-
Blood Coagulation & Fibrinolysis : An... Dec 2019: Rare bleeding disorders usually begin in childhood and manifest as varying degrees of bleeding, which can be life-threatening in severe cases. With the development of... (Review)
Review
: Rare bleeding disorders usually begin in childhood and manifest as varying degrees of bleeding, which can be life-threatening in severe cases. With the development of gene editing technology, it is expected that hereditary coagulation factor disorders will someday be fundamentally cured by gene therapy. On account of their rarity, comprehension of these diseases is essential for the application of new treatment strategies. We have compiled the features of some newly discovered mutations of prothrombin, factor VII, and factor X in recent years. In addition, this review introduces the advances and obstacles in gene therapy.
Topics: Blood Coagulation Disorders; Factor VII; Factor X; Genetic Therapy; Hemorrhagic Disorders; Humans; Mutation; Prothrombin; Rare Diseases
PubMed: 31738733
DOI: 10.1097/MBC.0000000000000852 -
Cureus Dec 2020Ischemic stroke is an acute episode of neurological dysfunction resulting from the focal brain and spinal cord infarction. Many etiologies have been reported and vary... (Review)
Review
Ischemic stroke is an acute episode of neurological dysfunction resulting from the focal brain and spinal cord infarction. Many etiologies have been reported and vary significantly with the age of the patients. This study aims to show the association of G20210A prothrombin gene mutation and cerebral ischemic stroke in young patients. The prothrombin gene mutation is the second most common inherited thrombophilia after the factor V mutation. In this single missense mutation, guanine is substituted by adenine base pair in the nucleotide position 20210 of the 3'-untranslated region of the prothrombin gene, resulting in abnormal thrombin production predisposing to both arterial or venous thrombosis. Forty-seven relevant articles were selected after a thorough screening process using a regular keyword 'G20210A Prothrombin' and/or 'Ischemic Stroke' mostly from the PubMed database. We included the studies that are published in the last 22 years with patients age ≤57 years. This review article depicts the association of G20210A prothrombin gene mutation with ischemic stroke in young patients irrespective of ethnicity and zygosity status of their genotype. However, more multicenter prospective studies are needed to better understand the application of prothrombin gene mutation in predicting the associated risk of ischemic stroke in young patients and its importance in deciding the patients' treatment or prognosis.
PubMed: 33437541
DOI: 10.7759/cureus.11984 -
Clinica Chimica Acta; International... Dec 2021Warfarin therapy influences generation of γ-carboxyglutamyl (Gla) residues in prothrombin, causing reduced coagulation activity. It will leave such inactive prothrombin...
BACKGROUND
Warfarin therapy influences generation of γ-carboxyglutamyl (Gla) residues in prothrombin, causing reduced coagulation activity. It will leave such inactive prothrombin in serum after clot formation, resulting in serum prothrombin constituting total inactive prothrombin in these patients.
METHODS
An ELISA was developed to measure biologically inactive prothrombin in serum, and applied to serum from warfarin therapy causing a decrease in Gla residues or direct oral anticoagulant (DOAC) therapy as its contrast.
RESULTS
The concentrations of serum prothrombin in both the warfarin and DOAC groups were higher than those in the healthy group (p < 0.01 and p < 0.001, respectively). When serum in the previous three groups was treated with barium carbonate to exclude prothrombin, which lost several Gla residues, the prothrombin concentration in the DOAC group decreased to the same level as that in the healthy group, indicating that prothrombin was obtained at a high level only in the warfarin group (p < 0.01).
CONCLUSIONS
Warfarin and DOAC led to increase in serum prothrombin concentration. The reason is that DOAC decreases prothrombin recruitment during fibrin clot formation, while warfarin leads to the accumulation of inactive prothrombin, which have a decreased number of Gla residues.
Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Blood Coagulation Tests; Humans; Prothrombin; Warfarin
PubMed: 34599901
DOI: 10.1016/j.cca.2021.09.023 -
Seminars in Thrombosis and Hemostasis Feb 2022Antiphospholipid antibodies (aPL) comprise a panel of autoantibodies that reflect a potential prothrombotic risk in several autoimmune conditions, most notably... (Review)
Review
Antiphospholipid antibodies (aPL) comprise a panel of autoantibodies that reflect a potential prothrombotic risk in several autoimmune conditions, most notably antiphospholipid (antibody) syndrome (APS). aPL can be divided into those that form part of the laboratory criteria for APS, namely, lupus anticoagulant (LA), as well as anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I antibodies (aβ2GPI) of the immunoglobulin G and M classes, and those that form a group considered as "noncriteria antibodies." The noncriteria antibodies include, for example, antiphosphatidylserine antibodies (aPS), antiprothrombin antibodies (aPT), and antiphosphatidylserine/prothrombin complex antibodies (aPS/PT). COVID-19 (coronavirus disease 2019) represents a prothrombotic disorder, and there have been several reports of various aPL being present in COVID-19 patients. There have also been similarities drawn between some of the pathophysiological features of COVID-19 and APS, in particular, the most severe form, catastrophic APS (CAPS). In this review, we critically appraise the literature on aPL and COVID-19. This is a companion piece to a separate review focused on LA. In the current review, we primarily concentrate on the so-called solid phase identifiable aPL, such as aCL and aβ2GPI, but also reflect on noncriteria aPL. We conclude that aPL positivity may be a feature of COVID-19, at least in some patients, but in general, identified "solid-phase" aPL are of low titer and not able to be well-linked to the thrombotic aspects of COVID-19. Also, most publications did not assess for aPL persistence, and where persistence was checked, the findings appeared to represent transient aPL. Importantly, high-titer aPL or multiple aPL positivity (including double, triple) were in the minority of COVID-19 presentations, and thus discount any widespread presence of APS, including the most severe form CAPS, in COVID-19 patients.
Topics: Antibodies, Anticardiolipin; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; COVID-19; Humans; Prothrombin; SARS-CoV-2
PubMed: 34130340
DOI: 10.1055/s-0041-1728832 -
Thrombosis and Haemostasis May 2022A patient with hematuria in our clinic was diagnosed with urolithiasis. Analysis of the patient's plasma clotting time indicated that both activated partial...
A patient with hematuria in our clinic was diagnosed with urolithiasis. Analysis of the patient's plasma clotting time indicated that both activated partial thromboplastin time (52.6 seconds) and prothrombin time (19.4 seconds) are prolonged and prothrombin activity is reduced to 12.4% of normal, though the patient exhibited no abnormal bleeding phenotype and a prothrombin antigen level of 87.9%. Genetic analysis revealed the patient is homozygous for prothrombin Y510N mutation. We expressed and characterized the prothrombin-Y510N variant in appropriate coagulation assays and found that the specificity constant for activation of the mutant zymogen by factor Xa is impaired approximately fivefold. Thrombin generation assay using patient's plasma and prothrombin-deficient plasma supplemented with either wild-type or prothrombin-Y510N revealed that both peak height and time to peak for the prothrombin mutant are decreased; however, the endogenous thrombin generation potential is increased. Further analysis indicated that the thrombin mutant exhibits resistance to antithrombin and is inhibited by the serpin with approximately 12-fold slower rate constant. Protein C activation by thrombin-Y510N was also decreased by approximately 10-fold; however, thrombomodulin overcame the catalytic defect. The Na-concentration-dependence of the amidolytic activities revealed that the dissociation constant for the interaction of Na with the mutant has been elevated approximately 20-fold. These results suggest that Y510 (Y184a in chymotrypsin numbering) belongs to network of residues involved in binding Na. A normal protein C activation by thrombin-Y510N suggests that thrombomodulin modulates the conformation of the Na-binding loop of thrombin. The clotting defect of thrombin-Y510N appears to be compensated by its markedly lower reactivity with antithrombin, explaining patient's normal hemostatic phenotype.
Topics: Antithrombin III; Antithrombins; Blood Coagulation Disorders, Inherited; Humans; Protein C; Prothrombin; Thrombin; Thrombomodulin
PubMed: 34256393
DOI: 10.1055/a-1549-6407 -
Blood May 2022The prothrombinase complex processes prothrombin to thrombin through sequential cleavage at Arg320 followed by Arg271 when cofactor, factor (f) Va, protease, fXa, and...
The prothrombinase complex processes prothrombin to thrombin through sequential cleavage at Arg320 followed by Arg271 when cofactor, factor (f) Va, protease, fXa, and substrate, prothrombin, are all bound to the same membrane surface. In the absence of the membrane or cofactor, cleavage occurs in the opposite order. For the less favorable cleavage site at Arg320 to be cleaved first, it is thought that prothrombin docks on fVa in a way that presents Arg320 and hides Arg271 from the active site of fXa. Based on the crystal structure of the prothrombinase complex from the venom of the Australian eastern brown snake, pseutarin C, we modeled an initial prothrombin docking mode, which involved an interaction with discrete portions of the A1 and A2 domains of fV and the loop connecting the 2 domains, known as the a1-loop. We interrogated the proposed interface by site-directed PEGylation and by swapping the a1-loop in pseutarin C with that of human fV and fVIII and measuring the effect on rate and pathway of thrombin generation. PEGylation of residues within our proposed binding site greatly reduced the rate of thrombin generation, without affecting the pathway, whereas those outside the proposed interface had no effect. PEGylation of residues within the a1-loop also reduced the rate of thrombin generation. The sequence of the a1-loop was found to play a critical role in prothrombin binding and in the presentation of Arg320 for initial cleavage.
Topics: Australia; Binding Sites; Elapid Venoms; Factor Va; Factor Xa; Humans; Prothrombin; Thrombin; Thromboplastin
PubMed: 35148539
DOI: 10.1182/blood.2021014878 -
Journal of Thrombosis and Haemostasis :... Dec 2022Prothrombin, protein C, and factors VII, IX, and X are vitamin K (VK)-dependent coagulation proteins that play an important role in the initiation, amplification, and...
BACKGROUND
Prothrombin, protein C, and factors VII, IX, and X are vitamin K (VK)-dependent coagulation proteins that play an important role in the initiation, amplification, and subsequent attenuation of the coagulation response. Blood coagulation evolved in the common vertebrate ancestor as a specialization of the complement system and immune response, which in turn bear close evolutionary ties with developmental enzyme cascades. There is currently no comprehensive analysis of the evolutionary changes experienced by these coagulation proteins during the radiation of vertebrates and little is known about conservation of residues that are important for zymogen activation and catalysis.
OBJECTIVES
To characterize the conservation level of functionally important residues among VK-dependent coagulation proteins from different vertebrate lineages.
METHODS
The conservation level of residues important for zymogen activation and catalysis was analyzed in >1600 primary sequences of VK-dependent proteins.
RESULTS
Functionally important residues are most conserved in prothrombin and least conserved in protein C. Some of the most profound functional modifications in protein C occurred in the ancestor of bony fish when the basic residue in the activation site was replaced by an aromatic residue. Furthermore, during the radiation of placental mammals from marsupials, protein C acquired a cysteine-rich insert that introduced an additional disulfide in the EGF1 domain and evolved a proprotein convertase cleavage site in the activation peptide linker that also became significantly elongated.
CONCLUSIONS
Sequence variabilities at functionally important residues may lead to interspecies differences in the zymogen activation and catalytic properties of orthologous VK-dependent proteins.
Topics: Pregnancy; Animals; Female; Vitamin K; Prothrombin; Protein C; Placenta; Blood Coagulation Factors; Sequence Analysis; Mammals
PubMed: 36156849
DOI: 10.1111/jth.15897 -
Biosensors Sep 2022Thrombin is a serine protease with an essential role in homeostasis and blood coagulation. During vascular injuries, thrombin is generated from prothrombin, a plasma... (Review)
Review
Thrombin is a serine protease with an essential role in homeostasis and blood coagulation. During vascular injuries, thrombin is generated from prothrombin, a plasma protein, to polymerize fibrinogen molecules into fibrin filaments. Moreover, thrombin is a potent stimulant for platelet activation, which causes blood clots to prevent bleeding. The rapid and sensitive detection of thrombin is important in biological analysis and clinical diagnosis. Hence, various biosensors for thrombin measurement have been developed. Biosensors are devices that produce a quantifiable signal from biological interactions in proportion to the concentration of a target analyte. An aptasensor is a biosensor in which a DNA or RNA aptamer has been used as a biological recognition element and can identify target molecules with a high degree of sensitivity and affinity. Designed biosensors could provide effective methods for the highly selective and specific detection of thrombin. This review has attempted to provide an update of the various biosensors proposed in the literature, which have been designed for thrombin detection. According to their various transducers, the constructions and compositions, the performance, benefits, and restrictions of each are summarized and compared.
Topics: Aptamers, Nucleotide; Biosensing Techniques; DNA; Fibrin; Fibrinogen; Prothrombin; Thrombin
PubMed: 36140153
DOI: 10.3390/bios12090767 -
Biochimica Et Biophysica Acta. Reviews... Nov 2023Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with high mortality. The realization of precision medicine in HCC relies upon efficient... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with high mortality. The realization of precision medicine in HCC relies upon efficient biomarkers. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an immature prothrombin with insufficient coagulation activity, overexpressing in HCC cells. Previous evidence confirmed the role of PIVKA-II in screening and diagnosing HCC. However, the increased PIVKA-II was observed not only in HCC, but also in non-HCC individuals such as vitamin K deficiency. The joint detection of PIVKA-II and other biomarkers could significantly improve diagnostic accuracy in HCC. Furthermore, PIVKA-II serves as a valuable prognostic predictor, transplantation eligibility, resectability, tumor recurrence, therapeutic efficacy, and malignant tumor behaviors. Additionally, PIVKA-II represents a potential target for agent development to establish new therapeutic strategies. Besides HCC, PIVKA-II also serves as a biomarker of vitamin K status. In this review, we assess the role of PIVKA-II in diagnosis, prediction, and treatment. Over the past decades, substantial progress has been achieved in the application of PIVKA-II. Exploration and innovation are required for further advances in the field of PIVKA-II investigation.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; alpha-Fetoproteins; Biomarkers; Prothrombin; Vitamin K
PubMed: 37944832
DOI: 10.1016/j.bbcan.2023.189016 -
Expert Review of Gastroenterology &... 2023The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing globally. We aimed to assess the performance of... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing globally. We aimed to assess the performance of alpha-fetoprotein (AFP), AFP-L3, des-gamma-carboxy prothrombin (DCP), and GALAD score in detecting NAFLD-related HCC.
METHODS
We searched the relevant literature in PubMed, Embase and Cochrane. Conventional and network meta-analyses were performed for sensitivity, specificity, Youden index (YI), and the area under the summary receiver operator characteristic curve (AUC).
RESULTS
Fifteen studies involving 2031 NAFLD participants were included in this meta-analysis. When detecting early-stage NAFLD-related HCC, GALAD score and DCP process excellent performance. The sensitivity and AUC of DCP (0.60, 0.74, respectively) were higher than AFP (0.34, 0.59, respectively). The network meta-analysis showed that DCP and GALAD score had similar performance. In detecting all-stage NAFLD-related HCC, GALAD score (sensitivity = 0.87; YI = 0.77) performed better than AFP (sensitivity = 0.56; YI = 0.50), AFP-L3 (sensitivity = 0.39; YI = 0.36) and DCP (sensitivity = 0.73; YI = 0.62). Network meta-analysis obtained consistent results with conventional meta-analysis.
CONCLUSIONS
Due to the lower cost-effectiveness, DCP was more suitable for detecting early NAFLD-related HCC. AFP could be used in detecting all-stage NAFLD-related HCC.
Topics: Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Network Meta-Analysis; Non-alcoholic Fatty Liver Disease; Liver Neoplasms; Protein Precursors; Prothrombin; Biomarkers; Biomarkers, Tumor
PubMed: 37929312
DOI: 10.1080/17474124.2023.2279175