdued (P < 0.05). Two patients in the COVID group and 3 in the non-COVID group died; there was no statistically significant difference in mortality. ConclusionsAlthough COVID-19 may have triggered the onset of VOC, it did not significantly influence VOC-related morbidity or mortality in this SCA cohort.

Hepatic cirrhosis causes pancytopenia: a case report

Hepatic cirrhosis is a slow process liver disease, persisting over a long period of time, resulting in a progressive destruction, and is the final common pathological pathway. We report a case of 60-year-old man with hepatic cirrhosis and pancytopenia. He came to emergency room with chronic fatigue, light headed, and abdominal pain. In laboratory examination, hemoglobin 6.0 g/dL, red blood cell counts 2.8×106/mm3, platelets 58.000×103/mm3, leukocytes 3.800×103/mm3, and reactive HbsAg. Abdominal ultrasound revealed small liver with irregular edges, ascitic fluid, and enlarged spleen. The patient was treated with furosemide, spironolactone, lactulose and propranolol. The liver, or the hepatocyte constitutes a significant storage site for iron, produce erythropoietin and thrombopoietin. Hypersplenism causes retention of a large number of leukocytes, erythrocytes, and platelets in the spleen, and the number of retained blood cells can be 5.5-20 times higher than the normal level, thus facilitating capture, phagocytosis or destruction of blood cells by phagocytes resulting in peripheral cytopenias. This case illustrated that hepatic cirrhosis can cause pancytopenia. Therefore, we must look for any cause of pancytopenia in a patient with chronic liver disease. Lack of thrombopoietin and erythropoietin production, lack of iron storage in damaged hepatocyte, also splenic sequestration were the reason of pancytopenia in hepatic cirrhosis. Bone marrow examination is one of modalities that can be use, and still being recommended examination.