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PubMed2006

Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery.

Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small molecule inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small molecules to directly inhibit the key proteases, factor IIa and factor Xa. Of the new oral anticoagulants in development, the two agents in the most advanced stage are dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factor IIa and factor Xa, respectively. Other agents in the early stages of development include several Xa inhibitors (LY-517717, YM150, DU-176b and apixaban [BMS-562247]), a factor IXa inhibitor (TTP889), and an orally active glycosaminoglycan enhancer (odiparcil [SB-424323]), which indirectly enhances thrombin inhibition via heparin cofactor II. Results have been reported from important, phase II dose-finding studies, and a number of registration-track phase III studies have been initiated, reflecting the drive towards potentially more effective, but primarily safer and more convenient therapies for the prevention and treatment of venous and arterial thrombosis. Indeed, two unmet needs for anticoagulation that can be easily identified are safety and ease of use. Safety relates primarily to the incidence of major bleeding and this remains the key concern of orthopaedic surgeons, over and above any efficacy advantage, and convenience of use, which centres on oral administration replacing the need for injections. The clinical development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies in major orthopaedic surgery, prior to development in arterial indications. There are a number of subtle issues, including the timing of the first perioperative dose, duration of prophylactic treatment and definition/assessment of study endpoints that can influence study outcome and require careful consideration when evaluating study results with new agents and in the comparison with established agents, and which are considered in this review. It is anticipated that over the next 3 years, at least one of these agents will be successfully licensed for the prevention of venous thromboembolism after major orthopaedic surgery, which will act as a springboard for the gradual replacement of current anticoagulants.

Administration, Oral↗
PubMed1999

Standardization of coagulation tests.

A lot of attempts have been made to standardise both activated partial thromboplastin time (APTT) and prothrombin time (PT). Only the standardization of PT has been successfully implemented while the standardization of APTT is still underway. The PT test is a common method for monitoring oral anticoagulant therapy. Owing to the variable response of the thromboplastins and the different ways of reporting, PT results obtained from patients treated with oral anticoagulants have not been interchangeable between laboratories. In 1977, the World Health Organization (WHO) designed a batch of human brain thromboplastin as the first international reference preparation (IRP) for thromboplastin and a calibration system was proposed in 1982, based on the assumption that a linear relationship exists between the logarithm of the PT obtained with the IRP and test thromboplastins. This calibration model is used to standardize the reporting of the PT by converting the PT ratio observed with the local thromboplastin into an International Normalized Ratio (INR). The INR system is being adopted by an increasing number of hospitals in many countries. With the increasing use of the INR system, a number of problems have been identified with the INR system. The most serious one is that the ISI of a thromboplastin depends on the coagulometer used. Besides, a number of investigators have noted that the ISI value provided by the manufacturer for each new batch of thromboplastin reagent may be incorrect and the use of inappropriate control plasma can lead to erroneous INR calculations. Four solutions have been proposed to solve the problems of the INR system as follows: (a) the local system calibration with lyophilized plasma calibrants with assigned manual PT determined in terms of the relevant IRP for thromboplastin; (b) the use of a mean normal prothrombin time (MNPT) obtained with the coagulometer to derive the prothrombin ratio: (c) PT standardization by means of the procedure using plasma calibrants: and (d) selection of sensitive thromboplastin with low ISI values. The INR system has been adopted in Thailand since 1984. There are 3 steps in the implementation as follows: (a) preparation of National Reference Thromboplastin; (b) selection of high sensitive thromboplastin; and (c) optimal therapeutic range for Thai patients. The anticoagulant effect of heparin is usually monitored by the APTT, a test that is sensitive to the inhibitory effects of heparin on thrombin, factor Xa. and factor IXa. However, the type of clot detection system, the contact activator; and the phospholipid composition of the reagent affect the APTT response. In 1995. ISTH/ICSH proposed a calibration model for APTT standardization. As the problem showed a great similarity to PT standardization, the same model of calibration was applied but no international reference preparation for the APTT is yet available. In 1998. van den Besselaar et al proposed a lyophilized APTT reagent comprising synthetic phospholipids and colloidal silica as a candidate IRP for the APTT.

Anticoagulants↗
PubMed2003

Approaches in anticoagulation: rationales for target positioning.

Heparin and warfarin are the most widely used anticoagulants for the prophylaxis and treatment of thrombus-based diseases. These anticoagulants, however, have well-known clinical limitations, such as a slow onset of action and a narrow therapeutic window. An ideal small-molecule non-peptide inhibitor should have an immediate onset of action, oral bioavailability and an improved therapeutic action and side-effect profile, compared to established therapies. In this review, the current concepts and hypotheses of the numerous anticoagulant approaches are analyzed and evaluated, with emphasis on animal models, genetic disorders and compound profiling. Selected factors of the coagulation cascade and modulators of endogenous fibrinolysis are examined to determine if they represent promising drug targets in antithrombotic therapy.

Animals↗
PubMed1992

Assembly and expression of an intrinsic factor IX activator complex on the surface of cultured human endothelial cells.

Endothelial cells expose specific receptors for blood clotting factors and, upon perturbation, can initiate and propagate the reactions of the extrinsic pathway of blood coagulation leading to fibrin formation on the cell surface. The existence of an intrinsic mechanism of Factor IX activation on cultured human umbilical vein cells (HUVECs) was investigated by studies of the interaction between HUVECs and two proteins of the contact activation system, the cofactor high molecular weight kininogen (H-kininogen) and the zymogen Factor XI. In the presence of zinc ions (10-300 microM), 125I-labeled H-kininogen bound to HUVECs in a time-dependent, reversible, and saturable manner, with calcium ions exerting an inhibitory effect on the zinc-dependent binding. Analysis of the binding data by the LIGAND computer program indicated that HUVECs, in the presence of 2 mM CaCl2 and 100 microM ZnCl2 at 37 degrees C, bound 1.14 x 10(7) H-kininogen molecules per cell with an apparent dissociation constant of 55 nM. HUVEC-bound H-kininogen functions as the cell surface receptor for both 125I-labeled Factor XI and 125I-labeled Factor XIa, since HUVECs cultured in contact factor-depleted serum do not detectably bind either the zymogen or the enzyme in the absence of H-kininogen and zinc ions. In the presence of saturating concentrations of H-kininogen, 2 mM CaCl2 and 100 microM ZnCl2, the binding of 125I-labeled Factor XI and Factor XIa to HUVECs was time-dependent, reversible, and saturable, with apparent dissociation constants of 4.5 and 1.5 nM, respectively. HUVEC-bound complexes of H-kininogen and Factor XI generated Factor XIa activity only after the addition of purified Factor XIIa, and cell-bound Factor XIa in turn activated Factor IX, as documented by a 3H-labeled activation peptide release assay for 3H-Factor IX activation. The results indicate that cultured HUVECs provide a surface for the assembly and expression of an intrinsic Factor IX activator complex that may participate in the initiation of blood coagulation at sites of vascular injury.

Binding, Competitive↗
PubMed1992

An unusual antibody that blocks tissue factor/factor VIIa function by inhibiting cleavage only of macromolecular substrates.

Tissue factor (TF), the cell surface receptor and cofactor for factor VIIa (FVIIa), is considered the major physiologic trigger of the coagulation cascade. Most monoclonal antibodies to TF have been reported to inhibit TF activity by blocking association of FVII(a) with TF. Using solution-phase kinetic analyses, we have reexamined two strongly inhibitory anti-TF monoclonal antibodies (TF8-11D12 and TF9-9C3) previously reported to block FVII binding in cell-binding assays. Kinetic analysis of TF9-9C3 was consistent with direct competition with FVIIa for binding to TF. However, antibody TF8-11D12 did not block FVIIa binding to TF as measured by ability of the TF:FVIIa complex to cleave a small peptide substrate or by enhanced reactivity of FVIIa with a tripeptidyl-chloromethylketone. Interestingly, TF8-11D12 strongly inhibited cleavage of all three known macromolecular substrates (factors VII, IX, and X) of the TF:FVIIa complex. We hypothesize that TF8-11D12 blocks access of macromolecular substrates to the active site of FVIIa by steric hindrance. This study identifies a useful probe for TF function and provides insights into the inhibitory mechanism of an unusual class of antibody proposed for therapeutic intervention in thrombotic disease.

Amino Acid Sequence↗
PubMed2004

New anticoagulants for venous thromboembolic disease.

Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. In the US, approximately 260000 cases are diagnosed annually. Current drugs for the prevention and treatment of venous thromboembolism (VTE) include heparin, low-molecular-weight heparins and warfarin. Since they possess several disadvantages, researchers are investigating improved anticoagulants. To understand how any promising anticoagulant would work, a review of the pathophysiology and regulation of the coagulation cascade is provided. The more prominent drugs reviewed include tissue factor pathway inhibitor protein, nematode anticoagulant protein, Factor IX inhibitors, anti-Factor Xa inhibitors (DX-9065a (Daiichi Seiyaku Co Ltd), YM-60828 (Yamanouchi Pharmaceutical Co Ltd), fondaparinux, idraparinux (Sanofi-Synthelabo/NV Organon)), selective thrombin inhibitors (oral heparin, ximelagatran (AstraZeneca plc)) and enhancers of natural anticoagulants (activated protein C, ART-123 (Asahi Kasei Pharma Corp)).

Animals↗
PubMed1992

Factor VIIa/tissue factor-catalyzed activation of factors IX and X on a cell surface and in suspension: a kinetic study.

The kinetics of activation of factor IX and factor X by factor VIIa was studied in the presence of various sources of tissue factor: (1) a surface membrane of human ovarian carcinoma cell line, OC-2008 (2) the cell lysate (of OC-2008) and (3) reconstituted purified human tissue factor. The rates of activation of factors IX and X were monitored in activation peptide release assays using tritiated substrates. The results indicate that the apparent Km values for factor IX and factor X were similar for a given tissue factor, but varied with tissue factor source. The source of tissue factor greatly influenced the apparent differences in Vmax for factors IX and X. When a surface of monolayer provided tissue factor, the Vmax of factor IX was only 2-3 fold lower than factor X, but when either a cell lysate or purified tissue factor was the source of cofactor activity, the difference in Vmax rose to about 8-10 fold. Although, the tissue factor apoprotein in the cells was expressed entirely on the outer surface membrane, the activity of tissue factor on the intact cell surface was 50 to 100-fold lower than in the lysed cell preparation.

Catalysis↗
PubMed1991

Cooperative activation of human factor IX by the human extrinsic pathway of blood coagulation.

The activation of human coagulation factor IX by human tissue factor.factor VIIa.PCPS.Ca2+ (TF.VIIa.PCPS.Ca2+) and factor Xa.PCPS.Ca2+ enzyme complexes was investigated. Reactions were performed in a highly purified system consisting of isolated human plasma proteins and recombinant human tissue factor with synthetic phospholipid vesicles (PCPS: 75% phosphatidylcholine (PC), 25% phosphatidylserine (PS)). Factor IX activation was evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, [3H]factor IX activation peptide assay, colorimetric substrate thiobenzyl benzyloxycarbonyl-L-lysinate (Z-Lys-SBzl) hydrolysis, and specific incorporation of a fluorescent peptidyl chloromethyl ketone. Factor IX activation by the TF.VIIa.PCPS.Ca2+ enzyme complex was observed to proceed through the obligate non-enzymatic intermediate species factor IX alpha. The simultaneous activation of human coagulation factors IX and X by the TF.VIIa.PCPS.Ca2+ enzyme complex were investigated. When factors IX and X were presented to the TF.VIIa complex, at equal concentrations, it was observed that the rate of factor IX activation remained unchanged while the rate of factor X activation slowed by 45%. When the proteolytic cleavage products of this reaction were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, it was observed that the intermediate species factor IX alpha was generated more rapidly when factor X was present in the reaction mixture. When factor IX was treated with factor Xa.PCPS in the presence of Ca2+, it was observed that factor IX was rapidly converted to factor IX alpha. The activation of factor IX alpha by the TF.VIIa.PCPS.Ca2+ complex was evaluated, and it was observed that factor IX alpha was activated more rapidly by the TF.VIIa.PCPS.Ca2+ complex than was factor IX itself. These data suggest that factors IX and X, when presented to the TF.VIIa.PCPS.Ca2+ enzyme complex, are both rapidly activated and that factor Xa, which is generated in the initial stages of the extrinsic pathway, participates in the first proteolytic step in the activation of factor IX, the generation of factor IX alpha.

Blood Coagulation↗
PubMed1987

Early experience with the use of anti-inhibitor coagulant complex to treat bleeding in hemophiliacs with inhibitors to factor VIII.

Early clinical experience with anti-inhibitor coagulant complex in the treatment of bleeding in patients with factor VIII inhibitors is described. Sixty patients with a total of 120 bleeding episodes were studied. Satisfactory responses were obtained in 86.6% of bleeding episodes. Efficacy was slightly better in open bleeding than in closed bleeding. Higher doses were significantly better than lower doses in treating open bleeding. The incidence of adverse reactions was low. The results reported support the safety and efficacy of anti-inhibitor coagulant complex in the treatment of bleeding in patients with factor VIII inhibitors.

Adolescent↗
PubMed1988

Immunological status and HIV antibodies in patients with haemophilia--a longitudinal study.

Various immunological parameters were investigated in 12 children suffering from severe haemophilia A or B receiving substitution therapy over a follow-up period of 3 1/2 years. At the beginning of the study, the therapy was changed to heat-treated concentrates of factors VIII or IX. Antibodies to HIV were found in 9 out of these patients. There were no AIDS-related clinical symptoms, but HIV antigen was detectable in one case. Abnormalities of immunological parameters were found independently of HIV infection, but were more pronounced in anti-HIV seropositive patients. Elevated levels of immunoglobulins gave evidence of polyclonal B-cell activation whilst increased levels of neopterin indicated activated T-cells and macrophages. There was no close association between these two types of activation. However, peak activation of both immune compartments was found approximately 1 year after changing the therapy. Thereafter a continuous tendency towards normalization of neopterin levels was observed. At the final visit immunoglobulin levels also tended to decrease. The HIV antigen seropositive child showed the highest neopterin levels during the whole study period. Our data indicate that the primarily high risk of developing AIDS in anti-HIV-seropositive haemophiliacs is declining.

Acquired Immunodeficiency Syndrome↗
PubMed1985

[Articular and muscular hemorrhages in hemophilia A with anti-factor VIII antibodies. Treatment with selected batches of PPSB (factor IX concentrate)].

Over a 10-month period, 65 bleeding episodes in 14 hemophilia A patients with anti-Factor VIII antibodies were treated with a non-activated Factor IX concentrate (PPSB). A single dose of 58-102 U/kg of Factor IX (average 80 U/kg) was used in 51 hemarthroses, 13 muscle hematomas and one dental bleed. Overall clinical results were satisfactory in 51% of cases. Forty nine per cent of acute hemarthroses were clinically improved. Safety tests were unchanged and no significant elevation of anti-VIII: C titers was recorded. These preliminary results ae similar to those obtained with single doses of activated prothrombin complex concentrates given to the same patients (Autoplex and FEIBA).

Adolescent↗