The heterogeneity of the anticoagulant response to heparin

Jw, Estes

doi:10.1136/jcp.25.1.45

Cited by 20 publications

(8 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Calculations based on the data reported graphically by Barrowcliffe et al (I978b) show that both preparations have similar elimination rates, but the half-lives of both as measured by the APTT are shorter (about 15 minutes) than when heparin concentration is measured by anti-Xa activity (about 2S minutes); the difference is probably significant. We noted earlier that the reverse was found by Estes (1972), Hirsh et al (1976), and by Teien and Bjornson (1976); one potential explanation may lie in the very small doses (only 1000 units) used in the later study (see section 2.1).…”

Section: Choices Among New Heparin Preparationsmentioning

confidence: 60%

“…One reason for the necessity for determining the optimum method for assessing the anticoagulant effect of heparin is the unexpected finding that the drug's half-life is proportional to its dose when concentrations of heparin in blood or plasma are measured, while the half-life of the drug's effect on clotting alone is not proportional to dose (Estes et aI., 1969;Estes, 1972;Olsson et aI., 1963). A second major reason is that we have no chemical methods for unambiguously measuring the drug directly in body fluids.…”

Section: Methods For Measuring the Anticoagulant Effect Of Heparinmentioning

confidence: 99%

“…However, the half·lives calculated by the 2 methods are not correlated (Estes, 1972;Teien and Bjornson, 1976). The anticoagulant effect of heparin would be expected to disappear more slowly than the drug itself, because it is bound to its site(s) of action in the plasma.…”

Section: Methods For Measuring the Anticoagulant Effect Of Heparinmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Pharmacokinetics of Heparin

1980

Clinical Pharmacokinetics

View full text Add to dashboard Cite

Heparin binds reversibly to its target sites of action, antithrombin and the other serine proteases involved in coagulation, especially activated factor X. It also binds to other plasma proteins, including fibrinogen, plasmin, albumin, and lipases. The volume of distribution of heparin is then, under most circumstances, limited to the plasma volume. Heparin has a very short half-life, about 1.5 hours, which is dose-dependent and varies with the assay method employed for its measurements. It is not eliminated enzymatically nor by glomerular filtration or renal tubular secretion. In all likelihood, the anticoagulant is transferred to reticuloendothelial cells, which may also provide the means for its degradation. Many of the difficulties inherent in assessing the kinetic properties of heparin, as well as its clinical efficacy, may be attributed to: (1) its molecular heterogeneity; (2) its wide spectrum of binding sites and their respective kinetic properties and dissociation constants; (3) differences among methods for measuring heparin effect and concentration; (4) the dose dependence of the drug's half-life; (5) variation in patient response to heparin; (6) the specific cation associated with it; and (7) the presence of hypercoagulation syndromes associated with deficits of antithrombin. Neither renal nor hepatic disease, nor the biological tissues from which heparins are extracted commercially, seem to influence the drug's kinetic properties as much as variations in clearance and response to heparin among individual patients. Many comparisons among available studies are difficult because of the wide variation in the assay methods employed in them. It would appear that optimum therapy with heparin can be achieved only when the individual patient's response to, and rate of elimination of, heparin are taken into account concurrently.

show abstract

Section: Choices Among New Heparin Preparationsmentioning

confidence: 60%

Section: Methods For Measuring the Anticoagulant Effect Of Heparinmentioning

confidence: 99%

See 1 more Smart Citation

Clinical Pharmacokinetics of Heparin

1980

Clinical Pharmacokinetics

View full text Add to dashboard Cite

show abstract

“…Furthermore, the large interindividual variations in biological response previously observed for conventional heparin (Estes 1972, Benchekroun et al 1986) and LMWH (Rostin et al 1990) were not apparent for the pharmacodynamic parameters derived from the models. Tinzaparin consists of heparin-derived material of various molecular weights, and plasma concentrations of this heterogeneous mixture are appropriately quantified by radioactivity measurements of radiolabelled tinzaprin.…”

Section: Discussionmentioning

confidence: 86%

Relationship between pharmacokinetics and pharmacodynamics of tinzaparin (logiparin), a low molecular weight heparin, in dogs

Brindley¹,

Taylor²,

Diness

et al. 1993

Xenobiotica

View full text Add to dashboard Cite

I. Pharmacodynamic models relating the plasma concentrations (C) of radioactive heparin material to anticoagulant effect (E) have been investigated after single i.v. and S.C. doses of 'H-tinzaparin (1 and 4 mg/kg), a radiolabelled low molecular weight heparin, to six dogs.2. A counterclockwise hysteresis, characterizing the C versus E relationship, was observed in all animals after s.c., but not i.v., doses indicating a possible delay (lag-time) in the systemic availability of pharmacologically-active heparin material following extravascular administration. A constant (K.) was introduced into the model to account for this hysteresis.3. At high plasma concentrations of radioactivity (> lOpg/ml), E was related to C by a sum of two sigmoid Em,, models, whereas, at lower concentrations, this reduced to the wellknown sigmoid Em,, model. It was proposed that tinzaparin activates two 'receptors' having different affinities for the drug. T h e values of EC,, associated with the activation of a single 'receptor' and of a proposed additional 'receptor' were 3 and 13 pg/ml of heparin material, respectively. 4.Heparin material was predominantly eliminated b y renal excretion and underwent widespread tissue distribution. After S.C. administration, input of heparin material into systemic plasma was complete within 1 2 h post-dose, and the absorption process was characterized by a bi-exponential function. 5.We conclude that sigmoid Em,, models adequately describe the C versus E relationship after S.C. and i.v. doses of 'H-tinzaparin in dogs and that the interindividual variation of the pharmacodynamic parameters derived from this model was relatively small.

show abstract

“…Unfractionated heparin (UFH) therapy is monitored because the response can vary markedly from patient to patient. [1][2][3][4] The current consensus is that UFH dosing should result in plasma heparin activity (HA) of approximately 0.2-0.4 U/ml by protamine-polybrene titration assay (measuring predominantly antifactor IIa activity), which is approximately equivalent to 0.3-0.7 U/ml by chromogenic antifactor Xa assay. [5][6][7][8] Although UFH monitoring with antifactor Xa HA is common in some European countries, most laboratories in the United States do not perform the assay and instead use activated partial thromboplastin time (aPTT).…”

mentioning

confidence: 99%