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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 -
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 -
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 -
Eye (London, England) Oct 2022To assess patients with indirect carotid-cavernous fistulas (CCF) for evidence of hypercoagulable state (HS) by combination of comprehensive medical questionnaire and...
BACKGROUND
To assess patients with indirect carotid-cavernous fistulas (CCF) for evidence of hypercoagulable state (HS) by combination of comprehensive medical questionnaire and laboratory testing.
METHODS
Patients with confirmed diagnosis of CCF treated between 2003 and 2019 were included and administered a questionnaire screening for HS risk factors and undergone laboratory investigations which included complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody titres), Factor V Leiden, prothrombin, protein C, protein S, antithrombin III, homocysteine, prothrombin G20210, CALR and JAK2 mutation screening. Participants with abnormal laboratory testing and/or past history of ischemic stroke, atrial fibrillation, cancer or hypercoagulability-associated hereditary disorders were deemed to have HS.
RESULTS
Twenty-two patients were enrolled. Seventeen were women and the mean age at diagnosis was 60. Fourteen (64%) had evidence of HS: six on medical history, three with laboratory evidence and five with both. Eight (36%) had current abnormal hypercoagulability markers. One had a diagnosis of Klippel-Trenaunay Syndrome, but no others had evidence of hereditary thrombophilia. Nine were on anti-coagulation initiated after diagnosis of stroke or atrial fibrillation discovered on average 5.5 years after the diagnosis of CCF.
CONCLUSION
A total of 64% percent of patients with previous indirect CCF had evidence of underlying HS indicating that hypercoagulability might play a role in the pathogenesis of CCF. The results support need for comprehensive testing for underlying HS in patients with indirect CCFs to better identify, manage, and prevent further thromboembolic events.
Topics: Antibodies, Anticardiolipin; Antithrombin III; Atrial Fibrillation; Female; Fibrinogen; Fistula; Homocysteine; Humans; Lupus Coagulation Inhibitor; Male; Protein C; Prothrombin; Thrombophilia
PubMed: 34635794
DOI: 10.1038/s41433-021-01801-w -
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 -
Blood Reviews Jan 2016The hemostatic system is often subverted in patients with cancer, resulting in life-threatening venous thrombotic events. Despite the multifactorial and complex etiology... (Review)
Review
The hemostatic system is often subverted in patients with cancer, resulting in life-threatening venous thrombotic events. Despite the multifactorial and complex etiology of cancer-associated thrombosis, changes in the expression and activity of cancer-derived tissue factor (TF) - the principle initiator of the coagulation cascade - are considered key to malignant hypercoagulopathy and to the pathophysiology of thrombosis. However, many of the molecular and cellular mechanisms coupling the hemostatic degeneration to malignancy remain largely uncharacterized. In this review we discuss some of the tumor-intrinsic and tumor-extrinsic mechanisms that may contribute to the prothrombotic state of cancer, and we bring into focus the potential for circulating tumor cells (CTCs) in advancing our understanding of the field. We also summarize the current status of anti-coagulant therapy for the treatment of thrombosis in patients with cancer.
Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation; Blood Platelets; Factor VIIa; Fibrin; Fibrinogen; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplastic Cells, Circulating; Platelet Activation; Prothrombin; Thromboplastin; Thrombosis
PubMed: 26219246
DOI: 10.1016/j.blre.2015.07.001 -
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 -
Clinical Gastroenterology and... Nov 2014We conducted a systematic review and meta-analysis to evaluate the associations of the coagulation factor V (encoded by F5) Leiden (FVL) or prothrombin (encoded by F2)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
We conducted a systematic review and meta-analysis to evaluate the associations of the coagulation factor V (encoded by F5) Leiden (FVL) or prothrombin (encoded by F2) G20210A mutation with Budd-Chiari syndrome or portal vein thrombosis (PVT).
METHODS
Relevant articles were identified in searches of the PubMed, EMBASE, Cochrane Library, and ScienceDirect databases. The prevalence of the FVL and prothrombin G20210A mutations were compared between patients with Budd-Chiari syndrome or PVT without cirrhosis and healthy individuals (controls) and between patients with cirrhosis, with and without PVT. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.
RESULTS
We initially identified 869 articles, and included 27 in our final analysis. Compared with controls, patients with Budd-Chiari syndrome had a significantly higher prevalence of the FVL mutation (OR, 6.21; 95% CI, 3.93-9.79) and a similar prevalence of the prothrombin G20210A mutation (OR, 1.90; 95% CI, 0.69-5.23); patients with PVT without cirrhosis had a significantly higher prevalence of the FVL mutation (OR, 1.85; 95% CI, 1.09-3.13) or the prothrombin G20210A mutation (OR, 5.01; 95% CI, 3.03-8.30). Compared with patients with cirrhosis without PVT, patients with cirrhosis and PVT had a significantly higher prevalence of the FVL mutation (OR, 2.55; 95% CI, 1.29-5.07). We observed a trend toward a higher prevalence of the prothrombin G20210A mutation in patients with cirrhosis and PVT, but the difference was not statistically significant (OR, 2.93; 95% CI, 0.94-9.07).
CONCLUSIONS
Based on a meta-analysis, the FVL mutation is associated with an increased risk of Budd-Chiari syndrome, PVT without cirrhosis, and PVT in cirrhosis. The prothrombin G20210A mutation is associated with PVT, but not Budd-Chiari syndrome. Studies are needed to confirm these findings in different racial and ethnic groups.
Topics: Budd-Chiari Syndrome; Factor V; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Mutation; Portal Vein; Prothrombin; Thrombosis
PubMed: 24793031
DOI: 10.1016/j.cgh.2014.04.026