-
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 -
BMC Emergency Medicine Aug 2012Rupture of the spleen in the absence of trauma or previously diagnosed disease is largely ignored in the emergency literature and is often not documented as such in... (Review)
Review
BACKGROUND
Rupture of the spleen in the absence of trauma or previously diagnosed disease is largely ignored in the emergency literature and is often not documented as such in journals from other fields. We have conducted a systematic review of the literature to highlight the surprisingly frequent occurrence of this phenomenon and to document the diversity of diseases that can present in this fashion.
METHODS
Systematic review of English and French language publications catalogued in Pubmed, Embase and CINAHL between 1950 and 2011.
RESULTS
We found 613 cases of splenic rupture meeting the criteria above, 327 of which occurred as the presenting complaint of an underlying disease and 112 of which occurred following a medical procedure. Rupture appeared to occur spontaneously in histologically normal (but not necessarily normal size) spleens in 35 cases and after minor trauma in 23 cases. Medications were implicated in 47 cases, a splenic or adjacent anatomical abnormality in 31 cases and pregnancy or its complications in 38 cases. The most common associated diseases were infectious (n = 143), haematologic (n = 84) and non-haematologic neoplasms (n = 48). Amyloidosis (n = 24), internal trauma such as cough or vomiting (n = 17) and rheumatologic diseases (n = 10) are less frequently reported. Colonoscopy (n = 87) was the procedure reported most frequently as a cause of rupture. The anatomic abnormalities associated with rupture include splenic cysts (n = 6), infarction (n = 6) and hamartomata (n = 5). Medications associated with rupture include anticoagulants (n = 21), thrombolytics (n = 13) and recombinant G-CSF (n = 10). Other causes or associations reported very infrequently include other endoscopy, pulmonary, cardiac or abdominal surgery, hysterectomy, peliosis, empyema, remote pancreato-renal transplant, thrombosed splenic vein, hemangiomata, pancreatic pseudocysts, splenic artery aneurysm, cholesterol embolism, splenic granuloma, congenital diaphragmatic hernia, rib exostosis, pancreatitis, Gaucher's disease, Wilson's disease, pheochromocytoma, afibrinogenemia and ruptured ectopic pregnancy.
CONCLUSIONS
Emergency physicians should be attuned to the fact that rupture of the spleen can occur in the absence of major trauma or previously diagnosed splenic disease. The occurrence of such a rupture is likely to be the manifesting complaint of an underlying disease. Furthermore, colonoscopy should be more widely documented as a cause of splenic rupture.
Topics: Databases, Bibliographic; Diagnosis, Differential; Emergency Medical Services; Humans; Rupture, Spontaneous; Splenic Rupture
PubMed: 22889306
DOI: 10.1186/1471-227X-12-11 -
Postgraduate Medical Journal May 1969Three cases of defibrination syndrome and bleeding tendency are described. In each case the aetiology was completely different but thrombocytopenia and fibrinogenopenia...
Three cases of defibrination syndrome and bleeding tendency are described. In each case the aetiology was completely different but thrombocytopenia and fibrinogenopenia were present together. This combination is invariably due to diffuse intravascular clotting and it is suggested that these simple investigations should be asked for in cases of unexplained shock, acute renal failure of obscure origin, severe intravascular haemolysis, septic abortions, etc. Heparin would appear to be of value in these cases of defibrination. However, if there is no thrombocytopenia, defibrination may be due to excessive fibrinolysis. This should be treated with anti-fibrinolytics only when an underlying clotting defect has been excluded.
Topics: Adolescent; Adult; Afibrinogenemia; Blood Coagulation Disorders; Female; Heparin; Humans; Male; Middle Aged; Thrombocytopenia
PubMed: 5790930
DOI: 10.1136/pgmj.45.523.319 -
Haemophilia : the Official Journal of... Nov 2022Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes...
Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia.
INTRODUCTION
Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC).
AIM
This post-hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a- and hypofibrinogenaemia.
METHODS
The analysis used data from the FORMA-01 (Phase 2), FORMA-02 and FORMA-04 (Phase 3) multinational, prospective, open-label studies in patients with a- and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA-01) and children (<12 years; FORMA-04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA-02 and FORMA-04 using an objective 4-point scale, with success defined as excellent/good.
RESULTS
Median (range) age was 23 years for FORMA-01 (12-53; n = 22), 26.5 years for FORMA-02 (12-54; n = 25), and 6 years for FORMA-04 (1-10; n = 13). Mean PK parameters were lower for children (AUC, C , IVR; p = .02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41 mg/kg (32.12-273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91 mg/kg (47.45-262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis.
CONCLUSION
As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable.
Topics: Adolescent; Adult; Child; Humans; Young Adult; Afibrinogenemia; Fibrinogen; Hemorrhage; Hemostatics; Prospective Studies; Rare Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic
PubMed: 35925493
DOI: 10.1111/hae.14619 -
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 -
Minerva Anestesiologica Jan 2014Coagulation is a complex cascade whose intact functioning is essential in helping control hemorrhage after injury. While traditionally ascribed to the combined effects... (Review)
Review
Coagulation is a complex cascade whose intact functioning is essential in helping control hemorrhage after injury. While traditionally ascribed to the combined effects of acidosis, hypothermia, factor consumption and factor dilution, coagulopathy is also directly related to injury as well as hypofibrinogenemia and hyperfibrinolysis. Low fibrinogen concentration is readily determined with standard laboratory profiling, but direct analysis of hyperfibrinolysis relies on either thromboelastography or rotational thromboelastometry. Both conditions offer opportunities for therapeutic intervention, and inhibition or abrogation of hyperfibrinolysis in particular may significantly improve survival in patients with injury and massive hemorrhage. Herein, we explore the underpinnings of trauma associated coagulopathy, the basic science behind the role of fibrinogen in acute traumatic coagulopathy, and the rationale behind and the data derived from management of hypofibrinogenemia as well as hyperfibrinolysis.
Topics: Afibrinogenemia; Animals; Antifibrinolytic Agents; Blood Component Transfusion; Fibrin; Fibrinogen; Fibrinolysis; Hemorrhage; Hemostasis; Hemostatic Techniques; Humans; Multicenter Studies as Topic; Plasma; Randomized Controlled Trials as Topic; Tranexamic Acid; Wounds and Injuries
PubMed: 23857437
DOI: No ID Found -
British Medical Journal Jul 1951
Topics: Afibrinogenemia; Blood Coagulation; Coagulants; Extracellular Space; Fibrinogen; Hemostatics; Humans
PubMed: 14848515
DOI: 10.1136/bmj.2.4723.86