The Influence of Prior Oral Anticoagulation Therapy on the Anticoagulant Effect of Low Molecular Weight Heparin.

Abstract Low Molecular Weight Heparins (LMWHs) have been suggested by the ACCP as an alternative to UFH for the anticoagulation of patients on chronic oral anticoagulation therapy (OAT) with warfarin. However, the optimal way to manage these patients remains to be established particularly for high-risk patients who require any type of general surgery or urgent invasive PCI procedures. The purpose of this study is to evaluate the LMWH point-of-care (POC) HEMONOXTM assay (Edison, NJ) in patients on chronic OAT. This clot-based test uses rTF reagents and the Hemochron Jr. Signature+ system. The Hemonox clotting time (CT) was analyzed at baseline and at peak response post enoxaparin treatment. Following IRB approval, blood samples from patients on chronic OAT (5 to 20 years, n=13) were evaluated with the Hemonox assay within 12– 18 hours of their last warfarin dose, patients were evaluated weekly for 4 –12 consecutive weeks. In vitro enoxaparin dose response was evaluated by adding 1 U/ml to blood samples obtained from the OAT patients. In supplemental clinical evaluation, 2 PCI cases on OAT were performed at Newark Beth Israel Medical Center, Newark, NJ. Patients were anticoagulated during their PCI procedure with enoxaparin at a final IV dose of 0.5 mg/kg Hemonox CT baseline response was patient specific and the same response profile was obtained for each patient on OAT who underwent consecutive weekly testing. The majority of patients on OAT (9/13; 69%) exhibited elevated Hemonox baseline CT (150–350 secs) when compared to the previously reported range for PCI patients without prior OAT (baseline CT < 100 secs in 100% of cases, Mean = 71.2 ± 9.0, n= 39). Three patients on OAT (23%) showed CT≤150 secs, and only one patient (8%) yielded a baseline < 100 secs. When the blood of the patient with baseline < 100 sec (baseline value = 70 secs) was spiked in vitro with 1 U/ml enoxaparin, the Hemonox CT was 339 secs which was comparable with the peak response (386 and 308 secs; anti-Xa activity = 0.70 ± 0.01 U/ml; concentration of enoxaparin in the circulation = 0.77± 0.13) observed in the PCI patients receiving enoxaparin (0.5 mg/kg IV) and with a prior OAT who showed similar baseline values. Spiked samples from clinic patients with Hemonox baseline > 150 secs were > 700 secs. Our results demonstrate that prior to administration of LMWH, baseline monitoring may be helpful in patients on OAT to alert clinicians to appropriate alterations of enoxaparin dosing and target anticoagulation times due to the influence of warfarin.

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Anti-Xa Potentiating Effect Of Low Molecular Weight Heparin

10.1055/s-0038-1652691 ◽

1981 ◽

Author(s):

W Junker ◽

J Harenberg ◽

F Fussi ◽

K Mattes ◽

R Zimmermann ◽

...

Keyword(s):

Molecular Weight ◽

Intestinal Mucosa ◽

Low Molecular Weight Heparin ◽

Bleeding Complications ◽

Low Molecular Weight ◽

Chromogenic Substrate ◽

Clotting Time ◽

Blood Samples ◽

Increased Risk

Recently special attention has been drawn to bleeding complications of commercial heparins in patients with increased risk for haemorrhages. Alternative heparin preparations with high antithrombotic and low haemostaseological properties have been developed. We now report on a new low molecular weight (LMW) heaprin (mean MW 5000, 85 USP/mg), which has been obtained by depolymerisation of a heparin from pig intestinal mucosa (mean MW 15000, 154 USP/mg).In vitro the anti-Xa-activity (chromogenic substrate S2222) was 15% higher for the LMW heparin in a range of 0.01-2.0 USP/ml plasma. No difference was seen on the anti-IIa-activity (thrombin clotting time)and the aPTT for both heparins in the same range. Both Heparins were injected s.c. in a dose of 100, 50 and 25 USP/kg bodyweight into each of six volunteers randomly at weekly intervalIs. The pharmacodynamic effects were controlled for 6-10 hrs by 8-12 blood samples in relation to the dose applied. Increasing dosis the effects of each heparin increased in all test systems. The anti- Xa-activity of LMW heparin was somewhat higher at 100 and 25 USP/kg. At 50 USP/kg the effect of LMW heaprin was in the same range as 100 USP/kg of the original preparation (MW 15000). The factor Ila activity and aPTT were not influenced differently by the two heparins at each dose.The data indicate, that the LMW heparin presented here may have a more pronounced antithrombotic property by a specific anti-Xa-activity than the compaired commercial heparin. This effect is most pronounced at doses, which have only small haemostaseological effects.

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Computer-aided dosage in oral anticoagulation therapy using phenprocoumon

Hämostaseologie ◽

10.1055/s-0037-1619051 ◽

2010 ◽

Vol 30 (04) ◽

pp. 183-189 ◽

Cited By ~ 2

Author(s):

H. Völler ◽

F. Gäbler ◽

A. Salzwedel ◽

U. Taborski ◽

L. Cromme

Keyword(s):

Oral Anticoagulation ◽

Vitamin K Antagonists ◽

Anticoagulation Therapy ◽

Target Range ◽

Patient Specific ◽

Oral Anticoagulation Therapy ◽

Delayed Effects ◽

Measurement Results ◽

Computer Aided ◽

And Control

SummaryOral anticoagulation using vitamin K antagonists has been established for over 50 years. Although it is highly effective in preventing thromboembolic incidents, its therapeutic control still remains problematic. Therefore, a computer-aided approach is recommended for deriving dosages. Up to now, the dosage is often based on the visual inspection of previous INR measurements, average weekly doses, and the INR target range. Statistical variations of measurement results and time-delayed effects of dosages, however, frequently result in the misinterpretation of data and suggest pseudo-trends. Treating physicians are not only responsible for determining the patient-specific maintenance dose, but must also respond to deviating INR values, overdosage or underdosage, initiate the oral anticoagulation therapy, and control the INR level in case of a new target range (bridging). Instructive examples are provided to illustrate the described difficulties.A computer-aided expert system is currently developed to ensure the therapeutic safety under the specified conditions. We present preliminary results from a study designed to validate mathematical models underlying such expert systems.

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Multi-Modal Mechanisms and Anti-Sickling of Novel Sulfated Non-Anticoagulant Low Molecular Weight Heparin in Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-115121 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 265-265

Author(s):

Shaker A Mousa ◽

Noureldien Hassan Elsayed Darwish ◽

Vandhana Muralidharan-Chari ◽

Mohamed Qari ◽

Chen Qiukan ◽

...

Keyword(s):

Molecular Weight ◽

Side Effects ◽

Sickle Cell ◽

Low Molecular Weight Heparin ◽

Low Molecular Weight ◽

Cell Disease ◽

Blood Samples ◽

Dose Dependent

Abstract The pathogenesis of Sickle Cell Disease (SCD) comprises a complex interplay of factors associated with vascular endothelial activation, intense inflammation, and increased sickle cell adhesion. Microvascular occlusion in SCD is initiated by adhesion of sickle red blood cells (RBCs) to the endothelium, leading to acute painful vasoocclusive crisis (VOC) and clinical morbidity. Current treatment strategies remain sub-optimal and are limited by significant side effects. The inherent complexity of SCD makes it unlikely that a single therapeutic strategy will be universally beneficial. We have previously shown that the low molecular weight heparin (LMWH) tinzaparin significantly shortened both duration of VOC crisis and hospitalizations by ~40%, and resulted in statistically significant and rapid reduction of pain). However, safety concerns associated with the narrow therapeutic index (bleeding risks) of LMWH are a major barrier to dose escalation/optimization of treatments. We have developed a novel sulfated non-anticoagulant LMWH, named S-NACH, with an extensive range of bioactivities that would constitute a multi-modal approach to management of SCD. We generated and significantly optimized S-NACH for VOC to: 1) exert its beneficial activities without causing hemostatic (bleeding) side effects that are associated with the clinical use of LMWHs; and 2) incorporate an additional, potent direct anti-sickling property besides its anti-selectin and anti-inflammatory activities. We conducted in vitro and in vivo investigations on the efficacy of S-NACH on the biophysical properties of RBCs. For the in vitro study, 21 subjects comprising 12 SCD patients with hemoglobin (Hb) SS on hydroxurea and 9 normal subjects with Hb AA of both sexes and of different ages were randomly recruited. To assess the effects of S-NACH on the sickling, the SS blood samples were incubated under hypoxia (2% O2 gas, balance N2 gas) at 37°C for 1.5 h, in the absence (control) or presence of 1, 5, or 10 ug/mL of S-NACH or LMWH. For the in vivo study, we obtained pre-treatment samples from Townes' SCD mice (n=6 mice/treatment group) and treated the mice subcutaneously with PBS or 30-100 mg/kg S-NACH. Two hours after treatment, blood samples were evaluated for the percentage of sickled cells in pre- and post-administration samples using Leishman's stain and wet smears. Incubation with S-NACH in vitro under hypoxia showed a dose-dependent, significant inhibition of sickling (up to 80%) in samples from all subjects while LMWH showed no anti-sickling effect. S-NACH had no effect on the osmotic fragility of both AA and SS RBCs. Importantly, we observed a 40-50% decrease in levels of circulating sickled cells in treated SCD mice, an effect that persisted for up to 6 h. Our in vitro studies show that the direct anti-sickling effect is partly due to dose-dependent modification of Hb S to the high-affinity adduct form and the corresponding increase in oxygen affinity, as demonstrated with cation HPLC and oxygen equilibrium analyses. Summarily, our previous findings showed the efficacy of S-NACH as anti-adhesive and anti-inflammatory in SCD, and our current results demonstrate the direct anti-polymerization action of S-NACH on sickle RBCs. Our data document for the first time the supplemental direct anti-sickling effects of a novel S-NACH derivative, suggesting a rational mode of action for these effects and make a compelling case for future studies. Planned detailed structural studies of our S-NACH derivatives complexed with Hb are expected to further illuminate the anti-sickling properties. Our novel Nanoformulated S-NACH for subcutaneous and oral administration would facilitate broader investigation of this promising molecule with multiple modes of action in animal models, with relatively quick translation to successful studies in individuals with SCD. Disclosures Mousa: Vascular Vision Pharmaceuticals Co.: Patents & Royalties: Patent Holder.

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In vitro cytotoxic and immunomodulative activities of low molecular weight ι-carageenans partially methylated and pyruvated

Planta Medica ◽

10.1055/s-0028-1084246 ◽

2008 ◽

Vol 74 (09) ◽

Author(s):

S Bondu ◽

E Deslandes ◽

MS Fabre ◽

C Berthou ◽

G Yu

Keyword(s):

Molecular Weight ◽

Low Molecular Weight ◽

Partially Methylated

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Effects of Unfractionated and Low Molecular Weight Heparins on Platelet Thromboxane Biosynthesis “In Vivo”

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648988 ◽

1994 ◽

Vol 72 (06) ◽

pp. 942-946 ◽

Cited By ~ 20

Author(s):

Raffaele Landolfi ◽

Erica De Candia ◽

Bianca Rocca ◽

Giovanni Ciabattoni ◽

Armando Antinori ◽

...

Keyword(s):

Molecular Weight ◽

Unfractionated Heparin ◽

Low Molecular Weight Heparin ◽

Primary Source ◽

In Vivo Studies ◽

Low Molecular Weight ◽

Heparin Administration ◽

To Receive

SummarySeveral “in vitro” and “in vivo” studies indicate that heparin administration may affect platelet function. In this study we investigated the effects of prophylactic heparin on thromboxane (Tx)A2 biosynthesis “in vivo”, as assessed by the urinary excretion of major enzymatic metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2. Twenty-four patients who were candidates for cholecystectomy because of uncomplicated lithiasis were randomly assigned to receive placebo, unfractionated heparin, low molecular weight heparin or unfractionaed heparin plus 100 mg aspirin. Measurements of daily excretion of Tx metabolites were performed before and during the treatment. In the groups assigned to placebo and to low molecular weight heparin there was no statistically significant modification of Tx metabolite excretion while patients receiving unfractionated heparin had a significant increase of both metabolites (11-dehydro-TxB2: 3844 ± 1388 vs 2092 ±777, p <0.05; 2,3-dinor-TxB2: 2737 ± 808 vs 1535 ± 771 pg/mg creatinine, p <0.05). In patients randomized to receive low-dose aspirin plus unfractionated heparin the excretion of the two metabolites was largely suppressed thus suggesting that platelets are the primary source of enhanced thromboxane biosynthesis associated with heparin administration. These data indicate that unfractionated heparin causes platelet activation “in vivo” and suggest that the use of low molecular weight heparin may avoid this complication.

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The Effect of Dextran of Various Molecular Weight on the Coagulation in Dogs

Thrombosis and Haemostasis ◽

10.1055/s-0038-1654535 ◽

1961 ◽

Vol 06 (01) ◽

pp. 015-024 ◽

Cited By ~ 32

Author(s):

Sven Erik Bergentz ◽

Oddvar Eiken ◽

Inga Marie Nilsson

Keyword(s):

Molecular Weight ◽

Body Weight ◽

High Molecular Weight ◽

Bleeding Time ◽

Factor Vii ◽

Low Molecular Weight ◽

Factor V ◽

Coagulation Mechanism ◽

Coagulation Defects

Summary1. Infusions of low molecular weight dextran (Mw = 42 000) to dogs in doses of 1—1.5 g per kg body weight did not produce any significant changes in the coagulation mechanism.2. Infusions of high molecular weight dextran (Mw = 1 000 000) to dogs in doses of 1—1.5 g per kg body weight produced severe defects in the coagulation mechanism, namely prolongation of bleeding time and coagulation time, thrombocytopenia, pathological prothrombin consumption, decrease of fibrinogen, prothrombin and factor VII, factor V and AHG.3. Heparin treatment of the dogs was found to prevent the decrease of fibrinogen, prothrombin and factor VII, and factor V otherwise occurring after injection of high molecular weight dextran. Thrombocytopenia was not prevented.4. In in vitro experiments an interaction between fibrinogen and dextran of high and low molecular weight was found to take place in systems comprising pure fibrinogen. No such interaction occurred in the presence of plasma.5. It is concluded that the coagulation defects induced by infusions of high molecular weight dextran are due to intravascular coagulation.

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Neutralization of a Low Molecular Weight Heparin (LHN-1) and Conventional Heparin by Protamine Sulfate in Rats

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661675 ◽

1986 ◽

Vol 56 (03) ◽

pp. 318-322 ◽

Cited By ~ 18

Author(s):

V Diness ◽

P B Østergaard

Keyword(s):

Molecular Weight ◽

Low Molecular Weight Heparin ◽

Thrombus Formation ◽

Experimental Models ◽

Protamine Sulfate ◽

Low Molecular Weight ◽

Antithrombotic Effect ◽

Higher Doses

SummaryThe neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized.In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.

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