Heparin: Mechanism of Action, Pharmacokinetics, Dosing Considerations, Monitoring, Efficacy, and Safety

Hirsh, Jack; Raschke, Robert; Warkentin, Theodore E.; Dalen, James E.; Deykin, Daniel; Poller, L.

doi:10.1378/chest.102.4_supplement.337s

Cited by 333 publications

(84 citation statements)

References 175 publications

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“…Both also cause a decrease in the number of rolling cells and an increase in their rolling velocities at all concentrations tested, including concentrations attained in the plasma during clinical administration (ie, 0.2-0.4 U/mL). 37 At 5 U/mL to 50 U/mL, rolling adhesion was approximately the same as that of the basal adhesion to BSA. These results indicate a similarity in the effects of laboratory and clinical grades of heparin with regard to the inhibition of P-selectin-dependent sickle cell-endothelial cell adhesion and indicate their potential therapeutic relevance.…”

Section: Heparin Inhibits Sickle Rbc Adhesion To P-selectin 3793mentioning

confidence: 83%

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Matsui

Varki

Embury

2002

Blood

115

110

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The adhesion of sickle erythrocytes to vascular endothelium is important to the generation of vascular occlusion. Interactions between sickle cells and the endothelium use several cell adhesion molecules. We have reported that sickle cell adhesion to endothelial cells under static conditions involves P-selectin. Others have shown that sickle cell adhesion is decreased by unfractionated heparin, but the molecular target of this inhibition has not been defined. We postulated that the adhesion of sickle cells to P-selectin might be the pathway blocked by unfractionated heparin. In this report we demonstrate that the flow adherence of sickle cells to thrombin-treated human vascular endothelial cells also uses P-selectin and that this component of adhesion is inhibited by unfractionated heparin. We also demonstrate that sickle cells adhere to immobilized recombinant P-selectin under flow conditions. This adhesion too was inhibited by unfractionated heparin, in a concentration range that is clinically attainable. These findings and the general role of P-selectin in initiating adhesion of blood cells to the endothelium suggest that unfractionated heparin may be useful in preventing IntroductionVascular occlusion is responsible for much of the morbidity associated with sickle cell disease. 1,2 Although the underlying cause of sickle cell disease is a single nucleotide mutation that directs the production of an easily polymerized hemoglobin protein, 3,4 both the erythrocyte sickling caused by hemoglobin polymerization and the interactions between a proadhesive population of sickle cells and the vascular endothelium are essential to vascular occlusion. 5,6 The correlation between sickle cell adhesiveness and the severity of vascular occlusion 7 led to extensive studies of the molecular mechanisms of adhesion. These pathways recently have been reviewed [8][9][10][11][12] and are briefly described here. Sickle red cells express adhesion molecules including integrin ␣ 4 ␤ 1 , CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine, and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), CD36, and integrins. Activation of endothelial cells by specific agonists enhances adhesion by inducing the expression of cellular adhesion molecules and by causing cell contraction, which exposes extracellular matrix proteins, such as thrombospondin (TSP), laminin, and fibronectin. Bridging molecules from the plasma such as von Willebrand factor (VWF) and TSP also participate in certain of these adhesive interactions.Sickle cell adhesion has been studied under both static and flow conditions. 13 The relevance of both types of adhesion is suggested by in vivo observations of laminar, intermittent, and antegraderetrograde flow in the microvasculature of sickle cell subjects and sickle cell mouse models. [14][15][16] Initial events likely involve the adhesion of sickle erythrocytes to activated endothelial cells under ...

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Section: Heparin Inhibits Sickle Rbc Adhesion To P-selectin 3793mentioning

confidence: 83%

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Matsui

Varki

Embury

2002

Blood

115

110

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“…Recent research makes it clear that the traditional use of 1.5 times control as the lower limit of the therapeutic range is frequently inaccurate because the therapeutic range actually varies considerably among lots of reagent and among laboratories. 18 It was not feasible to perform such studies on the reagents being used in each facility, so the traditional range was used. The second end point was whether at least one platelet count was obtained during the first 3 and the first 7 days of therapy.…”

Section: Discussionmentioning

confidence: 99%

Anticoagulation therapy in patients with venous thromboembolic disease

Whittle

Johnson

1998

J Gen Intern Med

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OBJECTIVE:To determine, in a representative sample of patients drawn from a variety of hospitals, the degree of adherence to consensus recommendations for anticoagulation among patients with deep vein thrombosis or pulmonary embolism. DESIGN:Cross-sectional review of a population-based random sample.SETTING: Twenty-one randomly selected Pennsylvania hospitals. PATIENTS:Of 357 randomly selected Medicare beneficiaries discharged from study hospitals with a diagnosis of deep venous thrombosis or pulmonary embolism during 1992, 43 charts were not reviewed for administrative reasons, 31 were miscoded or not treated with intravenous administration of heparin, and 13 were excluded for other reasons, leaving 270 in the final sample. MEASUREMENTS AND MAIN RESULTS:Overall, 179 patients (66%, 95% confidence interval [CI] 59%, 72%) received therapeutic anticoagulation (two consecutive partial thromboplastin times more than 1.5 times control) within 24 hours of starting heparin. Platelet counts were checked at least once during the first week of heparin therapy in 66% (95% CI 58%, 74%). At least 5 days of heparin therapy was given to 84% (95% CI 79%, 87%). Among 266 (99%) of the patients receiving warfarin, 193 (72%; 95% CI 63%, 80%) received heparin until the prothrombin time ratio or International Normalized Ratio was therapeutic. Patients who were started on warfarin therapy within 2 days of heparin had decreased length of stay (geometric mean 8.2 vs 9.7 days, p ‫؍‬ .003). Compliance varied among hospitals. CONCLUSIONS:In a wide variety of hospitals, we found fair, but variable, compliance with consensus recommendations for anticoagulation of patients with venous thromboembolic disease. Simple interventions to improve compliance with these recommendations might improve quality of care and reduce costs. The most dreaded complication, pulmonary embolism, has a high mortality rate in this population, and most deaths occur before the pulmonary embolism is treated. 2 The standard approach to treatment is acute anticoagulation with carefully administered and monitored intravenous (IV) heparin, followed by a period of oral anticoagulation with warfarin. 3 Since 1985, the National Heart Lung and Blood Institute (NHLBI) and/or the American College of Chest Physicians (ACCP) have convened four consensus conferences on anticoagulation therapy, which have provided guidance for anticoagulant use in this setting. 3-6 At these conferences, experts in anticoagulation therapy generate consensus recommendations for therapy, based on a thorough review of the literature using strict rules of evidence. 7 These conferences have suggested that early achievement of therapeutic levels of anticoagulation might decrease recurrences; routine monitoring of platelet counts is indicated because of heparin-induced thrombocytopenia; heparin should be administered for at least 5 days in patients with DVT or pulmonary embolism, and until therapeutic anticoagulation with warfarin has been achieved and maintained for 2 days; and warfarin therapy can be insti...

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“…SH acts mainly by binding to and enhancing the effect of antithrombin III, which results in a rapid inhibition of a number of serine proteinases, notably thrombin (factor Ila), factor IXa and factor Xa [5,6]. When administered intravenously as a bolus, SH has an effective concentration-dependent half-life of about 1^ hours.…”

Section: L Standard Unfractionated Heparin (Sh)mentioning

confidence: 99%

“…Another side-effect of SH or LMWH is thrombo cytopenia, an allergic reaction [5,38], It typically appears 5 or more days after the start of therapy. The thrombocytopenia is caused by heparin-dependent IgG antibodies that activate platelets through their Fc receptors [52], Paradoxically, thrombotic complica tions develop in some patients with heparin-induced thrombocytopenia, possibly because of in vivo platelet activation [53].…”

Section: H Janssen Et Al /Netherlands Journal Ofmentioning

confidence: 99%

“…The thrombocytopenia is caused by heparin-dependent IgG antibodies that activate platelets through their Fc receptors [52], Paradoxically, thrombotic complica tions develop in some patients with heparin-induced thrombocytopenia, possibly because of in vivo platelet activation [53]. With these patients the use of danaparoid (a combination of heparan sulphate and dennatan sulphate) should be considered [5,54], It has been demonstrated that thrombocytopenia occurs less in patients treated with LMWH [55]. Other adverse reactions including osteoporosis, alopecia, local skin necrosis from hypersensitivity and anaphy lactic shock are rare.…”

Section: H Janssen Et Al /Netherlands Journal Ofmentioning

confidence: 99%

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New developments in the treatment of deep venous thrombosis

Janssen¹,

Nováková²,

Verbruggen³

et al. 1997

The Netherlands Journal of Medicine

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An initial course of standard heparin (SH) or low-molecular-weight heparins (LMWH) is regarded as the treatment of choice for patients with deep venous thrombosis (DVT). LMWH have better bioavailability after subcutaneous administra tion, have a longer half-life, and show higher and more predictable anticoagulant activity. As a result they can be given subcutaneously and without laboratory control, using a dose that is determined by body weight. Because of these multiple advantages of LMWH they will replace SH in the future and subsequently home treatment with LMWH of selected patients seems feasible. The currently accepted approach is to start with SH or LMWH therapy combined with oral anticoagulant therapy (OAT) at the time of diagnosis. The course of SH or LMWH should continue for at least 5 days, provided that international normalized ratio (INR) is in the therapeutic range on 2 consecutive days. OAT should be continued for at least 3 months to prolong the prothrombin time to an INR of 2 -3 . When oral anticoagulants are either contraindicated or inconvenient, SH or LMWH can be used at the middosing interval. The role of anti-platelet treatment is not yet established 4 and should be compared with coumarin therapy in the future.

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Heparin: Mechanism of Action, Pharmacokinetics, Dosing Considerations, Monitoring, Efficacy, and Safety

Cited by 333 publications

References 175 publications

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Anticoagulation therapy in patients with venous thromboembolic disease

New developments in the treatment of deep venous thrombosis

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