bims-sicedi 2025-11-23 papers

Blood Adv. 2025 Nov 19. pii: bloodadvances.2025016958. [Epub ahead of print]

Comprehensive analysis of complement activation in a hydroxyurea-treated sickle cell disease patient cohort.

Daniel Diatlov, Arlette Bohorquez, Melanie Ann Kirby-Allen, Christoph Licht.

Sickle cell disease (SCD) is an understudied, life-threatening genetic disorder affecting around 300,000 infants yearly with limited treatment options. The complement system, a critical part of innate immunity, has emerged as a contributor to SCD pathophysiology, thus presenting a potential new treatment target. Our aim was to assess complement activity in children with SCD receiving hydroxyurea (HU) therapy during vaso-occlusive crisis (VOC) and steady state. Blood samples were collected from 46 paediatric SCD patients during VOC (early and late) and steady state, with control samples from healthy volunteers. Clinical data were obtained from patient records, and patient heme levels were measured using colorimetric assay. Complement deposition on endothelial cells (ECs) was quantified using high throughput automated immunofluorescence imaging. Complement protein concentration was measured using ELISA and multiplex assays. We found that, in vitro, heme drove C3b and C5b-9 deposition on ECs. Patients had increased heme levels during both VOC and steady state compared to healthy controls. However, complement activation correlated with total hemoglobin concentration in steady state patients, but not heme levels. C5b-9 deposition on ECs was significantly higher in early crisis compared to late crisis, suggesting heightened complement activity early in VOC, with C5b-9 deposition also strongly correlating with circulating sC5b-9 levels. A significant increase in the C3b/C3 ratio further indicated early complement activation during VOC. In conclusion, complement activity is likely highest in early VOC in SCD patients and presents a critical potential treatment target, but is overall attenuated by HU therapy despite elevated heme or hemoglobin levels.

DOI: https://doi.org/10.1182/bloodadvances.2025016958

medRxiv. 2025 Sep 30. pii: 2025.09.27.25336804. [Epub ahead of print]

Sickle cell visualization in vivo in humans: microvascular occlusion formation and hemorheological indices.

Marisa M Morakis, Luojie Huang, Gregory N McKay, Sophie Lanzkron, Lydia H Pecker, Nicholas J Durr.

Vaso-occlusion is a signature pathology of sickle cell disease (SCD). However, the lack of in vivo methods to observe individual blood cell dynamics in humans limits our understanding of occlusion formation mechanisms. We present a novel in vivo , non-invasive, label-free, and high-resolution imaging technique to study blood flow and sickled cell behavior in affected individuals. We used oblique back-illumination microscopy (OBM) to capture videos of 91.0 ± 42.3 sublingual capillaries in each of ten subjects with SCD before and after red cell transfusions and compared measurements to ten unaffected control subjects. With direct observation of blood cell activity, we identified microvascular occlusions initiated by red blood cells (RBCs) that adhered to the endothelium and caused mechanical vessel obstruction. Often, the RBCs were sickled. Then, in each observed vessel, we classified blood flow as fast, slow, or no flow, and counted adhered RBCs. Compared to controls, SCD subjects before transfusion had fewer fast-flowing vessels (48.7% vs. 77.7%, p=5.8×10 -4 ), more no flow vessels (16.1% vs. 2.4%, p=0.0010), and more adhered RBCs (1.37 vs. 0.01 cells per vessel, p=0.0025). From before to after transfusion, SCD subjects' microvasculature had increased fast-flowing (48.7% vs. 65.8%, p=0.0098) and decreased no flow vessels (16.1% vs. 6.0%, p=0.0039); adhered RBCs decreased (1.37 vs. 0.71 cells per vessel, p=0.043). These hemorheological indices captured transfusion-induced changes to vascular dynamics and events leading to microvascular dysfunction and occlusion in SCD. Our findings demonstrate the potential of OBM to study vaso-occlusion pathobiology, accelerate therapeutic evaluation, and personalize treatment strategies in people with SCD.
Key Points: Non-invasive in vivo blood imaging in humans reveals sickle cells initiate vaso-occlusion via endothelial interactions. In vivo hemorheological indices capture changes in blood flow related to sickle cell disease and transfusion response.

DOI: https://doi.org/10.1101/2025.09.27.25336804

Int J Infect Dis. 2025 Nov 14. pii: S1201-9712(25)00432-1. [Epub ahead of print] 108210

Clinical, laboratory manifestations and outcome of human parvovirus B19 infections in sickle cell anemia-impact of hydroxyurea.

Alkindi S, Al-Riyami Fm, Al Naaimi G, Al Zadjali M, Pathare Av.

OBJECTIVES: This study aim at assessing the clinical, laboratory features, and outcomes of HPVB19 infection in Sickle cell anemia (SCA) patients, with particular emphasis on impact of hydroxyurea therapy.
METHODS: following institutional ethical approval, Data from 124 SCA patients with are confirmed to have HPVB19 (via DNA viral load testing) were retrospectively analyzed.
RESULTS: The mean age for our cohort was 23.3 years (range 2-57). Splenectomy was noted in 27.4%, and splenomegaly in 54%. Hydroxyurea use was used in 31.5% of patients. HPVB19 infection led to significant reductions in RBC, hemoglobin, WBC, and platelet counts (p<0.05). All patients tested positive for HPVB19 IgM and viral DNA; 62% also had IgG. The median viral load was 263,000 × 10⁶ copies/mL. Blood transfusions were required in 84.7% of cases. Transient red cell aplasia occurred in 12.1%, requiring 84 units of blood (mean 5.6 units/patient). Complications included hepatic failure (9 patients), renal failure (5), fat embolism syndrome (4), multiorgan failure (1), and death in 2 patients (1.6%). Although hydroxyurea use was associated with lower WBC nadirs, but no significant impact on hospital stay, transfusion needs, or major hematologic parameters. There was fewer complications and shorter hospital stays, hinting at possible protective benefits of hydroxyurea.
CONCLUSIONS: HPVB19 infection in SCA patients can lead to transient aplastic crisis, pancytopenia, and serious complications, underlining the need for prompt diagnosis and management. Hydroxyurea seems to have protective effect against severe HPVB19 infection.

Keywords: Human Parvovirus B19, aplastic crisis, splenectomy, hydroxyurea; Sickle cell anemia

DOI: https://doi.org/10.1016/j.ijid.2025.108210

J Clin Apher. 2025 Dec;40(6): e70072

Challenges in Trials in Sickle Cell Disease: Thromboprophylaxis in Sickle Cell Disease With Central Venous Catheters (THIS) Pilot Study.

Jameel Abdulrehman, Stéphanie Forté, George Tomlinson, Ziad Solh, Lauren Bolster, Haowei Linda Sun, Kevin H M Kuo.

Individuals with sickle cell disease (SCD) often require central venous catheter (CVC) use; however, this is associated with a high incidence of venous thromboembolism (VTE). We conducted a pilot randomized controlled trial (RCT) to assess if it is feasible and safe to conduct an adequately powered RCT comparing rivaroxaban to placebo as thromboprophylaxis in adult SCD participants with CVC. In this pilot investigator-initiated, double-blinded, multi-center RCT, we assessed feasibility outcomes to explore if a full RCT is possible, and also exploratory outcomes of thrombosis and bleeding. THIS pilot trial was closed prematurely due to slow recruitment, lack of funding, and non-feasibility of the complete trial. Of 21 participants who met eligibility criteria, 4 were recruited into the study. Adherence to study procedures was 100% and loss to follow-up was 0%. One participant was noted to have a VTE during follow-up, but of unknown chronicity. Another participant developed a new VTE post-randomization, but prior to starting study drug. No major or clinically relevant bleeding events occurred during study follow-up. Challenges in running the study were largely due to a limited eligible population, and low participation interest in study involvement. Trial Registration: ClinicalTrials.gov identifier: NCT05033314.

Keywords: anticoagulants; pilot study; randomized controlled trial; sickle cell disease; venous thromboembolism

DOI: https://doi.org/10.1002/jca.70072

Thromb J. 2025 Nov 17. 23(1): 110

Abnormalities of hemostasis in sickle cell patients and predisposition to thrombotic risk: a systematic review and meta-analysis.

Romaric De Manfouo Tuono, Josué Louokdom Simo, Maryline Seuko Njopwouo, Claude Tagny Tayou.

BACKGROUND: Sickle cell disease is a hemoglobinopathy characterized by alterations in the components of hemostasis. Despite efforts and individual and multiple studies carried out to understand the pathophysiology of the disease, particularly regarding abnormalities of hemostasis and coagulation, questions remain. This meta-analysis aimed to evaluate the studies linking inflammatory, coagulation, and fibrinolysis abnormalities in sickle cell patients, putting them in an intrinsic state of hypercoagulability and predisposing them to thrombotic risk.
METHODS: The systematic review of databases and search engines was conducted over 24 years (2000-2024) and worldwide according to the reporting guidelines of PRISMA and the Cochrane Handbook. The research articles listed were searched in the PubMed and Web of Science databases. Only case-control articles were retained. Data were extracted from the articles and analyzed using the statistical software R version 4.3.2. The standardized mean difference (SMD) was used to assess the extent of the disease on the different parameters studied. Heterogeneity across individual studies was assessed using Higgins's inconsistency Q statistics and reported as I2 and p-value. ROBINS-E was used to assess the risk of bias in the included studies.
RESULTS: 303 studies were initially identified; after the elimination of duplicates and of works not meeting the objective of the study, 17 studies were finally included for meta-analyses. The standardized mean difference (SMD) using the common effect model is 0.79 [0.58, 1.00] for prothrombin time for 5 studies analyzed (p < 0.01), 0.26 [0.06, 0.46] for fibrinogen for 6 studies analyzed (p < 0.01), and 0.87 [0.62, 1.11] for D-dimer for 6 studies analyzed (p < 0.01); thus reflecting the strong influence of sickle cell disease on the production of Prothrombin, fibrinogen and D-dimer when compared to normal controls. For protein C, the SMD with the common effect model is -1.32 [-1.54, -1.09] for 5 studies analyzed (p < 0.01), and for protein S, it is -1.45 [-1.69, -1.22] for 5 studies analyzed (p < 0.01); thus reflecting a significant negative influence of sickle cell disease on protein C and protein S production when compared to normal controls. Finally, the SMD for antithrombin using the common effect model is 0.66 [0.35, 0.98] for 5 studies analyzed (p < 0.01), thus reflecting the strong influence of sickle cell disease on the production of antithrombin when compared to normal controls.
CONCLUSION: Analyses performed from these studies reported a large influence of sickle cell disease on the inflammatory, coagulation, fibrinolysis, and natural anticoagulant system when compared to normal controls, assessed by a SMD that ranged from moderate to large. These results provide more information on research related to coagulation abnormalities in sickle cell disease and will help improve patient care.

Keywords: Coagulation; Fibrinolysis; Inflammation; Natural anticoagulants; Sickle cell disease

DOI: https://doi.org/10.1186/s12959-025-00804-x

Clin Biochem. 2025 Nov 19. pii: S0009-9120(25)00187-0. [Epub ahead of print]141 111058

Association of hypertension and genetic variants in MYH9 and BMPR1B with increased proteinuria in sickle cell disease.

BACKGROUND: Sickle cell nephropathy (SCN) is a major chronic complication of sickle cell disease, and its progression may be influenced by genetic factors. This study aimed to investigate the association between variants in the MYH9 and BMPR1B genes and increased total proteinuria in patients with sickle cell anemia.
MATERIALS AND METHODS: This cross-sectional study included patients with homozygous (SS) sickle cell disease who were followed up in Dakar. Urinary albumin, total proteins, and creatinine levels, along with serum creatinine and urea concentrations, were measured. Genotyping of the single nucleotide variants MYH9-rs4821469, MYH9-rs3752462, MYH9-rs2032487, and BMPR1B-rs17022863 was performed using mass spectrometry (MassARRAY technology). Associations were evaluated using multivariate logistic regression analysis.
RESULTS: The 150-patient cohort had a mean age of 20.44 ± 9.86 years, with a slight female majority (51 %). A high prevalence of increased total proteinuria (urine proteins-to-creatinine ratio ≥150 mg/g) was observed, affecting 50.67 % of this young population. Multivariate analysis identified relative systemic hypertension (blood pressure ≥130/80 mmHg) as a powerful and independent risk factor for increased total proteinuria. While an initial analysis suggested a protective association for the MYH9 - rs4821469 variant, this signal was unstable and lost statistical significance in more stringent models.
CONCLUSION: Increased total proteinuria is highly prevalent in this young cohort, indicating early onset of kidney damage. Relative systemic hypertension is a major modifiable risk factor, underscoring the need for rigorous blood pressure control. The instability of the initial genetic signal for MYH9-rs4821469, coupled with its strong linkage disequilibrium with APOL1, suggests that the observed association is likely confounded by ungenotyped APOL1 variants. This highlights the critical importance of including APOL1 analysis in future SCN genetic studies in African-ancestry populations.

Keywords: Albuminuria; BMPR1B; Chronic kidney disease; Hypertension; MYH9; Proteinuria; Sickle cell disease; Sickle cell nephropathy

DOI: https://doi.org/10.1016/j.clinbiochem.2025.111058