Levels Of Coagulation Factors Research Articles

Poly (ADP-ribose) Polymerase-1 modulations in the genesis of thrombosis.

Thrombosis, a coagulation disorder, occurs due to altered levels of coagulation, fibrinolytic and immune factors, which are otherwise known to maintain hemostasis in normal physiological conditions. Here, we review the direct and indirect participation of a multifunctional nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP1) in the expression of key genes and cellular processes involved in thrombotic pathogenesis. PARP1 biological activities range from maintenance of genomic integrity, chromatin remodeling, base excision DNA repair, stress responses to cell death, angiogenesis and cell cycle pathways. However, under homeostatic imbalances, PARP1 activities are linked with the pathogenesis of diseases, including cancer, aging, neurological disorders, and cardiovascular diseases. Disease-associated distressed cells employ a variety of PARP-1 functions such as oxidative damage exacerbations, cellular energetics and apoptosis pathways, regulation of inflammatory mediators, promotion of endothelial dysfunction, and ERK-mediated signaling in pathogenesis. Thrombosis is one such pathogenesis that comprises exacerbation of coagulation cascade due to biochemical alterations in endothelial cells, platelet activation, overexpression of adhesion molecules, cytokines release, and leukocyte adherence. Thus, the activation of endothelial and inflammatory cells in thrombosis implicates a potential role of PARP1 activation in thrombogenesis. This review article explores the direct impact of PARP1 activation in the etiology of thrombosis and discusses PARP1-mediated endothelial dysfunction, inflammation, and epigenetic regulations in the disease manifestation. Understanding PARP1 functions associated with thrombosis may elucidate novel pathogenetic mechanisms and help in better disease management through newer therapeutic interventions targeting PARP1 activity.

Treatment of thrombotic cardiovascular diseases in people with haemophilia: A Japanese consensus study.

Cardiovascular diseases (CVD) that require long-term anticoagulant and antiplatelet therapy presents a problem in people with haemophilia (PWH) who receive factor replacement therapy to reduce bleeding risk. Currently, there are no Japanese guidelines for the management of PWH with CVD. To develop expert guidance on managing CVD in PWH in Japan. A steering committee of four experts (two haemophilia specialists, one thrombosis specialist, one cardiologist) identified 44 statements related to five key themes. An online questionnaire was produced comprising a mix of 4-point Likert scale and multiple-choice questions that was sent to specialists in the management of PWH with CVD in Japan. Consensus was defined as high or very high if a respective ≥75% or ≥90% of respondents agreed with a statement. Of 16 potential respondents, responses were received from 15 specialists. Of the Likert scale questions, 71% (29/41) achieved ≥90% agreement (very strong agreement), 17% (7/41) achieved 75%-89% agreement (strong agreement) and 15% (6/41) did not achieve consensus agreement. The three multiple-choice questions failed to identify a strong preference. Agreement on specific target trough clotting factor levels for managing certain clinical situations, such as when in the presence of non-valvular atrial fibrillation or myocardial infarction, was also achieved. The results of this consensus study provide a framework for cardiologists and haematologists to manage PWH who are at risk of, or who have, CVD. Implementation of the recommendations provided herein may improve outcomes for PWH with CVD.

The role of Peripheral Inflammatory Markers and Coagulation factors in patients with CNS immune disease and glioma.

Gliomas are associated with high rates of disability and mortality, and currently, there is a lack of specific and sensitive biomarkers for diagnosis. The ideal biomarkers should be detected early through non-invasive methods. Our research aims to develop a rapid, convenient non-invasive diagnostic method for gliomas, as well as for grading and differentiation. We retrospectively collected data from patients who underwent surgery for glioma, Trigeminal neuralgia/Hemifacial spasm, schwannoma, and those diagnosed with multiple sclerosis at our institution from January 2018 to December 2020. Inflammatory markers and coagulation factor levels were collected on admission, and NLR, dNLR, PLR, LMR, and PNI were calculated for patients. Analyze the significance of biomarkers in the diagnosis and grading of gliomas, the diagnosis of MS, and the differential diagnosis of them. We evaluated 155 healthy individuals, 64 TN/HS patients, 47 MS patients, 316 schwannoma patients, and 814 with gliomas patients. Compared with healthy controls and MS group, the preoperative levels of NLR, dNLR, D-dimer, Fibrinogen, Antithrobin and Factor VIII of glioma patients were significantly higher in glioma patients and positively correlated with the grade of glioma. Conversely,0020LMR and PNI were significantly lower and negatively correlated with glioma grading. ROC curves confirmed that for the diagnosis of glioma, NLR showed a maximum AUC value of 0.8616 (0.8322-0.8910), followed by D-dimer and Antithrombin, with AUC values of 0.8205 (0.7601-0.8809) and 0.8455 (0.8153-0.8758), respectively. NLR and d-dimer also showed great sensitivity in the diagnosis of MS and differential diagnosis with gliomas. Our study demonstrated that multiple inflammatory markers and coagulation factors could be utilized as biomarkers for the glioma diagnosis, grading, and differential diagnosis of MS. Furthermore, the combination of these markers exhibited high sensitivity and specificity.

Clinical analysis and quality of life survey of hemophilia B patients in the central and western regions of China.

To study the current status of hemophilia B (HB) patients in the central and western regions of China. This cross-sectional, multicenter study was conducted in seven provinces in the central and western regions of China from April 2019 to June 2023. Samples were collected for the factor IX activity, inhibitor screen, and gene mutation. Furthermore, the status of six index joints and quality of life (QoL) were assessed. A total of 185 HB patients (mild 15, moderate 75, and severe 95) with a median age of 12.17 years were enrolled. 30.3% (56/185) of patients had a family history of HB. 34.6% (64/185) of HB patients had diagnostic delay and 38.5% (69/179) experienced treatment delay. The incidence of inhibitors was 6.1% (11/179). We identified 123 genetic variants in this study, with missense mutations being the most common. 84.0% (89/106) of HB mothers were genetically identified as carriers, with 27.7% (13/47) of carriers having clotting factor levels less than 0.40 IU/ml. 71.4% (132/185) of HB patients had a history of joint hemorrhage, with a rate of target joint in these patients was 64.4% (85/132). Lower extremity joints were most often affected in patients. The Hemophilia Joint Health Score (HJHS) score was significantly positively correlated with the Hemophilia Early Arthropathy Detection with Ultrasound in China (HEAD-US-C) (r = 0.542, P < 0.001). Patients who received prevention treatment, inhibitor negative, without treatment delay, and without high-intensity replacement therapy showed a higher total score of the short form-36 health survey (SF-36). One-third of HB patients had delay in diagnosis and treatment, and the incidence of inhibitors was 6.1%. Target joints were present in nearly half of HB patients. Missense was the main mutation type. 84.0% of mothers of HB patients in this study were found to be carriers. HEAD-US-C and HJHS can complement each other in the evaluation of joint status and give a valid basis for early clinical management. Early detection and preventive treatment, as well as reducing high-intensity replacement therapy and inhibitor generation, can effectively improve the QoL of patients.

COAGULATION AND ANTICOAGULATION PARAMETERS IN MULTIPLE SCLEROSIS PATIENTS WITH AND WITHOUT COVID-19

The aim. To investigate plasma levels of main coagulation and fibrinolytic factors in MS patients with and without COVID-19 history. Materials and methods. A total of 127 participants were enrolled in this study, including 97 MS patients and 30 healthy controls (HC). Patients with MS were divided into two groups: MS+Covid group (n=41) – patients with MS, who had a laboratory-verified diagnosis of COVID-19 in the past 3-6-month period and MS group (n=56) – patients with MS, who did not suffer from COVID-19 previously. Determination of plasma levels of prothrombin, plasminogen, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), protein C (PC), soluble thrombomodulin (TM) was performed by means of enzyme-linked immunosorbent assay. Spectrophotometric techniques were used to determine concentrations of fibrinogen, soluble fibrin monomeric complexes (SFMC) as well as plasminogen activity and inhibitory potential of α-2-antiplasmin. Results. The MS group was characterized by elevated levels of plasma prothrombin, fibrinogen, D-dimer, SFMC, soluble TM compared to HC, while PC concentration did not differ between MS and HC groups. Plasma plasminogen level as well as plasma level of the potential plasmin activity were significantly decreased in MS patients compared to HC group. The plasma tPA level was significantly reduced while plasma PAI-I level was significantly increased in MS patients compared to HC. Patients of MS group had an increased level of plasma α-2-antiplasmin activity compared with HC group. To note, most of studied parameters did not differ between two MS groups, except protein C, soluble thrombomodulin levels and plasma α-2-antiplasmin activity. Conclusions. The results of our study showed that MS patients have got altered hemostasis parameters; however, further study is necessary to find out the relationship between particular components of coagulation and fibrinolytic systems and pathophysiology of MS. Additionally, our findings demonstrated that a SARS-CoV-2 infection had a limited effect on hemostasis parameters in MS patients, causing changes in only a few parameters, including thrombomodulin and protein C levels as well as α-2-antiplasmin activity.

Elevated plasma levels of factor VIII enhance arterial thrombus formation on erosive smooth muscle cell-rich neointima but not normal intima in rabbits

BackgroundPlaque erosion, a type of coronary atherothrombosis, involves superficial injury to smooth muscle cell (SMC)-rich plaques. Elevated levels of coagulation factor VIII (FVIII) correlate with an increased ischemic heart disease risk. FVIII may contribute to thrombus formation on eroded plaques. AimsWe aimed to elucidate the role of elevated FVIII in arterial thrombus formation within SMC-rich neointima in rabbits. Methods and resultsWe assessed the effect of recombinant human FVIII (rFVIII) on blood coagulation in vitro and platelet aggregation ex vivo. An SMC-rich neointima was induced through balloon injury to the unilateral femoral artery. Three weeks after the first balloon injury, superficial erosive injury and thrombus formation were initiated with a second balloon injury of the bilateral femoral arteries 45 min after the administration of rFVIII (100 IU/kg) or saline. The thrombus area and contents were histologically measured 15 min after the second balloon injury. rFVIII administration reduced the activated partial thromboplastin time and augmented botrocetin-induced, but not collagen- or adenosine 5′-diphosphate-induced, platelet aggregation. While rFVIII did not influence platelet-thrombus formation in normal intima, it increased thrombus formation on SMC-rich neointima post-superficial erosive injury. Enhanced immunopositivity for glycoprotein IIb/IIIa and fibrin was observed in rFVIII-administered SMC-rich neointima. Neutrophil count in the arterial thrombus on the SMC-rich neointima correlated positively with thrombus size in the control group, unlike the rFVIII group. ConclusionsIncreased FVIII contributes to thrombus propagation within erosive SMC-rich neointima, highlighting FVIII's potential role in plaque erosion-related atherothrombosis.

Clinical Analysis and Mental Health Survey of Hemophilia Carriers: a Cross-sectional Study.

Hemophilia carriers (HCs), who are heterozygous for mutations in the clotting factor VIII/clotting factor IX gene (F8 or F9), may have a wide range of clotting factor levels, from very low, similar to afflicted males, to the upper limit of normal, and may experience mental health issues. The purpose of this study was to provide genetic information on mothers of hemophilia patients and to understand the clotting factor activity and phenotype of HCs. Additionally, we aimed to investigate the mental health status of HCs in China. A total of 127 hemophilia mothers, including 93 hemophilia A (HA) mothers and 34 hemophilia B (HB) mothers, were enrolled in this study. Long distance PCR, multiplex PCR, and Sanger sequencing were used to analyze mutations in F8 or F9. Coagulation factor activity was detected by a one-stage clotting assay. The Symptom Checklist 90 (SCL-90, China/Mandarin version) was given to HCs at the same time to assess their mental health. A total of 90.6% of hemophilia mothers were diagnosed genetically as carriers, with inversion in intron 22 and missense mutations being the most common mutation types in HA and HB carriers, respectively. The median clotting factor level in carriers was 0.74 IU/mL (ranging from 0.09 to 1.74 IU/mL) compared with 1.49 IU/mL (ranging from 0.93 to 1.89 IU/mL) in noncarriers, of which 14.3% of HCs had clotting factor levels of 0.40 IU/mL or below. A total of 53.8% (7/13) of HA carriers with low clotting factor levels (less than 0.50 IU/mL) had a history of bleeding, while none of the HB carriers displayed a bleeding phenotype. The total mean score and the global severity index of the SCL-90 for surveyed HCs were 171.00 (±60.37) and 1.78 (±0.59), respectively. A total of 67.7% of the respondents had psychological symptoms, with obsessive-compulsive disorder being the most prevalent and severe. The pooled estimates of all nine factors were significantly higher than those in the general population (P<0.05). The detection rate of gene mutations in hemophilia mothers was 90.6%, with a median clotting factor level of 0.74 IU/mL, and 14.3% of HCs had a clotting factor level of 0.40 IU/mL or below. A history of bleeding was present in 41.2% of HCs with low clotting factor levels (less than 0.50 IU/mL). Additionally, given the fragile mental health status of HCs in China, it is critical to develop efficient strategies to improve psychological well-being.

Challenges in ageing persons with haemophilia.

As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear-cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non-factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person-centred, holistic, multi-disciplinary approach to support and optimise long-term physical functioning and overall quality of life.

Modern Treatment of Valvulopathies in Patients with Congenital Hemophilia.

Hemophiliacs can develop cardiovascular diseases, including valvulopathies of various etiologies and severities. Some require surgical treatment. Performing cardiac surgery in hemophiliacs is a challenge because they maintain an increased risk of bleeding throughout their lives. Our review shows that with a multidisciplinary team and careful planning, cardiac surgery can be safely performed in these patients. Valve repair and bioprosthetic valves should be preferred over mechanical valves to avoid life-long anticoagulation. In patients who cannot receive a bioprosthetic valve, the use of the On-X mechanical valve might be considered because it requires less intensive anticoagulation after 3 months of treatment. Antithrombotic treatment is feasible in hemophiliacs only if the coagulation factor level is kept constantly above a specific trough limit. Our review is valuable because, for the first time, the available data on the modern surgical treatment of valvular disease in hemophiliacs have been synthesized and systematized.

Mathematical models of coagulation—are we there yet?

BackgroundMathematical models of coagulation have been developed to mirror thrombin generation in plasma, with the aim of investigating how variation in coagulation factor levels regulates hemostasis. However, current models vary in the reactions they capture and the reaction rates used, and their validation is restricted by a lack of large coherent datasets, resulting in questioning of their utility. ObjectivesTo address this debate, we systematically assessed current models against a large dataset, using plasma coagulation factor levels from 348 individuals with normal hemostasis to identify the causes of these variations. MethodsWe compared model predictions with measured thrombin generation, quantifying and comparing the ability of each model to predict thrombin generation, the contributions of the individual reactions, and their dependence on reaction rates. ResultsWe found that no current model predicted the hemostatic response across the whole cohort and all produced thrombin generation curves that did not resemble those obtained experimentally. Our analysis has identified the key reactions that lead to differential model predictions, where experimental uncertainty leads to variability in predictions, and we determined reactions that have a high influence on measured thrombin generation, such as the contribution of factor XI. ConclusionThis systematic assessment of models of coagulation, using large dataset inputs, points to ways in which these models can be improved. A model that accurately reflects the effects of the multiple subtle variations in an individual’s hemostatic profile could be used for assessing antithrombotics or as a tool for precision medicine.

AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life

The hemophilias are the most common severe inherited bleeding disorders and are caused by deficiency of clotting factor (F) VIII (hemophilia A) or FIX (hemophilia B). The resultant bleeding predisposition significantly increases morbidity and mortality. The ability to improve the bleeding phenotype with modest increases in clotting factor levels has enabled the development and regulatory approval of adeno-associated viral (AAV) vector gene therapies for people with hemophilia A and B. The canine hemophilia model has proven to be one of the best predictors of therapeutic response in humans. Here, we report long-term follow-up of 12 companion dogs with severe hemophilia that were treated in a real-world setting with AAV gene therapy. Despite more baseline bleeding than in research dogs, companion dogs demonstrated a 94% decrease in bleeding rates and 61% improvement in quality-of-life over a median of 4.1 years (range 2.6-8.9). No new anti-transgene immune responses were detected; 1 dog with a preexisting anti-FVIII inhibitor achieved immune tolerance with gene therapy. Two dogs expressing 1-5% FVIII post gene therapy experienced fatal bleeding events. These data suggest AAV liver-directed gene therapy is efficacious in a real-world setting, but should target expression > 5% and closely monitor those with levels in the 1-5% range.

Association between venous thromboembolism-associated genetic variants, coagulation factor levels, and thrombin generation potential.

Recently three large meta-analyses of genome-wide association studies for venous thromboembolism (VTE) identified over 130 genetic variants. However, mechanisms by which newly identified and therefore underexplored VTE-associated genetic variants influence VTE remain unclear. To elucidate the mechanism, we investigated the association between 61 newly identified VTE-associated genetic variants and the levels of coagulation factor (F) VIII, FIX, FXI, and fibrinogen as well as thrombin generation parameters (lag time, peak, endogenous thrombin potential, time-to-peak, and velocity), which are well-known biological traits associated with VTE. This study was conducted on 5341 participants of the Netherlands Epidemiology of Obesity study. The associations between VTE-associated genetic variants and coagulation factor levels and thrombin generation parameters were examined using linear regression analyses, adjusted for age, sex, body mass index, oral contraceptive use, hormone replacement therapy, and menopausal status. Of 61 genetic variants, 33 were associated with one or more of the coagulation factor levels and thrombin generation parameters. Following multiple testing corrections, five genetic variants remained significant, of which MAP1A rs55707100 exhibited the most robust association with thrombin generation parameters and FXI levels (β=-5.33%, 95% confidence interval: -8.44, -2.22). Our findings shed light on the underlying mechanisms by which these genetic variants influence the risk of VTE.

Thromboembolism in peripartum cardiomyopathy: a systematic review.

Women with peripartum cardiomyopathy (PPCM) are at an increased risk of arterial and venous thromboembolic events. The review summarizes the evidence on the incidence of thromboembolic complications in women with PPCM, diagnostic approaches, related outcomes, and effects of therapies that have been used. English articles were retrieved from Web of Science and PubMed using search terms to capture studies related to PPCM (or postpartum cardiomyopathy) and all combinations of thrombosis- and embolism-related keywords. A total of 347 articles from PubMed and 85 from Web of Science were obtained, and after removing duplicates, 327 articles were screened for original data and classified into four domains: epidemiology, risk factors, diagnosis, and therapy of thromboembolism in PPCM. Ultimately, 30 articles were included. Data were synthesized in summary tables for each domain. Studies in the United States and Europe reported varying incidence for thromboembolism in PPCM, up to 14% in 6 months. Risk factors include elevated levels of coagulation factors, decreased protein C and S activity, decreased fibrinolysis, and a low left ventricular ejection fraction (LVEF). Cesarean delivery and post-operative status were correlated with a higher incidence of thromboembolic complications. Diagnosis relied mostly on ultrasonography and magnetic resonance and depended on the suspected location of thrombus. Anticoagulation has been used mostly for PPCM patients with a reduced LVEF, with the duration varying across guidelines and healthcare systems. Unfractionated heparin and low molecular weight heparin (LMWH) were considered safe choices during pregnancy, while warfarin and novel oral anticoagulants (NOACs) were used postpartum. The association of bromocriptine with risk of thromboembolic complications remains debated. There are important gaps in our understanding of the epidemiology, risk stratification, and optimal secondary prevention of thromboembolism in PPCM. Larger prospective studies with detailed phenotyping are required.

Associations between coagulation factors and livedoid vasculopathy and the efficacy and safety of rivaroxaban in patients with livedoid vasculopathy: a retrospective study.

The mechanism of livedoid vasculopathy (LV) remains unknown. To investigate the association between coagulation factors and LV and to assess the efficacy and safety of rivaroxaban in the treatment of patients with LV. From May 2019 to July 2022, 89 LV patients and 35 healthy controls were included in the cross-sectional cohort to measure the levels of coagulation factors. In addition, 55 LV patients treated with rivaroxaban were included in the treatment cohort to assess the complete remission rate of ulcers (n=44) and retiform purpura (n=11) within 12 weeks. In the cross-sectional cohort, the activities of coagulation factor X in LV patients were significantly higher than healthy controls (median [IQR]: 110.5% [97.5-127.0%] vs 101.3% [91.6-115.6%]; P=0.047). In addition, the coagulation factor X activities in the progressive stage were higher than in the stable stage (median [IQR]: 111.6% [102.3-132.5%] vs 105.4% [92.9-118.8%]; P=0.037). Moreover, the coagulation factor X activities were higher in the progressive stage than in the stable stage in the paired LV patients (P=0.035). In the treatment cohort of rivaroxaban, 90.9% (40/44) of patients with ulcers achieved complete remission within 12 weeks, and 72.7% (8/11) of patients with retiform purpura achieved complete remission within 12 weeks. Mild side effects occurred in 25.5% of patients, including menorrhagia (n=10), gingival bleeding (n=3), and hemorrhage (n=1). It was demonstrated that coagulation factor X was associated with the incidence and severity of LV. In addition, rivaroxaban was an effective and safe treatment for ulcers and retiform purpura of LV.

The Association between Coagulation and Atrial Fibrillation.

The existing literature highlights the presence of numerous coagulation factors and markers. Elevated levels of coagulation factors are associated with both existing and newly diagnosed cases of atrial fibrillation (AF). However, this article summarizes the role of coagulation in the pathogenesis of AF, which includes fibrinogen and fibrin, prothrombin, thrombomodulin, soluble urokinase plasminogen activator receptor, von Willebrand factor, P-selectin, D-dimer, plasminogen activator inhibitor-1, and platelet activation. Coagulation irregularities play a significant role in the pathogenesis of AF.

Association between intraoperative blood salvage and coagulation disorder after cardiopulmonary bypass

BackgroundThis study investigated whether intraoperative blood salvage was associated with coagulation disorder diagnosed by conventional coagulation tests and thromboelastography (TEG) after cardiopulmonary bypass (CPB).Study design and methodsThis was a prospective, observational study. Ninety-two patients who underwent cardiovascular surgery with CPB were enrolled. We evaluated coagulation function in patients with or without cell salvage blood transfusion at the following time points: before CPB, just after protamine administration, and 1 h after protamine administration. We evaluated platelet count, fibrinogen concentration, and TEG parameters. Patients were considered to have coagulation disorder if one or more of the following criteria were present: (1) residual heparin, (2) low platelet count, (3) low fibrinogen level, (4) low clotting factor level, and (5) hyperfibrinolysis.ResultsFifty-three of 92 patients (57.6%) received intraoperative cell salvage. Coagulation disorder was observed in 56 of 92 patients (60.9%) after CPB. There was no significant difference between patients with or without intraoperative blood salvage in terms of the incidence of coagulation disorder (p = 0.542) or the total volume of blood from the drain after CPB (p = 0.437). Intraoperative blood salvage was not associated with coagulation disorder diagnosed by either TEG or conventional coagulation tests (odds ratio 1.329, 95% confidence interval: 0.549–3.213, p = 0.547). There were no significant interactions between patients with or without intraoperative blood salvage regarding coagulation parameters derived from TEG.ConclusionsThe incidence of coagulation disorder and the total blood volume from the drain after CPB did not differ significantly between patients with or without intraoperative blood salvage.

Impact of inherited bleeding disorders on maternal bleeding and other pregnancy outcomes: A population-based cohort study.

Increasing rate of postpartum haemorrhage (PPH) has been observed between 2003 and 2010 in Canada. Inherited bleeding disorders contribute to the risk of PPH. To identify the trend in PPH in the last decade, assess the impact of bleeding disorders on pregnancy outcomes and evaluate their coagulation workup during pregnancy. We conducted a population-based retrospective cohort study using the Alberta Pregnancy Birth Cohort from 2010 to 2018. We included women with von Willebrand disease (VWD) and haemophilia, identified by previously validated algorithm and matched with controls. Logistic regression was used to compute odds of PPH and other pregnancy outcomes. We identified 311,330 women with a total of 454,400 pregnancies with live births. The rate of PPH did not change significantly from 10.13 per 100 deliveries (95% CI 10.10-10.16) in 2010-10.72 (95% CI 10.69-10.75) in 2018 (p for trend=.35). Women with bleeding disorders were significantly more likely to experience PPH (odds ratio [OR] 2.3; 95% CI 1.5-3.6), antepartum haemorrhage (OR 2.9; 95% CI 1.5-5.9) and red cell transfusion (OR 2.8; 95% CI 1.1-7.0). We observed a nonsignificant rise in the rate of PPH in women with VWD and haemophilia. Only 49.5% pregnancies with bleeding disorders had third trimester coagulation factor levels checked. Higher odds of PPH and antepartum haemorrhage were observed even with factor levels ≥0.50IU/mL in third trimester. Despite comprehensive care in women with bleeding disorders, they are still at higher risk of adverse pregnancy outcomes compared to population controls.

Advances and challenges with gene therapy for haemophilia

Summary:&#x0D; Haemophilia rare inherited bleeding disorder caused by deficiency in clotting factor that affects around 6,000 people in the UK. Patients with haemophilia require regular prophylactic infusions of the deficient clotting factor intravenously, which causes a large burden on patients and their families. Gene therapy holds promise as a potential cure for Haemophilia. This article critically evaluates the existing evidence for gene therapy in Haemophilia.&#x0D; Relevance:&#x0D; There are several gene therapies in development for inherited conditions such as Haemophilia. Valoctocogene Roxaparvovec, a gene therapy for Haemophilia, is currently being assessed by regulatory authorities worldwide. Medical students and practicing physicians must be aware of the current evidence base for gene therapy for Haemophilia as well as the limitations thereof to help patients make informed decisions on whether gene therapy is a suitable treatment option for them. &#x0D; Take Home Messages:&#x0D; The current evidence shows that gene therapy is likely to be effective in increasing clotting factor levels and reducing bleeds for at least 3 years. However, long-term data is limited, and therefore, the durability of the treatment is unknown. Additionally, there is limited evidence on the safety and efficacy of gene therapy in patients with pre-existing antibodies to the viral vector, patients with inhibitors to the clotting factor, and children.

Developmental adcyap1b loss leads to hemorrhage, disrupted hemostasis, and a blood coagulation cascade in zebrafish

BackgroundPituitary adenylate cyclase–activating polypeptide is a neuropeptide with diverse roles in biological processes. Its involvement in the blood coagulation cascade is unclear. ObjectivesThis study unraveled adcyap1b’s role in blood coagulation using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 in zebrafish. Effects were validated via adcyap1b knockdown. Gene expression changes in adcyap1b mutants were explored, linking them to clotting disorders. An analysis of proca gene splicing illuminated its role in adcyap1b-related anticoagulation deficiencies. MethodsZebrafish were genetically modified using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to induce adcyap1b knockout. Morpholino-mediated gene knockdown was employed for validation. Expression levels of coagulation factors, anticoagulant proteins, and fibrinolytic system genes were assessed in adcyap1b mutant zebrafish. Alternative splicing of proca gene was analyzed. ResultsAdcyap1b mutant zebrafish exhibited severe hemorrhage, clotting disorders, and disrupted blood coagulation. Morpholino-mediated knockdown replicated observed phenotypes. Downregulation in transcripts related to coagulation factors V and IX, anticoagulation protein C, and plasminogen was observed. Abnormal alternative splicing of the proca gene was identified, providing a mechanistic explanation for anticoagulation system deficiencies. ConclusionAdcyap1b plays a crucial role in maintaining zebrafish blood coagulation and hemostasis. Its influence extends to the regulation of procoagulant and anticoagulant pathways, with abnormal alternative splicing contributing to observed deficiencies. These findings unveil a novel aspect of adcyap1b function, offering potential insights into similar processes in mammalian systems.

Adherence tool for prophylactic haemophilia treatment in adult and adolescent patients: A systematic review and meta-analysis protocol

Hemophilia is a congenital bleeding disorder resulting from a low level or deficiency of clotting factors. It is an x-linked recessive disease and happens almost exclusively in males whereas females are the carrier of the affected gene. The most common types of hemophilia are hemophilia A and Hemophilia B. Hemophilia is classified into mild, moderate and severe. Prophylaxis treatment has more advantages clinically compare to on-demand therapy. It may reduce the bleeding frequency, gives protection from joint damage, may lower the number of total bleeding episodes per year, and may reduce annualised spontaneous and trauma related bleeding events. However, prophylaxis treatment needs regular weekly infusions therefore it is painful to administer especially if the vein is difficult to access. It may cause pain at the site of injections and may lead to non-adherence to treatment. Non-adherence to a regimen will result in insufficient clotting factor levels in the body. The efficacy of the medication is reduced and may lead to a high bleeding tendency. Thus far, the study on adult haemophilic patient adherence tool is scarce and limited; and therefore this review is warranted. The study protocol is conducted as per the PRISMA-P guideline. There are 4 concepts in this systematic review which are Haemophilia, adult and adolescence, preventive treatment and adherence. Articles will be sought from electronic databases PUBMED, Ovid EMBASE, CINAHL, and SCOPUS using the MeSH term, synonym free-text word, truncation, and proximity operators as per each database. The proposed keywords within each concept will be joined using the Boolean operator “OR “and the 4 different concepts combined using the Boolean operator “AND”. Search will be limited to Human, English language, and publication until 2022. Studies will be included if they meet the study inclusion criteria. The quality of the studies will be appraised using the Newcastle-Ottawa quality assessment scale (NOS) for observation-based studies. This systematic review does not require formal ethical approval as data will be extracted from selected published studies. The results will be disseminated through a peer-reviewed publication and relevant conference presentations.(PROSPERO registration CRD42021273813)