Coagulopathy Research Articles

Characterization of recombinant factor IX fusion proteins enabling subcutaneous administration

BackgroundThe X-linked bleeding disorder hemophilia B, caused by mutation(s) in the coagulation factor (F)IX gene, leads to partial or total loss of its function, requiring lifelong FIX replacement therapy. Although new recombinant FIX (rIX) therapeutics like albumin fusion proteins (rIX-FP) enable longer plasma half-life and thus less frequent administration, the complexity of intravenous (i.v.) injection remains. ObjectivesThe study aimed to characterize rIX-FP variants with anticipated enhanced specific activity, which would leverage rIX-FP’s superior pharmacokinetic profile with beneficial characteristics for subcutaneous (s.c.) administration. MethodsTwo rIX-FP variants, R338L (“Padua variant”) and R338L/E410K, were characterized in vitro. Pharmacokinetic profiles of FIX antigen and activity levels were evaluated in FIX-deficient mice after i.v. and s.c. administration of these variants (dosing based on antigen levels). The efficacy of the most promising variant was tested after i.v. and s.c. administration (dosing based on activity) in a tail clip bleeding model. A marketed wild-type (WT) rIX-FP product served as the comparator. ResultsBoth rIX-FP variants showed a 4- to 5-fold increase in specific activity in vitro compared with rIX(WT)-FP, while FXIa-mediated activation was the fastest for rIX(WT)-FP and rIX(R338L)-FP. Compared with rIX(WT)-FP and rIX(R338L/E410K)-FP, rIX(R338L)-FP exhibited higher FIX activity exposure after i.v. and s.c. administration and demonstrated comparable efficacy with rIX(WT)-FP in reducing bleeding time and blood loss in FIX-deficient mice requiring ∼4 times lower protein amount. ConclusionrIX(R338L)-FP was shown to be a promising candidate for s.c. administration, exhibiting increased specific activity combined with higher activity-based exposure and indicating efficacy at a lower protein dose.

In Utero Gene Therapy and its Application in Genetic Hearing Loss.

For monogenic genetic diseases, in utero gene therapy (IUGT) shows the potential for early prevention against irreversible and lethal pathological changes. Moreover, animal models have also demonstrated the effectiveness of IUGT in the treatment of coagulation disorders, hemoglobinopathies, neurogenetic disorders, and metabolic and pulmonary diseases. For major alpha thalassemia and severe osteogenesis imperfecta, in utero stem cell transplantation has entered the phase I clinical trial stage. Within the realm of the inner ear, genetic hearing loss significantly hampers speech, cognitive, and intellectual development in children. Nowadays, gene therapies offer substantial promise for deafness, with the success of clinical trials in autosomal recessive deafness 9 using AAV-OTOF gene therapy. However, the majority of genetic mutations that cause deafness affect the development of cochlear structures before the birth of fetuses. Thus, gene therapy before alterations in cochlear structure leading to hearing loss has promising applications. In this review, addressing advances in various fields of IUGT, the progress, and application of IUGT in the treatment of genetic hearing loss are focused, in particular its implementation methods and unique advantages.

Glanzmann Thrombasthenia – A Rare Case Report

Glanzmann thrombasthenia is a rare inherited bleeding disorder resulting from mutation in platelet membrane glycoprotein (GP) IIb or IIIa leading to impaired platelet function which is characterized by defective platelet aggregation and diminished clot retraction. Glanzmann thrombasthenia patients commonly visit to physician with features of bleeding. Here we discuss about the case of a 32-years-old young female presented with menorrhagia, ecchymosis and occasional gum bleeding. Her coagulation profile was in favor of Glanzmann thrombasthenia. This rare disease has a good outcome if early diagnosis and proper management can be ensured. Delta Med Col J. Jan 2021;9(2): 101-103

Development and internal validation of a model for predicting cefoperazone/sulbactam-associated coagulation disorders in Chinese inpatients

Background and aimThe use of cefoperazone/sulbactam (CPZ/SAM) could commonly cause vitamin K-dependent coagulation disorders and even hemorrhage sometimes. However, there is a lack of prediction tools estimating the risk for this. This study aimed at developing and internally validating a model for predicting CPZ/SAM-associated coagulation disorders in Chinese inpatients.MethodsA case-control study was conducted in 11,092 adult inpatients admitted to a Chinese general hospital between 2020 and 2021 and treated with CPZ/SAM. Patients with CPZ/SAM-associated coagulation disorders were identified through the Adverse Drug Events Active Surveillance and Assessment System-II and subsequent manual evaluation. Controls were selected from eligible patients who didn’t develop coagulation disorders after CPZ/SAM therapy, with a 1:1 propensity score matching. The final predictors were obtained by univariable and multivariable logistic regression analyses. Internal validation and calibration for the model were performed using 1000 bootstrap resamplings.Results258 patients were identified as CPZ/SAM-associated coagulation disorders in 2184 patients eligible for inclusions and exclusions and the incidence was 11.8%. A final population of 252 cases and 252 controls was included for model development and validation. Malnutrition (OR = 2.41 (1.56–3.77)), history of recent bleeding (OR = 1.95 (1.32–2.90)), treatment duration (OR = 1.10 (1.07–1.14)), combination with carbapenems (OR = 4.43 (1.85–11.88)), and serum creatinine (OR = 1.01 (1.00–1.01)) were identified as final predictors. The model showed good discrimination, calibration, and clinical practicality, with the validated area under the receiver operating characteristic curve being 0.723 (0.683–0.770).ConclusionsThe model with good performance quantifies the risk for CPZ/SAM-associated coagulation disorders, and may support individual assessment and interventions to mitigate the risk after external validation.

Background incidence rates of health outcomes of interest for COVID-19 vaccine safety monitoring in a US population: a claims database analysis

ObjectiveTo evaluate background incidence rates of 59 health outcomes of interest (HOI) in a diverse population, including important subpopulations, during the pre-COVID-19 era (1 January 2017–31 December 2019) and the...

Unravelling the spectrum of von Willebrand factor variants in quantitative von Willebrand disease: results from a German cohort study

BackgroundVon Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF). ObjectivesThis large cohort study aims to offer a comprehensive exploration of mutation spectra and laboratory features in quantitative VWF deficiencies, shedding light on genetic underpinnings and genotype-phenotype associations. MethodsOur cohort consisted of 221 Caucasian index patients with quantitative VWD, along with 47 individuals whose plasma VWF levels fell within the lower normal boundaries (50-70 IU/dL). We conducted comprehensive VWF assays and genetic analyses, encompassing VWF gene sequencing, copy number variation investigations, and bioinformatic assessments. ResultsFollowing International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee VWF guidelines, 77 index patients were characterized as having type 1 VWD (VWF antigen [VWF:Ag] < 30 IU/dL), 111 as having type 1 VWD (VWF:Ag, 30-50 IU/dL), and 33 as having type 3 VWD. Mutation detection rates were 88%, 65%, and 92%, respectively. Notably, blood group O overrepresentation was evident in type 1 with VWF:Ag of 30 to 50 IU/dL, particularly among mutation-negative patients, suggesting a potential causal role of blood group O. A total of 223 VWF variants, comprising 147 distinct variations, were identified in quantitative VWD patients, of which 57 were novel variants (39%). Additionally, approximately 70% of individuals with VWF levels within the lower normal boundaries (50-70 IU/dL) displayed VWF variants. ConclusionOur data advance our understanding of the molecular mechanisms underlying quantitative VWD, offering valuable insights for future research and clinical management. Distinct mutation patterns were observed among subgroups, particularly the contrast between type 1 VWD (VWF:Ag < 30 IU/dL) and type 1 VWD (VWF:Ag, 30-50 IU/dL), an area with limited prior investigation.

A clinical practice guideline for primary care physiotherapy in patients with haemophilia.

As a result of centralisation of haemophilia care to a limited number of intramural settings, many persons with haemophilia have to travel long distances to attend their haemophilia specialised treatment centre. However, regular physiotherapy treatment can be provided by primary care physiotherapists in the person's own region. Due to the rarity of the disease most primary care physiotherapists have limited experience with this population. This study aims to provide a clinical practice guideline for primary care physiotherapists working with persons with bleeding disorders. A list of the most urgent key-questions was derived from a previous study. Literature was summarised using the grading of recommendations assessment, development, and evaluation (GRADE) evidence-to-decision framework. Recommendations were drafted based on four 90min consensus meetings with expert physiotherapists. Recommendations were finalised after feedback and >80% consensus of all stakeholders (including PWH, physiotherapists, haematologists and the corresponding societies). A list of 82 recommendations was formulated to support primary care physiotherapists when treating a person with a bleeding disorder. These recommendations could be divided into 13 categories: two including recommendations on organisation of care, six on therapy for adult patients with bleeding disorders and five on therapy adaptations for paediatric care. Therapy recommendations included treatment after a joint- or muscle bleed, haemophilic arthropathy, chronic synovitis, non-haemophilia related conditions and orthopaedic surgery. An evidence-based practice guideline, based on current evidence from literature and clinical expertise, has been developed for primary care physiotherapists treating a person with haemophilia. To improve care, the recommendations should be implemented in daily practice.

Trauma patients have reduced ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model of vessel injury.

Trauma is the leading cause of death in individuals up to 45 years of age. Alterations in platelet function are a critical component of trauma-induced coagulopathy (TIC), yet these changes and the potential resulting dysfunction is incompletely understood. The lack of clinical assays available to explore platelet function in this patient population has hindered detailed understanding of the role of platelets in TIC. The objective of this study was to assess trauma patient ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model. We hypothesized that trauma patients would have flow-regime dependent alterations in platelet function. Blood was collected from trauma patients with level I activations (N = 34) within 60 min of hospital arrival, as well as healthy volunteer controls (N = 10). Samples were perfused through a microfluidic model of injury at venous and arterial shear rates, and a subset of experiments were performed after incubation with fluorescent anti-CD41 to quantify platelets. Complete blood counts were performed as well as plasma-based assays to quantify coagulation times, fibrinogen, and von Willebrand factor (VWF). Exploratory correlation analyses were employed to identify relationships with microfluidic hemostatic parameters. Trauma patients had increased microfluidic bleeding times compared to healthy controls. While trauma patient samples were able to deposit a substantial amount of clot in the model injury site, the platelet contribution to microfluidic hemostasis was attenuated. Trauma patients had largely normal hematology and plasma-based coagulation times, yet had elevated D-Dimer and VWF. Venous microfluidic bleeding time negatively correlated with VWF, D-Dimer, and mean platelet volume (MPV), while arterial microfluidic bleeding time positively correlated with oxygenation. Arterial clot growth rate negatively correlated with red cell count, and positively with mean corpuscular volume (MCV). We observed changes in clot composition in trauma patient samples reflected by significantly diminished platelet contribution, which resulted in reduced hemostatic function in a microfluidic model of vessel injury. We observed a reduction in platelet clot contribution under both venous and arterial flow ex vivo in trauma patient samples. While our population was heterogenous and had relatively mild injury severity, microfluidic hemostatic parameters correlated with different patient-specific data depending on the flow setting, indicating potentially differential mechanistic pathways contributing to platelet hemostatic capacity in the context of TIC. These data were generated with the goal of identifying key features of platelet dysfunction in bleeding trauma patients under conditions of flow and to determine if these features correlate with clinically available metrics, thus providing preliminary surrogate markers of physiological platelet dysfunction to be further studied across larger cohorts. Future studies will continue to explore those relationships and further define mechanisms of TIC and their relationship with patient outcomes.

Giant subcapsular hematoma of the liver — a rare complication after laparoscopic cholecystectomy

The article shows a clinical case of an extremely rare complication after laparoscopic cholecystectomy — a giant subcapsular hematoma of the liver. The clinical, laboratory and instrumental data of the patient and the results obtained were analyzed. Analysis of the data from the operated patient did not reveal the main reason that could have caused the development of a giant subcapsular hematoma of the liver. The patient had no bleeding disorders, had not previously suffered any bleeding, and did not take anticoagulants as an outpatient. During the operations, no source of bleeding or damage to the liver parenchyma was identified. In addition, there was no evidence of focal liver lesions according to the preoperative ultrasound scan. Outpatient use of a drug from the group of antiplatelet agents, as well as short-term irregular use of analgesics to relieve periodic pain could provoke the development of this complication. Treatment of subcapsular hematoma of the liver mainly depends on the clinical condition of the patient and the size of the hematoma. With conservative management, the condition of the formed hematoma should be more carefully monitored over time using radiation diagnostic methods. If necessary and according to indications, do not exclude possible repeated laparoscopic intervention, including conversion to laparotomy, taking into account the data of clinical, laboratory and radiological research methods. In most cases, this condition requires conservative treatment. Patients with such a complication require careful hemodynamic monitoring and visual monitoring of the complications development. Probably, preference should be given to magnetic resonance imaging, since this method is the most objective and does not carry a radiation load. The main task is not to miss the moment of hematoma rupture and the development of fatal bleeding.

Renal bleeding: imaging and interventions in patients with tumors.

In patients with cancer, spontaneous renal bleeding can stem from a range of underlying factors, necessitating precise diagnostic tools for effective patient management. Benign and malignant renal tumors are among the primary culprits, with angiomyolipomas and renal cell carcinomas being the most common among them. Vascular anomalies, infections, ureteral obstructions, and coagulation disorders can also contribute to renal-related bleeding. Cross-sectional imaging techniques, particularly ultrasound and computed tomography (CT), play pivotal roles in the initial detection of renal bleeding. Magnetic resonance imaging and CT are preferred for follow-up evaluations and aid in detecting underlying enhancing masses. IV contrast-enhanced ultrasound can provide additional information for active bleeding detection and differentiation. This review article explores specific disorders associated with or resembling spontaneous acute renal bleeding in patients with renal tumors; it focuses on the significance of advanced imaging techniques in accurately identifying and characterizing renal bleeding in these individuals. It also provides insights into the clinical presentations, imaging findings, and treatment options for various causes of renal bleeding, aiming to enhance the understanding, diagnosis, and management of the issue.

Type 2N von Willebrand disease: genotype drives different bleeding phenotypes and treatment needs

BackgroundType 2 Normandy von Willebrand disease (VWD2N) is usually perceived as a mild bleeding disorder that can be treated with desmopressin (DDAVP). However, VWD2N patients can be compound heterozygous or homozygous for different variants, with p.Arg854Gln (R854Q) being the most frequent causative one. There are limited data about the impact of 2N variants on VWD2N phenotype and DDAVP response. ObjectivesThis study aims to describe the phenotype of VWD2N, including DDAVP response, according to genotype. MethodsVWD2N patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score, were eligible to be included in the study. Results of the DDAVP trial were also collected. ResultsA total of 123 VWD2N patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n = 114) or absence (R854QNeg, n = 9) of at least 1 R854Q allele. Three R854QPos subgroups were further individualized: patients homozygous (R854QHmz, n = 55), compound heterozygous for R854Q and a null allele (R854Q/3, n = 48), or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n = 11). FVIII:C levels were significantly lower in R854QNeg and R854Q/3 patients compared with R854QHmz ones (P < .001 and P < .0001, respectively). R854QNeg patients were diagnosed earlier due to bleeding symptoms and had a higher bleeding score than R854QPos patients (P < .001). In DDAVP trial, FVIII:C survival was lower in VWD type 2N than in type 1 patients. R854QPos patients had a heterogeneous DDAVP response, which was best predicted by baseline FVIII:C level. ConclusionThe heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP trial to identify patients potentially eligible to alternative therapeutic options.

SARS-CoV-2 spike protein potentiates platelet aggregation via upregulating integrin αIIbβ3 outside-in signaling pathway.

Platelet hyperreactivity is one of the crucial causes of coagulative disorders in patients with COVID-19. Few studies have indicated that integrin αIIbβ3 may be a potential target for spike protein binding to platelets. This study aims to investigate whether spike protein interacts with platelet integrin αIIbβ3 and upregulates outside-in signaling to potentiate platelet aggregation. In this study, we found that spike protein significantly potentiated platelet aggregation induced by different agonists and platelet spreading in vitro. Mechanism studies revealed that spike protein upregulated the outside-in signaling, such as increased thrombin-induced phosphorylation of β3, c-Src. Moreover, using tirofiban to inhibit spike protein binding to αIIbβ3 or using PP2 to block outside-in signaling, we found that the potentiating effect of spike protein on platelet aggregation was abolished. These results demonstrate that SARS-CoV-2 spike protein directly enhances platelet aggregation via integrin αIIbβ3 outside-in signaling, and suggest a potential target for platelet hyperreactivity in patients with COVID-19. HIGHLIGHTS: •Spike protein potentiates platelet aggregation and upregulates αIIbβ3 outside-in signaling. •Spike protein interacts with integrin αIIbβ3 to potentiate platelet aggregation. •Blocking outside-in signaling abolishes the effect of spike protein on platelets.

COVID-19-Related Hypercoagulability as a Long-term Complication in SARS-CoV-2: Lessons from SARS and MERS

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to a various clinical and laboratory finding in affected patients. Similar to the previous outbreak, patients with SARS-CoV-2 showed elevated levels of D-dimer, thrombocytopenia, prolonged prothrombin time, and the activated partial thromboplastin time. Meanwhile, two lethal coagulation disorders of disseminated intravascular coagulation and pulmonary embolism have already been reported in patients with SARS-CoV-2. Although further cohort studies are needed to document long-term complications, considering the similar pathogenicity of SARS-CoV and SARS-CoV-2, the same chronic cardiovascular impairments could be expected.

Using microfluidic shear to assess transfusion requirements in trauma patients

BackgroundViscoelastic assays have widely been used for evaluating coagulopathies but lack the addition of shear stress important to in vivo clot formation. Stasys technology subjects whole blood to shear forces...

Machine learning opportunities to predict obstetric haemorrhages

Obstetric hemorrhages (OH) are the main preventable cause of morbidity, mortality and cases of "near miss" among obstetric complications worldwide. Early preventive measures based on the OH prediction allow to profoundly reduce the rate of female mortality and morbidity as well as prevent the economic costs of patient intensive care, blood transfusion, surgical treatment and long-term hospitalization. Postpartum haemorrhage (PPH) is the most frequent obstetric haemorrhage determined by one of the four causes: a uterine tonus disorder, maternal birth trauma, retention of placenta parts and blood-clotting disorder. There is still a need for the continued search for an accurate and reliable prediction method despite multiple attempts to develop an effective system for predicting OH. The solution to this may be reasonably considered an innovative method such as artificial intelligence (AI) including computer technologies capable of obtaining conclusions similar to human thinking. One of the particular AI variants is presented by machine learning (ML), which develops accurate predictive models using computer analysis. Machine learning is based on computer algorithms, the most common among them in medicine are the decision tree (DT), naive Bayes classifier (NBC), random forest (RF), support vector machine (SVM), artificial neural network (ANNs), deep neural network (DNN) or deep learning (DL) and convolutional neural network (CNN). Here, we review the main stages of ML, the principles of algorithms action, and the prospects for using AI to predict OH in real-life clinical practice.

Endothelial biomarkers (Von willebrand factor, BDCA3, urokinase) as predictors of mortality in COVID-19 patients: cohort study

BackgroundSARS-CoV-2 is a systemic disease that affects endothelial function and leads to coagulation disorders, increasing the risk of mortality. Blood levels of endothelial biomarkers such as Von Willebrand Factor (VWF), Thrombomodulin or Blood Dendritic Cell Antigen-3 (BDCA3), and uUokinase (uPA) increase in patients with severe disease and can be prognostic indicators for mortality. Therefore, the aim of this study was to determine the effect of VWF, BDCA3, and uPA levels on mortality.MethodsFrom May 2020 to January 2021, we studied a prospective cohort of hospitalized adult patients with polymerase chain reaction (PCR)-confirmed COVID-19 with a SaO2 ≤ 93% and a PaO2/FiO2 ratio < 300. In-hospital survival was evaluated from admission to death or to a maximum of 60 days of follow-up with Kaplan-Meier survival curves and Cox proportional hazard models as independent predictor measures of endothelial dysfunction.ResultsWe recruited a total of 165 subjects (73% men) with a median age of 57.3 ± 12.9 years. The most common comorbidities were obesity (39.7%), hypertension (35.4%) and diabetes (30.3%). Endothelial biomarkers were increased in non-survivors compared to survivors. According to the multivariate Cox proportional hazard model, those with an elevated VWF concentration ≥ 4870 pg/ml had a hazard ratio (HR) of 4.06 (95% CI: 1.32–12.5) compared to those with a lower VWF concentration adjusted for age, cerebrovascular events, enoxaparin dose, lactate dehydrogenase (LDH) level, and bilirubin level. uPA and BDCA3 also increased mortality in patients with levels ≥ 460 pg/ml and ≥ 3600 pg/ml, respectively.ConclusionThe risk of mortality in those with elevated levels of endothelial biomarkers was observable in this study.

Self-Organization of Sinusoidal Vessels in Pluripotent Stem Cell-derived Human Liver Bud Organoids.

The induction of tissue-specific vessels in in vitro living tissue systems remains challenging. Here, we directly differentiated human pluripotent stem cells into CD32b+ putative liver sinusoidal progenitors (iLSEP) by dictating developmental pathways. By devising an inverted multilayered air-liquid interface (IMALI) culture, hepatic endoderm, septum mesenchyme, arterial and sinusoidal quadruple progenitors self-organized to generate and sustain hepatocyte-like cells neighbored by divergent endothelial subsets composed of CD32blowCD31high, LYVE1+STAB1+CD32bhighCD31lowTHBD-vWF-, and LYVE1-THBD+vWF+ cells. Wnt2 mediated sinusoidal-to-hepatic intercellular crosstalk potentiates hepatocyte differentiation and branched endothelial network formation. Intravital imaging revealed iLSEP developed fully patent human vessels with functional sinusoid-like features. Organoid-derived hepatocyte- and sinusoid-derived coagulation factors enabled correction of in vitro clotting time with Factor V, VIII, IX, and XI deficient patients' plasma and rescued the severe bleeding phenotype in hemophilia A mice upon transplantation. Advanced organoid vascularization technology allows for interrogating key insights governing organ-specific vessel development, paving the way for coagulation disorder therapeutics.

Evaluation of Child Oral Health Related Quality of Life in Bleeding Disorders

Abstract Background Oral bleeding is a common symptom for many inherited and acquired bleeding disorders in children. Understanding oral health and treatment needs of patients with bleeding disorders is necessary for patients' primary oral health prevention. Aim of the Work To evaluate the oral health problems in children with bleeding disorders both clinically and with child oral health related quality of life questionnaire score. To assess the effect of intervention (education and any necessary dental procedure) on the child oral health related quality of life questionnaire score. Patients and Methods This cross-sectional study was conducted on 70 patients aged from (2-18 years), males represent n = 47 (67.1%), females n = 23 (32.9%). Inherited bleeding disorders represent n = 37 (52.9%) and acquired bleeding disorders represent n = 33 (47.1%). ITP n = 33 (47.1%), hemophilia A n = 27 (38.6%), Von Willebrand’s disease n = 7 (10%) and Glanzmann n = 3 (4.3%) and all subjected to full history taking, examination, dental health estimation, oral health education, dental management and replacement therapy as needed at baseline and after 6 months of follow up from October 2021 to April 2022. ITP bleeding score (ISTH SSC bleeding assessment tool) used to assess severity of ITP patients. Child oral health related quality of life and child oral health impact profile questionnaires were filled by patients/parents at base line and after 6 months follow up. Results The current study revealed that (57.1%) of patients have dental caries. Regarding oral hygiene status, (10%) of patients have poor oral hygiene. Regarding gingival health, (50%) of patients have moderate gingivitis and (11.4%) have severe gingivitis. Oral symptomatology, Psychological domain for child, Psychological domain for family, Social domain for child and Total oral health score were significantly affected more with long duration of disease (p-value =0.0005, 0.0015, 0.010, 0.022 and 0.0045 respectively). There was statistically significant improvement in oral health related quality of life questionnaire score after 6 months of follow up with total oral health score (p-value = 0.000). Conclusion Oral health was significantly affected among patients with acquired and inherited bleeding disorders. Oral health education and management had significant impact on oral health related quality of life scores after 6 months of follow up.

O-086 Risk of serious adverse event after fertility preservation procedures: a comparison of cancer and non-cancer patients

Abstract Study question Do cancer patients have a higher risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients ? Summary answer No increased risk of adverse event after fertility preservation procedures was identified in cancer patients compared to non-cancer patients undergoing fertility preservation for other indications. What is known already Current recommendations encourage a prompt and exhaustive discussion on the different techniques of fertility preservation that can be performed in cancer patients of reproductive age prior to cancer treatments. Although cryopreservation of mature oocytes and/or embryos is the technique of reference in the absence of contraindication, ovarian stimulation and subsequent oocyte retrieval are associated to complications. Cancer patients might present an additional risk given tumoral hypervascularity and proinflammatory environment, as well as possible immune or coagulation disorders. However, whether cancer patients have an increased risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients remains unknown. Study design, size, duration A bicentric, retrospective study between January 1st, 2014 and December 31st, 2021. Participants/materials, setting, methods All women undergoing fertility preservation procedures by oocyte and/or embryo cryopreservation after controlled ovarian stimulation or in vitro maturation.The main endpoint was the occurrence of a serious adverse event (hospitalization for ovarian hyperstimulation syndrome, hemorrhage, infection, thromboembolic event, ovarian torsion, acute urine retention or death) in cancer patients compared to non-cancer patients undergoing fertility procedures. Main results and the role of chance A total of 4476 cycles (n = 3180 patients) were included, of which 3761 after controlled ovarian stimulation and 715 in vitro maturation cycles. Among the 4476 cycles, 1678 were performed in an oncological context (n = 1546 cancer patients) and 2798 were fertility preservation cycles for an indication other than cancer (n = 1634 patients). A total of 29 serious adverse events associated to fertility preservation procedures were registered, of which 17 intraperitoneal hemorrhages, 8 cases of ovarian hyperstimulation syndrome, 3 cases of infection and 1 case of acute urine retention. The risk of serious adverse event associated to fertility preservation procedures was not significantly different between cancer patients and non-cancer patients (0.36% vs. 0.82%, respectively, P = 0.06). Young age (P = 0.002), a higher number of oocytes retrieved (P = 0.006) and a higher number of oocytes vitrified (P = 0.002) were significantly associated to the risk of presenting a serious adverse event after fertility preservation. Limitations, reasons for caution Although rates of serious adverse events in our study are similar to that reported in previous literature and that the declaration and registration of any serious adverse event is mandatory according to French legislation, it is possible that not all serious adverse events were declared and registered. Wider implications of the findings Given the trend of delaying parenthood and the improved survival rates after cancer treatments, these findings are of particular importance, emphasizing the safety of performing fertility preservation procedures for cancer patients of reproductive age who might have a pregnancy desire after cancer treatment. Trial registration number not applicable

Role of Vascular Endothelial Growth Factor A in Pediatric Hemophilic Arthropathy

Abstract Background Hemophilia A is a hereditary bleeding disorder caused by the lack of blood clotting factor VIII. The incidence is about 1 in 5000. Although some progresses have been made in the treatment of the disease, arthropathy caused by joint bleeding is still a challenge to prevent and treat, which often results in joint deformity and disability, Biomarkers may give us the chance to early predict the joint arthropathy. Objective assess the level of serum VEGF-A as a vascular biomarker in children with hemophilia A to identify its possible role in hemophilic arthropathy and its severity. Methods This study included thirty child patients with clinical evidence of hemophilic arthropathy and thirty healthy matched age and sex as controls. All underwent history taking, clinical examination, Laboratory investigations including Vascular endothelial growth factor A. Results serum VEGF-A levels were significantly higher in patients than control group (p &amp;gt; 0,001) with sensitivity of 83.33% and specificity of 70.0%.it showed significant positive correlation with hemophilia severity (r=-0.734)(p &amp;lt; 0.001). Conclusion serum VEGF-A level was higher in Hemophilic patients which serve as a diagnostic marker for HA, also its significant correlation with severity may serve as a marker for disease progression and severity.