scholarly journals Evaluation of the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) in animal models

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258192
Author(s):  
Subhajit Ghosh ◽  
Wilfred Krege ◽  
Baerbel Doerr ◽  
Marcel Mischnik ◽  
Ingo Pragst ◽  
...  
Keyword(s):  
Animal Models ◽  
Therapeutic Dose ◽  
Prothrombin Complex Concentrate ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Bleeding Risk ◽  
Venous Stasis ◽  
The Third ◽  
The Impact

Objectives Acquired coagulopathy may be associated with bleeding risk. Approaches to restore haemostasis include administration of coagulation factor concentrates, but there are concerns regarding potential prothrombotic risk. The present study assessed the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) versus activated PCC (aPCC) and recombinant factor VIIa (rFVIIa), using three preclinical animal models. Methods The first model was a modified Wessler model of venous stasis-induced thrombosis in rabbit, focusing on dilutional coagulopathy; the second model employed the same system but focused on direct oral anticoagulant reversal (i.e. edoxaban). The third model assessed the prothrombotic impact of 4F-PCC, aPCC and rFVIIa in a rat model of ferric chloride-induced arterial thrombosis. Results In the first model, thrombi were observed at aPCC doses ≥10 IU/kg (therapeutic dose 100 IU/kg) and rFVIIa doses ≥50 μg/kg (therapeutic dose 90 μg/kg), but not 4F-PCC 50 IU/kg (therapeutic dose 50 IU/kg). The impact of 4F-PCC (up to 300 IU/kg) on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCC-induced thrombus formation was lower after haemodilution versus non-haemodilution. In the second model, no prothrombotic effect was confirmed at 4F-PCC 50 IU/kg. The third model showed lower incidence of thrombus formation for 4F-PCC 50 IU/kg versus aPCC (50 U/kg) and rFVIIa (90 μg/kg). Conclusions These results suggest that 4F-PCC has a low thrombotic potential versus aPCC or rFVIIa, supporting the clinical use of 4F-PCC for the treatment of coagulopathy-mediated bleeding.

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

2012 ◽  
Vol 107 (02) ◽  
pp. 253-259 ◽  
Author(s):  
Toshio Fukuda ◽  
Yuko Honda ◽  
Chikako Kamisato ◽  
Toshiro Shibano ◽  
Yoshiyuki Morishima
Keyword(s):  
Venous Thrombosis ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Thrombosis Model ◽  
Haemostatic Agents

SummaryEdoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

Treatment of Dabigatran-Associated Bleeding

2012 ◽  
Vol 26 (3) ◽  
pp. 264-269 ◽  
Author(s):  
Lisa M. Harinstein ◽  
Joseph W. Morgan ◽  
Nicholas Russo
Keyword(s):  
Clinical Practice ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Treatment Algorithm ◽  
Bleeding Event ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Thrombin Inhibitor ◽  
Reversal Agents ◽  
Life Threatening

Dabigatran etexilate is a competitive, direct thrombin inhibitor that works in the coagulation cascade to ultimately prevent thrombus formation. It is recommended by the 2012 American College of Chest Physicians evidence-based clinical practice guidelines as first-line therapy over vitamin k antagonists for long-term antithrombotic therapy in patients with paroxysmal or persistent nonrheumatic atrial fibrillation who are at intermediate to high risk of stroke and systemic embolism (grade 2B). However, serious postmarketing events involving life-threatening bleeding are emerging with no antidote for reversal of the anticoagulant effect being available for use. Potential reversal agents are being used in clinical practice with questionable efficacy and safety profiles. We report a case involving an 84-year-old male with acute kidney injury who developed life-threatening gastrointestinal and surgical site bleeding secondary to dabigatran accumulation. Use of the Naranjo probability scale indicated a probable cause between the bleeding event and dabigatran use. After discontinuation of drug therapy, fresh frozen plasma, recombinant coagulation factor VIIa, and cryoprecipitate were administered as potential reversal agents with negligible benefit. However, this patient appeared to slowly benefit with administration of continuous venovenous hemodialysis. Based upon our experience with this patient and literature review, the most effective treatment algorithm for dabigatran-associated bleeding may be to utilize hemodialysis initially.

A novel inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) – Part II: Enhancement of both exogenous and endogenous fibrinolysis in animal models of thrombosis

2007 ◽  
Vol 97 (01) ◽  
pp. 54-61 ◽  
Author(s):  
Valdeci da Cunha ◽  
Jon Vincelette ◽  
Lei Zhao ◽  
Mariko Nagashima ◽  
Kohichi Kawai ◽  
...  
Keyword(s):  
Animal Models ◽  
Small Molecule ◽  
Low Dose ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Bleeding Risk ◽  
Fibrinolysis Inhibitor ◽  
Pre Treatment ◽  
Endogenous Fibrinolysis ◽  
Lung Microcirculation

SummaryWe have discovered a novel small-molecule TAFIa inhibitor, BX 528, which is potent, highly selective against other carboxypeptidases and safe. The present study was to determine if BX 528 can enhance exogenous and endogenous thrombolysis in four different animal models. In the first three models, a thrombus was induced by FeCl2 (dogs) or laser (rats) injury of the femoral artery, or formed ex vivo and implanted in the jugular vein in rabbits. A low dose of exogenous t-PA was given to induce a lowlevel thrombolysis on an established thrombus. Co-treatment with BX 528 further enhanced the thrombolytic effects induced by the exogenous t-PA and, thus, r educed thrombosis in all three animal models. In a second rat model, fibrin deposition in the lungs was induced by batroxobin, which was spontaneously resolved in 30 minutes due to the activation of endogenous fibrinolysis. Pre-treatment with lipopolysaccharide (LPS) attenuated this spontaneous fibrinolysis. Co-treatment with 10 mg/kg BX 528 prevented the LPS-induced attenuation of endogenous fibrinolysis. Thus, these studies demonstrated that inhibition ofTAFIa by BX 528, our newly discovered small-molecule TAFIa inhibitor, enhanced both the exogenous (induced by a low dose of t-PA) and endogenous (LPS-induced resistance) thrombolysis without increasing the bleeding risk in four different animal models of thrombosis in different species (rat, dog and rabbit) employing different thrombogenic stimuli (FeCl2, laser, ex vivo and batroxobin) to induce thrombus formation in different tissues (artery, vein and lung microcirculation).

scholarly journals Defective thrombus formation in mice lacking coagulation factor XII

2005 ◽  
Vol 202 (2) ◽  
pp. 271-281 ◽  
Author(s):  
Thomas Renné ◽  
Miroslava Pozgajová ◽  
Sabine Grüner ◽  
Kai Schuh ◽  
Hans-Ulrich Pauer ◽  
...  
Keyword(s):  
Factor Viia ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Factor Xii ◽  
Flow Measurements ◽  
Novel Target ◽  
Unexpected Findings ◽  
Blood Flow Measurements ◽  
Deficient Mice

Blood coagulation is thought to be initiated by plasma protease factor VIIa in complex with the membrane protein tissue factor. In contrast, coagulation factor XII (FXII)–mediated fibrin formation is not believed to play an important role for coagulation in vivo. We used FXII-deficient mice to study the contributions of FXII to thrombus formation in vivo. Intravital fluorescence microscopy and blood flow measurements in three distinct arterial beds revealed a severe defect in the formation and stabilization of platelet-rich occlusive thrombi. Although FXII-deficient mice do not experience spontaneous or excessive injury-related bleeding, they are protected against collagen- and epinephrine-induced thromboembolism. Infusion of human FXII into FXII-null mice restored injury-induced thrombus formation. These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo. The results establish FXII as essential for thrombus formation, and identify FXII as a novel target for antithrombotic therapy.

Experimental Studies on a Recombinant Hirudin, CGP 39393

1991 ◽  
Vol 65 (04) ◽  
pp. 355-359 ◽  
Author(s):  
E Gray ◽  
J Watton ◽  
S Cesmeli ◽  
T W Barrowcliffe ◽  
D P Thomas
Keyword(s):  
Thrombin Generation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Experimental Studies ◽  
Venous Stasis ◽  
Antithrombotic Agent ◽  
Recombinant Hirudin ◽  
Excessive Bleeding ◽  
Generation Test

SummaryThe in vitro anticoagulant activities of recombinant desulphatohirudin (r-hirudin) were studied in the activated partial thromboplastin time (APTT) and the thrombin generation test : systems. In the APTT at concentrations below 5 μg/ml, r-hirudin showed a dose-response curye. At concentrations above 5 μg/ml, the plasma became unclottable, but in the thrombin generation test , at least 10 μg/ml of r-hirudin was required for full inhibition of thrombin generation. The antithrombotic effect was assessed using a rabbit venous stasis model; 150 μg/ml r-hirudin completely prevented thrombus formation at 10 and 20 min stasis. At antithrombotic dose, the mean bleeding time ratio measured in a rabbit ear template model, was not prolonged over control values. At higher doses, the bleeding time ratios were higher than those observed for the same dosage of heparin. These data indicate that while r-hirudin is an effective antithrombotic agent, antithrombotic doses have to be carefully titrated to avoid excessive bleeding.

Social and political dimension of stigmatization: The development of Natasha and Maria images for immigrants in Istanbul

2016 ◽  
Vol 13 (1) ◽  
pp. 159-168
Author(s):  
Bayram Unal
Keyword(s):  
Public Perception ◽  
Daily Life ◽  
Legal Framework ◽  
State Law ◽  
Migrant Women ◽  
Political Dimension ◽  
Security Forces ◽  
Official Discourse ◽  
The Third ◽  
The Impact

This study aims at understanding how the perceptions about migrants have been created and transferred into daily life as a stigmatization by means of public perception, media and state law implementations.  The focus would be briefly what kind of consequences these perceptions and stigmatization might lead. First section will examine the background of migration to Turkey briefly and make a summary of migration towards Turkey by 90s. Second section will briefly evaluate the preferential legal framework, which constitutes the base for official discourse differentiating the migrants and implementations of security forces that can be described as discriminatory. The third section deals with the impact of perceptions influential in both formation and reproduction of inclusive and exclusive practices towards migrant women. Additionally, impact of public perception in classifying the migrants and migratory processes would be dealt in this section.

Graves' disease and radioiodine therapy

2008 ◽  
Vol 47 (04) ◽  
pp. 153-166 ◽  
Author(s):  
I. Weber ◽  
W. Eschner ◽  
F. Sudbrock ◽  
M. Schmidt ◽  
M. Dietlein ◽  
...  
Keyword(s):  
Success Rate ◽  
Thyroid Function ◽  
Therapeutic Dose ◽  
Radioiodine Therapy ◽  
Antithyroid Drugs ◽  
Graves Disease ◽  
Inclusion Criteria ◽  
End Point ◽  
Point Measure ◽  
The Impact

SummaryAim: This study was performed to analyse the impact of the choice of antithyroid drugs (ATD) on the outcome of ablative radioiodine therapy (RIT) in patients with Graves' disease. Patients, material, methods: A total of 571 consecutive patients were observed for 12 months after RIT between July 2001 and June 2004. Inclusion criteria were the confirmed diagnosis of Graves' disease, compensation of hyperthyroidism and withdrawal of ATD two days before preliminary radioiodine-testing and RIT. The intended dose of 250 Gy was calculated from the results of the radioiodine test and the therapeutically achieved dose was measured by serial uptake measurements. The end-point measure was thyroid function 12 months after RIT; success was defined as elimination of hyperthyroidism. The pretreatment ATD was retrospectively correlated with the results achieved. Results: Relief from hyperthyroidism was achieved in 96 % of patients. 472 patients were treated with carbimazole or methimazole (CMI) and 61 with propylthiouracil (PTU). 38 patients had no thyrostatic drugs (ND) prior to RIT. The success rate was equal in all groups (CMI 451/472; PTU 61/61; ND 37/38; p=0.22). Conclusion: Thyrostatic treatment with PTU achieves excellent results in ablative RIT, using an accurate dosimetric approach with an achieved post-therapeutic dose of more than 200 Gy.

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