scholarly journals Analysis of 180 genetic variants in a new interactive FX variant database reveals novel insights into FX deficiency

TH Open ◽  
2021 ◽  
Author(s):  
Victoria Anne Harris ◽  
Weining Lin ◽  
Stephen J Perkins
Keyword(s):  
Genetic Variants ◽  
Case Reports ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Type I ◽  
Type Ii ◽  
Factor X ◽  
Coagulation Proteins ◽  
Set Up ◽  
Variant Database

Coagulation Factor X (FX), often termed Stuart-Prower Factor, is a plasma glycoprotein composed of the γ-carboxyglutamic acid (Gla) domain, two epidermal growth factor domains (EGF-1, EGF-2) and the serine protease (SP) domain. FX plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in FX disrupt coagulation and lead to FX or Stuart-Prower Factor deficiency. To better understand the relationship between FX deficiency and disease severity, an interactive FX variant database has been set up at https://www.factorx-db.org, based on earlier websites for the Factor XI and IX coagulation proteins. To date (April 2021), we report 427 case reports on FX deficiency corresponding to 180 distinct F10 genetic variants. Of these, 149 are point variants (of which 128 are missense), 22 are deletions, three are insertions and six are polymorphisms. FX variants are phenotypically classified as being Type I or Type II. Type I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas Type II variants involve a reduction in FX:C with normal FX:Ag plasma levels. Both types of variants were distributed throughout the FXa protein structure. Analyses based on residue surface accessibilities showed the most damaging variants to occur at residues with low accessibilities. The interactive FX web database provides a novel easy-to-use resource for clinicians and scientists to improve the understanding of FX deficiency. Guidelines are provided for clinicians who wish to use the database for diagnostic purposes.

Close Reduction Percutaneous Pinning (CRPP) versus Open Reduction Internal Fixation (ORIF) for Pediatric Supracondylar Humerus Fractures Gartland Type II and III: A Systematic Review and Meta-analysis

2021 ◽  
Vol 71 (4) ◽  
pp. 187-193
Author(s):  
Putu Astawa ◽  
Made Agus Maharjana ◽  
Surya Adisthanaya ◽  
Made Winatra Satya Putra ◽  
Agus Suarjaya Putra ◽  
...  
Keyword(s):  
Systematic Review ◽  
Case Reports ◽  
Meta Analysis ◽  
Fixed Effect Model ◽  
Cosmetic Outcome ◽  
Type I ◽  
Type Ii ◽  
Supracondylar Humerus Fractures ◽  
Significant Difference ◽  
Humerus Fractures

Introduction: Displaced supracondylar fracture in children is a challenging injury that may result in impaired functional and cosmetic outcome if not well-treated. Utilization of Closed Reduction and Percutaneus Pinning (CRPP) increased for this pathology, some authors believe ORIF results better anatomical reduction and lower rate of loss of reduction. Study aims to compare CRPP and ORIF for pediatric supracondylar humerus fracture. Method: Systematic review was conducted based on PRISMA guideline. Inclusion criteria were age <18 years old, comparing CRPP and ORIF for Supracondylar Humerus Fractures Gartland Type II, II.Studies of one surgical technique, Gartland type I, case reports were excluded. For meta-analysis, 6 studies were included and fixed effect model used to pool the result. In each study, mean difference (MD) with 95% confidence interval (CI) was calculated for dichotomous outcomes using Review Manager. Result: Total of 252 patients aged 0-15 years old were included. CRPP more often performed than ORIF. Satisfactory outcomes measured by Flynn’s criteria were achieved in 87.74% in CRPP and 86.73% in ORIF patient group, indicating significant difference (Heterogeneity, I2 = 23%; WMD, 1.26; 0.58 to 2.73; P =0.56). Conclusion: Current systematic review and meta-analysis suggest that for displaced supracondylar humerus fractures, ORIF offers a comparable functional and cosmetic outcome compared to CRPP.

DISTINCTIVE FEATURES OF PROCOAGULANT RESPONSE OF MONOCYTES FROM DIABETIC PATIENTS

1987 ◽  
Author(s):  
B JUDE ◽  
A WATEL ◽  
D FONTAINE ◽  
P FONTAINE ◽  
A COSSON
Keyword(s):  
Type I Diabetes ◽  
Vascular Complications ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Diabetic Patients ◽  
Type I ◽  
Factor X ◽  
Female Ratio ◽  
Male Female Ratio

Hypercoagulability is one of the possible factors reported in genesis or aggravation of vascular complications in diabetes mellitus. We therefore examined procoagulant activity (PCA) of disrupted monocytes frcm 26 patients with Type I diabetes and 6 with Type II, versus 32 control subjects (male/ female ratio = 1 in each group).Diabetes monocytes exhibited a slight but detectable PCA before any incubation or in vitro stimulation, whereas control monocytes did not. Data obtained with coagulation factor deficient plasmas or phospholipase C indicated that PCA was tissue factor (TF) alone in 22 cases and TF associated with a significant amount of factor VII/VIIa activity in 10 cases.Incubation in serum free medium led to significant raise of PCA in diabetes cells when stimulated with endotoxin or not, and in control cells only after stimulation. Furthermore, PCA appeared earlier in diabetes monocytes than in control ones, (4 hours, versus 20 hours). PCA frcm control cells was FT-like. PCA frcm diabetes cells was FT-like when no VII/VIIa activity was present on non-stimulated cells, and prothrombinase-like when VII/VIIa activity was early associated with the cells. In the latter case, trace amounts of factor X activity were also detectable. Whether factor VII and factor X activities were of plasmatic origin and associated to the cells, or synthesized in vitro by the cells remains unclear. The characteristics of PCA were net correlated with clinical features (age, diabetic complications) nor with the type of diabetes.Our data suggest that in diabetes patients, monocytes exhibit an increased PCA, possibly corresponding to a baseline stimulation, or at least a higher responsiveness to undergoing stimuli in vitro.

scholarly journals Allergy Associated Myocardial Infarction: A Comprehensive Report of Clinical Presentation, Diagnosis and Management of Kounis Syndrome

Vaccines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 38
Author(s):  
Anastasios Roumeliotis ◽  
Periklis Davlouros ◽  
Maria Anastasopoulou ◽  
Grigorios Tsigkas ◽  
Ioanna Koniari ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Arteries ◽  
Case Reports ◽  
Type I ◽  
Type Ii ◽  
Kounis Syndrome ◽  
Normal Coronary Arteries ◽  
St Segment Elevation ◽  
Type Iii ◽  
Coronary Syndrome

Kounis syndrome (KS) has been defined as acute coronary syndrome (ACS) in the context of a hypersensitivity reaction. Patients may present with normal coronary arteries (Type I), established coronary artery disease (Type II) or in-stent thrombosis and restenosis (Type III). We searched PubMed until 1 January 2020 for KS case reports. Patients with age <18 years, non-coronary vascular manifestations or without an established diagnosis were excluded. Information regarding patient demographics, medical history, presentation, allergic reaction trigger, angiography, laboratory values and management were extracted from every report. The data were pulled in a combined dataset. From 288 patients with KS, 57.6% had Type I, 24.7% Type II and 6.6% Type III, while 11.1% could not be classified. The mean age was 54.1 years and 70.6% were male. Most presented with a combination of cardiac and allergic symptoms, with medication being the most common trigger. Electrocardiographically, 75.1% had ST segment elevation with only 3.3% demonstrating no abnormalities. Coronary imaging was available in 84.8% of the patients, showing occlusive lesions (32.5%), vascular spasm (16.2%) or normal coronary arteries (51.3%). Revascularization was pursued in 29.4% of the cases. In conclusion, allergic reactions may be complicated by ACS. KS should be considered in the differential diagnosis of myocardial infarction with non-obstructive coronary arteries.

scholarly journals Exosites expedite blood coagulation

2020 ◽  
Vol 295 (45) ◽  
pp. 15208-15209
Author(s):  
Maria Luiza Vilela Oliva ◽  
Ingrid Dreveny ◽  
Jonas Emsley
Keyword(s):  
Active Site ◽  
Serine Proteases ◽  
Critical Role ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation Cascade ◽  
Factor X ◽  
Inhibitor Development ◽  
Prothrombinase Complex ◽  
Factor X Activation

A careful balance between active-site and exosite contributions is critically important for the specificity of many proteases, but this balance is not yet defined for some of the serine proteases that serve as coagulation factors. Basavaraj and Krishnaswamy have closed an important gap in our knowledge of coagulation factor X activation by the intrinsic Xase complex by showing that exosite binding plays a critical role in this process, which they describe as a “dock and lock.” This finding not only significantly enhances our understanding of this step in the coagulation cascade and highlights parallels with the prothrombinase complex, but will also provide a novel rationale for inhibitor development in the future.

Regulation of human coagulation factor X gene expression by GATA-4 and the Sp family of transcription factors

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 946-951 ◽  
Author(s):  
Hsiao-Ling Hung ◽  
Eleanor S. Pollak ◽  
Rama D. Kudaravalli ◽  
Valder Arruda ◽  
Kirk Chu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Binding ◽  
Promoter Activity ◽  
Critical Role ◽  
Coagulation Factor ◽  
Proximal Promoter ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Factor X ◽  
Specific Expression

Abstract Serine protease factor Xa plays a critical role in the coagulation cascade. Zymogen factor X is synthesized and modified in the liver. To understand the mechanisms governing the liver-specific expression of factor X, the proximal promoter of human factor X was previously characterized. Two crucial cis elements at −73 and −128 and their cognate binding proteins, HNF-4 and NF-Y, respectively, were identified. In this report, studies are extended to 3 additionalcis elements within the factor X promoter. Using gel mobility shift assays, the liver-enriched protein GATA-4 was identified as the protein binding to the GATA element at −96. GATA-4 transactivates the factor X promoter 28-fold in transient transfection experiments. It was also determined that the Sp family of transcription factors binds 2 DNase I–footprinted sites at −165 and −195. Disruption of Sp protein binding at either site reduces the promoter activity by half. Simultaneous disruption of both sites reduces the promoter activity 8-fold. This is the first report indicating the involvement of GATA-4 in the regulation of clotting factor expression. These observations provide novel insight into mechanisms by which the vitamin K–dependent coagulation factors are regulated.

scholarly journals Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

2020 ◽  
Vol 120 (10) ◽  
pp. 1357-1370
Author(s):  
Georg Gelbenegger ◽  
Christian Schoergenhofer ◽  
Paul Knoebl ◽  
Bernd Jilma
Keyword(s):  
Clinical Trials ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor X ◽  
Current Standard ◽  
Bleeding Events ◽  
Recombinant Activated Factor Vii

AbstractHemophilia A, characterized by absent or ineffective coagulation factor VIII (FVIII), is a serious bleeding disorder that entails severe and potentially life-threatening bleeding events. Current standard therapy still involves replacement of FVIII, but is often complicated by the occurrence of neutralizing alloantibodies (inhibitors). Management of patients with inhibitors is challenging and necessitates immune tolerance induction for inhibitor eradication and the use of bypassing agents (activated prothrombin complex concentrates or recombinant activated factor VII), which are expensive and not always effective. Emicizumab is the first humanized bispecific monoclonal therapeutic antibody designed to replace the hemostatic function of activated FVIII by bridging activated factor IX and factor X (FX) to activate FX and allow the coagulation cascade to continue. In the majority of hemophilic patients with and without inhibitors, emicizumab reduced the annualized bleeding rate to almost zero in several clinical trials and demonstrated a good safety profile. However, the concurrent use of emicizumab and activated prothrombin complex concentrate imposes a high risk of thrombotic microangiopathy and thromboembolic events on patients and should be avoided. Yet, the management of breakthrough bleeds and surgery remains challenging with only limited evidence-based recommendations being available. This review summarizes published clinical trials and preliminary reports of emicizumab and discusses the clinical implications of emicizumab in treatment of hemophilia A.

scholarly journals Agreement between results of meta-analyses from case reports and clinical studies, regarding efficacy and safety of idursulfase therapy in patients with mucopolysaccharidosis type II (MPS-II). A new tool for evidence-based medicine in rare diseases

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Miguel Sampayo-Cordero ◽  
Bernat Miguel-Huguet ◽  
Almudena Pardo-Mateos ◽  
Andrea Malfettone ◽  
José Pérez-García ◽  
...  
Keyword(s):  
Rare Diseases ◽  
Clinical Studies ◽  
Case Reports ◽  
Meta Analysis ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Mucopolysaccharidosis Type Ii ◽  
Mps Ii ◽  
Meta Analyses

Abstract Background A preliminary exploratory study shows solid agreement between the results of case reports and clinical study meta-analyses in mucopolysaccharidosis Type I (MPS-I) adult patients. The aim of the present study is to confirm previous results in another patient population, suffering from mucopolysaccharidosis Type II (MPS-II). Methods A systematic review and meta-analysis of case reports published by April 2018 was conducted for MPS-II patients treated with enzyme replacement therapy (ERT). The study is reported in accordance with PRISMA and MOOSE guidelines (PROSPERO database code CRD42018093408). The assessed population and outcomes were the same as previously analyzed in a meta-analysis of MPS-II clinical studies. The primary endpoint was the percent of clinical cases showing improvement in efficacy outcome, or no harm in safety outcome after ERT initiation. A restrictive procedure to aggregate case reports, by selecting standardized and well-defined outcomes, was proposed. Different sensitivity analyses were able to evaluate the robustness of results. Results Every outcome classified as “acceptable evidence group” in our case report meta-analysis had been graded as “moderate strength of evidence” in the aforementioned meta-analysis of clinical studies. Sensitivity, specificity, and positive-negative predictive values for results of both meta-analyses reached 100%, and were deemed equivalent. Conclusions Aggregating case reports quantitatively, rather than analyzing them qualitatively, may improve conclusions in rare diseases and personalized medicine. Additionally, we propose some methods to evaluate publication bias and heterogeneity of the included studies in a meta-analysis of case reports.

scholarly journals Monopolar and Bipolar Combination Injuries of the Clavicle: Retrospective Incidence Analysis and Proposal of a New Classification System

2021 ◽  
Vol 10 (24) ◽  
pp. 5764
Author(s):  
Mustafa Sinan Bakir ◽  
Roman Carbon ◽  
Axel Ekkernkamp ◽  
Stefan Schulz-Drost
Keyword(s):  
Case Reports ◽  
Clavicle Fracture ◽  
Type I ◽  
Type Ii ◽  
New Classification ◽  
Joint Dislocations ◽  
Type Ia ◽  
Icd 10 ◽  
Bipolar Type ◽  
Incidence Analysis

Clavicle injuries are common, but only few case reports describe combined clavicular injuries (CCI). CCI include combinations between clavicular fractures and acromioclavicular/sternoclavicular joint dislocations (SCJD). We present the first general therapeutic recommendations for CCI based on a new classification and their distribution. A retrospective, epidemiological, big data analysis was based on ICD-10 diagnoses from 2012 to 2014 provided by the German Federal Statistical Office. CCI represent 0.7% of all clavicle-related injuries (n = 814 out of 114,003). SCJD show by far the highest proportion of combination injuries (13.2% of all SCJD were part of CCI) while the proportion of CCI in relation to the other injury entities was significantly less (p < 0.023). CCIs were classified depending on (1) the polarity (monopolar type I, 92.2% versus bipolar type II, 7.8%). Monopolar type I was further differentiated depending on (2) the positional relationship between the combined injuries: Ia two injuries directly at the respective pole versus Ib with an injury at one end plus an additional midshaft clavicle fracture. Type II was further differentiated depending on (3) the injured structures: IIa ligamento-osseous, type IIb purely ligamentous (rarest with 0.6%). According to our classification, the CCI severity increases from type Ia to IIb. CCI are more important than previously believed and seen as an indication for surgery. The exclusion of further, contra-polar injuries in the event of a clavicle injury is clinically relevant and should be focused.

scholarly journals Functional assembly of intrinsic coagulation proteases on monocytes and platelets. Comparison between cofactor activities induced by thrombin and factor Xa.

1992 ◽  
Vol 176 (1) ◽  
pp. 27-35 ◽  
Author(s):  
M P McGee ◽  
L C Li ◽  
M Hensler
Keyword(s):  
Factor Viii ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Factor X ◽  
Regulatory Pathways ◽  
Factor Ixa ◽  
Factor Viiia ◽  
Human Factor Viii

Generation of coagulation factor Xa by the intrinsic pathway protease complex is essential for normal activation of the coagulation cascade in vivo. Monocytes and platelets provide membrane sites for assembly of components of this protease complex, factors IXa and VIII. Under biologically relevant conditions, expression of functional activity by this complex is associated with activation of factor VIII to VIIIa. In the present studies, autocatalytic regulatory pathways operating on monocyte and platelet membranes were investigated by comparing the cofactor function of thrombin-activated factor VIII to that of factor Xa-activated factor VIII. Reciprocal functional titrations with purified human factor VIII and factor IXa were performed at fixed concentrations of human monocytes, CaCl2, factor X, and either factor IXa or factor VIII. Factor VIII was preactivated with either thrombin or factor Xa, and reactions were initiated by addition of factor X. Rates of factor X activation were measured using chromogenic substrate specific for factor Xa. The K1/2 values, i.e., concentration of factor VIIIa at which rates were half maximal, were 0.96 nM with thrombin-activated factor VIII and 1.1 nM with factor Xa-activated factor VIII. These values are close to factor VIII concentration in plasma. The Vsat, i.e., rates at saturating concentrations of factor VIII, were 33.3 and 13.6 nM factor Xa/min, respectively. The K1/2 and Vsat values obtained in titrations with factor IXa were not significantly different from those obtained with factor VIII. In titrations with factor X, the values of Michaelis-Menten coefficients (Km) were 31.7 nM with thrombin-activated factor VIII, and 14.2 nM with factor Xa-activated factor VIII. Maximal rates were 23.4 and 4.9 nM factor Xa/min, respectively. The apparent catalytic efficiency was similar with either form of factor VIIIa. Kinetic profiles obtained with platelets as a source of membrane were comparable to those obtained with monocytes. These kinetic profiles are consistent with a 1:1 stoichiometry for the functional interaction between cofactor and enzyme on the surface of monocytes and platelets. Taken together, these results indicate that autocatalytic pathways connecting the extrinsic, intrinsic, and common coagulation pathways can operate efficiently on the monocyte membrane.

scholarly journals Anticoagulant activity of direct factor Xa inhibitors as a tool to ensure the effectiveness and safety of drugs intake

Kardiologiia ◽  
2019 ◽  
Vol 59 (11S) ◽  
pp. 28-35 ◽  
Author(s):  
T. V. Vavilova
Keyword(s):  
Clinical Presentation ◽  
Anticoagulant Activity ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Factor X ◽  
Direct Factor Xa Inhibitors ◽  
Thematic Review ◽  
Generation Test

The thematic review presents modern solutions using oral anticoagulants with a focus on direct coagulation factor X inhibitors. It contains information about the pharmacodynamics and pharmacokinetics of apixaban and rivaroxaban against the background of different drug intake regimens - twice and once per day. There are shown studies of concentration dynamics and the corresponding functional response, measured using the integral method - the thrombin generation test, which is widely used in scientific research to describe hemostatic processes based on an objective quantitative assessment of the thrombin formation – a key coagulation cascade serine protease. The logical relationship between the pharmacodynamics of anticoagulant action and the clinical presentation of the effectiveness and safety of drugs is traced. The review provides links to actual literature and current clinical guidelines.

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