Partial depletion of tissue factor pathway inhibitor during subcutaneous administration of unfractionated heparin, but not with two low molecular weight heparins

Tissue factor pathway inhibitor (TFPI) is released to circulating blood after intravenous (i.v.) and subcutaneous (s.c.) injections of heparins, and may thus contribute to the antithrombotic effect of heparins. We have recently shown that total TFPI activity, plasma free TFPI antigen, and heparin releasable TFPI were partially depleted during repeated and continuous i.v. infusion of unfractionated heparin (UFH), but not during s.c. treatment with a low molecular weight heparin (LMWH). The difference may be attributed to a different mode of action or the different mode of administration. In the present randomized cross-over study, s.c. administration of therapeutic doses of UFH was compared with s.c. administration of two LMWHs. 12 healthy male volunteers were treated for 3 d with UFH, 250 U/kg twice daily, dalteparin, 200 U/kg once daily, and enoxaparin, 1.5 mg/kg once daily. Six participants were also treated with UFH, 300 U/kg once daily. On day 5 a single dose of either drug was given. Peak levels of total TFPI activity and free TFPI antigen were detected 1 h after injection, whereas maximal prolongation of activated partial thromboplastin time (APTT) and peak levels of anti-factor Xa activity and anti-factor IIa activity were detected after 4 h. On UFH administered twice daily, free TFPI antigen decreased by 44% from baseline level before the first injection on day 1 to pre-injection level on day 5. On UFH administered once daily, basal free TFPI antigen decreased by 50%, 56% and 27% on day 2, 3 and 5 respectively, compared with day 1. Minimal depletion of TFPI was detected during treatment with LMWHs. The study demonstrates the different modes of action of LMWHs and UFH and may help to explain the superior antithrombotic efficacy of LMWHs.     

Blocking inhibition of prothrombinase by tissue factor pathway inhibitor alpha: a procoagulant property of heparins

Unfractionated heparin (UFH) has procoagulant activity in antithrombin/heparin cofactor II (HCII)‐depleted plasma. UFH prevents tissue factor pathway inhibitor alpha (TFPIα) from inhibiting the procoagulant enzyme complex, prothrombinase, providing a possible mechanism for its procoagulant activity. The procoagulant potential of UFH and various low molecular weight heparins (LMWHs) were characterized for TFPIα dependence, using thrombin generation assays performed with antithrombin/HCII‐depleted plasma. UFH, the LMWHs enoxaparin and dalteparin, and the low anticoagulant LMWH 2‐O, 3‐O desulphated heparin (ODSH) all promoted thrombin generation, but fondaparinux did not, and this activity was blocked by a TFPIα antibody. UFH, enoxaparin, and dalteparin were anticoagulant in reactions containing 1–2% normal plasma. In prothrombinase activity assays, UFH, enoxaparin, dalteparin and ODSH blocked prothrombinase inhibition by TFPIα, while again fondaparinux did not. In both the plasma and purified assays, LMWHs displayed greater procoagulant potential than UFH, even when normalized to saccharide concentration. These biochemical data reveal that UFH and LMWHs, but not fondaparinux, block prothrombinase inhibition by TFPIα, thereby producing their paradoxical procoagulant activity observed in the absence of antithrombin/HCII. The findings may help to understand the complex pathophysiology and treatment of patients that are simultaneously bleeding and clotting, such as those with disseminated intravascular coagulation.     

Tissue factor and tissue factor pathway inhibitor levels in unstable angina patients during short-term low-molecular-weight heparin administration

High tissue factor (TF), tissue factor pathway inhibitor (TFPI) levels and a hypercoagulability state have been documented in unstable angina patients. We evaluated whether short-term enoxaparin administration (100 IU/kg b.i.d. for 3 d) reduces the high TF levels and the hypercoagulability state, and whether it influences the fibrinolytic system in 20 unstable angina patients. On d 3, we observed a significant reduction in TF levels both 1 h and 4 h after the morning injection (-25.6% and -21.7%; P < 0.001 respectively) in comparison with the base-line levels. Both 1 and 4 h after the morning injection on the d 3, TFPI levels significantly (P < 0.001) increased (+96.4%, +96.9% respectively) with respect to the base-line values. After enoxaparin administration, at all observation times, thrombin-antithrombin complexes and prothrombin fragment F1 + 2 levels were significantly (P < 0.001) lower with respect to base-line levels. We observed a slight but significant increase in tissue plasminogen activator antigen levels in preinjection samples, as well as 1 h and 4 h after enoxaparin administration, in comparison with the base-line values. This study provides evidence that low-molecular-weight heparin (LMWH) administration, in addition to a reduction of hypercoagulability and a mild fibrinolytic activation, is associated with decreased TF levels, so indicating a novel mechanism of interference of LMWH with the haemostatic system.     

Tissue factor pathway inhibitor (TFPI) release after heparin stimulation is increased in Type 1 diabetic patients with albuminuria.

AIMS: To study heparin-stimulated TFPI release in relation to complications in Type 1 diabetic patients. SUBJECTS AND METHODS: Nineteen uncomplicated Type 1 diabetic patients (group I) were compared with 18 patients with retinopathy (group II), and nine patients with retinopathy and albuminuria (group III). Blood samples were taken before (basal) and till 30 min after 5000 IU of heparin i.v. (post-heparin). TFPI activity was measured chromogenically. Von Willebrand factor, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and thrombomodulin were also measured. RESULTS: Basal TFPI activity was higher in group III (121 +/- 10%) compared with group II (111 +/- 8%) or group I (110 +/- 13%) (P < 0.05), and strongly correlated with albuminuria (r = 0.66, P < 0.05). At all time points after heparin administration, TFPI activity in group III was significantly higher than in group I. TFPI activity was also higher in group III than in group II 5-30 min post-heparin. The increase in post-heparin TFPI activity, measured as the incremental area under the curve, was higher in group III compared with group I (65 +/- 7 vs. 59 +/- 4; P < 0.05). Of the other parameters, only thrombomodulin was higher in group III (44 +/- 24 vs. 26 +/- 7 (group II) and 28 +/- 9 ng/ml (group I); P < 0.01). CONCLUSIONS: We conclude that basal and post-heparin TFPI activity is increased in albuminuric patients. The increase in heparin-stimulated TFPI release in patients with albuminuria is higher than in patients with retinopathy or without complications. This could be the result of altered endothelial glycosaminoglycan characteristics.     

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).     

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.     

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 l) to 19 min (p = 0.00003) and 54.1 l (p = 0.0021) after UFH and to 13 min (p = 0.008) and 29.0 l (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 (0.05).     

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).     

In vitro effects of heparin and tissue factor pathway inhibitor on factor VII assays. possible implications for measurements in vivo after heparin therapy.

The coagulant activity of blood coagulation factor VII (FVII:C) can be lowered by changes in lifestyle and by therapeutic intervention, e.g. heparin infusion. The question is, however, whether FVII:C determined ex vivo is a valid measure of the FVII activity in vivo. We measured plasma FVII:C, activated FVII (FVIIa), FVII protein (FVII:Ag), tissue factor pathway inhibitor (TFPI), triglycerides, and free fatty acids (FFA) before and 15 min after infusion of a bolus of unfractionated heparin (50 IU/kg body weight) in 12 healthy subjects. Additionally, we conducted in vitro experiments to investigate the effect of unfractionated heparin and TFPI, which is released from the endothelium by heparin, on FVII:C, FVIIa, and FVII:Ag. Heparin infusion decreased triglycerides and increased FFA and TFPI. This was accompanied by significant reductions in FVIIa, FVII:C and FVII:Ag. In vitro, anti-TFPI antibodies increased FVIIa and FVII:C, and heparin reduced FVIIa. The heparinase Hepzyme was unable to abolish the effect of heparin. There were no in vitro effects on FVII:Ag. We conclude that, due to interference by TFPI and heparin in post-heparin plasma, it is impossible to measure the in vivo FVII activity by means of FVII clotting assays. These assays should therefore not be used to measure the coagulation status of patients in heparin therapy, unless extraordinary precautions are taken to eliminate TFPI and heparin effects ex vivo. The observed effect of heparin on FVII:Ag should be investigated further.     

Effects of unfractionated and low molecular weight heparins on plasma levels of hemostatic factors in patients with acute coronary syndromes.

BACKGROUND AND OBJECTIVES: Unfractionated heparin (UFH) and enoxaparin (low molecular weight heparin) constitute fundamental therapies in the treatment of patients with acute coronary syndrome (ACS). Since enoxaparin appears to offer clinical advantages over UFH in managing ACS, markers of thrombin generation, endothelial function and acute phase response could manifest different responses to UFH or enoxaparin. The purpose of the present study was to investigate the effect that treatment with either UFH or enoxaparin has on plasma hemostatic markers in 24 patients with ACS. DESIGN AND METHODS: The patients were randomized to receive 5,000 IU intravenous bolus and continuous infusion of 18 IU/Kg/h UFH (n=11) or 1 mg/kg/12h subcutaneous enoxaparin (n=13). The plasma levels of fibrinogen (Fg), prothrombin fragment 1+2 (F1+2), thrombin antithrombin complex (TAT), von Willebrand factor (vWF), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) were assayed at admission and 6, 12, 24 and 48 hours after heparin treatment. RESULTS: Upon admission, UFH and enoxaparin patients showed a significant increase in all the hemostatic parameters measured with respect to the levels in the control subjects. In comparison with the baseline levels of the UFH- and enoxaparin-treated patients, Fg showed a significant increase at 48 h and TFPI at 6, 12 and 24 hours. However, at 48 hours TFPI levels were not significantly higher than the basal values. There were no significant changes in F1+2, TAT, vWF or TF. INTERPRETATION AND CONCLUSIONS: Markers of thrombin generation, endothelial function and acute-phase reactants manifest a similar response to UFH and enoxaparin. An increase in thrombin generation may be a result of persistently activated inflammatory and endothelial processes, despite UFH and enoxaparin treatment.     

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.     

Physiological function of tissue factor pathway inhibitor and interaction with heparins

Tissue factor pathway inhibitor (TFPI) is now recognized as a major physiological anticoagulant. Its main role is to modulate factor VIIa/tissue factor catalytic activity. Another important role is to potentiate the effect of heparins. TFPI is released from the vascular endothelium after injection of either unfractionated heparin (UFH) or low-molecular-weight heparins (LMWHs), which may then provide high concentrations of TFPI at sites of tissue damage and ongoing thrombosis. In dilute prothrombin-time-based assays, released TFPI contributes approximately one-third to the anticoagulant effect of heparin, the remaining being accounted for by antithrombin. Released TFPI, but not plasma TFPI, contains the basic carboxy-terminal tail which is important for the anticoagulant effect. UFH and LMWH exert differential effects on intravascular TFPI. UFH, but not LMWH, given in therapeutic doses, is associated with a progressive depletion of TFPI, which is associated with a strong rebound activation of coagulation after cessation of treatment. Such depletion may explain the apparent superior efficacy of LMWH observed in clinical trials.     

Novel interactions between UFH and TFPI in children

The impact of age upon therapeutic response to unfractionated heparin (UFH) in children is proposed to reflect quantitative and potentially qualitative differences in coagulation proteins across childhood. This study explores the UFH-dependent tissue factor pathway inhibitor (TFPI) release in children compared to previously published data in adults. Children <16 years of age undergoing cardiac angiography formed the population for this prospective cohort study. TFPI release was measured prior to (baseline) and at 15, 30, 45 and 120 min post-UFH dose. This study demonstrated that, whilst the immediate release of TFPI post-UFH was similar in children compared to adults, TFPI release in children remained increased and consistent for a significantly longer period post-UFH administration compared to adults. Plasma TFPI levels in children did not demonstrate an UFH concentration -dependent reduction, as has been previously reported in adults. The prolonged TFPI-mediated anticoagulant levels observed in children administered UFH may contribute to the increased rate of major bleeding reported in children compared to adults. Furthermore, we postulate that this sustained UFH-dependent increase in TFPI levels in children may influence the binding of UFH to competitive plasma proteins, such as those involved in the immunological response to UFH associated with heparin-induced thrombocytopenia.     

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo

Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA)(n) tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [K(d)], approximately 50 nM), similar potencies in neutralizing anti-Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA)(3)VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4- to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti-Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans.     

Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis.

AIMS: To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint. METHODS AND RESULTS: We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97). CONCLUSIONS: When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.     

Audit of the peri-delivery use of unfractionated heparin in women on therapeutic low-molecular weight heparin

There is no evidence-based approach for the optimal management of peri-delivery anticoagulation in women receiving therapeutic dose of low-molecular weight heparin (LMWH) during pregnancy. Nevertheless, the maintenance of anticoagulation for the maximal period peri-delivery appears appropriate in women considered to be at high risk of venous or arterial thromboembolism. We developed a regimen based on fixed thromboprophylactic dose of unfractionated heparin (UFH) peri-delivery and undertook an audit to evaluate the use and feasibility of this approach and any adverse events. Fixed intravenous thromboprophylactic dose of UFH (15 000 units/24 h) was commenced on the evening prior to a planned delivery [induction of labour or elective caesarean section (CS)], stopped 4 h predelivery and restarted 2–6 h postdelivery. Compliance was good with 32/38 consecutive deliveries managed according to the regimen. There were no cases of postpartum haemorrhage and no thrombosis associated with these 32 deliveries. Twenty-one patients were delivered by CS (11 elective) and eight patients received epidural/spinal anaesthesia without complication. In conclusion, the fixed thromboprophylactic dose UFH regimen provided maintenance of anticoagulation except for a matter of hours without excessive bleeding risk (conducive to neuroaxial anaesthesia) and was simple, flexible and acceptable to staff and patients.     

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.     

Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a common adverse effect of unfractionated heparin (UFH) therapy. In contrast, only a few patients have been reported with HIT following low-molecular-weight heparin (LMWH) therapy (LMW-HIT). To define the clinical and biological characteristics of LMW-HIT, 180 patients treated for suspected HIT at 15 French centres were investigated. Clinical history was recorded and HIT was confirmed in 59 patients with positive serotonin release assay results: 57 of them had high levels of antibodies (Abs) to heparin-platelet factor 4 complexes (H/PF4) and two had Abs to interleukin 8. Eleven patients were treated exclusively with LMWH (LMW-HIT) and 48 with UFH either alone (UF-HIT, n = 34) or combined with LMWH (UF/LMW-HIT, n = 14). The LMW-HIT and UF-HIT groups were similar with respect to sex, age, platelet count before heparin therapy, frequency of bleeding and occurrence of disseminated intravascular coagulation. The interval to onset of HIT was longer in LMW-HIT patients compared with UF-HIT patients (P = 0.03). Severe thrombocytopenia (platelets < 15 x 10(9)/l) was more frequent in the LMW-HIT group (P = 0.04). Thrombosis occurred in three of 11 LMW-HIT patients, i.e. as frequently as in UF-HIT patients. LMW-HIT is potentially severe and may be observed after longer heparin treatment compared with UF-HIT. It is highly recommended, therefore, that platelet counts be monitored carefully whenever LMWH is administered.     

A multicentre comparison of once-daily subcutaneous dalteparin (low molecular weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis

Objectives. To compare the efficacy and safety of the low molecular weight heparin (LMWH) dalteparin with unfractionated heparin (UFH) in the acute treatment of DVT patients who had not previously received UFH.
Design. An open randomized multicentre trial with blinded analysis of venograms.
Setting. Seven hospitals in Sweden, Finland and the USA.
Subjects. A total of 330 patients, of 20 years or older, with suspected DVT, verified using venography.
Interventions. Fixed-dose dalteparin (200 IU kg^-1) given as a once-daily subcutaneous injection, or aPTT adjusted i.v. UFH infusion for 6 to 10 days.
Main outcome measures. Change in Marder score in patients with confirmed DVT and two evaluable venograms; PE, bleeding events and follow-up.
Results. Marder scores improved in 51% (95% CI 42–60%) of 92 patients treated with dalteparin and in 62% (95% CI 53–70%) of 98 patients treated with UFH ( P =0.152). One dalteparin-treated patient had a PE confirmed by V/Q scan; another had progressive thrombosis with swelling in the affected limb. Bleeding complications occurred in six patients in each group. One patient treated with dalteparin and five treated with UFH died during the 6-month follow-up period as a result of underlying malignancy or heart disease. The 6-month recurrence rate was low with both treatments (dalteparin, 3/97; UFH, 2/103).
Conclusions. Fixed-dose subcutaneous dalteparin given once daily from the start of treatment is of equivalent efficacy and safety to conventional UFH therapy in the routine management of DVT.     

Effects of pre-analytical variables on the anti-activated factor X chromogenic assay when monitoring unfractionated heparin and low molecular weight heparin anticoagulation.

The purpose of this study was to determine whether the anti-activated factor X (anti-FXa) assay is less affected by pre-analytical variables in monitoring patients on unfractionated heparin (UFH) and low molecular weight heparin (LMWH) than the activated partial thromboplastin time (aPTT). Forty-six subjects receiving either enoxaparin (LMWH) or UFH were randomly selected. Each study subject had six vacutainer tubes (3.8% sodium citrate, 3.2% sodium citrate) drawn by an atraumatic venipuncture. One tube from each set had a blood to anticoagulant ratio of 9: 1. The other tube had an intentional "short-draw" of approximately 6: 1 blood to anticoagulant ratio. All specimens had an aPTT and a chromogenic anti-FXa assay performed on each specimen regardless of heparin type. The aPTT assay mean with the 3.8% sodium citrate tube short-draw tube was statistically different from the other aPTT assays (P = 0.06). However, all six of the mean anti-FXa assays for the UFH and LMWH heparin subjects were not statistically or clinically different (analysis of variance, P = 0.9878 for UFH and P = 0.9060 for LMWH). The intentional short-draw tube did not affect the anti-FXa assay regardless of the anticoagulant. The anti-FXa assay appears to be a better method for monitoring heparin subjects than the aPTT due to the lack of effect of pre-analytical variables.