scholarly journals Screening of the Promising Direct Thrombin Inhibitors from Haematophagous Organisms. Part I: Recombinant Analogues and Their Antithrombotic Activity In Vitro

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 11
Author(s):  
Maria A. Kostromina ◽  
Elena A. Tukhovskaya ◽  
Elvira R. Shaykhutdinova ◽  
Gulsara A. Slashcheva ◽  
Alina M. Ismailova ◽  
...  
Keyword(s):  
High Specificity ◽  
Coronary Intervention ◽  
Percutaneous Transluminal Coronary Angioplasty ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Thrombin Time ◽  
Biotechnological Production ◽  
Recombinant Hirudin ◽  
Natural Analog

The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis(desirudin), being the first-known and most well-studied natural anticoagulant, along with recombinant analogs of haemadin from the leech Haemadipsa sylvestris, variegin from the tick Amblyomma variegatum, and anophelin from Anopheles albimanus. These polypeptides were chosen due to their high specificity and affinity for thrombin, as well as their distinctive inhibitory mechanisms. We have developed a universal scheme for the biotechnological production of these recombinant peptides as pharmaceutical substances. The anticoagulant activities of these peptides were compared using the thrombin amidolytic activity assay and prolongation of coagulation time (thrombin time, prothrombin time, and activated partial thromboplastin time) in mouse and human plasma. The preliminary results obtained suggest haemadin as the closest analog of recombinant hirudin-1, the active substance of the medicinal product Iprivask (Aventis Pharmaceuticals, USA) for the prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery. In contrast, variegin can be regarded as a natural analog of bivalirudin (Angiomax, The Medicines Company), a synthetic hirudin-1 derivative certified for the treatment of patients undergoing percutaneous coronary intervention and of patients with unstable angina pectoris after percutaneous transluminal coronary angioplasty.

scholarly journals Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1248-1255 ◽  
Author(s):  
Krystin Krauel ◽  
Christine Hackbarth ◽  
Birgitt Fürll ◽  
Andreas Greinacher
Keyword(s):  
Factor Xa ◽  
Platelet Factor 4 ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Alternative Anticoagulation ◽  
Heparin Complexes ◽  
History Of

Abstract Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti-PF4/heparin Abs with platelets. In contrast, ODSH inhibited PF4 binding to gel-filtered platelets, displaced PF4 from a PF4-transfected cell line, displaced PF4/heparin complexes from platelet surfaces, and inhibited anti-PF4/heparin Ab binding to PF4/heparin complexes and subsequent platelet activation. Dabigatran and rivaroxaban seem to be options for alternative anticoagulation in patients with a history of HIT. ODSH prevents formation of immunogenic PF4/heparin complexes, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin.

scholarly journals Bivalirudin Use in an Infant With Persistent Clotting on Unfractionated Heparin

2011 ◽  
Vol 16 (2) ◽  
pp. 108-112
Author(s):  
Katherine M. Malloy ◽  
Tara A. McCabe ◽  
Robert J. Kuhn
Keyword(s):  
Unfractionated Heparin ◽  
Pediatric Population ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
First Year ◽  
Heparin Infusion ◽  
Percutaneous Coronary ◽  
First Year Of Life

ABSTRACT Bivalirudin is a direct thrombin inhibitor approved for use in adult patients with heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention. Recently, its use in the pediatric population has increased due to its anti-thrombin-independent mechanism of action. As heparin products produce great inter- and intraindividual variability in pediatric patients, often due to decreased anti-thrombin concentrations in the first year of life, some practitioners have turned to direct thrombin inhibitors, such as bivalirudin, for more predictable pharmacokinetics and effects on bound and circulating thrombin. We report our experience using bivalirudin in a 2-month-old female with recurrent systemic thrombi despite continuous unfractionated heparin infusion. Due to the patient's inability to maintain therapeutic activated partial thromboplastin time (aPTT) values during heparin infusion, bivalirudin was initiated at 0.1 mg/kg/h and increased due to subtherapeutic aPTTs to a maximum of 0.58 mg/kg/h. Therapeutic aPTTs were achieved at the increased dose; however, the patient's worsening renal impairment with resultant drug accumulation and overwhelming sepsis on day 5 of therapy led to discontinuation of the infusion and the initiation of comfort measures.

scholarly journals Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cho Yeow Koh ◽  
Norrapat Shih ◽  
Christina Y. C. Yip ◽  
Aaron Wei Liang Li ◽  
Weiming Chen ◽  
...  
Keyword(s):  
Antiplatelet Therapy ◽  
Anticoagulant Activity ◽  
Standard Of Care ◽  
Therapeutic Index ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Human Antibody ◽  
Next Generation ◽  
Pharmacologic Activity

AbstractDespite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.

The Effect of Antithrombin III-Independent Thrombin Inhibitors and Heparin on Fibrin Accretion onto Fibrin-Coated Polyethylene

1993 ◽  
Vol 69 (02) ◽  
pp. 130-134 ◽  
Author(s):  
F D Rubens ◽  
J I Weitz ◽  
J L Brash ◽  
R L Kinlough-Rathbone
Keyword(s):  
Vascular Graft ◽  
Antithrombin Iii ◽  
Vascular Grafts ◽  
Barium Chloride ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Recombinant Hirudin ◽  
Graft Thrombosis ◽  
Polyethylene Tubing

SummaryProsthetic vascular grafts become coated with a layer of fibrin that contributes to graft thrombosis and occlusion. We compared the effect of antithrombin III-independent inhibitors of thrombin with heparin for their ability to prevent fibrin accretion onto a model of a vascular graft formed in vitro by coating polyethylene tubing with thrombin bound to a layer of polymerized fibrin. Equivalent antithrombin concentrations of heparin, D-Phe-Pro-Arg CH2Cl (PPACK), recombinant hirudin (r-hirudin), and Hirulog-1 were added to barium chloride-adsorbed plasma containing radiolabelled fibrinogen. Whereas, PPACK and r-hirudin persistently inhibited fibrin accretion, the inhibition by heparin was transient. Hirulog-1 had no effect on early fibrin accretion and was actually associated with enhanced accretion at 30 min (control 11.7 ± 2.0 μg fibrin/cm2; Hirulog-1, 18.4 ± 3.5 μg fibrin/cm2, p <0.001). Both Hirulog-1 and r-hirudin displaced radiolabelled thrombin from the fibrin surface. Whereas hirudin-thrombin complexes are stable, Hirulog-1 produces only transient inhibition of the displaced thrombin thereby accounting for the enhanced fibrin accretion with this anticoagulant. These studies show that the antithrombin III-independent inhibitors, r-hirudin and PPACK, are more effective inhibitors of fibrin accretion onto fibrin-coated polyethylene than heparin or Hirulog-1. In addition, they emphasize the importance of determining the ability of anticoagulants to displace thrombin from fibrin and to form stable thrombin-inhibitor complexes; lack of stability of thrombin-inhibitor complexes must be countered by levels of anticoagulant that are adequate to maintain its effectiveness.

A marriage of enhancement: fibrinolysis and conjunctive therapy

2004 ◽  
Vol 92 (12) ◽  
pp. 1194-1200 ◽  
Author(s):  
Robert Welsh ◽  
Paul Armstrong
Keyword(s):  
Coronary Intervention ◽  
The Elderly ◽  
Added Value ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
St Segment Elevation ◽  
St Segment ◽  
Percutaneous Coronary

SummaryPharmacologic reperfusion of patients with acute ST segment elevation myocardial infarction is designed to achieve prompt high-quality reperfusion, prevent recurrent ischemia and reinfarction, maintain long-term patency, and to enhance patient survival and quality of life. Because monotherapy with fibrinolytics is by itself unable to achieve all of these objectives, antithrombotic, anti-platelet, and other novel agents are required. We discuss herein the role of unfractionated and enoxaparin, the potential added value of direct thrombin inhibitors, and the importance of aspirin. Despite the promise of glycoprotein IIb/IIIa inhibitors, risks associated with intracranial hemorrhage in the elderly have led to restraint in their application to broad populations. Facilitation of urgent percutaneous coronary intervention with combination reduced-dose fibrinolytic and glycoprotein IIb/IIIa inhibitors remains a promising potential future path. The future is likely to emphasize greater application of the already effective therapies at our disposal and the development of novel anti-platelet and anti-thrombin agents as well as those directed toward inflammation.

The Research Progress of Direct Thrombin Inhibitors

2020 ◽  
Vol 20 (16) ◽  
pp. 1574-1585
Author(s):  
Zhi-Gang Sun ◽  
Yang-Liu ◽  
Jin-Mai Zhang ◽  
Shi-Chang Cui ◽  
Zhi-Gang Zhang ◽  
...  
Keyword(s):  
High Specificity ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Thrombin Inhibitors ◽  
Research Progress ◽  
Direct Thrombin Inhibitors ◽  
Design Synthesis ◽  
Anticoagulant Drug ◽  
Strong Action ◽  
Important Significance

Blood coagulation is the process of changing the blood from the flowing state to the gel state. It is an important part of the hemostatic function. Coagulation is a process by which a series of coagulation factors are sequentially activated, and finally thrombin is formed to form fibrin clot. Direct thrombin inhibitors are important anticoagulant drug. These drugs can selectively bind to the active site of thrombin, inhibit thrombin activity, have strong action and high specificity, and have important significance in the clinical treatment of thrombus diseases. Some of them come from natural products of animals or plants, and many of them have been applied in the clinic. The other part is derived from the design, synthesis and activity studies of small molecule inhibitors. This review discusses the progress of direct thrombin inhibitors in recent years.

The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis

2010 ◽  
Vol 103 (05) ◽  
pp. 1076-1084 ◽  
Author(s):  
Margareta Blombäck ◽  
Niklas Bark ◽  
Hans Johnsson ◽  
N. Hakan Wallen ◽  
Shu He
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Thrombin Inhibitors ◽  
Therapeutic Window ◽  
Bleeding Complications ◽  
Direct Thrombin Inhibitors ◽  
Vitro Assay ◽  
Fibrin Network

SummaryThe present study aimed to assess whether the fibrin network structure is modified by the direct thrombin-inhibitors lepirudin, argatroban or bivalirudin and by the indirect Xa-inhibitor danaparoid. Using an in vitro assay that imitates the physiological process of coagulation from thrombin generation to fibrin formation, we examined a normal plasma pool spiked with one of the inhibitors. At concentrations considered to be the plasma levels observed during therapy, almost no influence was detected for lepirudin despite clear-cut effects on “clotting time”. However, argatroban, bivalirudin and danaparoid increased the fibrin gel permeability (Ks) to a similar extent. At concentrations higher than the “therapeutic” levels, the dose-response curve in the Ks assay became very steep for lepirudin while those were shallow for the others. In parallel with the drug-induced increases of Ks, larger network pores in 3D-microscopic images and significant shortenings in “clot lysis time” induced by addition of rtPA were observed. Recombinant factor VIII (rFVIII) added to danaparoid-treated samples profoundly counteracted the increase of Ks but had only a slight or no effect on the other drugs. Thus, in vitro, argatroban, bivalirudin and danaparoid have comparable anticoagulating effects, rendering the fibrin network more permeable and less resistant to fibrinolysis. For lepirudin, the steep dose-response curve supports previous clinical findings, i.e. this thrombin inhibitor has a narrow therapeutic window. Furthermore, our data suggest that the haemostatic agent, rFVIII, might be effective in treatment of bleeding complications induced by danaparoid.

New Treatment Options for Heparin-Induced Thrombocytopenia

2002 ◽  
Vol 15 (4) ◽  
pp. 305-317
Author(s):  
Sallie K. Young
Keyword(s):  
Cardiopulmonary Bypass ◽  
Treatment Options ◽  
Common Adverse Effect ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Type I ◽  
Type Ii ◽  
Heparin Induced Thrombocytopenia ◽  
Increased Risk

Heparin, in various forms, is used in a variety of conditions including prophylaxis and treatment of thromboembolic disorders. Although the most common adverse effect related to the use of heparin is bleeding, heparin-induced thrombocytopenia (HIT) can also occur. Two types of HIT exist, HIT type I and type II. HIT type I is a mild and self-limiting disease in which the patient’s platelet count may decrease slightly but will recover with continued treatment. This is in contrast to HIT type II, which may lead to potentially devastating complications. Patients with HIT type II are at increased risk for thromboembolic complications that are mediated through autoimmune reactions and therefore require anticoagulation with danaparoid or one of the direct thrombin inhibitors, including lepirudin, argatroban, or bivalirudin. Limited data are available on the use of these agents in special populations including patients who are pregnant or those undergoing procedures such as percutaneous coronary intervention, cardiopulmonary bypass and dialysis, and pregnancy. Future therapies may include the use of unfractionated heparin in combination with glycoprotein IIb/IIIa inhibitors during cardiopulmonary bypass.

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