Studies on the Molecular Pathology and Pathogenesis of Bleeding in Severe Fibrinolytic States in Dogs

Summary1. In the course of fibrinogen digestion by plasmin in a plasma medium in vitro “early” and “late” fibrinogen degradation products (FDP) are formed.2. The formation of the early FDP is correlated with the appearance of the “peak”, e.g. the highest plasma anticlotting activity. This activity after further FDP digestion with plasmin and formation of late FDP attains lower “plateau” values.3. A similar effect is observed after SKP1 infusion into dogs.4. The close similarity between the course of in vitro and in vivo digestion of fibrinogen allows to conclude that, as has been shown in purified systems, early FDP act predominantly as inhibitors of thrombin-fibrinogen reaction, whereas late FDP are responsible for the inhibition of fibrin monomer polymerization.5. Methods for identification and differentation of circulating FDP are described.6. The appearance of early FDP circulating in blood is correlated with the most pronounced prolongation of the bleeding time and with prof used bleeding.7. It has been shown that circulating FDP interference with platelet adhesiveness, aggregation and viscous metamorphosis, the effect of early FDP being more pronounced than that of late FDP.8. A concept is put forward according to which bleeding in plasma proteolytic states is due to the impairment of hemostatic function of platelets by FDP.

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In Vitro Formation of Fibrin-Monomer Complexes in the Presence of Isotope Labelled Fibrinogen-Fibrin Degradation Products. An Agarose Gel Filtration Study

10.1055/s-0039-1689556 ◽

1975 ◽

Author(s):

F. Asbeck ◽

van de J. Loo

Keyword(s):

Molecular Weight ◽

Complex Formation ◽

Degradation Products ◽

Gel Filtration ◽

Agarose Gel ◽

Fibrinogen Degradation Products ◽

Molecular Weights ◽

Fibrin Degradation Products ◽

Fibrin Monomer

Human citrated plasmas were mixed with purified 131I-fibrinogen and 131I-fibrinogen degradation products (FDP) or 125I-fibrin degradation products (fdp). After incubation with small amounts of thrombin (0.01–0.02 imits/ml Pl.), these mixtures were gel filtrated on Biogel A5m columns and the elution patterns of the 131I- and -labelled materials were determined.In control experiments without thrombin incubation, no complex formation between fibrinogen, FDP or fdp in citrated plasmas could be detected. This was even true for fdp with a higher molecular weight than fibrinogen.After thrombin incubation, up to 11% fibrin-monomer complexes were formed. Irrespective of their molecular weights, labelled fdp were not incorporated into these complexes.Only large FDP – presumably derivative X – did partially copolymerize with fibrin-monomer complexes in citrated plasmas.

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Change on Blood Coagulation, Platelet Function and Fibrinolysis in Diabetes Mellitus - Preliminary Report

10.1055/s-0039-1682387 ◽

1977 ◽

Author(s):

R. Giustolisi ◽

R. Musso ◽

T. Lombardo ◽

M. Russoand ◽

E. Cacciola

Keyword(s):

Diabetes Mellitus ◽

Degradation Products ◽

Vascular Wall ◽

Diabetic Patients ◽

Platelet Adhesiveness ◽

Platelet Factor ◽

Protamine Sulphate ◽

At Iii

Some coagulation aspects are studied in diabetes mellitus because this dismetabo-lic disease represents a “high risk factor” of predisposition leading to classical lesions of the vascular wall and thrombosis. Were studied 24 diabetic patients between 16 and 68 years old and 14 healthy subjects. Tests performed are followed: partial thromboplastyn time(PTT), plasma coagulation time RVV(RVV-T), antithrombin III(At-III), alpha2macroglobulin(a2M), fibrin/fibrinogen degradation products(FDP), ethanol gelation(EG) and protamine sulphate(PS), euglobulin lysis time(ELT), platelet adhesiveness to glass(PAG), platelet adhesiveness in vivo (PAV), platelet factor-3 availability(PF-3), platelet aggregation by ristocetin 1, 2-1, 5-1, 8 mg/ml(RIPA),Diabetics showed a fall in At-III, increase a2M, a significant decrease ELT and increase FDP with often positivity EG. We also noted a shortening of PTT, PF-3 rate and RVV-T. In vitro platelets adhesiveness rises more than it does in vivo. Besides the PPP from diabetics increased the control subjects PAG. The RIPA is increased. Our findings showed, therefore, in diabetic patients a thrombophilic pattern by blood hypercoagulability and fibrinolytic activity decreased.

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Comparison of High Purity Factor IX Concentrates and a Prothrombin Complex Concentrate in a Canine Model of Thrombogenicity

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646468 ◽

1991 ◽

Vol 66 (05) ◽

pp. 609-613 ◽

Cited By ~ 14

Author(s):

I R MacGregor ◽

J M Ferguson ◽

L F McLaughlin ◽

T Burnouf ◽

C V Prowse

Keyword(s):

High Purity ◽

Time Course ◽

Prothrombin Complex Concentrate ◽

Degradation Products ◽

Canine Model ◽

Factor Ix ◽

In Vitro Tests ◽

Albumin Infusion

SummaryA non-stasis canine model of thrombogenicity has been used to evaluate batches of high purity factor IX concentrates from 4 manufacturers and a conventional prothrombin complex concentrate (PCC). Platelets, activated partial thromboplastin time (APTT), fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A (FPA) were monitored before and after infusion of concentrate. Changes in FPA were found to be the most sensitive and reproducible indicator of thrombogenicity after infusion of batches of the PCC at doses of between 60 and 180 IU/kg, with a dose related delayed increase in FPA occurring. Total FPA generated after 100-120 IU/kg of 3 batches of PCC over the 3 h time course was 9-12 times that generated after albumin infusion. In contrast the amounts of FPA generated after 200 IU/kg of the 4 high purity factor IX products were in all cases similar to albumin infusion. It was noted that some batches of high purity concentrates had short NAPTTs indicating that current in vitro tests for potential thrombogenicity may be misleading in predicting the effects of these concentrates in vivo.

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Accumulation of Macromolecular Particles in the Reticuloendothelial System (RES) Mediated by Platelet Aggregation and Disaggregation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651386 ◽

1969 ◽

Vol 22 (03) ◽

pp. 496-507 ◽

Cited By ~ 17

Author(s):

W.G van Aken ◽

J Vreeken

Keyword(s):

Platelet Aggregation ◽

Degradation Products ◽

Reticuloendothelial System ◽

Caproic Acid ◽

Carbon Particles ◽

Carbon Clearance ◽

Aggregation And Disaggregation ◽

Platelet Aggregates

SummaryCarbon particles cause platelet aggregation in vitro and in vivo. Prior studies established that substances which modify thrombocyte aggregation also influence the rate at which carbon is cleared from the blood.This study was performed in order to elucidate the mechanism by which the carbon-platelet aggregates specifically accumulate in the RES.Activation of fibrinolysis by urokinase or streptokinase reduced the carbon clearance rate, probably due to generated fibrinogen degradation products (FDP). Isolated FDP decreased the carbon clearance and caused disaggregation of platelets and particles in vitro. Inhibition of fibrinolysis by epsilon-amino-caproic acid (EACA), initially accelerated the disappearance of carbon and caused particle accumulation outside the RES, predominantly in the lungs. It is supposed that platelet aggregation and locally activated fibrinolysis act together in the clearance of particles. In the normal situation the RES with its well known low fibrinolytic activity, becomes the receptor of the particles.

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The Effects of Brinolase (Fibrinolytic Enzyme from Aspergillus Oryzae) on Platelet Aggregation of Dog and Man

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649039 ◽

1972 ◽

Vol 28 (01) ◽

pp. 031-048 ◽

Cited By ~ 4

Author(s):

W. H. E Roschlau ◽

R Gage

Keyword(s):

Platelet Aggregation ◽

Aspergillus Oryzae ◽

Degradation Products ◽

Blood Platelet ◽

Human Platelets ◽

Fibrinolytic Enzyme ◽

Inhibitory Effects ◽

Blood Platelet Aggregation

SummaryInhibition of blood platelet aggregation by brinolase (fibrinolytic enzyme from Aspergillus oryzae) has been demonstrated with human platelets in vitro and with dog platelets in vivo and in vitro, using both ADP and collagen as aggregating stimuli. It is suggested that the optimal inhibitory effects of brinolase occur indirectly through the generation of plasma fibrinogen degradation products, without compromising platelet viability, rather than by direct proteolysis of platelet structures.

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Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648055 ◽

1976 ◽

Vol 36 (02) ◽

pp. 401-410 ◽

Cited By ~ 6

Author(s):

Buichi Fujttani ◽

Toshimichi Tsuboi ◽

Kazuko Takeno ◽

Kouichi Yoshida ◽

Masanao Shimizu

Keyword(s):

Guinea Pig ◽

Acetylsalicylic Acid ◽

Guinea Pigs ◽

Glass Bead ◽

Animal Species ◽

Inhibitory Effect ◽

Rabbit Platelet ◽

Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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The Spectrum of von Willebrand’s Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655015 ◽

1967 ◽

Vol 18 (01/02) ◽

pp. 040-056 ◽

Cited By ~ 13

Author(s):

E. J Walter Bowie ◽

P Didisheim ◽

J. H Thompson ◽

C. A Owen

Keyword(s):

Factor Viii ◽

Bleeding Time ◽

Severe Bleeding ◽

Platelet Adhesiveness ◽

Platelet Activity ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

The Third ◽

Generation Test

SummaryPatients (from 5 kindreds) with variants of von Willebrand’s disease are described. In one kindred the depression of factor VIII was moderate (20 to 40% of normal) and transfusion of 500 ml of normal plasma led to an increase higher than anticipated and to an almost normal level of factor VIII 17 to 24 hrs later. This represents the usual type of von Willebrand’s disease.In the second kindred the concentration of factor VIII was less than 2 % of normal in the son and daughter, who had severe bleeding and hemarthroses.The third kindred was characterized by reduction of factor VIII and a long bleeding time as well as by a serum defect in the thromboplastin-generation test comparable to that seen in patients with hemophilia B, yet with normal levels of factors IX, X, and VII. The severity of the serum defect, the positive result with the Rumpel-Leede test, and the reduced platelet activity in the thromboplastin-generation test are all compatible with the diagnosis of thrombopathy or ‘‘thrombopathic hemophilia.” In two other kindreds, one patient had a long bleeding time and normal levels of factor VIII and another had a normal bleeding time and decrease of factor VIII. The last patient had the type of response to transfusion usually seen in von Willebrand’s disease.In four kindreds, platelet adhesiveness in vivo was found to be strikingly abnormal (virtually absent).It would appear, therefore, that von Willebrand’s disease forms a spectrum, and whether the kindreds reported simply reflect variations of a single genetic disease state or represent separate entities will be answered only by clarification of the underlying etiology of that disease.

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The Leukocyte Digestion of Fibrinogen Degradation Products (FDP)

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653705 ◽

1971 ◽

Vol 26 (03) ◽

pp. 523-525

Author(s):

K Gibiński ◽

B Lipiński ◽

M Trusz-Gluza

Keyword(s):

Degradation Products ◽

Fibrinogen Degradation Products

SummaryWhile the native fibrinogen is not digested by the leucocyte proteases both the early and late FDP are digestible without any denaturating reagent. Thus, this reaction may occur in vivo indicating an unknown role of granulocytes in paracoagulation.

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Solubility and ADMET profiles of short oligomers of lactic acid

ADMET & DMPK ◽

10.5599/admet.843 ◽

2020 ◽

Cited By ~ 1

Author(s):

Daniela Dascălu ◽

Diana Larisa Roman ◽

Madalina Filip ◽

Alecu Aurel Ciorsac ◽

Vasile Ostafe ◽

...

Keyword(s):

Molecular Weight ◽

Glucocorticoid Receptors ◽

Degradation Products ◽

Organic Anion ◽

Toxicity Tests ◽

Medical Applications ◽

Eye Injuries ◽

Toxicological Effects

<p class="ADMETkeywordsheading">Polylactic acid (PLA) is a polymer with an increased potential to be used in different medical applications, including tissue engineering and drug-carries. The use of PLA in medical applications implies the evaluation of the human organism's response to the polymer inserting and to its degradation products. Consequently, within this study, we have investigated the solubility and ADMET profiles of the short oligomers (having the molecular weight lower than 3000 Da) resulting in degradation products of PLA. There is a linear decrease of the molar solubility of investigated oligomers with molecular weight. The results that are obtained also reveal that short oligomers of PLA have promising pharmacological profiles and limited toxicological effects on humans. These oligomers are predicted as potential inhibitors of the organic anion transporting peptides OATP1B1 and OATP1B3, they present minor probability to affect the androgen and glucocorticoid receptors, have a weak potential of hepatotoxicity, and may produce eye injuries. These outcomes may be used to guide or to supplement in vitro and/or in vivo toxicity tests such as to enhance the biodegradation properties of the biopolymer.</p>

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A Validated HPLC-PDA-HRMS Method to Investigate the Biological Stability and Metabolism of Antiparasitic Triterpenic Esters

Molecules ◽

10.3390/molecules26237154 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7154

Author(s):

Laura Schioppa ◽

Fanta Fall ◽

Sergio Ortiz ◽

Jacques H. Poupaert ◽

Joelle Quetin-Leclercq

Keyword(s):

Medicinal Plants ◽

Degradation Products ◽

Biological Stability ◽

Acidic Media ◽

Microsomal Metabolism ◽

Plasma Enzymes ◽

Absorption Studies ◽

H 30

Pentacyclic triterpenes (PTs) are commonly found in medicinal plants with well-known antiparasitic effects. Previous research on C-3 and C-27 triterpenic esters showed effective and selective in vitro antiparasitic activities and in vivo effectiveness by parenteral routes. The aim of this study was to determine triterpenic esters’ stability in different biological-like media and the main microsomal degradation products. An HPLC-PDA method was developed and validated to simultaneously analyze and quantify bioactive triterpenic esters in methanol (LOQ: 2.5 and 1.25–100 µg/mL) and plasma (LOQ: 5–125 µg/mL). Overall, both triterpenic esters showed a stable profile in aqueous and buffered solutions as well as in entire plasma, suggesting gaining access to the ester function is difficult for plasma enzymes. Conversely, after 1 h, 30% esters degradation in acidic media was observed with potential different hydrolysis mechanisms. C-3 (15 and 150 µM) and C-27 esters (150 µM) showed a relatively low hepatic microsomal metabolism (<23%) after 1 h, which was significantly higher in the lowest concentration of C-27 esters (15 µM) (>40% degradation). Metabolic HPLC-PDA-HRMS studies suggested hydrolysis, hydroxylation, dehydration, O-methylation, hydroxylation and/or the reduction of hydrolyzed derivatives, depending on the concentration and the position of the ester link. Further permeability and absorption studies are required to better define triterpenic esters pharmacokinetic and specific formulations designed to increase their oral bioavailability.

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