Limitations Of Heparin Research Articles

Perfusion Strategies for Bivalirudin Anticoagulation: AIIMS Protocol

AbstractAnticoagulation strategies for cardiac surgery are witnessing a change with the identification of serious limitations of heparin, including development of resistance in 3 to 13% of patients undergoing cardiac surgery and heparin-induced thrombocytopenia/thrombosis syndrome in 1 to 5.5% of patients. Heparin alternatives have a potential role in these scenarios. Bivalirudin, a reversible direct thrombin inhibitor, has an onset time of 2 to 4 minutes and half-life of 25 minutes, is eliminated mainly by a proteolytic mechanism, does not require antithrombin III for effect, and is nonimmunogenic. The considerations for extracorporeal circulation are peculiar with its use, and this article outlines the aspects of initiating, maintaining, and terminating cardiopulmonary bypass and extracorporeal membrane oxygenation with bivalirudin as the anticoagulant.

Apixaban: An oral anticoagulant having unique mechanism of action with better safety and efficacy profile

Anticoagulants are routinely used in stroke, embolism, infarct, etc. Blood clotting profile in such patients needs to be monitored frequently. Anticoagulants which can be administered orally such as warfarin and dicoumarol are preferred in such patients. Injectable anticoagulants such as heparin are prescribed when anticoagulation therapy is required for short duration. Absence of oral form of heparin makes it impractical for long-term use. Currently, warfarin and coumarone derivatives are the best available oral anticoagulants in market. They act by inhibiting decarboxylation of blood clotting factors II, VII, IX, and X. Pharmacological response of warfarin and dicoumarol needs to be monitored by frequent assessments of prothrombin time (PT) and international normalized ratio (INR). There is a need for a drug which can overcome these limitations. Apixaban is an oral anticoagulant which acts by inhibiting factor Xa. It does not require laboratory monitoring of PT and INR. Hence, it overcomes the limitations of heparin and warfarin. It acts by selectively inhibiting the activated factor Xa in a reversible manner. Apixaban has an oral bioavailability of ~50%. It is administered as twice daily dose. It is excreted in urine and feces. Apixaban is useful in atrial fibrillation, venous thromboembolism, and pulmonary embolism. Bleeding is the major side effect of apixaban. It has been found that apixaban has superiority over warfarin and aspirin in terms of efficacy and safety. Further studies are required to monitor and assess the pharmacokinetics, efficacy, adverse effects, and drug interaction data in many populations and sub-populations throughout the world.

Primary Anticoagulation With Bivalirudin for Patients With Implantable Ventricular Assist Devices

Bivalirudin is a direct thrombin inhibitor that is increasingly used in patients undergoing mechanical circulatory support as it presents many advantages compared with unfractionated heparin. The aim of this study was to describe our experience with bivalirudin as primary anticoagulant in patients undergoing ventricular assist device (VAD) implantation. An observational study was performed on 12 consecutive patients undergoing VAD implantation at our institution. Patients received a continuous infusion of bivalirudin, with a starting dose of 0.025 mg/kg/h; the target activated partial thromboplastin time (aPTT) was between 45 and 60 s. Patients never received heparin during hospitalization nor had a prior diagnosis of heparin-induced thrombocytopenia (HIT). All patients received a continuous flow pump except one. Preoperative platelets count was 134 000 ± 64 000 platelets/mm(3) . Mean bivalirudin dose was 0.040 ± 0.026 mg/kg/h over the course of therapy (5-12 days). Lowest platelets count during treatment was 73 000 ± 23 000 platelets/mm(3) . No thromboembolic complications occurred. Two episodes of minor bleeding from chest tubes that subsided after reduction or temporary suspension of bivalirudin infusion were observed. Intensive care unit stay was 8 (7-17) days, and hospital stay was 25 (21-33) days. Bivalirudin is a valuable option for anticoagulation in patients with a VAD and can be easily monitored with aPTT. The use of a bivalirudin-based anticoagulation strategy in the early postoperative period may overcome many limitations of heparin and, above all, the risk of HIT, which is higher in patients undergoing VAD implantation. Bivalirudin should no longer be regarded as a second-line therapy for anticoagulation in patients with VAD. [Correction added on 6 December 2013, after first online publication: The dose of bivalirudin in the Abstract to 0.025 mg/kg/h].

New anticoagulants.

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.

Direct antithrombins: new perspectives in cardiovascular medicine.

Thrombin converts fibrinogen to fibrin and is the most powerful activator of platelets thus playing a crucial role in arterial and venous thrombosis. The limitations of heparin, largely used in the therapy of arterial and venous thromboembolism, has prompted the development of new antithrombotic drugs, able to directly inhibit thrombin. They comprise hirudin, bivalirudin and argatroban, which are antithrombins for parenteral use, and the orally active ximelagatran which, once absorbed, is converted to the active compound melagatran. Hirudin is a polypeptide able to irreversibly block both the active site and the fibrin(ogen) binding site of thrombin; bivalirudin, a synthetic hirudin derivative, has the same binding sites of hirudin to thrombin but has a shorter pharmacological action and is safer for clinical use. Several clinical trials which tested these drugs in acute coronary syndromes, coronary angioplasty and venous thromboembolism. demonstrate that hirudin and bivalirudin are superior to heparin in significantly reducing cardiac major events. The advantage of hirudin and bivalirudin over heparin was also confirmed in adjuncts to thrombolytic therapy as well as in percutaneous angioplasty relating to thrombotic events but not to restenosis. Hirudin was also significantly better than both unfractionated heparin and low molecular weight heparin (LMWH) in the prophylaxis of venous thromboembolism in patients undergoing elective arthroplasty. Major bleeding associated to hirudin was not different from that observed with heparin. Preliminary data also indicate that melagatran/ximelagatran may be used in the prophylaxis of venous thromboembolism and in the prevention of arterial embolism in patients with non-valvular atrial fibrillation.

New anticoagulants and antiplatelet agents

EMOSTASIS in cardiovascular patients is a challenge that clinicians have only begun to embrace. Caring for patients with cardiovascular disease requires an understanding of the etiology of the disease and the predisposing characteristics that make these patients hypercoagulable, hyperthrombotic, both, or neither. Patients host a heterogeneous complement of genetic and environmental factors which render them susceptible to arterial injury, atherosclerosis, inflammatory processes, thrombosis, and fibrinolysis. Coupled with the complex pathophysiology of the vascular patient, are the unique hemostatic perturbations that occur as a result of cardiac surgery utilizing cardiopulmonary bypass (CPB). The presence of extracorporeal circuitry and the oxygenator have demanded meticulous attention to maintaining adequate anticoagulation during CPB. As we understand more about the limitations of heparin, and as new drugs become available for use, the search for new anticoagulants and alternative monitoring techniques during CPB will continue to progress. Hemostasis after CPB is still a vexing problem. Patients having been exposed to antiplatelet medications in the preoperative period are particularly prone to bleeding after CPB. This is due to the additive effects of the antiplatelet therapeutics and the wellknown platelet defects that occur as a result of CPB. The two opposing processes of anticoagulation and hemostasis must be managed carefully and modified with respect to the patient’s hematologic status and desired hemostatic outcome. This review will summarize some potential new drugs for use as anticoagulants for cardiovascular procedures. Additionally, the new antiplatelet medications, and their respective mechanisms of activity will be described.

Dendritic polyglycerol sulfates as new heparin analogues and potent inhibitors of the complement system.

Due to several limitations of heparin, a widely used antithrombotic drug, there is large interest to develop alternatives. The aim of the presented study was to produce fully synthetic highly branched heparin mimetics. For this purpose, a new type of 'treelike' polysulfated polymers based on dendritic polyglycerol was synthesized. An efficient synthetic approach has been chosen to prepare several polyglycerol sulfates with different molecular weights as well as a polyglycerol carboxylate analogue and to evaluate them for their anticoagulant and anticomplementary activities. In contrast to the nonderivatized and the carboxylated polyglycerols, the polyglycerol sulfates prolong the activated partial thromboplastin time (APTT) and thrombin time (TT) and inhibit both the classical (CCA) and alternative complement activation (ACA). Whereas their anticoagulant activity in the APTT and in the TT amounts to 5.7-8.1% and 15.7-33.6%, respectively, of that of unfractionated heparin (UFH), their CCA and ACA inhibitory activity is 13.4-23.9 and 2.7-3.7 times, respectively, higher. In contrast to sulfated polysaccharides, the activities are not clearly dependent on the molecular weight, which might be due to the globular 3D-structure of the dendritic molecules. Due to the coherence between coagulation, complement activation and inflammation in the pathophysiology of numerous diseases, polyglycerol sulfates with both anticoagulant and anticomplementary activities represent promising candidates for the development of potential drugs.

An Update on New Anticoagulants

A variety of new anticoagulants for the prevention and treatment of venous and arterial thromboembolism are under development. Designed to overcome the limitations of heparin and vitamin K antagonists, these new agents are at various stages of clinical testing. This paper reviews venous and arterial thrombogenesis, discusses the regulation of coagulation, identifies the molecular targets for new anticoagulants, describes new anticoagulants in more advanced stages of clinical testing, and provides perspective on how these agents will impact on practice.

New anticoagulants.

The limitations of heparin and warfarin have prompted the search for new anticoagulants for the prevention and treatment of venous and arterial thromboembolism. Although many such agents are in development, only a few have reached phase II or higher levels of clinical testing. This article reviews venous and arterial thrombogenesis, discusses the regulation of coagulation, identifies the molecular targets for new anticoagulants currently under development, describes the agents in more advanced stages of clinical testing, and provides clinical perspective on the opportunities for new anticoagulant drugs.

The Effect of Thrombin Inhibitors on Tissue Plasminogen Activator Induced Thrombolysis in a Rat Model

Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg-1 h-1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables.(ABSTRACT TRUNCATED AT 250 WORDS)