The Influence of Intravenous Injections of Heparin in Man on the Time of Coagulation.<sup>1</sup>

Hedenius, P; Wilander, Olof

doi:10.1111/j.0954-6820.1936.tb12566.x

Cited by 27 publications

(3 citation statements)

References 4 publications

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“…The first reported administration of heparin in humans was by Godlowski [1933]; however, he used a low potency, impure form and reported low level toxicity with its use. Hedenius and Wilander [1936], are reported to have initially self-injected heparin (manufactured by Professor Jorpes according to the Charles and Scott method), followed by administration to patients, and found that 100mg or more of heparin was needed for heparinising man for a few hours.…”

Section: First In Man Studiesmentioning

confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Patel

Green

Patel

et al. 2012

Blood

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503 The optimal dosing strategy of low molecular weight heparins (LMWH) for the treatment of antenatal venous thromboembolism (VTE) is not known. The physiological changes associated with pregnancy alter the pharmacokinetic (PK) profile of LMWH, and this has led to controversy and subsequent variation in practice, when pregnant women are managed with LMWH for VTE [Voke et al., 2009]. The perceived impact of these PK changes has led to the Royal College of Obstetrics and Gynaecologists (RCOG) recommending a twice daily dose of LMWH, whilst the American College of Chest Physicians recommend that either a once or twice daily dose of LMWH can be used in this setting. We conducted a population PK modelling study of enoxaparin during pregnancy in order to address this issue. Women requiring antenatal enoxaparin, all indications and doses, referred to the specialist haematology clinic at King's College Hospital, a London teaching hospital, were eligible to enrol in the study. Recruited women were reviewed monthly in clinic during their pregnancy, and had up to three anti-Xa activities (trough, 1 hour post dose, and 3 hours post dose) drawn at each clinic attendance. This anti-Xa sampling strategy was based on d-optimal design, to ensure gestation related changes in enoxaparin clearance (CL) and volume of distribution (Vd) were captured in the PK model developed [van Hasselt et al., 2012]. Women under 18 years of age, those with impaired renal function and those non-adherent to enoxaparin were excluded. Compartmental PK modelling was conducted using non linear mixed effects modelling (NONMEM version 7.2.2). One hundred and twenty three patients contributed 795 anti-Xa activities (712 antenatal, 83 postnatal), for PK modelling purposes. A one compartment model with exponential between subject variability on CL and Vd, with a combined proportional and additive error model best fitted the data, with both enoxaparin CL and Vd found to have increased during pregnancy (table). Enoxaparin PK parameter CL (L/hr) Vd (L) Non-pregnancy (literature values) 0.5-0.7 3-7 Pregnancy (this study) 1.6 13.2 Time dependent changes during pregnancy were found to be significant covariates on both CL and Vd. A full covariate analysis identified weight to be a significant covariate for enoxaparin CL and gestation and baseline lean body weight to be significant covariates for Vd during pregnancy. The final pregnancy enoxaparin PK models for CL and Vd can be represented mathematically as: where Wt is the women's actual weight, GEST is their gestational stage, and LBW is their baseline lean body weight. Goodness of fit plots, a bootstrap analysis and a visual predictive check revealed that a robust enoxaparin model for use in pregnancy had been developed. Simulations of women injecting enoxaparin once versus twice daily demonstrate that both dosing regimens will reach RCOG target 3 hour plasma concentrations throughout the duration of the pregnancy (Figure 1). This should provide confidence to clinicians who prescribe a once daily dose of enoxaparin for the antenatal population. Perhaps the more important concentration to assess however is the trough anti-Xa activity, due to the historical thinking that during pregnancy CL increases, therefore so should the dose/dosing frequency. When the trough activity is simulated, the majority of women on a once daily dose, will have measurable anti-Xa activity; with both once and twice daily regimes demonstrating an increase in trough anti-Xa activity with the progression of pregnancy. This occurs due to the increase in Vd and demonstrates that enoxaparin never reaches a steady state during pregnancy. The measurable trough activity confirms the appropriateness of a once daily dose of enoxaparin in this setting. Our work provides compelling evidence that a once daily dose of enoxaparin for the treatment of antenatal VTE is appropriate. As a result, the current guidelines should be revised. Figure 1: Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Figure 1:. Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Disclosures: Off Label Use: Enoxaparin use during the antenatal period.

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Section: First In Man Studiesmentioning

confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Patel

Green

Patel

et al. 2012

Blood

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“…In the meantime, heparin had found widespread application as a clinical anticoagulant [18] and in the 1970s structure-activity quests were started to understand and ultimately to improve on its effectivity. Thus, the all-important activation of antithrombin AT-III was nailed down to an essential IdoAS-containing pentasaccharide sequence [19] in the heparin polymer potentiating the anticoagulant action.…”

Section: Introductionmentioning

confidence: 99%

The conformation of the idopyranose ring revisited: How subtle O-substituent induced changes can be deduced from vicinal 1H-NMR coupling constants

Haasnoot¹,

Gelder²,

Kooijman

et al. 2020

Carbohydrate Research

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“…9,10 Of the long list of anticoagulant therapies, heparin formulations have the longest history of clinical use. 11 Unfractionated and low molecular weight heparin (LMWH) are standard treatments for myocardial infarction, cardiovascular surgery, coronary angioplasty, coronary stents and numerous other conditions. 4 LMWH, which can be delivered subcutaneously, offers advantages over unfractionated heparins, which require IV delivery, such as reduced risk of hemorrhage, 12 improved clearance rates, 13 and more predictable pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

In situ crosslinkable heparin‐containing poly(ethylene glycol) hydrogels for sustained anticoagulant release

Baldwin

Robinson

Militar

et al. 2012

J Biomedical Materials Res

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Low molecular weight heparin (LMWH) is widely used in anticoagulation therapies and for the prevention of thrombosis. LMWH is administered by subcutaneous injection usually once or twice per day. This frequent and invasive delivery modality leads to compliance issues for individuals on prolonged therapeutic courses, particularly pediatric patients. Here, we report a long-term delivery method for LMWH via subcutaneous injection of long-lasting hydrogels. LMWH is modified with reactive maleimide groups so that it can be crosslinked into continuous networks with four-arm thiolated polyethylene glycol (PEG-SH). Maleimide-modified LMWH (Mal-LMWH) retains bioactivity as indicated by prolonged coagulation time. Hydrogels comprising PEG-SH and Mal-LMWH degrade via hydrolysis, releasing bioactive LMWH by first-order kinetics with little initial burst release. Separately dissolved Mal-LMWH and PEG-SH solutions were co-injected subcutaneously in New Zealand White rabbits. The injected solutions successfully formed hydrogels in situ and released LMWH as measured via chromogenic assays on plasma samples, with accumulation of LMWH occurring at day two and rising to near-therapeutic dose equivalency by day 5. These results demonstrate the feasibility of using LMWH-containing, crosslinked hydrogels for sustained and controlled release of anticoagulants.

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The Influence of Intravenous Injections of Heparin in Man on the Time of Coagulation.¹

Cited by 27 publications

References 4 publications

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

The conformation of the idopyranose ring revisited: How subtle O-substituent induced changes can be deduced from vicinal 1H-NMR coupling constants

In situ crosslinkable heparin‐containing poly(ethylene glycol) hydrogels for sustained anticoagulant release

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The Influence of Intravenous Injections of Heparin in Man on the Time of Coagulation.1

Cited by 27 publications

References 4 publications

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

The conformation of the idopyranose ring revisited: How subtle O-substituent induced changes can be deduced from vicinal 1H-NMR coupling constants

In situ crosslinkable heparin‐containing poly(ethylene glycol) hydrogels for sustained anticoagulant release

Contact Info

Product

Resources

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The Influence of Intravenous Injections of Heparin in Man on the Time of Coagulation.¹