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1
Mutch, Nicola J. "Regulation of Coagulation by Polyphosphate." Blood 134, Supplement_1 (November 13, 2019): SCI—18—SCI—18. http://dx.doi.org/10.1182/blood-2019-121062.
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Polyphosphate (polyP) is a biomolecule comprised of repeating units of inorganic phosphate residues linked by energy-rich phosphoanhydride bonds. PolyP is highly conserved throughout evolution and plays a vital role in the survival of prokaryotes and single-cell eukaryotes1 by functioning in processes such as motility, virulence and stress. Its role in mammalian systems was less well defined, however, identification of polyP in the dense granules of human platelets2 prompted analysis of the function of polyP in hemostasis. Stimulation of platelets by conventional agonists such as ADP, thrombin and collagen induces release of polyP, and promotes coagulation by acting at several points in the cascade3. These include 1) providing a surface for activation of the contact pathway protein factor XII, 2) augmenting conversion of factor V to factor Va which participates in the prothrombinase complex and 3) accelerating thrombin-mediated activation of factor XI4. The net outcome is a reduction in the lag time to thrombin formation thereby driving clot formation. The effect of polyP on thrombin generation has down-stream repercussions in terms of clot breakdown, as it augments the early activation of thrombin activatable fibrinolysis inhibitor (TAFI). There has been a degree of uncertainty and debate over whether polyP is capable of reaching adequate concentrations within the plasma milieu to elicit these profound effects on haemostasis. However, the observations that polyP can bind directly to fibrin5, allowing it to be incorporated into the forming clot, localise the biomolecule to its site of action. In addition, binding alters the structure of the fibrin clot altering its susceptibility to degradation by fibrinolytic enzymes6. These observations led to the hypothesis that polyP operates as a timed switch, being released from platelets upon activation thereby allowing rapid repair of an injury while simultaneously preventing clot breakdown until sufficient wound healing has occurred3. The ability of polyP to promote FXII-dependent coagulation has been reported in several studies but has been contested, as shorter soluble polymers, such as those found in platelets, are relatively inefficient in this process. Recent work from our group7 and others8 documents the retention of polyP on the surface of degranulated platelets. This pool of polyP is of longer chain length than the soluble secreted form and is complexed to divalent metal ions8 thereby augmenting its ability to stimulate factor XII activation. These studies highlight the potential that polyP may exert its biological cofactor activity when anchored to a surface such as platelets, fibrin and potentially other blood cells. Many questions remain as to how this polymer regulates its plethora of functions and whether the binding surface impacts on the target reaction and the half-life of the polymer. However, taken together these in vitro and in vivo studies have delineated a role for polyP in hemostasis and highlight the requirement for more efficient tools to quantify this interesting biomolecule in subsets of patients. References Kornberg A. Inorganic polyphosphate: a molecule of many functions. Prog Mol Subcell Biol. 1999;23:1-18. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem. 2004;279(43):44250-44257. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A. 2006;103(4):903-908. Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood. 2011;118(26):6963-6970. Whyte CS, Chernysh IN, Domingues MM, Connell S, Weisel JW, Ariens RA, Mutch NJ. Polyphosphate delays fibrin polymerisation and alters the mechanical properties of the fibrin network. Thromb Haemost. 2016;116(5):897-903. Mutch NJ, Engel R, Uitte de Willige S, Philippou H, Ariens RA. Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin. Blood. 2010;115(19):3980-3988. Mitchell JL, Lionikiene AS, Georgiev G, Klemmer A, Brain C, Kim PY, Mutch NJ. Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity. Blood. 2016;128(24):2834-2845. Verhoef JJ, Barendrecht AD, Nickel KF, Dijkxhoorn K, Kenne E, Labberton L, McCarty OJ, Schiffelers R, Heijnen HF, Hendrickx AP, Schellekens H, Fens MH, de Maat S, Renne T, Maas C. Polyphosphate nanoparticles on the platelet surface trigger contact system activation. Blood. 2017;129(12):1707-1717. Disclosures No relevant conflicts of interest to declare.
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Groeneveld, Dafna, David Pereyra, Zwanida Veldhuis, Jelle Adelmeijer, Petra Ottens, Anna K. Kopec, Patrick Starlinger, Ton Lisman, and James P. Luyendyk. "Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans." Blood 133, no. 11 (March 14, 2019): 1245–56. http://dx.doi.org/10.1182/blood-2018-08-869057.
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AbstractPlatelets play a pivotal role in stimulating liver regeneration after partial hepatectomy in rodents and humans. Liver regeneration in rodents is delayed when platelets are inhibited. However, the exact mechanisms whereby platelets accumulate and promote liver regeneration remain uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy (PHx) in mice, but the role of fibrin(ogen) deposits in liver regeneration has not been investigated. We tested the hypothesis that fibrin(ogen) contributes to liver regeneration by promoting intrahepatic platelet accumulation and identified the trigger of rapid intrahepatic coagulation after PHx. PHx in wild-type mice triggered rapid intrahepatic coagulation, evidenced by intrahepatic fibrin(ogen) deposition. Intrahepatic fibrin(ogen) deposition was abolished in mice with liver-specific tissue factor deficiency, pinpointing the trigger of coagulation after PHx. Direct thrombin activation of platelets through protease-activated receptor-4 did not contribute to hepatocyte proliferation after PHx, indicating that thrombin contributes to liver regeneration primarily by driving intrahepatic fibrin(ogen) deposition. Fibrinogen depletion with ancrod reduced both intrahepatic platelet accumulation and hepatocyte proliferation after PHx, indicating that fibrin(ogen) contributes to liver regeneration after PHx by promoting intrahepatic platelet accumulation. Consistent with the protective function of fibrin(ogen) in mice, low postoperative plasma fibrinogen levels were associated with liver dysfunction and mortality in patients undergoing liver resection. Moreover, increased intrahepatic fibrin(ogen) deposition was evident in livers of patients after liver resection but was remarkably absent in patients displaying hepatic dysfunction postresection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and liver regeneration after PHx.
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Okwusidi, J. I., and F. A. Ofosu. "Bioregulatory roles for fibrin(ogen) on blood coagulation." Medical Hypotheses 39, no. 2 (October 1992): 152–55. http://dx.doi.org/10.1016/0306-9877(92)90177-e.
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Moiseyev, Gilead, Sefi Givli, and Pinhas Z. Bar-Yoseph. "Fibrin polymerization in blood coagulation—A statistical model." Journal of Biomechanics 46, no. 1 (January 2013): 26–30. http://dx.doi.org/10.1016/j.jbiomech.2012.09.019.
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Johnson, Lawrence L., Kiera N. Berggren, Frank M. Szaba, Wangxue Chen, and Stephen T. Smiley. "Fibrin-mediated Protection Against Infection-stimulated Immunopathology." Journal of Experimental Medicine 197, no. 6 (March 10, 2003): 801–6. http://dx.doi.org/10.1084/jem.20021493.
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Fibrin, a product of the blood coagulation cascade, accompanies many type 1 immune responses, including delayed-type hypersensitivity, autoimmunity, and graft rejection. In those settings, fibrin is thought to exacerbate inflammation and disease. Here, we evaluate roles for coagulation during infection with Toxoplasma gondii, a pathogen whose control requires robust type 1 immunity. We establish that fibrin prevents infection-stimulated blood loss, thereby performing a protective function that is essential for survival. Remarkably, fibrin does not simply protect against vascular damage caused directly by the infectious agent, but rather, protects against hemorrhage evoked by interferon-γ, a critical mediator of type 1 immunity. This finding, to our knowledge, is the first to document a beneficial role for coagulation during type 1 immunity, and suggests that fibrin deposition protects host tissue from collateral damage caused by the immune system as it combats infection.
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Vdovin, V. M., A. P. Momot, D. A. Orekhov, I. I. Shakhmatov, N. A. Lycheva, and D. A. Momot. "Assessment of the effect of exogenous fibrin monomer on post-traumatic bleeding in hypofibrinogenemia caused by administration of snake venom Agkistrodon rhodostoma." Kazan medical journal 101, no. 5 (October 27, 2020): 704–12. http://dx.doi.org/10.17816/kmj2020-704.
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Aim. To assess the effect of fibrin monomer on the rate of blood loss after controlled liver injury in hypofibrinogenemia induced by systemic administration of Malayan pit viper venom (Agkistrodon rhodostoma).
Methods. A placebo-controlled study of the hemostatic effect of fibrin monomer administered intravenously at 0.25 mg/kg, and coagulation parameters in the controlled liver injury with profound hypofibrinogenemia caused by administration of Malayan pit viper venom was conducted in 34 male Chinchilla rabbits. The distribution of the studied parameters was investigated by the ShapiroWilk test. Statistical differences between groups were tested by Students t-test, MannWhitney U test, or Wilcoxon test, as appropriate. Differences in mortality rate were examined using Fisher's exact test.
Results. A model of experimental toxogenic disseminated intravascular coagulation was reproduced, manifested by high mortality of animals (50.0%), severe blood loss (increased blood loss by 1.78 times), hemolysis, a decreased platelet count (by 19.6% of median) and platelet dysfunction, fibrinogen consumption (protein content less than 0.9 g/l), hypocoagulation as well as intensive D-dimer production (increased concentration by 25.0 times of median). A high level of the fibrin derivative demonstrated activation of fibrin formation and fibrinolysis in the bloodstream of the animals. Systemic prophylactic administration of exogenous fibrin monomer after receiving snake venom did not lead to a decrease in post-traumatic bleeding, whereas earlier, during reproduction of disseminated intravascular coagulation caused by streptokinase infusion, such a hemostatic effect of fibrin monomer was shown.
Conclusion. The absence of fibrin monomer effect (at a dose of 0.25 mg/kg) on the severity of blood loss in toxogenic disseminated intravascular coagulation may be associated with more profound disseminated intravascular coagulation and a sharp 25-fold increase in D-dimer levels that can act as a fibrin monomer polymerization inhibitor.
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Walsh, Peter N., and Syed S. Ahmad. "Proteases in blood clotting." Essays in Biochemistry 38 (October 1, 2002): 95–111. http://dx.doi.org/10.1042/bse0380095.
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The serine proteases, cofactors and cell-receptor molecules that comprise the haemostatic mechanism are highly conserved modular proteins that have evolved to participate in biochemical reactions in blood coagulation, anticoagulation and fibrinolysis. Blood coagulation is initiated by exposure of tissue factor, which forms a complex with factor VIIa and factor X, which results in the generation of small quantities of thrombin and is rapidly shutdown by the tissue factor pathway inhibitor. The generation of these small quantities of thrombin then activates factor XI, resulting in a sequence of events that lead to the activation of factor IX, factor X and prothrombin. Sufficient thrombin is generated to effect normal haemostasis by converting fibrinogen into fibrin. The anticoagulant pathways that regulate blood coagulation include the protein C anticoagulant mechanism, the serine protease inhibitors in plasma, and the Kunitz-like inhibitors, tissue factor pathway inhibitor and protease nexin 2. Finally, the fibrinolytic mechanism that comprises the activation of plasminogen into plasmin prevents excessive fibrin accumulation by promoting local dissolution of thrombi and promoting wound healing by reestablishment of blood flow.
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Fickenscher, Karl, Angela Aab, and Werner Stüber. "A Photometric Assay for Blood Coagulation Factor XIII." Thrombosis and Haemostasis 65, no. 05 (1991): 535–40. http://dx.doi.org/10.1055/s-0038-1648185.
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SummaryAn assay for a direct photometric determination of F XIII in untreated and undiluted plasma was developed. In a one-step procedure F XIII is activated by thrombin and Ca2+ and crosslinks glycine-ethylester to a specific glutamine containing peptide substrate. The released ammonia is incorporated into α-keto-glutarate by glutamate dehydrogenase, and the NADH consumption of this reaction is measured photometrically at 340 nm. NADH-consumption is directly proportional to the F XIII activity. Fibrin polymerization and the corresponding turbidity is avoided by the use of a fibrin aggregation inhibitor.The procedure is rapid and simple and enables to measure within the range of 0 to 150% F XIII. It can be performed with automated analyzers as well as with common photometric equipment.The normal range of F XIII activity in 167 healthy donors was determined to be 70 to 140%.
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Rijken, Dingeman C., and Shirley Uitte de Willige. "Inhibition of Fibrinolysis by Coagulation Factor XIII." BioMed Research International 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/1209676.
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The inhibitory effect of coagulation factor XIII (FXIII) on fibrinolysis has been studied for at least 50 years. Our insight into the underlying mechanisms has improved considerably, aided in particular by the discovery that activated FXIII cross-linksα2-antiplasmin (α2AP) to fibrin. In this review, the most important effects of different cross-linking reactions on fibrinolysis are summarized. A distinction is made between fibrin-fibrin cross-links studied in purified systems and fibrin-α2AP cross-links studied in plasma or whole blood systems. While the formation ofγchain dimers in fibrin does not affect clot lysis, the formation ofαchain polymers has a weak inhibitory effect. Only strong cross-linking of fibrin, associated with high molecular weightαchain polymers and/orγchain multimers, results in a moderate inhibition fibrinolysis. The formation of fibrin-α2AP cross-links has only a weak effect on clot lysis, but this effect becomes strong when clot retraction occurs. Under these conditions, FXIII preventsα2AP being expelled from the clot and makes the clot relatively resistant to degradation by plasmin.
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Chudzinski-Tavassi, Ana Marisa, Eva Maria Kelen, Ana Paula de Paula Rosa, Stephane Loyau, Claudio Sampaio, Cassian Bon, and Eduardo Anglés-Cano. "Fibrino(geno)lytic Properties of Purified Hementerin, a Metalloproteinase from the Leech Haementeria depressa." Thrombosis and Haemostasis 80, no. 07 (1998): 155–60. http://dx.doi.org/10.1055/s-0037-1615155.
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SummaryThe fibrino(geno)lytic protein designated hementerin contained in crude extracts of the salivary complex of Haementeria depressa leeches was purified to apparent homogeneity by gel filtration, ion exchange chromatography and preparative SDS-PAGE. It is a single-chain 80 kDa, PhMeSO2F-resistant, calcium-dependent, metalloproteinase, which specifically degrades fibrin(ogen) through a plasminogen-independent pathway. The amino terminal sequence of 8 residues shows 80% similarity with hementin, another fibrino(geno)lytic protein purified from Haementeria ghilianii leeches. However, their activities differ somewhat in terms of kinetics and with regard to the structure of the fibrin(ogen) fragments they may produce. Cleavage by hementerin of fibrinogen Aα, γ and Bβ chains, in that order, produces 270 kDa to 67 kDa fragments which differ from those produced by plasmin. Hementerin was also able to degrade cross-linked fibrin although at a lower rate as compared to fibrinogen. In conclusion, hementerin is a plasminogen-independent fibrino(geno)lytic metalloproteinase that degrades fibrinogen faster than fibrin, prevents blood coagulation and destroys fibrin clots in vitro.
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Li, Tao, Xiaoyan Yang, Yan Zhang, Baorong LI, Yinmiao Liu, Cong Zhang, Yan Kou, et al. "The Role of Prothrombinase Complex Assembly and in Situ Fibrin Deposition on the Surface of Acute Promyelocytic Leukemia Cells in Hemorrhage." Blood 132, Supplement 1 (November 29, 2018): 3770. http://dx.doi.org/10.1182/blood-2018-99-113785.
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Abstract Background: Despite dramatic improvement in treatment for acute promyelocytic leukemia (APL), early death due to hemorrhage remains a major obstacle to achieving a complete cure. In contrast to classical disseminated intravascular coagulation, APL-associated coagulopathy is characterized by rare microvascular fibrin thrombi. Thus, it is attractive to speculate whether other unknown mechanisms depleting coagulation factors and unrecognized fibrin-deposition location exist. Procoagulant activity associated with APL cells plays a direct role in bleeding complicationsin. We have shown that exposed phosphatidylserine (PS) on APL cells supports purified prothrombinase (Zhou J et al, JTH 2010) and fibrin preferentially deposits on promyelocytic chromatin from ETosis or apoptosis (Cao M et al, Blood 2017). However, relatively little is known about the PS-driven prothrombinase complex assembly and in situ fibrin deposition on APL cells. Aims: Our objectives were to determine how APL cells promote thrombin generation and modulate fibrin formation and distribution, as well as to explore the relationship between in situ fibrin deposition and consumptive hemorrhage in APL patients. Methods: Twenty-seven newly diagnosed APL patients were included. Fresh APL blasts were obtained from bone marrow specimens by centrifugation through Ficoll-Hypaque. Lactadherin was used as a probe for PS exposure on the fresh APL blasts and on an immortalized APL cell line (NB4). PS exposure and fluorescein-labeled FV/X binding were evaluated by flow cytometry. Thrombin generation was measured by modifed thrombin generation test. Fibrin production was quantified by turbidity. The distribution of PS, prothrombinase complex and in situ fibrin deposition were imaged by confocal microscopy. For the inhibition assay, APL cells were pre-treated with lactadherin, DNase I or anti-TF antibody for 10 min at 37 °C before incubation with plasma. Results: Thrombin generation and fibrin formation supported by NB4 and APL cells increased approximately 1.5-fold after exposure to daunorubicin and decreased 80% after treatment with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO). Procoagulant activity corresponded to exposed PS on viable APL cells. PS exposure increased approximately 2.7-fold after treatment with daunorubicin, while ATRA and ATO initially led to a 70% reduction in PS exposure, which rose again on day 3 and 5 (P<0.001), respectively. Levels of externalized PS on APL cells paralleled levels of FV/FX binding, lag time, peak thrombin, endogenous thrombin potential and fibrin formation. Lactadherin inhibited the above parameters by approximately 80%, while anti-tissue factor antibody or DNase I produced no effect. Interestingly, confocal imaging showed that fibrin preferentially deposited on the surface of APL cells, which we defined as "in situ fibrin". Untreated viable APL and NB4 cells displayed discrete or occasionally annular fibrin deposition on the membrane. Moreover, fibrin formation supported by apoptotic APL cells displayed the following progression: (i) patchy deposition, (ii) diffuse rim, (iii) "fibrin coat", and (iv) network. The dynamic changes in fibrin formation paralleled the kinetics of PS exposure and prothrombinase assembly. Furthermore, initial percentage of PS-positive fresh APL cells was negatively correlated with plasma levels of fibrinogen and factor II, V, VIII, X in APL patients on admission (all P<0.01). Conclusion: PS-driven prothrombinase complex assembly and in situ fibrin deposition on the surface of APL cells consume massive coagulation factors, providing a novel explanation for consumptive hemorrhage in APL patients. Blockade of PS might be a novel therapeutic approach for preventing bleeding in APL via inhibiting invisible "in situ coagulation", especially in high-risk APL. Disclosures No relevant conflicts of interest to declare.
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Dunn, Emma J., Robert A. Ariëns, Marlies de Lange, Harold Snieder, John H. Turney, Timothy D. Spector, and Peter J. Grant. "Genetics of fibrin clot structure: a twin study." Blood 103, no. 5 (March 1, 2004): 1735–40. http://dx.doi.org/10.1182/blood-2003-07-2247.
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AbstractCoronary artery thrombosis following plaque rupture is an important feature of myocardial infarction, and studies have highlighted the role of coagulation in this condition. Although genetic and environmental influences on the variance in coagulation protein concentrations have been reported, there are no data on the heritability of structure/function of the final phenotype of the coagulation cascade, the fibrin clot. To assess genetic and environmental contributions to fibrin structure, permeation and turbidity studies were performed in 137 twin pairs (66 monozygotic, 71 dizygotic). The environmental influence (e2) on pore size (Ks) (e2 = 0.61 [95% confidence interval (CI), 0.45-0.80]) and fiber size (e2 = 0.54 [95% CI, 0.39-0.73]) was greater than the heritability (h2 = 0.39 [95% CI, 0.20-0.55] and 0.46 [95% CI, 0.27-0.62], respectively). After correction for fibrinogen levels, the environmental effect persisted for Ks (e2 = 0.61), but genetic influence assumed a greater importance in determining fiber size (h2 = 0.73). Multivariate analysis revealed an overlap in the influence of genetic and environmental factors on fibrinogen levels, Ks, and fiber size. Factor XIII B subunit showed environmental and genetic correlation with fibrinogen and fiber size and a genetic correlation with Ks. The results indicate that genetic and environmental influences are important in determining fibrin clot structure/function.
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Kirchhofer, D., TB Tschopp, B. Steiner, and HR Baumgartner. "Role of collagen-adherent platelets in mediating fibrin formation in flowing whole blood." Blood 86, no. 10 (November 15, 1995): 3815–22. http://dx.doi.org/10.1182/blood.v86.10.3815.bloodjournal86103815.
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Activated platelets provide assembly sites for coagulation enzyme complexes and in this way can mediate coagulation during hemostasis and thrombosis. In this study, we examined the procoagulant activity of platelets adhering directly to fibrillar collagen, a main thrombogenic constituent of subendothelium. For this purpose, we used a human ex- vivo thrombosis model in which collagen-coated coverslips were exposed to flowing nonanticoagulated blood (shear rate, 65/s) for 5.5 minutes, which led to the deposition of adherent platelets, platelet thrombi, and fibrin. To examine the procoagulant activity of adherent platelets only, a selective antagonist of the platelet GPIIb-IIIa complex, Ro 44- 9883, was infused via a mixing device, resulting in a complete abrogation of platelet thrombus formation but leaving the collagen- adherent platelet layer intact. This platelet layer generated increased postchamber fibrinopeptide A (FPA) levels (203 +/- 33 ng/mL) as compared with control experiments without infusion of inhibitor (95 +/- 13 ng/mL). Concomitantly, fibrin deposition measured by morphometric analysis of cross-sections was also increased, as was the platelet adhesion to collagen. An immunochemical staining of fibrin fibers further showed that the adherent platelets formed the nuclei for fibrin fiber formation. This increase in fibrin deposition was mediated by the intrinsic factor X (F.X) activation complex on adherent single platelets, because almost complete inhibition of FPA generation (9 ng/mL) and fibrin deposition (0.4% +/- 0.2% coverage) was achieved upon coinfusion of the GP IIb-IIIa antagonist and active site-inhibited F.IXa. The large platelet thrombi that were deposited in control experiments contained no significant amounts of immunodetectable fibrin except at the thrombus base, where adherent platelets anchored the thrombi to the collagen surface. These results suggest that the collagen-adherent platelets are important promoters of coagulation during the initial phase of thrombogenesis by providing assembly sites for the F.X activation complex.
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Uhrikova, I., K. Machackova, L. Rauserova-Lexmaulova, K. Rehakova, and J. Doubek. "Disseminated intravascular coagulation in dogs with gastric dilatation-volvulus syndrome." Veterinární Medicína 58, No. 11 (December 5, 2013): 587–90. http://dx.doi.org/10.17221/7141-vetmed.
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Gastric dilatation and volvulus syndrome is associated with changes in haemostatic profiles. The aims of this study were to compare selected haemostatic and fibrinolytic parameters between healthy dogs and dogs with gastric dilatation and volvulus syndrome, estimate the incidence of disseminated intravascular coagulation (DIC), and determine the most sensitive test for detection of DIC in these patients. Blood was collected from 22 dogs with gastric dilatation and volvulus syndrome, and nine healthy control dogs. Platelet counts, prothrombin time, activated partial thromboplastin time, fibrinogen concentrations and fibrin/fibrinogen degradation products were measured in all control dogs and patients with gastric dilatation and volvulus syndrome, before and after surgery. Significant differences between control dogs and patients were seen in activated partial thromboplastin time and fibrin/fibrinogen degradation products before surgery and all measured parameters after surgery. The incidence of DIC was 59%. The most sensitive tests for detection of DIC before surgery were those for activated partial thromboplastin time and fibrin/fibrinogen degradation products.
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Bartsch, P., U. Waber, A. Haeberli, M. Maggiorini, S. Kriemler, O. Oelz, and W. P. Straub. "Enhanced fibrin formation in high-altitude pulmonary edema." Journal of Applied Physiology 63, no. 2 (August 1, 1987): 752–57. http://dx.doi.org/10.1152/jappl.1987.63.2.752.
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Blood coagulation, fibrinolysis, and arterial blood gases were examined in 66 nonacclimatized mountaineers at 4,557 m. Subjects were classified according to a clinical score as healthy (n = 25), having mild acute mountain sickness (AMS) (n = 24), showing severe AMS (n = 13), and suffering from high-altitude pulmonary edema (HAPE) (n = 4). Coagulation times, euglobulin lysis time, and fibrin(ogen) fragment E were normal in all groups without significant changes. Fibrinopeptide A (FPA), a molecular marker of in vivo fibrin formation, was elevated in HAPE to 4.2 +/- 2.7 ng/ml (P less than 0.0001) compared with the other groups showing mean values between 1.6 +/- 0.4 and 1.8 +/- 0.7 ng/ml. FPA was normal in one patient with HAPE, however. Severe AMS was accompanied by a significant decrease in arterial PO2 due to an increase in alveolar-arterial O2 difference, whereas arterial PCO2 did not change significantly. We conclude that activation of blood coagulation is not involved in the pathogenesis of AMS and the impairment of gas exchange in this disease. Fibrin generation occurring in HAPE is probably an epiphenomenon of edema formation.
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Loof, Torsten G., Matthias Mörgelin, Linda Johansson, Sonja Oehmcke, Anders I. Olin, Gerhard Dickneite, Anna Norrby-Teglund, Ulrich Theopold, and Heiko Herwald. "Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense." Blood 118, no. 9 (September 1, 2011): 2589–98. http://dx.doi.org/10.1182/blood-2011-02-337568.
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Abstract Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII−/− mice developed severe signs of pathologic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system.
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Heestermans, Marco, Salam Salloum-Asfar, Tom Streef, El Houari Laghmani, Daniela Salvatori, Brenda M. Luken, Sacha S. Zeerleder, et al. "Mouse venous thrombosis upon silencing of anticoagulants depends on tissue factor and platelets, not FXII or neutrophils." Blood 133, no. 19 (May 9, 2019): 2090–99. http://dx.doi.org/10.1182/blood-2018-06-853762.
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Abstract Tissue factor, coagulation factor XII, platelets, and neutrophils are implicated as important players in the pathophysiology of (experimental) venous thrombosis (VT). Their role became evident in mouse models in which surgical handlings were required to provoke VT. Combined inhibition of the natural anticoagulants antithrombin (Serpinc1) and protein C (Proc) using small interfering RNA without additional triggers also results in a venous thrombotic phenotype in mice, most notably with vessel occlusion in large veins of the head. VT is fatal but is fully rescued by thrombin inhibition. In the present study, we used this VT mouse model to investigate the involvement of tissue factor, coagulation factor XII, platelets, and neutrophils. Antibody-mediated inhibition of tissue factor reduced the clinical features of VT, the coagulopathy in the head, and fibrin deposition in the liver. In contrast, genetic deficiency in, and small interfering RNA–mediated depletion of, coagulation factor XII did not alter VT onset, severity, or thrombus morphology. Antibody-mediated depletion of platelets fully abrogated coagulopathy in the head and liver fibrin deposition. Although neutrophils were abundant in thrombotic lesions, depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, thrombus morphology, or liver fibrin deposition. In conclusion, VT after inhibition of antithrombin and protein C is dependent on the presence of tissue factor and platelets but not on coagulation factor XII and circulating neutrophils. This study shows that distinct procoagulant pathways operate in mouse VT, dependent on the triggering stimulus.
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Zampolli, Antonella, Patrizia Marchese, Wolfram Ruf, Nigel Mackman, and Zaverio M. Ruggeri. "Contribution of Intrinsic and Extrinsic Coagulation Pathways to Thrombus Formation in the Mouse Carotid Artery." Blood 112, no. 11 (November 16, 2008): 1900. http://dx.doi.org/10.1182/blood.v112.11.1900.1900.
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Abstract We studied how the intrinsic and extrinsic coagulation pathways contribute to thrombus formation. Ex vivo experiments were performed with citrated blood re-calcified before perfusion over different thrombogenic substrates. This allowed evaluation of fibrin deposition along with platelet adhesion/aggregation in real time and under relevant shear rates. Under these conditions, human melanoma cells expressing human tissue factor (TF) supported platelet adhesion/aggregation and fibrin formation, but only under relatively low shear rate (200–800 s-1). Anti-TF antibodies markedly inhibited both platelet and fibrin deposition, and no reactivity was observed using the parental cell line not transfected with TF. Blood perfusion over fibrillar collagen type I resulted in platelet adhesion/aggregation and subsequent fibrin deposition even under relatively high shear rate (1500 s-1). Corn trypsin inhibitor (CTI), a specific inhibitor of coagulation factor XIIa, had no effect on platelet adhesion/aggregation but inhibited fibrin deposition, while anti-TF antibodies had no significant effect. Preincubation of blood with prostaglandin E1 or a monoclonal antibody against integrin αIIbβ3 blocked not only thrombus growth on the surface but also fibrin formation. Such a finding indicates that thrombin generation leading to fibrin deposition occurs after platelet activation. Blood perfusion over dermal fibroblast extracellular matrix (F-ECM) from mice expressing human but lacking murine TF resulted in the rapid formation of platelet- and fibrin-rich thrombi at all shear rates tested (up to 1500 s-1). Using this thrombogenic substrate containing both collagen and TF, we found that blockade of the intrinsic coagulation pathway with CTI had a minimal effect on platelet adhesion/aggregation and fibrin formation, while inhibition of the extrinsic coagulation pathway with anti-human TF antibodies reduced thrombus growth and stabilization and abolished fibrin formation. The results of these ex vivo studies demonstrate that the relative contribution of the intrinsic and extrinsic coagulation pathways to fibrin and platelets deposition depends on the composition of the thrombogenic surface exposed to blood flow, and indicate also that CTI and anti-TF antibodies can be used as specific inhibitors of thrombin generation through the intrinsic and extrinsic coagulation pathways, respectively. We then established a model of carotid artery injury induced by ferric chloride to evaluate whether the information obtained under controlled experimental conditions ex vivo can help interpret the mechanisms underlying arterial thrombus formation in vivo. In this model, all control C57BL6 mice exhibited a stable carotid artery occlusion within a predictable time frame. To obtain a quantitative parameter of the progression of thrombosis we calculated a flow index. This represents the ratio between the volume of blood that flew through the injured artery from the induction of the lesion to occlusion (or to the end of the predetermined 30 min observation period) and the volume of blood that during the same period of time should have flown through the artery if the initial (pre-injury) flow rate had been maintained. We found that blocking the intrinsic coagulation pathway with CTI injected through the jugular vein significantly delayed, and in most cases prevented, the formation of a stable occlusion, resulting in a significantly altered flow index. The injection of antibodies against human TF, on the other hand, resulted in a trend towards thrombus destabilization, but in most cases the artery still occluded and the flow index was less significantly altered that with CTI. Of note, CTI at a dose that inhibited carotid artery occlusion had no effect on the tail bleeding time. Co-administration of CTI and anti-TF antibodies showed a cooperative effect across the tested concentration range. In conclusion, extrinsic and intrinsic coagulation pathways have complementary roles in thrombus formation and stabilization, and the specific contribution of each depends upon the nature of the thrombogenic surface, i.e. of the causative lesion. The marked effect of factor XIIa inhibition in preventing carotid artery occlusion suggests that a functional link between contact phase activation and tissue factor pathway leading to thrombin generation may be operative under defined conditions in vivo.
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Clavería, Viviana, Patricia J. Yang, Michael T. Griffin, and David N. Ku. "Global Thrombosis Test: Occlusion by Coagulation or SIPA?" TH Open 05, no. 03 (July 2021): e400-e410. http://dx.doi.org/10.1055/s-0041-1732341.
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AbstractThe global thrombosis test (GTT) is a point of care device that tests thrombotic and thrombolytic status. The device exposes whole blood flow to a combination of both high and low shear stress past and between ball bearings potentially causing thrombin and fibrin formation. The question arises as to whether thrombosis in the GTT is dominated by coagulation-triggered red clot or high shear-induced white clot. We investigated the nature of the thrombus formed in the GTT, the device efficacy, human factors use, and limitations. The GTT formed clots that were histologically fibrin-rich with trapped red blood cells. The occlusion time (OT) was more consistent with coagulation than high shear white clot and was strongly lengthened by heparin and citrate, two common anticoagulants. The clot was lysed by tissue plasminogen activator (tPA), also consistent with a fibrin-rich red clot. Changing the bead to a collagen-coated surface and eliminating the low shear zone between the beads induced a rapid OT consistent with a platelet-rich thrombus that was relatively resistant to heparin or tPA. The evidence points to the GTT as occluding primarily due to fibrin-rich red clot from coagulation rather than high shear platelet aggregation and occlusion associated with arterial thrombosis.
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Wu, Zhuang, Ming-Cheh Liu, Mei Liang, and Jian Fu. "Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure." Blood 119, no. 10 (March 8, 2012): 2422–29. http://dx.doi.org/10.1182/blood-2011-04-350413.
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Abstract Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-κB acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. Our data show that PM exposure led to decreased lung KLF2 and TM expression in wild-type mice, and lung KLF2 and TM protein levels were further decreased in Sirt1 knock-out mice. Importantly, Sirt1 gene delivery inhibited TM and KLF2 down-regulation and reduced lung coagulation after PM exposure. Collectively, our studies indicate that Sirt1 functions as a suppressor of coagulation after particulate matter exposure.
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Engelmann, Bernd, and Steffen Massberg. "Innate Immunity, Coagulation, and Thrombosis." Blood 124, no. 21 (December 6, 2014): SCI—28—SCI—28. http://dx.doi.org/10.1182/blood.v124.21.sci-28.sci-28.
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Abstract In evolutionarily ancient animals such as insects and crustaceans, the host responses to physical injury and to invading pathogens can be mediated by the same mechanism of coagulum formation of the hemolymph. During vertebrate evolution hemostasis has emerged as an independent process primarily involved in the rapid repair of blood vessel injuries. The core processes of hemostasis are blood coagulation (resulting in fibrin formation) and platelet activation. Both processes can independently interact with inflammatory responses as apparent in a pathological context such as during development of disseminated intravascular coagulation (DIC). Moreover, extravascular fibrin formation can promote the trapping of pathogens and thereby help to contain infections. Nonetheless, the connections between fibrin formation, platelet activation and innate immunity are incompletely understood. We have recently shown that during early systemic infection with E. coli microvascular thrombi are formed which capture bacteria together with innate leukocytes. These thrombi are fibrin-rich and are in general observed in less than 10% of vessels with diameters < 25 µm. Their formation is not accompanied by marked activation of inflammation since the levels of pro-inflammatory markers are unchanged. Microvascular thrombosis is almost completely suppressed in mice deficient for the neutrophil serine proteases elastase and cathepsin G (NE/CG-/-) which are major microbicidal effectors of neutrophils. In the microcirculation of NE/CG-/- mice, microbes are mostly tissue-associated. In contrast, they are mostly present inside blood vessels in wild type mice. The results of experimental changes in microvascular fibrin formation show that intravascular blood coagulation is causally involved in the capturing of bacteria and of myeloid cells and, additionally, promotes the bacterial killing. Overall this suggests that microvascular thrombosis supports recognition, containment and elimination of bacteria without inducing noticeable damage to the host. It thus fulfills the criteria for a comprehensive intravascular process of innate immunity. This mechanism of intravascular immunity, which was termed "immunothrombosis," is supported by tissue factor (TF), the overall initiator of blood coagulation, and by factor XII, the starter protein of the contact pathway. In particular, extracellular nucleosomes (eNUC)/neutrophil extracellular traps (NETs) are indispensable for immunothrombosis. eNUC/NETs promote thrombosis by critically enhancing degradation of TFPI, the major antagonist of the coagulation start, via neutrophil elastase and by factor XII activation. Release of eNUC/NETs by neutrophils and induction of intravascular coagulation essentially require interaction of activated platelets with neutrophils. Interestingly, intravascular TF, factor XII, eNUC/NETs and innate leukocytes are almost completely dispensable for hemostasis. Furthermore, immunothrombosis in contrast to hemostasis develops in largely intact blood vessels. Together this indicates that thrombosis can be a physiological mechanism of innate immunity that is distinct from hemostasis. We have recently developed a new model for deep vein thrombosis (DVT) which closely reproduces the pathological changes in the vessel wall observed in most patients with DVT. Using this model, we show that intravascular TF, factor XII, eNUC/NETs, innate leukocytes and their interactions with platelets all critically promote DVT. Thus, DVT shares similar triggers (especially pathogens) and identical molecular and cellular mediators with immunothrombosis. In case of DIC, the connections to immunothrombosis are most likely similarly strong or even stronger. Finally, our results also show that mediators of immunothrombosis such as eNUC/NETs and neutrophil serine proteases are main triggers of arterial thrombosis. Hence, together with hemostasis, immunothrombosis likely constitutes the major biological template process for both (pathological) microvascular thrombosis and large vessel thrombosis. Disclosures No relevant conflicts of interest to declare.
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Kaibara, Makoto. "Rheological studies on blood coagulation and network formation of fibrin." Polymer Gels and Networks 2, no. 1 (January 1994): 1–28. http://dx.doi.org/10.1016/0966-7822(94)90021-3.
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Cao, Muhua, Tao Li, Zhangxiu He, Lixiu Wang, Xiaoyan Yang, Yan Kou, Lili Zou, et al. "Promyelocytic extracellular chromatin exacerbates coagulation and fibrinolysis in acute promyelocytic leukemia." Blood 129, no. 13 (March 30, 2017): 1855–64. http://dx.doi.org/10.1182/blood-2016-09-739334.
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Key Points ATRA promotes ETosis leading to procoagulant promyelocytic extracellular chromatin. Extracellular chromatin fosters excess thrombin production and fibrin deposition, increases plasmin, and causes endothelium damage.
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Wolberg, Alisa S. "Factor XIII and Red Blood Cells in Venous Thrombosis." Blood 126, no. 23 (December 3, 2015): SCI—14—SCI—14. http://dx.doi.org/10.1182/blood.v126.23.sci-14.sci-14.
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Blood coagulation culminates in the thrombin-mediated conversion of fibrinogen to fibrin and production of a fibrin network that stabilizes the clot. The transglutaminase factor XIII(a) [FXIII(a)] crosslinks fibrin and increases the clot's resistance to fibrinolysis and mechanical disruption. Consequently, fibrin formation and crosslinking are essential for hemostasis. However, the formation of clots with abnormal fibrin network structure and/or stability (resistance to mechanical disruption or pharmacological dissolution) is a risk factor for both arterial and venous thrombosis. Improved understanding of fibrin formation and crosslinking during coagulation is essential for understanding the pathophysiologic mechanisms that promote thrombotic disease. We have shown that elevated levels of fibrinogen accelerate vessel occlusion and enhance thrombus stability in mice, demonstrating etiologic contributions of fibrin(ogen) to thrombosis. Recently, we discovered that FXIIIa transglutaminase activity also mediates venous thrombosis via its ability to promote red blood cell retention during clot contraction in whole blood. Genetic deletion of FXIII or pharmacologic inhibition of FXIIIa activity reduces red blood cell retention in clots and consequently, reduces thrombus size in vitro and in vivo. Furthermore, FXIII zymogen binding to soluble, circulating fibrinogen is necessary for normal FXIII activation and activity. The fibrinogen motif that mediates FXIII binding involves C-terminal residues in the fibrinogen gamma chain (gamma 390-396); mice that express a variant fibrinogen that has mutations within these residues show reduced binding of FXIII zymogen to fibrinogen, and delayed activation of FXIII. In venous thrombosis models, these mice phenocopy FXIII-deficient mice, producing smaller venous thrombi with reduced red blood cell content compared to thrombi from wild-type mice. Intriguingly, these mice do not exhibit bleeding or poor wound healing normally associated with FXIII deficiency. Collectively, these findings provide new insight into the pathophysiology of venous thrombosis, and expose the fibrin(ogen)-FXIII axis as a central determinant of venous thrombus formation and composition. Disclosures No relevant conflicts of interest to declare.
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Iwanaga, Tomoko, Ryuji Fukushima, Tomoka Nagasato, Ikuro Maruyama, and Naoki Miura. "Analysis of blood clotting with the total thrombus analysis system in healthy dogs." Journal of Veterinary Diagnostic Investigation 33, no. 2 (February 9, 2021): 357–61. http://dx.doi.org/10.1177/1040638721991862.
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To date, coagulation tests are unable to reflect in vivo coagulation status in the same system, including platelet function, fibrin clot formation, and whole blood flow. The Total Thrombus Analysis System (T-TAS), which is a microfluidic assay that simulates conditions in vivo, measures whole blood flow at defined shear rates under conditions designed to assess platelet function (PL-chip) or coagulation and fibrin clot formation (AR-chip). The T-TAS records occlusion start time, occlusion time, and area under the curve. We evaluated this test in healthy control dogs. We also investigated the effect in vivo of acetylsalicylic acid (ASA), and the effect in vitro of an anticoagulation drug (dalteparin; low-molecular-weight heparin; LMWH). The CV of the AUC of both chips was good (CVs of 6.45% [PL] and 1.57% [AR]). The inhibition of platelet function by ASA was evident in the right-shift in the PL test pressure curve. The right-shift in the AR test pressure curves showed that the administration of LMWH inhibited both platelets and the coagulation cascade. The T-TAS may be useful in the evaluation of canine blood coagulation.
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Meijers, Joost C. M. "No contact, no thrombosis?" Blood 123, no. 11 (March 13, 2014): 1629. http://dx.doi.org/10.1182/blood-2014-01-549691.
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In this issue of Blood, Matafonov et al demonstrate that an inhibiting monoclonal antibody against coagulation factor XII (fXII) reduces fibrin formation and platelet accumulation in a primate thrombosis model.1
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Elmas, Elif, Nenad Suvajac, Bernd Jilma, Hartmut Weiler, Martin Borggrefe, and Carl-Erik Dempfle. "Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model." Blood 116, no. 5 (August 5, 2010): 801–5. http://dx.doi.org/10.1182/blood-2009-03-213215.
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Disseminated intravascular coagulation in sepsis is associated with microvascular thrombosis and organ dysfunction. It was expected that prothrombotic disposition such as factor V Leiden (FVL) mutation would worsen clinical outcome. Astonishingly, clinical trial and animal experimental data indicate that FVL can be associated with improved survival. This study investigated the effect of FVL on the response to endotoxin of the coagulation and fibrinolytic system in humans. Fourteen healthy male subjects without FVL and 15 healthy males with heterozygous FVL received an intravenous bolus dose of endotoxin, 2 ng/kg of body weight. Blood samples were drawn before and 1, 2, 4, 6, and 24 hours after administration of the endotoxin. Injection of endotoxin led to a more pronounced increase in soluble fibrin in patients with FVL than in controls. Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activator–induced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogen- and fibrin-degradation products.
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Bárdos, Helga, Attila Juhász, Gábor Répássy, and Róza Ádány. "Fibrin Deposition in Squamous Cell Carcinomas of the Larynx and Hypopharynx." Thrombosis and Haemostasis 80, no. 11 (1998): 767–72. http://dx.doi.org/10.1055/s-0037-1615356.
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SummaryExtravascular fibrin deposition is frequently observed within and around neoplastic tissue and has been implicated in various aspects of tumor growth. The distribution of fibrin deposits was investigated in squamous cell carcinomas representing different stages of tumor progression of the larynx (n = 25) and hypopharynx (n = 9) by immunofluorescent techniques. Double and treble labelings were used to detect fibrinogen and fibrin in combination with marker antigens for tumor cells (cytokeratin), endothelial cells (von Willebrand factor), macrophages (recognized by KiM7), as well as factor XIII subunit A (FXIIIA) and tenascin (an embryonic extracellular matrix protein newly expressed during tumorigenesis). All tissue samples showed specific staining for fibrinogen/fibrin. Fibrin deposition was localized almost exclusively in the connective tissue compartment of tumors with characteristic accumulation at the interface of connective tissue and the tumorous parenchyma. In certain tumor samples showing highly invasive characteristics, fibrin deposits were observed in close association with tumor blood vessels in the tumor cell nodules. The overlapping reactions with polyclonal antibody to fibrinogen/fibrin and monoclonal antibody to fibrin indicate the activation of the coagulation cascade resulting in in situ thrombin activation and fibrin formation. Fibrin was crosslinked and stabilized by FXIIIA as revealed by urea insolubility test. Accumulation of phagocytozing macrophages detected by Ki M7 monoclonal antibody could be seen in areas of fibrin deposition. The blood coagulation factor XIIIA was detected in and around the cells labeled with Ki M7 antibody. Tenascin and fibrin deposits were found in the same localization in the tumor stroma and in association with tumor blood vessels within the tumor cell nodules. Neither fibrin nor tenascin were detected in the histologically normal tissue adjacent to tumors. The close association between fibrin deposits and macrophage accumulation strongly suggests the active participation of tumor-associated macrophages in the formation of stabilized intratumoral fibrin that facilitates tumor matrix generation and tumor angiogenesis.
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Bärtsch, Peter, André Haeberli, and P. Werner Straub. "Blood Coagulation after Long Distance Running: Antithrombin III Prevents Fibrin Formation." Thrombosis and Haemostasis 63, no. 03 (1990): 430–34. http://dx.doi.org/10.1055/s-0038-1645060.
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SummaryPhysical exercise causes shortening of activated partial thromboplastin time (aPTT) and euglobulin clot lysis time. To investigate whether this activation of coagulation and fibrinolysis leads to in vivo thrombin or plasmin action after long distance running, 19 well trained male runners (36-65 years) were examined 5 to 53 min after termination of a 100 km race and 5 days later after at least 1 day without physical exercise. Compared to the control examination aPTT was decreased (30.2 ± 2.8 vs 35.3 ± 3.0 sec) and the following parameters were increased after the race: betathromboglobulin (40 ± 16 vs 23 ± 7 ng/ml), thrombin-antithrombin III (TAT) complexes (5.5 ± 3.4 vs 2.3 ± 0.7 pg/1), the fibrin(ogen) degradation products fragment E (57 ± 15 vs 35 ± 7 ng/ml) and B(3 15-42 (8.5 ± 2.5 vs 6.5 ± 2.5 ng/ml) (all p values <0.001). Platelet count, platelet factor 4, fibrinoepetide A (FPA) and haematocrit did not change significantly. Increased TAT complexes and unchanged FPA suggest that the generated thrombin was fully inactivated by antithrombin III (AT III) and did therefore not give rise to fibrin formation. The small increase of fibrin(ogen) degradation products indicates a minor in vivo activity of the fibrinolytic system. This investigation demonstrates the importance of AT III in the regulation of haemostasis in activated blood coagulation.
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Fiedel, B. A., and Cecilia S. L. Ku. "Further Studies on the Modulation of Blood Coagulation by Human Serum Amyloid P Component and Its Acute Phase Homologue C-Reactive Protein." Thrombosis and Haemostasis 55, no. 03 (1986): 406–9. http://dx.doi.org/10.1055/s-0038-1661574.
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SummarySerum amyloid P component (SAP), and its acute phase homologue C-reactive protein (CRP), prolonged activated partial thromboplastin times (APTT) in cell free plasma when assayed at physiological concentrations in the presence of heparin. SAP also inhibited clot formation initiated through the extrinsic and terminal phases of coagulation in heparinized cell free plasma, an activity not shared with CRP. When CRP and SAP were similarly evaluated in whole blood using the thromboelastograph (TEG), CRP delayed the onset of coagulation and the initial rate of fibrin formation/polymerization; final clot patency was unaltered. SAP suppressed the anticoagulant activity of heparin in the TEG assay, unlike results obtained in heparinized cell free plasma, by facilitating a more rapid onset of coagulation, increasing the rate of fibrin formation/polymerization, and correcting clot patency. The data provided offer further evidence that these homologues can intercede in blood coagulation.
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Gilbert, Gary E., Valerie A. Novakovic, Jialan Shi, Jan Rasmussen, and Steven W. Pipe. "Platelet binding sites for factor VIII in relation to fibrin and phosphatidylserine." Blood 126, no. 10 (September 3, 2015): 1237–44. http://dx.doi.org/10.1182/blood-2015-01-620245.
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Key Points Coagulation fVIII binds to a protein complex, including fibrin, on stimulated platelets rather than to membrane PS. Anti-fVIII antibodies inhibit function on platelets differently than on phospholipid vesicles used in clinical assays.
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Adam, Soheir S., Nigel S. Key, and Charles S. Greenberg. "D-dimer antigen: current concepts and future prospects." Blood 113, no. 13 (March 26, 2009): 2878–87. http://dx.doi.org/10.1182/blood-2008-06-165845.
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AbstractThe D-dimer antigen is a unique marker of fibrin degradation that is formed by the sequential action of 3 enzymes: thrombin, factor XIIIa, and plasmin. First, thrombin cleaves fibrinogen producing fibrin monomers, which polymerize and serve as a template for factor XIIIa and plasmin formation. Second, thrombin activates plasma factor XIII bound to fibrin polymers to produce the active transglutaminase, factor XIIIa. Factor XIIIa catalyzes the formation of covalent bonds between D-domains in the polymerized fibrin. Finally, plasmin degrades the crosslinked fibrin to release fibrin degradation products and expose the D-dimer antigen. D-dimer antigen can exist on fibrin degradation products derived from soluble fibrin before its incorporation into a fibrin gel, or after the fibrin clot has been degraded by plasmin. The clinical utility of D-dimer measurement has been established in some scenarios, most notably for the exclusion of VTE. This article consists of 2 sections: in the first, the dynamics of D-dimer antigen formation is discussed and an overview of commercially available D-dimer assays is provided. The second section reviews available evidence for the clinical utilization of D-dimer antigen measurement in VTE, as well as emerging areas of D-dimer utilization as a marker of coagulation activation in other clinical settings.
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Luyendyk, James P., Jonathan G. Schoenecker, and Matthew J. Flick. "The multifaceted role of fibrinogen in tissue injury and inflammation." Blood 133, no. 6 (February 7, 2019): 511–20. http://dx.doi.org/10.1182/blood-2018-07-818211.
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Abstract The canonical role of the hemostatic and fibrinolytic systems is to maintain vascular integrity. Perturbations in either system can prompt primary pathological end points of hemorrhage or thrombosis with vessel occlusion. However, fibrin(ogen) and proteases controlling its deposition and clearance, including (pro)thrombin and plasmin(ogen), have powerful roles in driving acute and reparative inflammatory pathways that affect the spectrum of tissue injury, remodeling, and repair. Indeed, fibrin(ogen) deposits are a near-universal feature of tissue injury, regardless of the nature of the inciting event, including injuries driven by mechanical insult, infection, or immunological derangements. Fibrin can modify multiple aspects of inflammatory cell function by engaging leukocytes through a variety of cellular receptors and mechanisms. Studies on the role of coagulation system activation and fibrin(ogen) deposition in models of inflammatory disease and tissue injury have revealed points of commonality, as well as context-dependent contributions of coagulation and fibrinolytic factors. However, there remains a critical need to define the precise temporal and spatial mechanisms by which fibrinogen-directed inflammatory events may dictate the severity of tissue injury and coordinate the remodeling and repair events essential to restore normal organ function. Current research trends suggest that future studies will give way to the identification of novel hemostatic factor-targeted therapies for a range of tissue injuries and disease.
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Greenberg, C. S., J. J. Enghild, A. Mary, J. V. Dobson, and K. E. Achyuthan. "Isolation of a fibrin-binding fragment from blood coagulation factor XIII capable of cross-linking fibrin(ogen)." Biochemical Journal 256, no. 3 (December 15, 1988): 1013–19. http://dx.doi.org/10.1042/bj2561013.
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Purified platelet Factor XIII was radioiodinated and then partially degraded by thrombin or trypsin, and a fibrin-binding fragment was identified by autoradiography and immunoblotting following separation by SDS/polyacrylamide-gel electrophoresis. Limited proteolysis of 125I-Factor XIII by thrombin or trypsin produced an 125I-51 kDa fragment and an unlabelled 19 kDa fragment. The 51 kDa fragment was purified by h.p.l.c. on a TSK-125 gel-filtration column. Partial amino acid sequence analysis of the 51 kDa fragment indicated that it was similar in sequence to the Gly38-Lys513 segment in placental Factor XIII a-chain. More than 70% of the 51 kDa fragment bound to fibrin, whereas the 19 kDa fragment did not bind. The active site was localized to the 51 kDa fragment since this fragment expressed transglutaminase activity, cross-linked fibrin and fibrinogen and incorporated iodo[14C]acetamide into the active-site cysteine residue. Isolation of a fibrin-binding fragment expressing transglutaminase activity demonstrates that each a-chain of the dimeric Factor XIIIa could function independently to cross-link fibrin. The fibrin-binding site could play an important role in localizing Factor XIIIa to the fibrin clot.
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Doi, Masaaki, Mitsuhiko Sugimoto, Hideto Matsui, Tomoko Matsumoto, and Midori Shima. "Critical Role of Immobilized Factor VIII In Solid-Phase Blood Coagulation During Mural Thrombogenesis Under Whole Blood Flow Conditions." Blood 116, no. 21 (November 19, 2010): 2199. http://dx.doi.org/10.1182/blood.v116.21.2199.2199.
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Abstract Abstract 2199 Coagulation factor VIII (FVIII), lacking in hemophilic blood, plays an essential role in mechanisms of fibrin plug formation to arrest bleeding at sites of injured vessel walls. Physiologic activity of FVIII circulating in bloodstream (soluble FVIII; S-FVIII) could be extensively evaluated so far by classic plasma coagulation assays such as activated partial thromboplastin time. However, the in vivo functional relevance of FVIII bound to von Willebrand factor (VWF) which is immobilized in subendothelium (immobilized FVIII; I-FVIII) is more complex and remains to be addressed. Using an in vitro perfusion chamber system, we have therefore evaluated the function of I-FVIII in the process of mural thrombus generation under whole blood flow conditions. FVIII-free VWF was purified in the presence of 0.35 M CaCl2 from cryoprecipitate, and coated on a glass plate. Various concentrations (0 as a control, 0.1, 0.3, 1, or 3 U/ml) of recombinant FVIII (Kogenate FS provided by Bayer Pharmaceutical Co.) were reacted with the FVIII-free VWF-coated glass plate. After non-adherent proteins were washed out, the amount of FVIII immobilized to a glass surface via VWF (I-FVIII) was measured by ELISA-based assay using a peroxidase-conjugated anti-FVIII polyclonal antibody. Whole blood was then perfused over a glass plate described above in a parallel plate flow chamber with various shear rates, and the thrombus generation process on a glass surface was observed in real time by confocal laser scanning microscopy. The development of intra-thrombus fibrin deposition was assessed by immune-staining of thrombi with a fluorescence-labeled anti-fibrin specific monoclonal antibody (NYB-T2G1; Accurate Chem.), reflecting solid-phase blood coagulation reaction during mural thrombogenesis. In perfusion of control blood with a high shear rate (1500 s-1), the intra-thrombus fibrin deposition was found to increase as a function of I-FVIII, resulting in the 2.5-fold greater fibrin deposition at the plateau as compared to control thrombi generated in the absence of I-FVIII. This I-FVIII effect on intra-thrombus fibrin deposition was also confirmed in perfusion of synthetic hemophilic blood (S-FVIII activity < 1%) which was prepared by the incubation of control blood with an anti-FVIII human IgG (final inhibitor titer in synthetic blood; 5, 10, or 20 Bethesda U/ml). Indeed, I-FVIII normalized in a dose-dependent manner the reduced fibrin deposition (20-35% of normal control) within synthetic hemophilic thrombi generated in the absence of S-FVIII under a high shear rate condition. The improvement of impaired fibrin deposition by I-FVIII was unvarying regardless of the anti-FVIII inhibitor titer in synthetic hemophilic blood. In contrast, the direct addition of recombinant FVIII into synthetic hemophilic blood was poorly effective in this regard, due to the immediate neutralization of S-FVIII by an inhibitor involved in synthetic blood. Thus, these results clearly indicate that I-FVIII, independent of S-FVIII, does play a considerable role on the intra-thrombus fibrin-network formation in the process of mural thrombus generation under whole blood flow conditions with high shear rate, most relevant physiologically for the in vivo hemostasis and thrombosis. Our results might imply a possibility of novel strategic design targeting I-FVIII against hemophilic patients with a high titer anti-FVIII inhibitor. Disclosures: No relevant conflicts of interest to declare.
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Calzavarini, Sara, Raja Prince-Eladnani, François Saller, Luca Bologna, Laurent Burnier, Anne C. Brisset, Claudia Quarroz, et al. "Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus." Blood 135, no. 22 (May 28, 2020): 1969–82. http://dx.doi.org/10.1182/blood.2019003630.
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Abstract Anticoagulant protein S (PS) in platelets (PSplt) resembles plasma PS and is released on platelet activation, but its role in thrombosis has not been elucidated. Here we report that inactivation of PSplt expression using the Platelet factor 4 (Pf4)-Cre transgene (Pros1lox/loxPf4-Cre+) in mice promotes thrombus propensity in the vena cava, where shear rates are low, but not in the carotid artery, where shear rates are high. At a low shear rate, PSplt functions as a cofactor for both activated protein C and tissue factor pathway inhibitor, thereby limiting factor X activation and thrombin generation within the growing thrombus and ensuring that highly activated platelets and fibrin remain localized at the injury site. In the presence of high thrombin concentrations, clots from Pros1lox/loxPf4-Cre− mice contract, but not clots from Pros1lox/loxPf4-Cre+ mice, because of highly dense fibrin networks. Thus, PSplt controls platelet activation as well as coagulation in thrombi in large veins, but not in large arteries.
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Konings, Joke, José W. P. Govers-Riemslag, Helen Philippou, Nicola J. Mutch, Julian I. Borissoff, Peter Allan, Sumitra Mohan, Guido Tans, Hugo ten Cate, and Robert A. S. Ariëns. "Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin." Blood 118, no. 14 (October 6, 2011): 3942–51. http://dx.doi.org/10.1182/blood-2011-03-339572.
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Abstract Recent data indicate an important contribution of coagulation factor (F)XII to in vivo thrombus formation. Because fibrin structure plays a key role in clot stability and thrombosis, we hypothesized that FXII(a) interacts with fibrin(ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of thrombin generation, as shown in clots made in prothrombin-deficient plasma initiated with snake venom enzyme and in clots made from plasma deficient in FXII and prothrombin. Purified FXII and α-FXIIa, but not β-FXIIa, bound to purified fibrinogen and fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense fibrin deposition, providing evidence for the in vivo modulation of fibrin structure by FXIIa. These data demonstrate that FXIIa modulates fibrin clot structure independently of thrombin generation through direct binding of the N-terminus of FXIIa to fibrin(ogen). Modification of fibrin structure by FXIIa represents a novel physiologic role for the contact pathway that may contribute to the pathophysiology of thrombosis.
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Dubova, Oksana A., Diana V. Feshchenko, Tetiana I. Bakhur, Oksana A. Zghozinska, Anatoliy A. Antipov, Serhii V. Rublenko, Volodymyr P. Goncharenko, Raisa V. Shahanenko, and Volodymyr S. Shahanenko. "Disseminated Intravascular Coagulation Syndrome as a Complication in Acute Spontaneous Canine Babesiosis." Macedonian Veterinary Review 43, no. 2 (October 1, 2020): 141–49. http://dx.doi.org/10.2478/macvetrev-2020-0027.
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AbstractThe polyetiological syndrome of disseminated intravascular coagulation (DIC) is characterized by changes in patients’ hemostasis. The aim of the current research was to elucidate the main factors for the development of DIC syndrome during canine babesiosis, and to assess their correlation level. Dogs included in this study were of various breeds and sex, weighing 10-40 kg and aged 2-7 years. They were separated in two groups (n=50) according to their diagnosis to babesiosis. Oscillometry (blood pressure, pulse rate), vascular-platelet hemostasis, coagulogram, hematological, biochemical (fibrinogen, fibrin degradation product, soluble fibrin-monomer complex) and hemodynamic (circulating blood volume) assessment methods were used. The group of dogs positive on Babesia spp., had clear manifestation of DIC with 5-7% of the erythrocyte population being affected. DIC was manifested by a significant increase in soluble fibrin-monomer complex and fibrin degradation product (p<0.001), hypofibrinogenemia (p<0.001), thrombocytopenia (p<0.001), and an increase in indicators of spontaneous aggregation ability of platelets and red blood cells (p<0.001). Significant hemodynamic disorders were observed: a decrease in circulating blood volume, circulating erythrocytes volume (p<0.05), specific circulating blood volume and hematocrit value (p<0.001). The average blood pressure was reduced (p<0.001), and the Allgöwer’s shock index was increased 2 times (p<0.05). A shock of II degree (medium, subcompensated) was confirmed. Therefore, it can be concluded that acute spontaneous dogs’ babesiosis can be characterized by the occurrence of DIC in a consumption coagulopathy form, and shock of II degree. This condition renders the patients for emergency admission.
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Cuker, Adam, Joseph Marturano, Maria Carinato, Thomas Lowery, and Douglas Cines. "T2 Magnetic Resonance to Monitor Hemostasis." Seminars in Thrombosis and Hemostasis 45, no. 03 (August 17, 2018): 247–52. http://dx.doi.org/10.1055/s-0038-1667114.
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AbstractThere is a clinical need for pragmatic approaches to measure integrated hemostatic reactions in whole blood rapidly, using small volumes of blood. The authors have applied T2 magnetic resonance (T2MR) to assess coagulation reactions based on partitioning of red blood cells and proteins that occurs during fibrin formation and platelet-mediated clot contraction. T2MR is amenable to measuring clotting times, individual coagulation factors, and platelet function. T2MR also revealed a novel “hypercoagulable” signature characterized by fibrin clots almost insusceptible to fibrinolysis that surround tessellated arrays of polyhedral erythrocytes (“third peak”). This signature, which develops under conditions associated with intense clot formation in vitro, may help identify patients at risk of developing thrombosis and for monitoring antithrombotic therapies in the future.
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Strickland, Sidney. "Impact of the Coagulation System on the Pathogenesis of Alzheimer's Disease." Blood 130, Suppl_1 (December 7, 2017): SCI—3—SCI—3. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-3.sci-3.
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Abstract Alzheimer's disease (AD) leads to cognitive impairment and is eventually fatal. The cognitive decline is associated with extensive neuronal degeneration. The most well-known pathological features of AD are extracellular Aβ plaques, intracellular tau tangles, neuroinflammation, and neuronal loss. Less discussed is that AD is often associated with cerebrovascular abnormalities. The symptoms of AD and cerebrovascular pathology could be independent co-morbidities, with both being increased in aging populations. However, it is also possible that there is a mechanistic link between AD and vascular pathology. The interaction of Aβ with fibrin(ogen) can lead to increased fibrin deposition in cerebral blood vessels, and these accumulated fibrin deposits may disrupt cerebral blood flow and induce microinfarcts, inflammation, and BBB damage, all of which are aspects of cerebrovascular dysfunction observed in AD. At the same time, Ab's ability to activate FXII may contribute to increased fibrin generation through the intrinsic coagulation pathway as well as to increased inflammation and vascular permeability through bradykinin release from HK. These possible roles of Aβ in thrombosis, fibrinolysis, and inflammation via its interaction with fibrinogen and FXII, summarized in Figure 1, will be discussed. Disclosures No relevant conflicts of interest to declare.
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Nagaraj, Gayathri, Manjula Balasubramanian, Sameer Kalghatgi, Andrew S. Wu, Ari D. Brooks, Gregory Fridman, Moogega Cooper, et al. "Mechanism of Blood Coagulation by Non-Thermal Atmospheric Pressure Dielectric Barrier Discharge Plasma." Blood 110, no. 11 (November 16, 2007): 3162. http://dx.doi.org/10.1182/blood.v110.11.3162.3162.
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Abstract Introduction: Non-thermal atmospheric pressure dielectric barrier discharge plasma (cold plasma due to its non-thermal nature) has emerged as a promising new tool in medicine due to its ability to coagulate blood rapidly, sterilize tissue without thermal damage and induce apoptosis in malignant tissue. The potential clinical applicability of non-thermal plasma lies in its use in controlling intra-operative microvascular bleeding in organs and in endoscopy. Non-thermal plasma can also be used to treat superficial wounds in trauma through hemostasis while simultaneously inducing surface sterilization. We have previously demonstrated that non-thermal plasma hastens blood coagulation on cut tissue surfaces and accelerates clot formation in whole blood five times faster than natural coagulation. A series of experiments were undertaken to investigate the mechanism of coagulation by non-thermal plasma. Methods/Results: We initially postulated that changes in pH and/or extracellular Ca2+ as a possible mechanism for non-thermal plasma mediated coagulation. Our studies however showed no significant changes in pH or Ca2+ in treated blood. Thermal energy triggered coagulation as seen in conventional electrocautery as well as electric field effects were eliminated as other possible mechanisms. The role of reactive oxygen species (ROS) in coagulation was studied, as non-thermal plasma is known to produce ROS in water. ROS production in blood was blocked with sodium pyruvate, an ROS scavenger, and the results showed no effect on non-thermal plasma induced coagulation. Specific effects of non-thermal plasma on citrated blood samples revealed extremely rapid coagulation with surface gel formation, while clotting studies (PT, aPTT) performed on the plasma beneath the gel revealed consumption of coagulation factors. Examination of the clot formed by non-thermal plasma using Scanning Electron Microscopy (SEM) showed platelet activation with pseudopodia formation, aggregation, and fibrin formation. The effects of non-thermal plasma on fibrinogen solution treated at physiologic pH showed a change in opacity suggesting clot formation. Dynamic Light Scattering (DLS) was used to measure particle size distributions of treated and untreated fibrinogen solutions. Treated fibrinogen exhibited a multi-modal distribution of sizes with the largest size corresponding to the size of fibrin-like structures. This suggests that non-thermal plasma may coagulate blood by the conversion of fibrinogen to fibrin. Evaluation of albumin, our control protein given its non-involvement in coagulation, showed no changes upon exposure to non-thermal plasma. Conclusion: Non-thermal plasma likely promotes coagulation by enhancing the physiologic coagulation process through direct activation of fibrinogen as well as platelet activation and aggregation. Future research will further evaluate the mechanisms of non-thermal plasma induced platelet activation and effects on other proteins in the coagulation cascade. This will lead to newer insights into the physiological aspects of coagulation and clinical utility of non-thermal plasma in medicine.
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Greineder, Colin F., Ian Johnston, Carlos Hipolito Villa, Douglas B. Cines, Mortimer Poncz, and Vladimir R. Muzykantov. "A Microfluidic Model of Microvascular Inflammation: Characterization and Testing of Endothelial-Targeted Therapeutics." Blood 126, no. 23 (December 3, 2015): 3454. http://dx.doi.org/10.1182/blood.v126.23.3454.3454.
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Abstract * These authors contributed equally to this work The microvasculature plays a key role in the pathogenesis of sepsis, ARDS, multiorgan dysfunction, and a variety of other human diseases characterized by a pro-coagulant, pro-adhesive endothelial phenotype. The complex interactions that occur at the interface of blood and activated endothelium are difficult to resolve in animal models and challenging to recreate in cell culture systems. While individual processes - e.g., leukocyte adhesion and transmigration - have been extensively studied, development of a well-characterized model integrating the full range of pathogenic processes (coagulation, barrier dysfunction, innate immune system activation, etc.) remains an important unmet goal, which could both elucidate mechanisms of disease and aid in the design and testing of putative therapeutics. To this end, we sought to model an inflamed vascular segment using a Fluxion Bioflux system. 3-dimensional confluent endothelial cell (EC) monolayers were established within fibronectin-coated laminar flow chambers. ECs were flow adapted, activated with TNFa, and then perfused with whole blood (WB) at a variety of shear stresses. Real time fluorescence microscopy allowed continuous monitoring of fibrin deposition and leukocyte and platelet adhesion. The multi-channel format, which allows simultaneous testing of multiple conditions with replicates, proved to be a critical asset, given substantial day-to-day variability. Both fibrin deposition and adhesive events showed dependence on dose (1 vs. 10 ng/mL) and duration (4 vs. 6hr) of TNF activation. Confocal microscopy revealed TNF-dependent, increases in EC expression of ICAM-1, VCAM-1, and tissue factor (TF), as well as suppression of endothelial thrombomodulin (TM). Activation of the coagulation system was completely abrogated by treatment of the EC monolayer with a TF-inhibiting antibody, suggesting a primary role for the extrinsic pathway. Hirudin also limited fibrin deposition when added to whole blood prior to perfusion, although "breakthrough clotting" was seen in some channels. Finally, the role of endothelial TM was investigated in several ways, including by the use of a blocking antibody, which prevents thrombin binding. Treatment of ECs with this antibody markedly increased fibrin deposition, whereas TM/R6.5 scFv, a novel targeted fusion protein therapeutic, which anchors recombinant TM to endothelial ICAM-1, inhibited fibrin deposition upon subsequent infusion of WB. Neither soluble TM (sTM) nor anti-ICAM-1 R6.5 scFv alone had any effect on coagulation when infused in this setting (i.e., prior to WB) and even addition of a large excess of sTM to whole blood was less effective in reducing TNF-dependent fibrin deposition than pre-treatment with the ICAM-targeted TM fusion protein, indicating potential importance of precision drug delivery on the microscale. In summary, the described microfluidic, "endothelialized", whole blood model of an inflamed microvessel may prove useful in interrogating specific aspects of a variety of vascular pathologies and in devising and improving therapeutic interventions. Figure 1. (a) Fibrin deposition and (b) leukocyte and platelet adhesion upon whole blood perfusion of endothelialized microchannels, pre-activated with 1 vs. 10ng/mL of TNF for 6 hours. (c) Role of endothelial TM in TNF-dependent microvessel thrombosis. TM blockade exacerbates fibrin deposition whereas ICAM-targeted TM fusion protein effectively eliminates coagulation. Figure 1. (a) Fibrin deposition and (b) leukocyte and platelet adhesion upon whole blood perfusion of endothelialized microchannels, pre-activated with 1 vs. 10ng/mL of TNF for 6 hours. (c) Role of endothelial TM in TNF-dependent microvessel thrombosis. TM blockade exacerbates fibrin deposition whereas ICAM-targeted TM fusion protein effectively eliminates coagulation. Disclosures No relevant conflicts of interest to declare.
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Tao, Yi, Yanhui Jiang, Weidong Li, and Baochang Cai. "Rapid magnetic solid-phase extraction combined with ultra-high performance liquid chromatography and quadrupole-time-of-flight mass spectrometry for analysis of thrombin binders from a crude extract and injection of Erigeron breviscapus." RSC Advances 6, no. 41 (2016): 34782–90. http://dx.doi.org/10.1039/c6ra04001b.
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Fedorov, V. E., B. S. Kharitonov, A. D. Aslanov, O. E. Logvina, and M. S. Narizhnaya. "Changes in the blood coagulation system that determine postoperative complications in patients with non-tumor mechanical jaundice." Grekov's Bulletin of Surgery 180, no. 2 (August 20, 2021): 12–20. http://dx.doi.org/10.24884/0042-4625-2021-180-2-12-20.
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The OBJECTIVE was to study the features of changes in the blood coagulation system that contribute to the development of postoperative complications in patients depending on the stage of non-tumor mechanical jaundice at admission.METHODS AND MATERIALS. A total of 537 patients with mechanical jaundice were examined and changes in the blood coagulation system were analyzed. Vascular-platelet hemostasis was characterized by the following tests: capillary resistance, the number of desquamated endothelial cells, the number of blood platelets. Plasma hemostasis was analyzed using activated partial thromboplastin time, plasma soluble fibrin level, thrombin time, prothrombin ratio, prothrombin index, and fibrinogen blood level. Then, XIIa-dependent fibrinolysis in the blood and the level of the fibrin D-dimer in the blood plasma were determined.RESULTS. It was found that in the first stage of mechanical jaundice, with cholestasis, there were no changes in blood coagulation system that go beyond the normal limits. In the second stage, during cytolysis of hepatocytes, hyperbilirubinemia and hypertransaminasemia contribute to the activation of platelet first, and then plasma hemostasis. In the third stage (cholangitis), the death of endotheliocytes increases and there is a deficiency of blood coagulation factors due to their consumption and increased fibrinolysis.CONCLUSION. In the stage of cholestasis in patients with non-tumors mechanical jaundice, the parameters of the coagulation system remain within the reference values. In the stage of cytolysis, as endotheliotoxicosis increases, platelet and plasma hemostasis begins to activate, which can lead to thrombosis and thromboembolism in vital organs. In the stage of cholangitis, further activation of plasma hemostasis causes hemorrhagic syndrome. The occurrence of the described disorders in blood coagulation system with the progression of MJ dictates the need to monitor the changes in the blood coagulation system and their correction for the prevention of intra-and postoperative complications.
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Zacharski, LR, VA Memoli, and SM Rousseau. "Coagulation-cancer interaction in situ in renal cell carcinoma." Blood 68, no. 2 (August 1, 1986): 394–99. http://dx.doi.org/10.1182/blood.v68.2.394.394.
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Abstract Fibrin was detected by immunospecific techniques associated with both intravascular and extravascular tumor deposits in renal cell carcinoma. In addition, coagulation factors VII and X were demonstrated in intercellular spaces within tumor tissue and adjacent to the surface of tumor cells. Scant accumulation of platelets on intravascular tumor masses was observed. These data suggest that tumor cells in renal cell carcinoma may induce fibrin formation locally by a factor VII-mediated (and thus tissue factor-initiated) pathway of blood coagulation. This mechanism may also account for the hypercoagulable state that exists with this tumor type. We postulate that local fibrin formation may contribute to the growth and spread of this particular type of cancer and that the course of renal cell carcinoma may be ameliorated by anticoagulant therapy.
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Zacharski, LR, VA Memoli, and SM Rousseau. "Coagulation-cancer interaction in situ in renal cell carcinoma." Blood 68, no. 2 (August 1, 1986): 394–99. http://dx.doi.org/10.1182/blood.v68.2.394.bloodjournal682394.
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Fibrin was detected by immunospecific techniques associated with both intravascular and extravascular tumor deposits in renal cell carcinoma. In addition, coagulation factors VII and X were demonstrated in intercellular spaces within tumor tissue and adjacent to the surface of tumor cells. Scant accumulation of platelets on intravascular tumor masses was observed. These data suggest that tumor cells in renal cell carcinoma may induce fibrin formation locally by a factor VII-mediated (and thus tissue factor-initiated) pathway of blood coagulation. This mechanism may also account for the hypercoagulable state that exists with this tumor type. We postulate that local fibrin formation may contribute to the growth and spread of this particular type of cancer and that the course of renal cell carcinoma may be ameliorated by anticoagulant therapy.
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Cheng, Qiufang, Yong Zhao, William E. Lawson, Vasiliy V. Polosukhin, Joyce E. Johnson, Timothy S. Blackwell, and David Gailani. "The effects of intrinsic pathway protease deficiencies on plasminogen-deficient mice." Blood 106, no. 9 (November 1, 2005): 3055–57. http://dx.doi.org/10.1182/blood-2005-02-0577.
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AbstractPlasminogen (Plg)–deficient mice experience wasting and have decreased longevity due to disseminated fibrin deposition. We generated mice with combined deficiencies of Plg and coagulation factor IX (fIX) or XI (fXI) to determine the effects on the Plg null phenotype. Mice lacking Plg and fIX (Plg–/–/fIX–/–) have lower mortality at age 6 months than Plg–/–/fIX+/+ mice (15% and 67%, respectively) and less severe wasting, consistent with the importance of fIX in fibrin formation. In contrast, combined Plg and fXI deficiency (Plg–/–/fXI–/–) reduces life span (more than 90% mortality at 6 months) and is associated with leukocyte infiltration of the lungs and pulmonary fibrosis. These abnormalities are not seen in Plg–/– or Plg–/–/fIX–/– animals. Activated fXI is thought to function primarily as a fIX activator; however, our observation suggests that fXI may have functions in regulation of inflammation or tissue repair distinct from its role in coagulation.
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Fernando, Deepani D., Simone L. Reynolds, Gunter Hartel, Bernard Cribier, Nicolas Ortonne, Malcolm K. Jones, and Katja Fischer. "A unique group of scabies mite pseudoproteases promotes cutaneous blood coagulation and delays plasmin-induced fibrinolysis." PLOS Neglected Tropical Diseases 15, no. 1 (January 6, 2021): e0008997. http://dx.doi.org/10.1371/journal.pntd.0008997.
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Background Scabies, a highly contagious skin disease affecting more than 200 million people worldwide at any time, is caused by the parasitic mite Sarcoptes scabiei. In the absence of molecular markers, diagnosis requires experience making surveillance and control challenging. Superficial microthrombi in the absence of vasculitis in scabies-affected skin are a recognised, yet unexplained histopathological differential of scabies infection. This study demonstrates that a family of Scabies Mite Inactivated Cysteine Protease Paralogues (SMIPP-Cs) excreted by the mites plays a role in formation of scabies-induced superficial microthrombi. Methodology/Principal findings A series of in vitro and ex vivo experiments involving two representative recombinant SMIPP-Cs was carried out. In the presence of SMIPP-Cs, the thrombin clotting time (TCT), fibrin formation and plasmin induced fibrinolysis were monitored in vitro. The ultrastructure of the SMIPP-C—modulated fibrin was analysed by Scanning Electron Microscopy (SEM). Immuno-histological analyses were performed ex vivo, to localise the SMIPP-C proteins within scabies infected skin biopsies. SMIPP-Cs displayed pro-coagulant properties. They bound calcium ions, reduced the thrombin clotting time, enhanced the fibrin formation rate and delayed plasmin-induced fibrinolysis. The SMIPP-Cs associated with fibrin clots during fibrinogen polymerisation and did not bind to preformed fibrin. Scanning electron microscopy revealed that the fibrin clots formed in the presence of SMIPP-Cs were aberrant and denser than normal fibrin clots. SMIPP-Cs were detected in microthrombi which are commonly seen in scabietic skin. Conclusions/Significance The SMIPP-Cs are the first scabies mite proteins found in sub-epidermal skin layers and their pro-coagulant properties promote superficial microthrombi formation in scabetic skin. Further research is needed to evaluate their potential as diagnostic or therapeutic target.
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Chandler, Wayne L., and Tomas Velan. "Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass." Blood 101, no. 11 (June 1, 2003): 4355–62. http://dx.doi.org/10.1182/blood-2002-08-2400.
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Abstract Our objective was to estimate the in vivo rates of thrombin and fibrin generation to better understand how coagulation is regulated. Studied were 9 males undergoing cardiopulmonary bypass (CPB). The rates of thrombin, total fibrin, and soluble fibrin generation in vivo were based on measured levels of prothrombin activation peptide F1.2, thrombin-antithrombin complex, fibrinopeptide A, and soluble fibrin, combined with a computer model of the patient's vascular system that accounted for marker clearance, hemodilution, blood loss, and transfusion. Prior to surgery, the average thrombin generation rate was 0.24 ± 0.11 pmol/s. Each thrombin molecule in turn generated about 100 fibrin molecules, of which 1% was soluble fibrin. The thrombin generation rate did not change after sternotomy or administration of heparin, then rapidly increased 20-fold to 5.60 ± 6.65 pmol/s after 5 minutes of CPB (P = .000 05). Early in CPB each new thrombin generated only 4 fibrin molecules, of which 35% was soluble fibrin. The thrombin generation rate was 2.14 ± 1.88 pmol/s during the remainder of CPB, increasing again to 5.47 ± 4.08 pmol/s after reperfusion of the ischemic heart (P = .000 08). After heparin neutralization with protamine, thrombin generation remained high (5.34 ± 4.01 pmol/s, P = .0002) and total fibrin generation increased, while soluble fibrin generation decreased. By 2 hours after surgery, thrombin and fibrin generation rates were returning to baseline levels. We conclude that cardiopulmonary bypass and reperfusion of the ischemic heart results in bursts of nonhemostatic thrombin generation and dysregulated fibrin formation, not just a steady increase in thrombin generation as suggested by previous studies.
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Kluft, Cornelis, Andrea Krug, Ulrich Winkler, Jørgen Jespersen, Jørgen Gram, and Johannes J. Sidelmann. "Fibrin clot structure - pro-fibrinolytic effect of oral contraceptives in apparently healthy women." Thrombosis and Haemostasis 117, no. 04 (2017): 700–705. http://dx.doi.org/10.1160/th16-10-0748.
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SummaryFibrin metabolism is influenced by many factors. The velocity of fibrin formation, genetic polymorphisms, fibrinolytic features and the structure of the fibrin clot are determinants of fibrin turnover. Oral contraceptives (OCs) have significant impact on the haemostatic system, by increasing the concentration of coagulation factors, plasminogen and tissue plasminogen activator activity, and decreasing the concentration of haemostatic inhibitors. The present study addresses the influence of OCs on fibrin structure and fibrin metabolism. The study included 70 women treated with seven different OC-formulations. Blood was collected at baseline and after six months of OCs. The plasma concentration of fibrinogen, thrombin-antithrombin complex (TAT), plasminogen, plasmin-antiplasmin complex (PAP), D-Dimer and thrombin generation measures were determined. Fibrin structure measures and fibrin clot lysis not affected by the plasma concentration of plasminogen activators and inhibitors were determined. OCs increased the concentration of fibrinogen, TAT, plasminogen, PAP and D-dimer significantly and affected measures of thrombin generation (p<0.001). The maximal optical density of fibrin (p<0.001), the fibrin fibre density (p=0.03), fibrin fibre diameter (p=0.003), fibrin mass-length ratio (p<0.001) and lysis per hour (p<0.001) increased significantly upon OC-treatment. Lysis per hour was not correlated to the concentration of plasminogen. We conclude that the effect of OCs on the coagulation system is balanced by alterations in fibrin structure, facilitating clot lysis and contributing to the fibrinolytic susceptibility already present in women treated with OC. These alterations may counterbalance the OC-induced increased thrombin generation and reduced coagulation inhibitory potential, contributing to maintenance of the haemostatic balance in women receiving OCs.