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International Journal of Molecular... Nov 2021Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is... (Review)
Review
Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.
Topics: Afibrinogenemia; Animals; Autophagy; Coagulants; Endoplasmic Reticulum; Fibrinogen; Gene Expression Regulation; Humans; Liver; Neuroprotective Agents; Parkinson Disease; Protease Inhibitors; Protein Aggregates; Protein Folding; Unfolded Protein Response; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; alpha-Synuclein
PubMed: 34830348
DOI: 10.3390/ijms222212467 -
PloS One 2014Though rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Though rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of consanguinity in many caste groups, these autosomal recessive bleeding disorders which are of rare occurrence in populations across the world, may not be as rare in India.
OBJECTIVES
To comprehensively analyze the frequency and nature of mutations in Indian patients with RBDs.
METHODS
Pubmed search was used (www.pubmed.com) to explore the published literature from India on RBDs using the key words "rare bleeding disorders", "mutations", "India", "fibrinogen", "afibrinogenemia", "factor II deficiency", "prothrombin" "factor VII deficiency", "factor V deficiency", "factor X deficiency", "factor XI deficiency", "combined factor V and VIII deficiency", "factor XIII deficiency", "Bernard Soulier syndrome" and "Glanzmanns thrombasthenia" in different combinations. A total of 60 relevant articles could be retrieved. The distribution of mutations from India was compared with that of the world literature by referring to the Human Gene Mutation Database (HGMD) (www.hgmd.org).
RESULTS
Taken together, 181 mutations in 270 patients with different RBDs have been reported from India. Though the types of mutations reported from India and their percentage distribution with respect to the world data are largely similar, yet much higher percentage of small deletions, duplication mutations, insertions, indels were observed in this analysis. Besides the identification of novel mutations and polymorphisms, several common mutations have also been reported, which will allow to develop a strategy for mutation screening in Indian patients with RBDs.
CONCLUSION
There is a need for a consortium of Institutions working on the molecular pathology of RBDs in India. This will facilitate a quicker and cheaper diagnosis of RBDs besides its utility in first trimester prenatal diagnosis of the affected families.
Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Databases, Genetic; Fibrinogen; Humans; India; Mutation; Pathology, Molecular; Rare Diseases
PubMed: 25275492
DOI: 10.1371/journal.pone.0108683 -
RSC Medicinal Chemistry Oct 2020Traumatic coagulopathy due to severe external injury and internal hemorrhage is life-threatening to accident victims and soldiers on the battlefield, causing... (Review)
Review
Traumatic coagulopathy due to severe external injury and internal hemorrhage is life-threatening to accident victims and soldiers on the battlefield, causing considerable number of deaths worldwide. Patients with inherited bleeding disorders (such as haemophilia, von Willebrand disease, inherited qualitative platelet defects, and afibrinogenemia) also contribute to the vast number of deaths due to abnormal bleeding, and these patients are difficult to handle during surgery. Platelets and different plasma proteins play an essential role in blood coagulation and in the maintenance of the body's hemostatic balance. The improper function or deficiency of these factors cause abnormal bleeding. To address such bleeding disorders, external clotting agents (such as extracellular protein-inspired natural and synthetic peptide-based sealants and peptide-functionalized polymer/liposome-based sealants) have been developed by different groups of researchers. The primary focus of this review is to provide molecular insights into the existing biologically inspired peptide-based sealants, highlighting the advantages and limitations of such reported designed sealants to handle blood clotting, and also provide insights into the design of improved next-generation surgical sealants.
PubMed: 33479616
DOI: 10.1039/d0md00204f -
Blood Jun 2021Due to the low prevalence of afibrinogenemia, epidemiologic data on afibrinogenemia are limited, and no data are available on health-related quality of life (HRQoL). We... (Clinical Trial)
Clinical Trial
Due to the low prevalence of afibrinogenemia, epidemiologic data on afibrinogenemia are limited, and no data are available on health-related quality of life (HRQoL). We conducted a cross-sectional international study to characterize the clinical features, the fibrinogen supplementation modalities, and their impact on HRQoL in patients with afibrinogenemia. A total of 204 patients (119 adults and 85 children) from 25 countries were included. The bleeding phenotype was severe: 68 (33.3%) patients having at least one bleed per month and 48 (23%) a history of cerebral bleeding. About 35% (n = 72) of patients were treated with fibrinogen concentrates or cryoprecipitates as prophylaxis, 18.1% (n = 37) received ≥1 injection per week, and 16.6% (n = 34) were on home treatment. A thrombotic event was reported in venous and/or arterial territories by 37 (18.1%) patients. Thrombosis occurred even in young patients, and recurrence was frequent (7.4%). The total HRQoL was lower in children than in adults. Discomfort linked to treatment and limitations to sports and leisure were the main concerns. Women and children were particularly affected in family relationships. In multivariate analyses, younger age, residence in Asia or Africa, and a previous thrombotic event were statistically correlated with a worse HRQoL. In summary, our study underlines the severe bleeding and thrombotic phenotype and their impact on HRQoL in afibrinogenemia. The optimal strategy for fibrinogen supplementation needs to be determined. This trial was registered at www.clinicaltrials.gov as #NCT03484065.
Topics: Adolescent; Adult; Afibrinogenemia; Age Factors; Cerebral Hemorrhage; Child; Child, Preschool; Factor VIII; Female; Fibrinogen; Humans; Male; Middle Aged; Quality of Life; Risk Factors; Thrombosis
PubMed: 33512441
DOI: 10.1182/blood.2020009472 -
Scandinavian Journal of Trauma,... Dec 2021In severely injured patients, fibrinogen supplementation is recommended when fibrinogenemia is < 1.5 g L, but some teams have suggested to use higher thresholds...
BACKGROUND
In severely injured patients, fibrinogen supplementation is recommended when fibrinogenemia is < 1.5 g L, but some teams have suggested to use higher thresholds (fibrinogenemia < 2.0 g L or FIBTEM clot amplitude at 5 min (A5) values < 11 mm). The goal of this study was to specify in patients with a moderate fibrinogen deficit (MFD) whether some admission characteristics would be associated with fibrinogen administration at 24 h.
METHODS
Prospective analysis of retrospectively collected data from a trauma registry (01/2011-12/2019). MFD-C was defined by a fibrinogenemia 1.51-1.99 g L or the corresponding FIBTEM-A5 values (MFD-A5) that were determined from linear regression and ROC curve analysis. Administration of fibrinogen were described according to the following admission parameters: shock index (SI) > 1, hemoglobin level < 110 g L (HemoCue®), and base deficit > 5 mEq L. Data are expressed as count (%), median [IQR].
RESULTS
1076 patients were included in the study and 266 (27%) had MFD-C, among them, 122/266 (46%) received fibrinogen. Patients with MFD-C who received fibrinogen were more severely injured (ISS: 27 [19-36] vs. 24 [17-29]) and had more impaired vital signs (base deficit: 5.4 [3.6-7.8] vs. 3.8 [2.0-6.0]). Linear regression analysis found a positive correlation between fibrinogen level and FIBTEM-A5 (r: 0.805). For a fibrinogen level < 1.5 g L and < 2.0 g L, FIBTEM-A5 thresholds were 6 mm (sensitivity 85%, specificity 83%, AUC: 0.934) and 9 mm (sensitivity 84%, specificity 69%, AUC: 0.874), respectively. MFD-A5 values (185 (27%) patients) were defined as a FIBTEM-A5 between 7 and 9 mm. More than 50% of MFD-C patients presenting a SI > 1, a hemoglobin level < 110 g L, or a base deficit > 5.0 mEq L received fibrinogen. The relative risk [95% CI] for fibrinogen administration (SI > 1) were 1.39 [1.06-1.82] for MFD-C, and 2.17 [1.48-3.19] for MFD-A5. Results were not modified after adjustment on the ISS.
CONCLUSIONS
We have shown in this study an association between shock parameters and fibrinogen administration. Further studies are needed to determine how these parameters may be used to guide fibrinogen administration in trauma patients with MFD.
Topics: Afibrinogenemia; Blood Coagulation Disorders; Fibrinogen; Humans; Retrospective Studies; Thrombelastography; Wounds and Injuries
PubMed: 34952618
DOI: 10.1186/s13049-021-00988-x -
International Journal of Molecular... Jun 2020Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of... (Review)
Review
Genetic Variants in the and Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype.
Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: , , and (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations.
Topics: Afibrinogenemia; Blood Coagulation Tests; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Hemorrhage; Hemostasis; Hemostatics; Humans; Phenotype; Thrombosis
PubMed: 32610551
DOI: 10.3390/ijms21134616 -
Thrombosis Research Jan 2021Low fibrinogen and platelet counts are associated with bleeding and the need for transfusion. In this study, we investigated whether the Quantra® QPlus® parameters... (Observational Study)
Observational Study
INTRODUCTION
Low fibrinogen and platelet counts are associated with bleeding and the need for transfusion. In this study, we investigated whether the Quantra® QPlus® parameters Fibrinogen Contribution (FCS) and Platelet Contribution (PCS) to clot stiffness could predict commonly used fibrinogen and platelet transfusion thresholds in patients undergoing major surgical procedures.
METHODS
This study used data from a multicenter, prospective observational study of adult patients undergoing cardiac or major orthopedic surgery. Quantra and laboratory assays were performed in parallel at multiple time points. Logistic regression models were used to assess the ability of FCS and PCS to predict fibrinogen and platelet thresholds used to guide transfusions. Receiver operating characteristics (ROC) curves were analyzed to determine the diagnostic accuracy and the optimal FCS and PCS values corresponding to the laboratory-based thresholds.
RESULTS
The areas under the ROC curves (AUCs) for FCS at fibrinogen thresholds of <120, 150, and 200 mg/dl ranged from 0.96 to 0.89. Similarly, for PCS at platelet thresholds of <50, 80, 100,000/μl, AUCs ranged from 0.95 to 0.89. The proposed optimal FCS and PCS cutoff values showed high negative predictive value and high sensitivity and specificity (both >86%) at the lowest fibrinogen and platelet threshold levels.
CONCLUSIONS
This study identifies potential cutoff values for QPlus FCS and PCS proposed for use in place of or in conjunction with laboratory-based assays fibrinogen and platelet thresholds to guide transfusion decisions in surgical patients. These cut-off values will need to be validated in future studies.
Topics: Adult; Afibrinogenemia; Cardiac Surgical Procedures; Fibrinogen; Humans; Point-of-Care Systems; Thrombelastography; Thrombocytopenia
PubMed: 33197797
DOI: 10.1016/j.thromres.2020.11.008 -
Journal of Thrombosis and Haemostasis :... Apr 2023Postpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment... (Observational Study)
Observational Study
BACKGROUND
Postpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment strategies based on data derived from trauma studies.
OBJECTIVES
To investigate hemostatic changes associated with PPH.
PATIENTS/METHODS
From a population of 11 279 maternities, 518 (4.6%) women were recruited with PPH ≥ 1000 mL or placental abruption, amniotic fluid embolism, or concealed bleeding. Routine coagulation and viscoelastometric results were collated. Stored plasma samples were used to investigate women with bleeds > 2000 mL or those at increased risk of coagulopathy defined as placenta abruption, amniotic fluid embolism, or need for blood components. Procoagulant factors were assayed and global hemostasis was assessed using thrombin generation. Fibrinolysis was investigated with D-dimer and plasmin/antiplasmin complexes. Dysfibrinogenemia was assessed using the Clauss/antigen ratio.
RESULTS
At 1000 mL blood loss, Clauss fibrinogen was ≤2 g/L in 2.4% of women and 6/27 (22.2%) cases of abruption. Women with very large bleeds (>3000 mL) had evidence of a dilutional coagulopathy, although hemostatic impairment was uncommon. A subgroup of 12 women (1.06/1000 maternities) had a distinct coagulopathy characterized by massive fibrinolysis (plasmin/antiplasmin > 40 000 ng/mL), increased D-dimer, hypofibrinogenemia, dysfibrinogenemia, reduced factor V and factor VIII, and increased activated protein C, termed acute obstetric coagulopathy. It was associated with fetal or neonatal death in 50% of cases and increased maternal morbidity.
CONCLUSIONS
Clinically significant hemostatic impairment is uncommon during PPH, but a subgroup of women have a distinct and severe coagulopathy characterized by hyperfibrinolysis, low fibrinogen, and dysfibrinogenemia associated with poor fetal outcomes.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Afibrinogenemia; Antifibrinolytic Agents; Blood Coagulation Disorders; Cohort Studies; Embolism, Amniotic Fluid; Fibrinogen; Fibrinolysin; Hemostatics; Placenta; Postpartum Hemorrhage
PubMed: 36696216
DOI: 10.1016/j.jtha.2022.11.036 -
Transfusion Sep 2022Congenital fibrinogen deficiency (CFD) is a rare coagulation disorder placing patients at increased bleeding risk. Human fibrinogen concentrate (HFC) represents current...
Efficacy and safety of fibrinogen concentrate for perioperative prophylaxis of bleeding in adult, adolescent, and pediatric patients with congenital fibrinogen deficiency: FORMA-02 and FORMA-04 clinical trials.
BACKGROUND
Congenital fibrinogen deficiency (CFD) is a rare coagulation disorder placing patients at increased bleeding risk. Human fibrinogen concentrate (HFC) represents current standard of care for fibrinogen replacement in CFD, however, limited data are available on HFC for prophylactic administration before/during surgery. Here, we report results and dosing considerations for HFC treatment in perioperative bleeding management in adult, adolescent, and pediatric patients with CFD.
STUDY DESIGN AND METHODS
FORMA-02/FORMA-04 were multinational, prospective, open-label, uncontrolled Phase 3 HFC efficacy/safety studies for surgical bleeding prophylaxis in adult/adolescent (≥12 years) and pediatric patients (<12 years) respectively. HFC dosing was calculated to achieve pre-established target fibrinogen plasma levels. Overall hemostatic efficacy was assessed as success/failure by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) according to objective criteria.
RESULTS
Twelve patients (≥12 years, N = 9; <12 years, N = 3) received HFC for surgical prophylaxis (15 surgeries; 13 minor, 2 major). Eleven minor surgeries in patients aged ≥12 years required a median of 1 infusion (range; 1-5), with a mean (±SD) dose of 93.50 mg/kg [±41.43] and two minor surgeries in patients <12 years required 1 infusion (91.55 mg/kg [±23.40]). The major surgery in an adult patient required eight infusions (225.3 mg/kg total dose). The major surgery in a pediatric patient required six infusions (450.4 mg/kg). All surgeries were rated successful by the IDMEAC.
DISCUSSION
In adults/adolescents and pediatric patients with fibrinogen deficiency, HFC treatment for hemostatic management during/after minor and major surgery was successful, with efficacy comparable across the different age groups.
Topics: Adolescent; Adult; Afibrinogenemia; Blood Loss, Surgical; Child; Fibrinogen; Hemostatics; Humans; Prospective Studies
PubMed: 35932202
DOI: 10.1111/trf.17029 -
BMC Pregnancy and Childbirth Sep 2023Preeclampsia complicated with hypofibrinogenemia is a rare disorder. We report two cases of severe preeclampsia complicated with hypofibrinogenemia followed by... (Review)
Review
BACKGROUND
Preeclampsia complicated with hypofibrinogenemia is a rare disorder. We report two cases of severe preeclampsia complicated with hypofibrinogenemia followed by postpartum haemorrhage (PPH).
CASE
Two women diagnosed as preeclampsia and hypofibrinogenemia developed severe PPH after undergoing Cesarean sections. Besides supplement with fibrinogen concentrate and supportive treatment, the second patient got administration of heparin after delivery and bleeding was stopped. The haemorrhage in case 1 didn't disappear until an hysterectomy. The two patients both recovered and were discharged soon.
CONCLUSIONS
Severe preeclampsia patients with hypofibrinogenemia could suffer PPH. It's necessary to detect and master coagulation function. Heparin could be considered to balance hypercoagulation and hypocoagulation to avoid catastrophic haemorrhage and hysterectomy.
Topics: Pregnancy; Humans; Female; Afibrinogenemia; Pre-Eclampsia; Fibrinogen; Postpartum Hemorrhage; Heparin
PubMed: 37658306
DOI: 10.1186/s12884-023-05965-z