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Journal of Thrombosis and Haemostasis :... Apr 2021The presence of lupus anticoagulant (LA) is an independent risk factor for thrombosis. This laboratory phenomenon is detected as a phospholipid-dependent prolongation of...
BACKGROUND
The presence of lupus anticoagulant (LA) is an independent risk factor for thrombosis. This laboratory phenomenon is detected as a phospholipid-dependent prolongation of the clotting time and is caused by autoantibodies against beta2-glycoprotein I (β2GPI) or prothrombin. How these autoantibodies cause LA is unclear.
OBJECTIVE
To elucidate how anti-β2GPI and anti-prothrombin antibodies cause the LA phenomenon.
METHODS
The effects of monoclonal anti-β2GPI and anti-prothrombin antibodies on coagulation were analyzed in plasma and with purified coagulation factors.
RESULTS
Detection of LA caused by anti-β2GPI or anti-prothrombin antibodies required the presence of the procofactor factor V (FV) in plasma. LA effect disappeared when FV was replaced by activated FV (FVa), both in a model system and in patient plasma, although differences between anti-β2GPI and anti-prothrombin antibodies were observed. Further exploration of the effects of the antibodies on coagulation showed that the anti-β2GPI antibody attenuated FV activation by activated faxtor X (FXa), whereas the anti-prothrombin antibody did not. Binding studies showed that β2GPI--antibody complexes directly interacted with FV with high affinity. Anti-prothrombin complexes caused the LA phenomenon through competition for phospholipid binding sites with coagulation factors as reduced FXa binding to lipospheres was observed with flow cytometry in the presence of these antibodies.
CONCLUSION
Anti-β2GPI and anti-prothrombin antibodies cause LA through different mechanisms of action: While anti-β2GPI antibodies interfere with FV activation by FXa through a direct interaction with FV, anti-prothrombin antibodies compete with FXa for phospholipid binding sites. These data provide leads for understanding the paradoxical association between thrombosis and a prolonged clotting time in the antiphospholipid syndrome.
Topics: Antiphospholipid Syndrome; Blood Coagulation Tests; Humans; Lupus Coagulation Inhibitor; Prothrombin; beta 2-Glycoprotein I
PubMed: 33421291
DOI: 10.1111/jth.15241 -
Journal of Medical Virology Feb 2023Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin...
Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a group of cases (n = 4092). This subgroup was age and gender-matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank. The ratio of males (31.08%; 27.01%) and the mean age (36.85 ± 15.20; 33.89 ± 14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL and not related to genotypes at the Prothrombin mutations. Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.
Topics: Humans; Male; Female; Prothrombin; Risk Factors; COVID-19; SARS-CoV-2; Genotype; Factor V; Thrombophilia; Thrombosis; Patient Acuity; Mutation
PubMed: 36597901
DOI: 10.1002/jmv.28457 -
Journal of Thrombosis and Haemostasis :... Aug 2019Blood coagulation factor Va serves an indispensable role in hemostasis as cofactor for the serine protease factor Xa. In the presence of an anionic phospholipid membrane... (Review)
Review
Blood coagulation factor Va serves an indispensable role in hemostasis as cofactor for the serine protease factor Xa. In the presence of an anionic phospholipid membrane and calcium ions, factors Va and Xa assemble into the prothrombinase complex. Following formation of the ternary complex with the macromolecular zymogen substrate prothrombin, the latter is rapidly converted into thrombin, the key regulatory enzyme of coagulation. Over the years, multiple binding sites have been identified in factor Va that play a role in the interaction of the cofactor with factor Xa, prothrombin, or the anionic phospholipid membrane surface. In this review, an overview of the currently available information on these interactive sites in factor Va is provided, and data from biochemical approaches and 3D structural protein complex models are discussed. The structural models have been generated in recent years and provide novel insights into the molecular requirements for assembly of both the prothrombinase and the ternary prothrombinase-prothrombin complexes. Integrated knowledge of functionally important regions in factor Va will allow for a better understanding of factor Va cofactor activity.
Topics: Binding Sites; Blood Coagulation; Cell Membrane; Factor Va; Factor Xa; Humans; Models, Molecular; Phospholipids; Protein Binding; Protein Interaction Domains and Motifs; Prothrombin; Structure-Activity Relationship; Thromboplastin
PubMed: 31102425
DOI: 10.1111/jth.14487 -
The Journal of Applied Laboratory... Nov 2020Protein induced by vitamin K absence-II (PIVKA-II) is produced by the liver during hepatoma and upon warfarin administration. Those patients have disturbed protein...
BACKGROUND
Protein induced by vitamin K absence-II (PIVKA-II) is produced by the liver during hepatoma and upon warfarin administration. Those patients have disturbed protein synthesis and glycosylation in the liver. This decreases the number of γ-carboxyglutamyl (Gla) residues on prothrombin, converting prothrombin into PIVKA-II. The mechanism of this conversion, however, is not clearly understood.
METHODS
Prothrombin was isolated from healthy and warfarin-treated individuals whose liver function of protein production was quantitatively normal. Glycan structures in the purified prothrombin containing PIVKA-II were qualitatively analyzed by high performance liquid chromatography after labeling the glycan with fluorophore 2-aminobenzamide.
RESULTS
The concentration of PIVKA-II was significantly higher in the warfarin-treated individuals than in the healthy individuals (P< 0.001). Although protein production in the liver was normal in both groups, the concentration of prothrombin was lower in the warfarin-treated individuals than in the healthy individuals (P < 0.001). The main glycan was A2 in the healthy and warfarin-treated individuals (86.6 ± 4.4% and 85.6 ± 3.4%, respectively). Eight types of glycan were characterized in both groups, although generation of PIVKA-II in the warfarin-treated individuals did not lead to variation in glycosylation of prothrombin.
CONCLUSIONS
Warfarin therapy leads to lower amounts of prothrombin and Gla residues within prothrombin without exerting qualitative and quantitative change in glycan profile and protein synthetic function in the liver.
Topics: Biomarkers; Humans; Protein Precursors; Protein Processing, Post-Translational; Prothrombin; Warfarin
PubMed: 32594109
DOI: 10.1093/jalm/jfaa069 -
American Journal of Reproductive... Jun 2023Assessment of the prevalence of anti-phosphatidylserine-prothrombin antibodies (aPS/PT) with OAPS and SN-OAPS in Chinese patients.
OBJECTIVE
Assessment of the prevalence of anti-phosphatidylserine-prothrombin antibodies (aPS/PT) with OAPS and SN-OAPS in Chinese patients.
METHODS
This retrospective study proceeded at Ren Ji Hospital, Shanghai, China, from January 2019 to January 2020. Two hundred eleven OAPS, 68 SN-OAPS, 81 disease controls, and 30 healthy donors were enrolled. IgM and IgG aPS/PT, IgM/IgG - aCL, and IgM/ IgG/ anti-β2GPI antibodies were tested by ELISA while LAC was tested by clotting assays. All the patients were followed up and tested at least twice over 12 weeks apart.
RESULTS
Thirty-three OAPS (15.64%) and 31 SN-OAPS (45.59%) were positive for aPS/PT. aPS/PT IgM showed a high Youden index (.813), which classified OAPS and SN-OAPS patients from healthy controls and other autoimmune diseases. aPS/PT showed a stronger relationship with LAC. Of the 25 OAPS women positive for IgM aPS/PT, 19 (79%) LAC were positive, while of the eight women positive for IgG aPS/PT, 100% were found LAC positive.
CONCLUSION
aPS/PT antibody showed an efficient diagnostic value for Chinese patients with OAPS and SN-OAPS, which could be a potential risk predictor for obstetric complications.
Topics: Pregnancy; Humans; Female; Antiphospholipid Syndrome; Antibodies, Antiphospholipid; Prothrombin; Retrospective Studies; China; Immunoglobulin G; Phosphatidylserines; Immunoglobulin M
PubMed: 36181461
DOI: 10.1111/aji.13621 -
Acta Biochimica Polonica Nov 2023Previously, the direct interactions of Bβ26-42 fibrin residues with prothrombin were demonstrated. It was also shown that forming prothrombin complexes with E- or...
Previously, the direct interactions of Bβ26-42 fibrin residues with prothrombin were demonstrated. It was also shown that forming prothrombin complexes with E- or DDE-fragments causes non-enzymatic prothrombin activation. The direct measuring of the prothrombin level in the blood plasma of patients with acute myocardial infarction (AMI) allowed us to find a situation where such an activation can occur in vivo. Blood coagulation parameters in the blood plasma of patients with AMI were measured at 2 hours, three days, and seven days after the thrombolysis by streptokinase accompanied with intravenous administration of anticoagulants: unfractionated high molecular weight heparin (HMWH) and low-molecular-weight heparin (LMWH). The prothrombin level in the blood plasma of patients with AMI was normal before thrombolytic therapy and substantially decreased after streptokinase administration. This effect was prominent in the case of concomitant anticoagulant therapy with LMWH and was not observed when HMWH was applied. It can be explained by the fact that LMWH preferentially inhibits factor Xa, while the HMWH is an effective inhibitor of both factor Xa and thrombin. This observation suggested that the prothrombin level decrease was caused by the thrombin-like activity and possible autolysis of prothrombin by thrombin. Also, thrombolytic therapy with streptokinase caused the accumulation of fibrin degradation products (FDPs), some of which were able to bind prothrombin. The dramatic decrease of prothrombin level in the blood plasma of patients with AMI during thrombolysis allowed us to conclude the non-enzymatic prothrombin activation with the following autolysis of prothrombin that contributes to the pathology.
Topics: Humans; Prothrombin; Heparin, Low-Molecular-Weight; Thrombin; Factor Xa; Myocardial Infarction; Heparin; Streptokinase; Thrombolytic Therapy; Anticoagulants
PubMed: 38011253
DOI: 10.18388/abp.2020_6962 -
Clinics in Liver Disease Nov 2020Hepatocellular carcinoma (HCC) is increasing in prevalence and is the third leading cause of cancer-related death worldwide. Unlike other malignancies, HCC can be... (Review)
Review
Hepatocellular carcinoma (HCC) is increasing in prevalence and is the third leading cause of cancer-related death worldwide. Unlike other malignancies, HCC can be diagnosed with dynamic imaging with very high accuracy, and tissue diagnosis is not needed for cancer therapy. There is a unique role of established as well as developing biomarkers in diagnosis, prognosis, and management of HCC. Sequencing HCC tumors has yielded substantial insights into HCC tumor biology and has raised the possibility of precision oncology in which therapy decisions are guided by cancer genetics. However, it is not ready for prime time yet.
Topics: Biomarkers; Biomarkers, Tumor; Biopsy; Carcinoma, Hepatocellular; Humans; Liquid Biopsy; Liver Neoplasms; Molecular Diagnostic Techniques; Plant Lectins; Precision Medicine; Prognosis; Protein Precursors; Prothrombin; alpha-Fetoproteins
PubMed: 33012446
DOI: 10.1016/j.cld.2020.07.001 -
International Journal of Environmental... Aug 2021Venous thromboembolism (VTE) constitutes a serious and potentially fatal disease, often complicated by pulmonary embolism and is associated with inherited or acquired... (Review)
Review
Venous thromboembolism (VTE) constitutes a serious and potentially fatal disease, often complicated by pulmonary embolism and is associated with inherited or acquired factors risk. A series of risk factors are known to predispose to venous thrombosis, and these include mutations in the genes that encode anticoagulant proteins as antithrombin, protein C and protein S, and variants in genes that encode instead pro-coagulant factors as factor V (FV Leiden) and factor II (FII G20210A). However, the molecular causes responsible for thrombotic events in some individuals with evident inherited thrombosis remain unknown. An improved knowledge of risk factors, as well as a clear understanding of their role in the pathophysiology of VTE, are crucial to achieve a better identification of patients at higher risk. Moreover, the identification of genes with rare variants but a large effect size may pave the way for studies addressing new antithrombotic agents in order to improve the management of VTE patients. Over the past 20 years, qualitative or quantitative genetic risk factors such as inhibitor proteins of the hemostasis and of the fibrinolytic system, including fibrinogen, thrombomodulin, plasminogen activator inhibitor-1, and elevated concentrations of factors II, FV, VIII, IX, XI, have been associated with thrombotic events, often with conflicting results. The aim of this review is to evaluate available data in literature on these genetic variations to give a contribution to our understanding of the complex molecular mechanisms involved in physiologic and pathophysiologic clot formation and their role in clinical practice.
Topics: Humans; Prothrombin; Pulmonary Embolism; Risk Factors; Venous Thromboembolism; Venous Thrombosis
PubMed: 34501736
DOI: 10.3390/ijerph18179146 -
Toxicon : Official Journal of the... Oct 2022Venoms are evolutionary novelties that have real-world implications due to their impact upon human health. However, relative to the abundant studies of elapid and...
Venoms are evolutionary novelties that have real-world implications due to their impact upon human health. However, relative to the abundant studies of elapid and viperid snake venoms, fewer investigations have been undertaken on those of rear-fanged snakes as they are more problematic for obtaining venom. While most rear-fanged venomous snakes are not considered to be of great medical importance, several species are capable of producing fatalities. Most notable among these are snakes from the genus Rhabdophis, the Asian "keelback" snakes. Prior work have described potent procoagulant toxicity suggesting Factor X and prothrombin activation, but did not investigate the ability to activate other clotting factors. Here we show that in addition to activating both Factor X and prothrombin (with prothrombin twice that of FX), the venom of Rhabdophis subminiatus is able to more potently activate Factor VII (ten times that of prothrombin), while also activating FXII and FIX equipotently to prothrombin, and with FXI also activated but at a much lower level. The ability to activate FVII represents a third convergent evolution of this trait. The Australian elapid clade of [Oxyuranus (taipans) + Pseudonaja (brown snakes)] was the first identified to have evolved this trait. and only recently was it shown to be independently present in another lineage (the Central American viperid species Porthidium volcanicum). In addition, the abilities to activate FXI and FXII are also convergent between R. subminiatus and P. volcanicum, but with R. subminiatus being much more potent. By testing across amphibian, avian, and mammalian plasmas we demonstrate that the venom is potently procoagulant across diverse plasma types. However, consistent with dietary preference, R. subminiatus venom was most potent upon amphibian plasma. While a Rhabdophis antivenom is produced in Japan to treat R. tigrinus envenomings, it is scarce even within Japan and is not exported. As this genus is very wide-ranging in Asia, alternate treatment options are in need of development. Hence we tested the ability of candidate, broad-spectrum enzyme inhibitors to neutralize R. subminiatus venom: marimastat was more effective than prinomastat but both marimastat and prinomastat were significantly more effective than DMPS (2,3-Dimercapto-1-propanesulfonic acid). The findings of this study shed light on the evolution of these fascinating rear-fanged snakes as well as explored their systemic effects upon blood coagulation and point to potential treatment options for the rare, but potentially lethal encounters.
Topics: Animals; Antivenins; Australia; Blood Coagulation; Blood Coagulation Factors; Colubridae; Elapidae; Factor VII; Factor X; Humans; Hydroxamic Acids; Mammals; Organic Chemicals; Prothrombin; Snake Venoms; Unithiol
PubMed: 36057394
DOI: 10.1016/j.toxicon.2022.08.017 -
The Journal of Emergency Medicine May 2020
Topics: Blood Coagulation Factors; Humans; International Normalized Ratio; Prothrombin; Warfarin
PubMed: 32546335
DOI: 10.1016/j.jemermed.2019.07.024