The anticoagulant capacity of plasmatic unfractionated heparin decreases at 23 degrees C.

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are important clinical anticoagulants. As polynegative molecules they are potential triggers of the contact phase of coagulation. An incubation temperature lower than the physiological 37 degrees C favours intrinsic haemostasis activation by the polynegative molecule SiO2. The efficiency of UFH and LMWH after a plasmatic preincubation at 37 or at 23 degrees C is therefore studied. Samples (150 mul) of unfrozen pooled normal plasma supplemented with 0, 0.01, 0.1, or 1 IU/ml heparin or dalteparin in 5-ml polystyrole tubes were incubated for 10-70 min at 37 or at 23 degrees C. The extrinsic coagulation activity assay (EXCA) was then performed. Preincubation at 37 degrees C of 0.1 IU/ml plasmatic UFH does not result in any thrombin generation in EXCA-1, whereas preincubation at 23 degrees C results in a thrombin generation of about 0.1 IU/ml thrombin. Plasmatic UFH (0.01 IU/ml) at 23 degrees C acts nearly half as efficiently as 0.01 IU/ml plasmatic LMWH. Polynegatively charged niches particularly in the larger UFH molecule might trigger the contact system of haemostasis, especially at 23 degrees C. In contrast, the anticoagulant capacity of LMWH does not change significantly with temperature.     

Efficacy of unfractionated heparin, low molecular weight heparin and both combined for releasing total and free tissue factor pathway inhibitor.

Unfractionated heparin (UFH) exerts its anticoagulant properties by increasing the inactivation of thrombin and activated factor X by antithrombin III. Apart from this main action release of tissue factor pathway inhibitor (TFPI) from endothelial cells could also be important for the antithrombotic activity of heparins. Four different heparin preparations were injected subcutaneously into 5 healthy volunteers 1 week apart: (1) UFH 2,500 IU fix dose (FixUFH), (2) 1 mg/kg body weight of low molecular weight heparin (LMWH), (3) the combined LMWH-adjusted dose plus UFH 2,500 IU fix dose (ComHep) and (4) UFH 2,500 IU/10 kg body weight (UFHvar). Plasma samples were drawn before and 1, 2, 4, 6, 12 and 24 h afterwards. FixUFH did not affect the concentration of total and free TFPI. Total TFPI increased in the 1st hour after LMWH injection from 74 to 124 ng/ml (p < 0.01), after ComHep from 82 to 144 ng/ml (p < 0.01), and after UFHvar from 91 to 113 ng/ml (p < 0.05). All observed elevations were significant at the peak value (+/- 2 h, p < 0.01 compared with baselines). The increase of free TFPI produced by UFHvar (74.5 and 70.5 ng/ml) was significantly higher than with LMWH (42.8 and 38.0 ng/ml) at 2 and 4 h (p < 0.001 and p < 0.01, respectively). UFHvar and ComHep but not LMWH produced a statistically significant increase of free TFPI compared with FixUFH at 2, 4 and 6 h (p < 0. 01). We concluded that at comparable therapeutic doses, subcutaneous UFHvar released more free TFPI than LMWH and ComHep. A synergism between LMWH and low dose of UFH was found in 4-, 6- and 12-hour blood samples.     

The effects of unfractionated heparin, low molecular weight heparin and danaparoid on the thromboelastogram (TEG): an in-vitro comparison of standard and heparinase-modified TEGs with conventional coagulation assays.

To investigate the effects of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and danaparoid (DPD) added to whole blood in vitro on standard and heparinase-modified thromboelastogram (TEG) parameters compared with conventional assays of coagulation. The effects of UFH, LMWH and DPD on standard TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-activated factor X (anti-FXa) activity, at concentrations of these anticoagulants ranging from 0.025 to 1 U/ml. In the second part of the study, the effects of very low concentrations (0.005-0.05 U/ml) of UFH, LMWH and DPD on the difference between standard and heparinase-modified TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-FXa activity. Standard TEG parameters were outside the reference range at lower concentrations of UFH, LMWH and DPD than most conventional coagulation assays were able to detect. Only anti-FXa activity was more sensitive to the presence of these anticoagulants than the standard TEG alone. The lowest concentration of UFH, LMWH and DPD used in this study (0.005 U/ml) caused significant differences between the standard and heparinase-modified alpha-angles of the TEG. In addition, the difference between standard and heparinase-modified TEG parameters distinguished between low concentrations (0.005-0.05 U/ml) of UFH with greater sensitivity than anti-FXa activity, but were less sensitive to LMWH and DPD. The standard TEG is more sensitive to UFH, LMWH and DPD than most conventional coagulation tests, with the exception of anti-FXa activity. Calculation of the difference between standard and heparinase-modified TEG parameters greatly increases the sensitivity of the assay for the effects of these anticoagulants, and is more sensitive to very low quantities of UFH than anti-FXa activity.     

Inhibition of extrinsic hemostasis activation by low-molecular-weight heparin.

Low-molecular-weight heparins (LMWHs) are very important drugs; unfortunately, the routine global hemostasis assays activated partial thromboplastin time and prothrombin time are not sensitive to LMWHs. Here the 50% inhibitory concentration (IC(50)) values of heparin and LMWHs on extrinsic thrombin generation are determined. Pooled normal plasma was supplemented with 0-2 IU/ml unfractionated heparin, 0-2 IU/ml LMWH dalteparin, or 0-20 microg/ml pentosanpolysulfate in 5-ml polystyrole tubes (23 degrees C) and tested in the tissue-factor-triggered extrinsic coagulation activity assay (EXCA): 50 microl plasma + 5 microl tissue factor/CaCl(2), 1 and 2 min incubation time at 37 degrees C (coagulation reaction time for EXCA-1 and EXCA-2); + 100 microl of 2.5 mol/l arginine (pH 8.6), 20 min at room temperature; + 50 microl of 1 mmol/l CHG-Ala-Arg-pNA, 1.25 mol/l arginine; increase in absorbance/time at 23 degrees C; calibrator = 1 IU/ml bovine thrombin in 6.7% human albumin replacing the plasma sample; in EXCA-1, about 1 IU/ml thrombin is generated in pooled unfrozen normal citrated plasma. The IC(50) values in EXCA-1 are 0.1 IU/ml heparin, 0.02 IU/ml LMWH, and 4.7 microg/ml pentosanpolysulfate. In ECXA-2 the IC(50) values are 0.07 IU/ml, 0.01 IU/ml, and 4.6 microg/ml, respectively. The EXCA reflects the efficiency of anticoagulants on plasmatic coagulation. It is suggested to adjust the dosage of LMWH according to the EXCA value; about 30% of normal extrinsic thrombin generation might be the correct dose for prophylactic anticoagulation.     

Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison between unfractionated and low-molecular-weight heparin

OBJECTIVES: This study compared rebound coagulation in patients with acute coronary syndrome patients after discontinuation of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). BACKGROUND: Up to a quarter of patients hospitalized for unstable angina experience recurrent ischemia after discontinuation of UFH or LMWH therapy, which may be the result of rebound coagulation activation and subsequent thrombosis. It is unknown whether UFH and LMWH differ in this respect. METHODS: We randomized 71 patients admitted with unstable angina to intravenous UFH or subcutaneous LMWH (dalteparin) and measured plasma markers of coagulation before, during, and after treatment. RESULTS: A complete series of measurements was obtained in 59 patients. Plasma prothrombin fragment 1+2 (F(1+2)) levels decreased in both groups during treatment. After loss of therapeutic plasma drug levels, F(1+2) increased (within 3 h) to a maximum level at 12 to 24 h that was higher than before or during treatment in both groups (p < 0.0001). In both groups, F(1+2) levels remained higher than pretreatment up to 24 h after discontinuation. Similarly, thrombin-antithrombin (TAT) levels exceeded treatment and pretreatment levels, at a slower rate after dalteparin than after UFH. However, after dalteparin a higher peak value of TAT was observed. CONCLUSIONS: Rebound coagulation activation occurs within hours after discontinuation of both UFH and dalteparin. With both drugs, thrombin generation is significantly greater after treatment than before or during treatment. A longer duration or weaning of treatment, or continuation with another anticoagulant treatment, may reduce rebound coagulation activation and ischemic events.     

Inhibition of coagulation and platelet adhesion to extracellular matrix by unfractionated heparin and a low molecular weight heparin

Summary In 7 healthy volunteers, the effect of a single i.v. injection of 52 mg (7,500 IU) of an unfractionated heparin (UFH) and of 52.5 mg (5,000 anti XaU) of a low molecular weight heparin (LMWH) on coagulation parameters and platelet function has been studied. Thrombininduced platelet aggregation was inhibited after the injection of both heparins. There was no significant change of ADP or collagen-induced aggregation after LMWH or UFH. Platelet adhesion to bovine extracellular matrix was not inhibited by UFH but was significantly reduced after addition in vitro and ex vivo after administration of LMWH. Further investigation should establish the time course of LMWH effects on platelet adhesion. A long duration of this effect could be partially correlated with the antithrombotic effects of LMWH.     

Comparison of fondaparinux, low molecular-weight heparin and unfractionated heparin in preventing thrombus formation on mechanical heart valves: results of an in-vitro study

BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the efficacy of three different anticoagulants in preventing thrombus formation on mechanical heart valves, using an in-vitro system. METHODS: Blood samples (470 ml) were taken from young and healthy male volunteers and anticoagulated with unfractionated heparin (UFH; n=18), low molecular-weight heparin (LMWH; n=18) or fondaparinux (n=16). Bileaflet mechanical heart valves were placed in a new device--the 'Thrombosis Tester'--and exposed in a continuous circulation at a rate of 80 beats per min to the anticoagulated blood samples for a total exposure time of 60 min. Results for thrombus weight were skewed distributed and presented as log-transformed values. RESULTS: The weight of each valve was measured before and after 1 h of perfusion; subsequent mean (+/-SD) thrombus weights were 0.739 +/- 0.573 g for UFH, 0.789 +/- 0.099 g for LMWH, and 0.934 +/- 0.145 g for fondaparinux (p = 0.397 for comparison of all groups by ANOVA). Electron microscopy showed concordant results with regard to thrombus formation on heart valve surfaces. CONCLUSION: Fondaparinux and LMWH were as effective as UFH in preventing thrombus formation on mechanical heart valves in vitro. The 'Thrombosis Tester' proved to be a new, unique instrument for investigating the ability of anticoagulants to prevent valve thrombosis on mechanical heart valves under in-vitro conditions.     

Low molecular weight heparin (Alfa LHWH) compared with unfractionated heparin in prevention of deep-vein thrombosis after hip fractures

Efficacy and safety of a low molecular weight heparin (Alfa LMWH) was compared with unfractionated heparin (UFH) in the prevention of post-operative venous thromboembolism after hip fractures. Forty-nine patients were randomized to treatment with Alfa LMWH 7500 anti-Xa coagulometric units twice daily or with UFH 5000 IU t.i.d. Screening for thrombosis was performed with 125-I-fibrinogen leg scanning and strain-gauge plethysmography. Positive results were confirmed by venography. Five patients in the Alfa LMWH group (20 per cent) developed venographycally proven deep vein thrombosis (DVT) versus seven (29 per cent) in the UFH group. One pulmonary embolism and two deaths occurred in the UFH group and none in the LMWH group. No differences in haemorrhagic complications and blood loss indices were observed. Alfa LMWH appears to be a promising drug for prevention of venous thromboembolism after orthopaedic surgery. A "flexible" schedule of administration is proposed on the basis of the results of plasma anti-Xa assays.     

静脉注射肝素钠和达肝素钠对血小板激活影响的对比研究

目的了解肝素钠(UFH)与低分子肝素(LWMH)对血小板激活的影响有无差别。方法59例新入院冠心病患者,随机分为UFH组和达肝素钠组,分别于基线状态下、给药(UFH或达肝素钠5000 IU)后30 min、1 h取血,测定CD62P、GPⅡb/Ⅲa、血管性假血友病因子(vWF)。结果UFH组静脉给药后30 min GPⅡb/Ⅲa、血浆CD62P及vWF的水平均明显高于给药前(P<0.05);给药后1 h GPⅡb/Ⅲa及vWF的水平仍显著高于给药前(P<0.05);血浆CD62P的水平虽仍较给药前增高,但差异无统计学意义(P>0.05)。静脉给予达肝素钠5000 IU30min后GPⅡb/Ⅲa及血浆CD62P的水平均明显高于给药前(P<0.05),但在给药后1 h即与基线值差异无统计学意义(P>0.05);vWF的水平在给予达肝素钠后30 min、1 h均与给药前相比,差异无统计学意义(P>0.05)。结论静脉注射UFH及达肝素钠均可激活血小板;但达肝素钠对血小板活化的影响较小。     

Differential effect of unfractionated heparin and low molecular weight heparin on intravascular tissue factor pathway inhibitor: evidence for a difference in antithrombotic action

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of tissue factor (TF)-induced blood coagulation, which is increased several-fold in post-heparin plasma and thought to contribute significantly to the antithrombotic action of heparin. In the present study we investigated whether subcutaneous (s.c.) administration of a low molecular weight heparin (LMWH), enoxaparin, had a different effect on intravascular pools of TFPI compared with continuous i.v. infusion of unfractionated heparin (UFH). 18 healthy male volunteers were randomly assigned to continuous i.v. infusion with UFH (initially 450 U/kg/24 h, n  = 6) or to s.c. treatment with LMWH once daily (enoxaparin, 1.5 mg/kg, n  = 12) for 72 h. A bolus injection of 5000 IU UFH i.v. caused an 8–13-fold increase in plasma-free TFPI antigen (TFPI Ag), followed by a progressive decrease (81 ± 4%, P  < 0.001) during the 72 h infusion with UFH. 4 h after discontinuation of the infusion, basal free TFPI Ag and heparin-releasable TFPI were significantly decreased compared with the concentrations before the infusion (30 ± 9% and 27 ± 7%, respectively). In contrast, LMWH treatment did not reduce either basal or heparin-releasable TFPI Ag. The changes in plasma TFPI Ag by UFH and LMWH were statistically different between groups both in pre- ( P  < 0.001) and post-heparin ( P  < 0.0001) plasma. The differential effect of UFH and LMWH on intravascular pools of TFPI may contribute to the understanding of the apparent superior efficacy of LMWHs in the treatment of both arterial and venous thrombosis.     

Non-ST elevation acute coronary syndrome: changes of parameters of hemostasis during and after treatment with unfractionated heparin and enoxaparin

AIM: To compare changes of parameters of hemostasis in patients with non-ST elevation acute coronary syndrome (NSTEACS) during and after treatment with unfractionated heparin (UFH) and low molecular weight heparin (LMWH) enoxaparin. MATERIAL: Control groups of 2 randomized studies of effects of thienopyridines in NSTEACS with similar inclusion criteria. METHODS: In patients (n=18) of study one UFH was infused intravenously for 54.2+/-22.3 h, in patients of study two subcutaneous enoxaparin 1 mg/kg b.i.d. was used for 76.2+/-28.3 h. Levels of D-dimer (DD), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), von Willebrand factor (vWF), fibrinogen, tissue plasminogen activator (TPA) and activity of its inhibitor (PAI), soon after start of treatment with heparins and in 1, 3, 7 and 14 days. RESULTS AND CONCLUSION: Short term lowering of DD and TAT levels occurred during UFH infusion apparently reflecting primary antithrombin action of UFH. During LMWH use DD level remained unchanged however its lowering was observed after cessation of LMWH (on days 7 and 14). The use of LMWH was not associated with increases of thrombinemia (TAT), thrombin generation (F1+2), and fibrinogen which were registered after end of UFH infusion (days 3, 7 and 14). Neither UFH nor LMWH prevented acute phase vWF elevation. The use of both heparins was associated with changes that could be interpreted as profibrinolytic. In LMWH treated patients these changes (elevations of TPA level) became manifested early (on day 3) and were short lived while in UFH treated patients they appeared later (on day 7) and were prolonged (as lowered PAI activity on day 14).     

Haemorrhagic effect of enoxaparin, a low molecular weight heparin. Comparison with unfractionated heparin in humans.

The haemorrhagic effects of unfractionated heparin (UFH) and the low molecular weight heparin (LMWH) enoxaparin were investigated and compared in the gastric mucosa (haemorrhage induced by biopsy) and skin (haemorrhage induced by Simplate) of 12 healthy volunteers. Administration of UFH and LMWH (given in a dose of 75 anti-Xa U/kg intravenously) increased median gastric bleeding time (3.5 min) and geometric mean blood loss (11.5 microliters) to 19 min (p = 0.00003) and 54.1 microliters (p = 0.0021) after UFH and to 13 min (p = 0.008) and 29.0 microliters (p = 0.275) after LMWH. Median skin bleeding time (4.25 min) increased to 6.0 min after UFH (p = 0.003) and to 6.75 min after LMWH (p = 0.0008). Mean heparin activity in plasma was 20% higher after LMWH than after UFH. The calculated gastric bleeding time to heparin activity ratio was significantly lower for LMWH than for UFH (p < 0.05).     

Heparin blunts endotoxin-induced coagulation activation

BACKGROUND: Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa-dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F(1+2) (P<0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; P<0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F(1+2) and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (P<0.01). Concomitantly, factor VIIa levels dropped by >50% at 50 minutes after initiation of either heparin infusion (P<0.01). CONCLUSIONS: This experimental model proved the anticoagulatory potency of UFH and LMWH in the initial phase of experimental LPS-induced coagulation. Successful inhibition of thrombin generation also translates into blunted activation of coagulation factors upstream and downstream of thrombin.     

The course of disseminated intravascular coagulation is predicted by changes in thrombin-antithrombin III complex levels--is there any difference between treatment with standard heparin or low-molecular-weight heparin?

Changes in thrombin-antithrombin III complex (TAT) over a one week period studied in 42 cases of disseminated intravascular coagulation (DIC); 19 treated with standard (or unfractionated) heparin (UFH) and 23 treated with low-molecular-weight heparin (LMWH). Closer examination of short term changes in TAT (determined 2, 6, 12, 24, 48, and 72 h after starting anticoagulant therapy) was performed in ten cases of DIC; six treated with UFH and four treated with LMWH. In twelve of the 19 cases of DIC treated with UFH and 19 of the 23 cases treated with LMWH, plasma levels of TAT decreased one day after starting anticoagulant therapy, and no exacerbation of DIC was observed for the following week. In the other cases, these levels further increased and most patients had persistently high levels of TAT for the next week. Plasma levels of TAT were significantly lower in patients treated with LMWH than in those treated with UFH, which may suggest that LMWH is more beneficial in DIC. A transient increase in plasma levels of TAT was observed 6 h after the start of anticoagulant therapy in two of the six cases treated with UFH and one of the four cases treated with LMWH. From these results we conclude that fluctuation of TAT was not influenced by the type of heparin (UFH or LMWH), and that the course of DIC for the following week can be predicted by the changes in plasma TAT levels one day after starting anticoagulant therapy.     

Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin : clinical implications for heparin-induced thrombocytopenia.

BACKGROUND: Cardiopulmonary bypass (CPB) induces platelet activation with release of platelet factor 4 (PF4), and patients are exposed to high doses of heparin (H). We investigated whether this contributes to the development of antibodies to H-PF4 and heparin-induced thrombocytopenia (HIT). METHODS AND RESULTS: CPB was performed with unfractionated heparin (UFH) in 328 patients. After surgery, patients received UFH (calcium heparin, 200 IU. kg-1. d-1) (group 1, n=157) or low-molecular-weight heparin (LMWH, Dalteparin, 5000 IU once daily) (group 2, n=171). Eight days after surgery, antibodies to H-PF4 were present in 83 patients (25.3%), 46 in group 1 and 37 in group 2 (P=0.12). Most patients (61%) had IgG1 to H-PF4, but only 8 samples with antibodies induced platelet activation with positive results on serotonin release assay. HIT occurred in 6 patients in group 1, but no thrombocytopenia was observed in subjects receiving LMWH, although 2 had high levels of antibodies with positive serotonin release assay results. When antibodies to H-PF4 were present, mean platelet counts were lower only in patients with FcgammaRIIA R/R131 platelets. CONCLUSIONS: These results provide evidence that the development of antibodies to H-PF4 after CPB performed with UFH is not influenced by the postoperative heparin treatment. The antibodies associated with high risk of HIT are mainly IgG1, which is present at high titers in the plasma of patients continuously treated with UFH.     

Long-term treatment of venous thromboembolism with low-molecular-weight heparin

Vitamin K antagonists are the most widely used form of long-term treatment of patients with venous thromboembolism (VTE). In certain patients, however, the desire to initiate oral anticoagulant therapy is tempered by concern about the risk of bleeding. In these cases, consideration should be given to alternative forms of treatment. Unfractionated heparin (UFH) may be an alternative, but it requires twice-daily subcutaneous administration, and the dosage must be adjusted after periodic blood tests. Therapy with low-molecular-weight heparin (LMWH) is the likely practical solution to this dilemma. Up to now, four small randomized trials have compared the efficacy and safety of LMWH therapy as an alternative to oral anticoagulants. When the results of the four studies are combined, a significant decrease is found in the bleeding rate in patients receiving LMWH. Two further studies by our group confirm this lower bleeding rate in patients on LMWH therapy. According to these data, we suggest that LMWH could be an alternative to oral anticoagulants in patients who cannot attend the laboratory for prothrombin time monitoring, as well as those who are at high risk for bleeding.     

Subcutaneous low-molecular-weight heparin for treatment of Trousseau's syndrome

 We report the case of a 76-year-old man with recurrent thromboses despite oral anticoagulation with phenprocoumon and low-grade chronic disseminated intravascular coagulation. Workup revealed a bronchial carcinoma (NSCCL) with hilar and mediastinal lymph node metastases. The clinical condition was consistent with Trousseau's syndrome. Based on reports in the literature, the therapy was changed to intravenous unfractionated heparin (UFH), which was effective in controlling the thrombotic coagulopathy. For practical reasons, despite a lack of evidence of its effectiveness in Trousseau's syndrome, therapy with UFH was changed to subcutaneous low-molecular-weight heparin (LMWH, nadroparine) in therapeutic doses of 100 IU/kg body wt. 12 hourly. On an outpatient basis, five chemotherapy cycles were administered, and after metastases of the brain had been detected radiotherapy was initiated. Following 7.5 months of progressive neoplastic disease the patient died. He had remained free of thromboembolic complications under continued LMWH therapy during the last 6.5 months of his life. LMWH might be a convenient alternative to the established therapy with UFH in Trousseau's syndrome. Received: 20 June 1997 / Accepted: 23 July 1997     

Intestinal absorption of low molecular weight heparin in animals and human subjects

INTRODUCTION: We had previously shown that the use of bile salts, which act as surfactants, facilitates the intestinal absorption of large molecules such as those of heparin and insulin. However, the bioavailability of unfractionated heparin (UFH) administered through the large intestine was low. The aim of the present study was to evaluate the absorption of low molecular weight heparin (LMWH) combined with bile salts through the gut mucosa in animals and human subjects. MATERIALS AND METHODS: LMWH (Fragmin, Kabi-Pharmacia, Stockholm) or UFH with or without sodium cholate (Sch) was administrated rectally in rats and healthy volunteers via a microenema. Absorption was estimated by the activated partial thromboplastin time (aPTT), the plasma anti-factor Xa activity and the plasma lipoprotein lipase (LPL) activation. RESULTS: In groups of 6 rats, LMWH at doses of 100--1,000 U with sodium cholate (10--20 mg/ml) was readily absorbed through the gut mucosa, as indicated by both, anti-factor Xa levels of up to 1 U/ml and a dose-dependent activation of LPL. The absorption was significantly superior to that of UFH with Sch or LMWH given without Sch (p < 0.001). The plasma anti-factor Xa levels in the 6 healthy volunteers who received a microenema containing 25,000 U of LMWH with 20 mg/ml of Sch were 0.38 U/ml at 15 min and 0.1 U/ml at 240 min. LPL activation and aPTT prolongation were also observed in these subjects. The plasma LMWH levels after rectal application were in the same range as those obtained after subcutaneous administration, however the elimination time (t 1/2) was shorter. There were no adverse reactions. CONCLUSIONS: Intestinal absorption of LMWH facilitated by Sch is both feasible and safe. A slow release formulation will be needed to prolong the plasma half-life.     

Orally active heparin and low-molecular-weight heparin

The heparins, (unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH)) given by subcutaneous or intravenous injection have been used extensively in the prevention and treatment of both venous and arterial thromboembolic disorders. The increasing use of the heparins, LMWHs in particular, in the out of hospital setting has stimulated interest in the development of orally absorbable antithrombotic agents that require little or no monitoring, and this includes the heparins. UFH or LMWH delivered orally has been shown to have an antithrombotic effect in animal thrombosis models although there is little change in plasma coagulation tests. The addition of a simple organic chemical N -(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) to UFH markedly enhances its absorption. A phase II study in patients undergoing total hip replacement indicated that SNAC heparin in two different doses was as effective and safe as UFH given subcutaneously. A phase III clinical trial comparing two doses of SNAC heparin given orally with LMWH by subcutaneous injection for the prevention of venous thromboembolism in patients undergoing total hip replacement is currently underway.     

Low molecular weight heparin and bleeding in patients with chronic renal failure

PURPOSE OF REVIEW: Low molecular weight heparin (LMWH) has largely replaced unfractionated heparin (UFH) in patients with venous thromboembolism because of its pharmacokinetic profile, ease of administration and lack of need for monitoring. The pharmacokinetic profile of LMWH is due to lower molecular weight and reduced charge resulting in less nonspecific protein binding than UFH. These same characteristics make LMWH more dependent on renal function compared with UFH. Consequently, care should be employed when LMWH is administered to patients with impaired renal function as reduced clearance and bioaccumulation may cause bleeding. RECENT FINDINGS: LMWHs vary in their likelihood of bioaccumulation in chronic renal failure. Enoxaparin bioaccumulates and causes bleeding if administered in therapeutic doses without dose adjustment to patients with impaired renal function. Less rigorous evidence suggests that tinzaparin does not bioaccumulate. Bioaccumulation appears to be greatest in patients with a creatinine clearance less than 30 ml/min, and when therapeutic LMWH doses are used. SUMMARY: Care should be used when LMWHs are administered to patients with impaired renal function, particularly those with severe impairment (creatinine clearance below 30 ml/min).