Experimental Pharmacology of Hirunorm: a Novel Synthetic Peptide Thrombin Inhibitor

1996 ◽  
Vol 76 (03) ◽  
pp. 384-392 ◽  
Author(s):  
Rocco Cirillo ◽  
Annalisa Lippi ◽  
Alessandro Subissi ◽  
Giancarlo Agnelli ◽  
Marco Criscuoli
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Coronary Thrombosis ◽  
Vena Cava ◽  
Thrombin Inhibitor ◽  
Similar Species ◽  
Thrombin Activity ◽  
Experimental Pharmacology ◽  
Anaesthetized Rats

SummaryEnhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking a-thrombin amidolytic activity (IC50 = 10 ± 2,15 ± 1 and 0.3 ± 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 μM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 μM for aPTT and 0.8 to 17 μM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against a-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (≤0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i. v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.

BCH-2763, a Novel Potent Parenteral Thrombin Inhibitor, Is an Effective Antithrombotic Agent in Rodent Models of Arterial and Venous Thrombosis – Comparisons with Heparin, r-Hirudin, Hirulog, Inogatran and Argatroban

1998 ◽  
Vol 79 (02) ◽  
pp. 431-438 ◽  
Author(s):  
Carolyn Finkle ◽  
Annie Pierre ◽  
Lorraine Leblond ◽  
Isabelle Deschenes ◽  
John DiMaio ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Antithrombotic Agent ◽  
Plasma Clot ◽  
Antithrombotic Efficacy

SummaryCurrent clinical use of heparin as an antithrombotic agent is limited by suboptimal efficacy and safety considerations. Thrombin’s central role in thrombosis makes it an attractive target to develop more effective and safer antithrombotic agents. BCH-2763 is a novel, potent (Ki: 0.11 nM), low molecular weight (1.51 kDa), bivalent direct thrombin inhibitor. The antithrombotic efficacy of BCH-2763 in vivo following i.v. bolus plus infusion in rats was compared in arterial and venous thrombosis models with two other bivalent direct thrombin inhibitors, r-hirudin and hirulog, with two catalytic site-directed thrombin inhibitors, inogatran and argatroban, and with heparin. In vivo efficacy was related to inhibition in vitro of fibrin clot formation, thrombin-induced aggregation of rat or human washed platelets and activity of free and plasma clot-bound thrombin. All the direct thrombin inhibitors were effective on both arterial and venous thrombosis at markedly lower fold aPTT increases than heparin. The antithrombotic doses of all inhibitors against venous thrombosis were less than against arterial thrombosis. The rank order of potency based on doses (mg/kg/h) required for full efficacy against arterial thrombosis was BCH-2763 (1.2) inogatran (1.5) r-hirudin (1.8) hirulog (3.3) argatroban ( 3.0); heparin required a markedly higher dose (5.7). In venous thrombosis the doses required for full efficacy were substantially lower for the bivalent (BCH-2763: 0.12; r-hirudin: 0.12; hirulog: 0.18) than for the catalytic site-directed (inogatran: 0.48; argatroban: 0.90) thrombin inhibitors; the dose required for heparin was 0.19. All the direct thrombin inhibitors caused similar shifts in aPTT at doses required to inhibit arterial thrombosis, but BCH-2763 inhibited venous thrombosis at lower aPTT fold increases. In vivo antithrombotic efficacy of direct thrombin inhibitors correlated with their inhibitory activity in vitro against fibrin clot formation and platelet aggregation. In contrast to heparin, all the direct thrombin inhibitors inhibited plasma clot-bound thrombin, but the relative IC50s did not correlate with their antithrombotic efficacy. In summary, direct thrombin inhibitors are more effective than heparin in inhibiting arterial and venous thrombosis in rats with less aPTT increases. BCH-2763 is effective at lower doses than the other direct thrombin inhibitors and for venous thrombosis at a smaller aPTT increase. BCH-2763 may offer an improved therapeutic index in the treatment of thromboembolic complications over heparin and other direct thrombin inhibitors.

The Antithrombotic Efficacy of AT-1459, a Novel, Direct Thrombin Inhibitor, in Rat Models of Venous and Arterial Thrombosis

2001 ◽  
Vol 86 (12) ◽  
pp. 1512-1520 ◽  
Author(s):  
Chi-ho Yun ◽  
Hyoung-sik Seo ◽  
Takaki Koga ◽  
Takashi Dan ◽  
Hak-yeop Kim ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Direct Thrombin Inhibitor ◽  
Vehicle Group ◽  
Thrombin Inhibitor ◽  
Rat Models ◽  
Vessel Patency ◽  
Antithrombotic Efficacy

SummaryThe antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis.After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50 (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively.In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P <0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively.The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times.These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.

EP217609, a neutralisable dual-action FIIa/FXa anticoagulant, with antithrombotic effects in arterial thrombosis

2015 ◽  
Vol 113 (02) ◽  
pp. 385-395 ◽  
Author(s):  
Ghina Alame ◽  
Pierre H. Mangin ◽  
Monique Freund ◽  
Nadia Riehl ◽  
Stéphanie Magnenat ◽  
...  
Keyword(s):  
Blood Loss ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Parent Compound ◽  
Thrombin Inhibitor ◽  
Potential Candidate ◽  
Low Doses ◽  
Response Curves ◽  
Dual Action

SummaryEP217609 is a new synthetic parenteral dual-action anticoagulant combining a direct thrombin inhibitor (α-NAPAP analog), an indirect factor Xa inhibitor (fondaparinux analog) and a biotin moiety allowing its neutralisation. EP217609 exhibited similar in vitro anticoagulant properties as its parent compounds. On the basis of dose-response curves, we identified low and moderate doses of EP217609 resulting in similar ex vivo prolongation of the APTT as α-NAPAP analog and comparable ex vivo anti-FXa activity as fondaparinux. The effects of EP217609 were compared to those of its parent compounds used alone or in combination in two models of experimental thrombosis induced by FeCl3 injury of the carotid artery or mechanical injury of atherosclerotic plaques in ApoE-deficient mice. When administered at low doses increasing the APTT by only 1.1 fold, EP217609 significantly reduced the thrombus area in both models as compared to α-NAPAP analog or fondaparinux alone, but not to the combination of these drugs. In contrast, at higher doses increasing the APTT 1.5 times, EP217609 was not superior to either parent compound. Low doses of EP217609 did not prolong the tail bleeding time or increase the volume of blood loss, although a tendency towards an increased blood loss was observed in five out of 12 mice. Finally, the effects of EP217609 could be neutralised in vivo by injection of avidin. The pharmacological profile of EP217609, its performance in arterial thrombosis models and its possible neutralisation make it an interesting molecule and a potential candidate as an antithrombotic drug.

Nitric Oxide and Prostacyclin Are Involved in Antithrombotic Action of Captopril in Venous Thrombosis in Rats

1998 ◽  
Vol 79 (06) ◽  
pp. 1208-1212 ◽  
Author(s):  
Ewa Chabielska ◽  
Janusz Golatowski ◽  
Arsalan Azzadin ◽  
Włodzimierz Buczko ◽  
Robert Pawlak
Keyword(s):  
Venous Thrombosis ◽  
Enzyme Inhibitors ◽  
Coronary Thrombosis ◽  
Vena Cava ◽  
Concomitant Administration ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Left Ventricular ◽  
Converting Enzyme Inhibitors ◽  
Term Administration ◽  
Synthase Inhibitor

SummaryThe long-term administration of captopril to patients with a left ventricular dysfunction after myocardial infarction reduces the rate of recurrent coronary thrombosis. Thus, in the present study we investigated the influence of angiotensin-converting enzyme inhibitors (ACE-Is) on experimental venous thrombosis in normotensive rats and the involvement of NO and PGI2 in this effect. Animals were treated with captopril (1.5, 5 or 25 mg/kg twice daily, CAP), enalapril (15 mg/kg once daily, ENA) or distilled water for 10 days, per os. After ligation of the vena cava the thrombus weight decreased in both CAP and ENA treated rats. The effect was most pronounced in animals given the highest dose of CAP (p<0.0001 vs. control) and was significantly stronger than observed in ENA treated animals (CAP vs. ENA p<0.01). The mean blood pressure measured by the “tail cuff” method and platelet aggregation were not altered by either of the ACE-Is. The antithrombotic activity of CAP was reduced by indomethacin (2.5 mg/kg, s.c.) and independently by the NO-synthase inhibitor NG-nitro L-arginine methyl ester (3 mg/kg i.v. bolus + 3 mg/kg/h i.v. infusion, L-NAME). In the latter case CAP regained its antithrombotic properties in rats pretreated with L-Arginine (300 mg/kg i.v. + 300 mg/kg/h i.v.) before administration of L-NAME (p<0.05 vs. control). Moreover, the concomitant administration of indomethacin and L-NAME failed to completely abolish the antithrombotic action of captopril. Similar effects were observed in respect to the incidence of venous thrombosis. Our study documents a novel and important effect of ACE-Is on the vein thrombotic process and demonstrates the involvement of NO and PGI2 in this phenomenon.

Study of a new benzimidazole derivative having in its structure a sterically hindered phenolic substituent on models of arterial and venous thrombosis

2020 ◽  
Author(s):  
А.А. Спасов ◽  
А.Ф. Кучерявенко ◽  
К.А. Гайдукова ◽  
В.С. Сиротенко ◽  
О.Н. Жуковская
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Benzimidazole Derivative ◽  
Vena Cava ◽  
Male Rats ◽  
Control Group ◽  
Vena Cava Inferior ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Venous Thromboses

Введение: Тромбоциты являются ключевыми медиаторами патогенеза артериальных тромбозов и атеросклероза. Поэтому изучение антиагрегантных средств на предмет антитромботической активности на различных моделях артериальных и венозных тромбозов является актуальным. Цель исследования: изучение антитромботической активности соединения РУ-1144 (производного бензимидазола) в сравнении с ацетилсалициловой кислотой (АСК) и клопидогрелом на моделях артериального и венозного тромбозов. Материалы и методы: Артериальный тромбоз моделировали на сонной артерии крыс-самцов аппликацией постоянного электрического тока. Воздействие на сосуд выполняли до момента полной окклюзии, регистрируемой на мониторе доплерографа. Венозной тромбоз моделировали на крысах-самцах полной перевязкой нижней полой вены на 24 ч; через сутки проводили изъятие тромба из сосуда и его взвешивание. В экспериментальных группах животным внутрижелудочно вводили соединение РУ-1144 и препараты сравнения — АСК и клопидогрел, в контрольной группе животным внутрижелудочно вводили дистиллированную воду. Для подтверждения отсутствия влияния хирургических манипуляций на организм животного в исследование модели венозного тромбоза была включена группа ложнооперированных крыс. Результаты: На модели артериального тромбоза установлена более высокая антитромботическая активность соединения РУ-1144 по сравнению с АСК и клопидогрелом в 2,5 и 7,4 раза соответственно. В модели венозного тромбоза соединение РУ-1144 уменьшало среднюю массу венозных тромбов в 5,3 раза по сравнению с группой контроля и превосходило по антитромботической активности АСК и клопидогрел в 3,5 и 1,9 раза. Заключение: Соединение РУ-1144 способно предотвращать патологические процессы, связанные с тромбообразованием, не только в сонной артерии, но и в нижней полой вене. Background: Platelets are key mediators of the pathogenesis of arterial thrombosis and atherosclerosis. So, that is actual to study antithrombotic activity of antiplatelet agents in various models of arterial and venous thromboses. Objectives: to study the antithrombotic activity of RU-1144 compound (benzimidazole derivative) as compared with acetylsalicylic acid (ASA) and clopidogrel on models of arterial and venous thromboses. Materials/Methods: Arterial thrombosis was modeled on the carotid artery of male rats by application of direct electric current. Exposure was performed until full vessel occlusion recorded by Dopplerograf. Venous thrombosis was modeled on male rats by complete ligation of vena cava inferior for 24 hours; a day later the thrombus was removed from the vessel and weighed. In the experimental groups the animals were injected intragastrically with the compound RU-1144 and the comparison drugs — ASA and clopidogrel; in the control group the animals were administered distilled water intragastrically. To confirm the absence of the effect of surgical manipulations on the animal’s organism, a group of false-operated rats was included in the study of venous thrombosis model. Results: In arterial thrombosis model RU-1144 compound had a higher antithrombotic activity as compared with ASA and clopidogrel by 2.5 and 7.4 times, respectively. In venous thrombosis model RU-1144 compound reduced the average weight of venous clots by 5.3 times as compared with the control group and exceeded antithrombotic activity of ASA and clopidogrel by 3.5 and 1.9 times. Conclusions: RU-1144 compound capable to prevent the pathological processes associated with thrombus formation in carotid artery as well as in vena cava inferior.

Inflammatory and Procoagulant Mediator Interactions in an Experimental Baboon Model of Venous Thrombosis

1993 ◽  
Vol 69 (02) ◽  
pp. 164-172 ◽  
Author(s):  
Thomas W Wakefield ◽  
Lazar J Greenfield ◽  
Mark W Rolfe ◽  
Alphonse DeLucia ◽  
Robert M Strieter ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Vena Cava ◽  
Venous Catheter ◽  
In Vivo Model ◽  
Cell Counts ◽  
Chemotactic Protein ◽  
White Blood Cell Counts ◽  
Differential White Blood Cell

SummaryTheoretic and in vitro evidence suggests that thrombosis and inflammation are interrelated. The purpose of the present study was to define the relationship between inflammation and deep venous thrombosis (DVT) in an in vivo model. Initiation of DVT was accomplished by administration of antibody to protein C (HPC4, 2 mg/kg) and tumor necrosis factor (TNF, 150 μg/kg); stasis; and subtle venous catheter injury. Thrombosis was assessed by thrombin-antithrombin assay (TAT), 125I-fibrinogen scanning (scan) over both the proximal and distal iliac veins, and ascending venography. Cytokines TNF, interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8) were measured along with differential white blood cell counts, platelet counts, fibrinogen (FIB), and erythrocyte sedimentation rates (ESR). Baboon pairs were sacrificed on day 3 (T + 3d), T + 6d, and T + 9d and veins removed. All animals developed inferior vena cava and left iliofemoral DVT by venography; no right DVT was found. TAT was elevated by T + 1hr and peaked at T + 3hrs. Left iliofemoral DVT was found at T + 1hr by scan and reached a 20% uptake difference between the affected left and nonaffected right side at T + 3hrs. TNF peaked at T + 1hr; MCP-1 peaked at T + 6hrs; IL-8 and IL-6 peaked on T + 2d; all cytokines declined to baseline. TNF and TAT elevations were found to correlate with all cytokines; elevations in IL-8 were correlated with elevations in MCP-1 and IL-6 (p <0.05). Correlation between cytokines and scan revealed a significant (p <0.05) relationship only between elevations in IL-6 and distal iliac fibrin accumulation; no significant correlation was found between IL-8 and MCP-1 and scan. Increased mature polymorphonuclear leukocytes were found by T + 2d; immature forms were prominent at T + 3hrs, T + 6hrs, and T + 2d. Increased monocytes were noted by T + 4d; increased lymphocytes and platelets by T + 8d. ESR and FIB were elevated by T + 3d. Histopathologic study revealed venous inflammation at T + 3d, with beginning thrombus organization by T + 6d. MCP-1 localized to areas of thrombus and phlebitis. The development of DVT in this model involves inflammatory as well as coagulant activity. We conclude that this model allows studies on the role of inflammatory mediators in the development and natural history of DVT.

Venous, Arterial and Endocardio Multiple Thrombosis with Consumption Coagulapathy and Cryofibrinogen due to Ovarian Carcinoma Temporary Improvement with Heparin

1975 ◽  
Author(s):  
J. Favre-Gilly ◽  
D. Michel ◽  
M. Tommasi
Keyword(s):  
Ovarian Carcinoma ◽  
Arterial Thrombosis ◽  
Coronary Thrombosis ◽  
Left Kidney ◽  
Vena Cava ◽  
Lower Limbs ◽  
Post Mortem ◽  
Cerebral Thrombosis ◽  
Recurrent Thrombosis ◽  
Post Mortem Examination

A 54 years old woman successively developed thrombophlebitis of lower limbs, cerebral thrombosis with right hemiplegia, coronary thrombosis and arterial thrombosis of upper and lower limbs. Haematuria and large bruises led to find thrombopenia and lower levels of fibrinogen, prothrombin, factors V and VIII, with cryofibrinogen. Heparin stopped haemorrages and defibrination and improved thrombosis during 2 weeks, but the patient died of recurrent thrombosis extended to upper vena cava. Post mortem examination allowed to find many thrombi on endocardium and in large and small vessles, both arterial and venous. There were many infarcts in brain, myocardium, splen, and left kidney. Ovaries were both carcinomatous.

“Inflammatory Bowel Disease—Not Just the Bowel’s Bane”: Peripheral Arterial and Venous Thrombosis in a Patient With Crohn Disease

2020 ◽  
Vol 54 (7) ◽  
pp. 646-649
Author(s):  
Leora Boussi ◽  
Aditya Safaya ◽  
Arun Goyal ◽  
Romeo Mateo ◽  
Igor Laskowski ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Lower Extremity ◽  
Venous Thrombosis ◽  
Crohn Disease ◽  
Bowel Disease ◽  
Arterial Thrombosis ◽  
Vena Cava ◽  
Vascular Complications ◽  
Arm Pain ◽  
Inflammatory Bowel

Introduction: Inflammatory bowel disease (IBD) is a chronic multisystem inflammatory condition with associated endothelial dysfunction and dysregulated coagulation. Although deep venous thrombosis (DVT) in IBD has been well described, arterial thrombosis and thromboembolism are less commonly appreciated. Methods: A 63-year-old male with a known history of Crohn disease presented with acute-onset right arm pain. His past vascular history was significant for left lower extremity DVT with an existing inferior vena cava filter and acute ischemia of the right lower extremity requiring a below-knee amputation a year ago. Imaging revealed acute brachial, ulnar, and radial artery thrombosis. Results: Patient underwent an open right brachial, radial, and ulnar thrombectomy to restore vascular flow. He required multiple exploration and thrombectomy for reocclusion of the vessels in the early postoperative period. He later developed a rapidly deteriorating clinical status, flank ecchymosis and swelling concerning for soft tissue ischemia, and compartment syndrome heralding an eventual hemodynamic collapse. On exploration, he was found to have chronic fibrosis of his left femoral vein and femoral artery occlusion. Clinically, the patient deteriorated rapidly, which resulted in his demise. Conclusion: The inflammatory reaction in IBD leads to arterial stiffening and hypercoagulability, which should theoretically increase the risk for vascular disease. Although the link between IBD and DVT is well established, arterial thrombosis and thromboembolism remain widely debated, with some implications for therapeutic intervention. The link between vascular thrombosis and IBD must be examined further, as the treatment and prevention of vascular complications in IBD depends on our understanding of this relationship.

Antithrombotic Properties of DU-176b, a Novel, Potent and Orally Active Direct Factor Xa Inhibitor in Rat Models of Arterial and Venous Thrombosis: Comparison with Fondaparinux, an Antithrombin Dependent Factor Xa Inhibitor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1852-1852 ◽  
Author(s):  
Toshio Fukuda ◽  
Chikako Matsumoto ◽  
Yuko Honda ◽  
Nobutoshi Sugiyama ◽  
Yoshiyuki Morishima ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Dose Range ◽  
Vena Cava ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Factor Xa Inhibitor ◽  
Rat Models ◽  
Fxa Inhibitor

Abstract Factor Xa (FXa) is an attractive target for the treatment of thrombosis due to its crucial role in the blood coagulation cascade. Fondaparinux, a selective FXa inhibitor, has been approved for clinical use to prevent deep vein thrombosis after orthopedic surgery; however, it requires antithrombin (AT) to exert its antithrombotic effect. It is reported that AT dependent anticoagulants such as heparin are less effective to suppress platelet-rich arterial-type thrombus due to its inaccessibility to thrombus-bound FXa/thrombin. We have developed a potent direct (i.e. AT independent) FXa inhibitor, DU-176b. The objective of this study is to compare the antithrombotic properties of a direct selective FXa inhibitor, DU-176b, with an AT dependent selective FXa inhibitor, fondaparinux. We evaluated the antithrombotic effects of DU-176b and fondaparinux in rat models of arterial and venous thrombosis. The arterial and venous thrombosis was induced by topical application of ferric chloride to the carotid artery and by insertion of a platinum wire into the inferior vena cava, respectively. DU-176b (0.05 – 1.25 mg/kg/h) and fondaparinux (1 – 10 mg/kg/h for arterial thrombosis and 0.03 – 1 mg/kg/h for venous thrombosis) were intravenously administered as continuous infusions. DU-176b prevented both arterial and venous thrombosis in the same dose range. In contrast, the effective doses of fondaparinux markedly differed between these models. A higher dose of fondaparinux more than 100 times was required to inhibit arterial thrombosis compared with venous thrombosis. These results suggest that direct inhibition of FXa is a preferable strategy to AT dependent inhibition for the prevention of thrombus formation in the arteries.

Relative Efficacy of Active Site-Blocked Factors IXa, Xa in Models of Rabbit Venous and Arterio-Venous Thrombosis

1997 ◽  
Vol 77 (06) ◽  
pp. 1143-1147 ◽  
Author(s):  
Arnold G Wong ◽  
Alice C Gunn ◽  
Paul Ku ◽  
Stanley J Hollenbach ◽  
Uma Sinha
Keyword(s):  
Venous Thrombosis ◽  
Vena Cava ◽  
Factor Xa ◽  
Relative Efficacy ◽  
Antithrombotic Activity ◽  
Chloromethyl Ketone ◽  
Venous Shunt ◽  
Ic50 Values ◽  
Cotton Threads

SummaryIn order to investigate the respective roles of prothrombinase and intrinsic tenase (IXa/VIIIa) in venous thrombosis, we compared the antithrombotic efficacy of inhibitors of these two coagulation complexes. The agents tested were dansyl-Glu-Gly-Arg chloromethyl ketone-inactivated bovine factor IXa (IXai) and Glu-Gly-Arg chloromethyl ketone- inactivated human factor Xa (Xai). In vitro formation of active complexes (prothrombinase or tenase) was inhibited by Xai and IXai resulting in IC50 values of 3 nM and 5 nM, respectively. Antithrombotic activity was measured by inhibition of clot accretion on cotton threads placed in the abdominal vena cava of anesthetized rabbits. Intravenous bolus dosing followed by infusion of Xai during the experimental protocol resulted in a dose dependent reduction of clot weight, a dosage of 16.0 μg/kg + 0.28 μg/kg/min being sufficient to produce a 96% inhibition of thrombosis. A much higher dose of IXai (1.0 mg/kg + 17.3 |ig/kg/min) resulted in a 39% reduction of clot weight. In a rabbit arterio-venous shunt model mimicking arterial thrombosis, the relative efficacy of the two agents was found to be more comparable. The doses required for optimum antithrombotic activity were 128.0 μg/kg + 2.2 μg/kg/min for Xai and 1.0 mg/kg+ 17.3 μg/kg/min for IXai. We conclude that, in this study, prothrombinase rather than tenase inhibition was more effective in reducing venous thrombosis and that these effects can be achieved without disruption of extravascular hemostasis.

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