Oral Anticoagulation Thresholds

Brummel, Kathleen E.; Paradis, Sara G.; Branda, Richard F.; Mann, Kenneth G.

doi:10.1161/hc4401.098492

Cited by 56 publications

(60 citation statements)

References 26 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Subsequently, other workers have noted individual differences in (1) platelet procoagulant activity, 91,108 (2) thrombin generation in platelet-rich plasma even when clotting factors were relatively constant, 113 and (3) platelet activation triggered by thrombin receptor-activating peptide. 114 Of particular interest is the variability seen in patients with factor XI deficiency.…”

Section: Variability Of Platelet Procoagulant Response In Individualsmentioning

confidence: 99%

Platelets and Thrombin Generation

Monroe

Hoffman

Roberts

2002

ATVB

596

479

View full text Add to dashboard Cite

Abstract-This review examines the evidence that platelets play a major role in localizing and controlling the burst of thrombin generation leading to fibrin clot formation. From the first functional description of platelets, it has been recognized that platelets supply factors that support the activation of prothrombin. Studies have demonstrated that on activation, the amount of one specific lipid, phosphatidylserine, is significantly increased on the outer leaflet of platelet membranes. When it was found that phosphatidylserine containing lipid extracts could be substituted for platelets in clotting assays, this suggested the possibility that changes in platelet lipid composition were necessary and sufficient to account for platelet surface thrombin generation. Because a growing body of data suggest that platelet-binding proteins provide much of the specificity for platelet thrombin generation, we review in this report data suggesting that changes in lipid composition are necessary but not sufficient to account for platelet surface regulation of thrombin generation. Also, we review data suggesting that platelets from different individuals differ in their capacity to generate thrombin, whereas platelets from a single subject support thrombin generation in a reproducible manner. Individual differences in platelet thrombin generation might be accounted for by differences in platelet-binding proteins.

show abstract

Section: Variability Of Platelet Procoagulant Response In Individualsmentioning

confidence: 99%

Platelets and Thrombin Generation

Monroe

Hoffman

Roberts

2002

ATVB

596

479

View full text Add to dashboard Cite

show abstract

“…These have included the following: (1) synthetic plasma, in which mixtures prepared from purified procoagulants and anticoagulants and a natural or synthetic membrane source are induced to react by the addition of lipid reconstituted tissue factor 9,10,41,55-60 ; (2) paravivo studies of coagulation, in which whole, contact pathway-suppressed blood obtained by phlebotomy and maintained at 37°is induced to clot by addition of a fixed amount of membrane reconstituted tissue factor 42,[61][62][63][64][65][66][67][68] ; (3) numerical (computer) models of the coagulation system, which are based on the ensemble of published (and estimated) rate constants and concentrations of procoagulants and stoichiometric inhibitors and the mechanisms of their interactions 69 -71 (also referred to as "in silico" simulations); and (4) in vivo studies of the hemostatic reaction, in which whole blood exuding from a microvascular wound is sequentially sampled for relevant product formation. [72][73][74][75] Each of the model systems used has specific benefits and limitations.…”

Section: Models Of the Blood Coagulation Reactionmentioning

confidence: 99%

The Dynamics of Thrombin Formation

Mann

Butenas

Brummel

2003

ATVB

Self Cite

472

394

View full text Add to dashboard Cite

Abstract-The central event of the hemostatic process is the generation of thrombin through the tissue factor pathway. This is a highly regulated, dynamic process in which thrombin itself plays many roles, positively and negatively its production and destruction. The hemostatic process is essential to normal physiology and is also the Achilles heel of our aging population. The inappropriate generation of thrombin may lead to vascular occlusion with the consequence of myocardial infarction, stroke, pulmonary embolism, or venous thrombosis. In this review, we summarize our present views regarding the tissue factor pathway by which thrombin is generated and the roles played by extrinsic and intrinsic factor Xa generating complexes in hemostasis and the roles of the stoichiometric and dynamic inhibitors that regulate thrombin generation. Key Words: coagulation Ⅲ fibrinogen Ⅲ aggregation Ⅲ coagulation inhibitors T he inventory of molecular components and the presumed physiology of the hemostatic process and its regulation have been established on the basis of plasma abundance, hemorrhagic or thrombotic pathology, in vitro tests, and chemical signatures. Two in vitro plasma tests, the prothrombin time and the activated partial thromboplastin time, were prominent in the development of the inventory. The former test relies on the addition of an extrinsic tissue factor source (thromboplastin), whereas the latter is based on the introduction of a foreign surface to initiate coagulation using only this surface contact and the biological constituents intrinsic to plasma. Both tests rely on a fibrin formation (clotting) end point. These assays permitted identification of connectivity between the component activities identified as required for plasma coagulation and defined the concept of intrinsic and extrinsic coagulation pathways, which converge at the step of formation of the prothrombinase complex. However, the mechanisms established by in vitro tests are not always mirrored in human pathology associated with bleeding or thrombosis. The primary pathway leading to hemostatic and thrombotic pathologies is associated with the tissue factorinitiated extrinsic coagulation pathway, whereas components unique to the intrinsic or contact pathway (factor XI, factor XII, prekallikrein, HMW kininogen) may have accessory roles in the process. Therefore, in this review, we focus on the dynamics of the reactions associated with the introduction of tissue factor to blood, leading to the formation of thrombin.An evaluation of the reactions involved in the formation of thrombin leads to the conclusion that the physiologically relevant hemostatic mechanism is composed of 3 procoagulant vitamin K-dependent enzyme complexes (which use the proteases factor IXa, factor Xa, and factor VIIa) and one anticoagulant vitamin K-dependent complex. 1 Each complex involves a vitamin K-dependent serine protease and a cofactor protein with the protein-protein complex assembled on a membrane surface provided by activated or damaged cells. The same hemostati...

show abstract

“…Presently, treatments are still not individualized but based upon population-based observations. Although these treatment algorithms have proven value, they are far from optimal [65]. This is illustrated schematically in Figure 4 which also represents the situation of the well-known treatment window for VKA anticoagulation.…”

Section: Discussionmentioning

confidence: 99%

Introduction to haemostasis from a pharmacodynamic perspective

Kluft

Burggraaf

2011

Brit J Clinical Pharma

View full text Add to dashboard Cite

Biochemical characterization of the haemostatic system has advanced significantly in the past decades. Sub-systems, such as coagulation, fibrinolysis, blood cells and platelets and the vessel wall have been studied by specialists, mostly separately and independently. The time has come to integrate the approaches, and, in particular, to develop tests to document the state of the whole system and to have available adequate pharmacodynamic tests to evaluate treatments. Many examples are available to show that traditional general methods of clotting and lysis do not provide the information that is desired. The present tendency is to use specific methods for specific factors or effects which are very limited in pharmacological information. There is also increasing awareness of the occurrence of rather broad interindividual variability in the haemostatic system. This suggests that individually tailored treatments are required. This is the more relevant since haemostasis is a balance and treatment should be positioned between efficacy and safety. The conclusion is reached that there is a need for integrated or global methods or sets of methods that reflect the complexity and individual status appropriately and allow the practitioner to judge the effects of interventions and their individual aspects. IntroductionMaintenance of blood fluidity within the vascular system is an important physiological theme. At the same time, the local formation of a clot serves to assist in preventing excessive blood leakages, and in aiding tissue repair. In addition clot formation is involved in host defence.A balance with, on the one hand, a deviation in excessive clot formation and, on the other hand, defective clot formation was proposed originally by Astrup in 1958 [1]. The system requires delicate biochemical regulation to maintain this balance and to serve the various functions adequately.Deviations in the haemostasis of excessive clot formation or thrombosis are involved in arterial diseases such as myocardial infarction and ischaemic stroke, in venous diseases such as deep vein thrombosis and pulmonary embolism, and in organ failure during trauma and infections.This is a major cause of death and disabilities. Another deviation concerns defects in clot formation and subsequent bleeding, known from congenital deficiencies in clotting factors such as factor VIII and IX, but also potentially life threatening during trauma and a major issue in critical care medicine.Many treatment options to reinforce the system or to inhibit parts of it have been developed and are still under active development. These treatments inevitably interfere with the balance mentioned earlier and besides the intended effect, the opposite effect (bleeding or thrombosis) is always associated with the treatments as a safety issue.The present introduction evaluates recent developments in concepts in haemostasis, the status of biomarker analysis and the desired development of pharmacodynamic tests. Development of concepts Biochemical conceptsHaemostasis is regulate...

show abstract

Oral Anticoagulation Thresholds

Cited by 56 publications

References 26 publications

Platelets and Thrombin Generation

Platelets and Thrombin Generation

The Dynamics of Thrombin Formation

Introduction to haemostasis from a pharmacodynamic perspective

Contact Info

Product

Resources

About