Experimental studies on the relative efficacy of dermatan sulphate and heparin as antithrombotic agents

In this study, the anticoagulant and antithrombotic properties of unfractionated heparin (UFH) and dermatan sulphate (DS) were compared. The ability of UFH and DS to impair thrombin generation in vitro and in ex vivo plasma samples was also studied. DS has minimal anticoagulant activity by conventional assays but impairs thrombin generation both in vitro and in ex vivo plasma samples. However, thrombin generation could not be suppressed below about 35% of control values at all doses of DS studied. While this was sufficient to impair experimental venous thrombosis during 10 minutes' stasis, DS was ineffective in preventing thrombosis following 20 minutes' stasis in doses up to 1.25 mg/kg. In contrast, 1 microgram/ml of UFH completely suppressed thrombin generation in vitro, and 150 micrograms/kg prevented thrombogenesis over a period of 20 minutes' stasis. Neither drug prolonged the bleeding time (BT) at effective antithrombotic doses, but 2.5 mg/kg UFH significantly increased the BT, whereas DS did not. While DS has antithrombotic activity, it is less effective than UFH in inhibiting thrombin generation, and as an antithrombotic agent.     

Signs of thrombin generation in pediatric cardiac catheterization with unfractionated heparin bolus or subcutaneous low molecular weight heparin for antithrombotic cover

Introduction: Thrombosis is one of the most frequent adverse events after cardiac catheterization, which can be reduced by anticoagulation with unfractionated heparin (UFH) in both children and adults. Low molecular weight heparin (LMWH) might possibly offer advantages. Laboratory signs of thrombin generation during pediatric cardiac catheterization, with unfractionated heparin (UFH) bolus or subcutaneous LMWH for thrombosis prophylaxis, were determined in a first step to investigate the potential of LMWH for antithrombotic cover. Materials and methods: Signs of thrombin generation (D-dimer and F₁₊₂), anti-Xa activity and activated clotting time (ACT) were measured in 65 patients with congenital heart disease. A total of 40 patients were treated with a UFH bolus of 100 IU/kg bodyweight and, in 25 children, enoxaparin was subcutaneously administered at a dosage of 1/1.6 mg/kg bodyweight. Results: The dose to plasma activity of enoxaparin was more consistent than in the UFH group. Only a slight elevation of F₁₊₂ was found in some patients, which was a little higher in the enoxaparin group, but no difference of incidence of increased F₁₊₂ generation was detected between the two groups. D-dimer was elevated in three children after UFH bolus application, but no such effect was observed in any child after LMWH administration. Conclusions: Application of LMWH was equally efficacious during pediatric cardiac catheterization than UFH bolus administration, as determined by plasma levels and markers of clotting activation. In contrast to UFH bolus, no further monitoring was necessary after the application of LMWH during cardiac catheterization due to a consistent dose to plasma activity.     

Pharmacological profile of the chemically synthesized antithrombin III binding fragment of heparin (pentasaccharide) in rats

The antithrombotic and haemostatic effects of a pentasaccharide, the chemically synthesized antithrombin III (AT-III) binding fragment of heparin (PENTA), were investigated in rats in comparison with heparin. PENTA showed a dose-dependent antithrombotic effect in three thrombosis models in which thrombus formation was induced by different triggers. PENTA was consistently less potent than heparin in these models if doses were expressed in anti-Xa U/kg but PENTA showed more or less the same potency as heparin if doses were expressed in mg/kg. The antithrombotic effect of PENTA was strongly related to its anti-Xa activity as judged from its antithrombotic potency in the various models and from the time courses of both activities. PENTA caused a dose-dependent increase in blood loss in a bleeding model but the dose response curve was rather flat; the effect of PENTA on blood loss was small compared to that of heparin. The duration of action of PENTA as measured by the plasma anti-Xa levels was long compared to that of heparin and the duration of the antithrombotic effect was that expected on the basis of the plasma anti-Xa levels. Finally, PENTA showed comparable antithrombotic activity after s.c. and i.v. administration, as expected because of the approximately 100% bioavailability of the anti-Xa activity after s.c. administration.     

Dose response relationships of anticoagulant activities after subcutaneous administration of two low molecular weight heparins in healthy individuals

This study was performed to estimate appropriate dosages of two low molecular weight heparins (LMWH) for clinical trials on subcutaneous perioperative thrombosis prophylaxis. Anticoagulatory activities and platelet function were investigated after single doses of two LMWH and of unfractionated sodium heparin (UFH) in 24 healthy individuals. Twelve subjects received subcutaneous injections of 1000, 1500, and 2500 i.u. (aPTT) of LMHW 1, and the other 12 received LMWH 2 at same dosages. The following parameters were determined before 30 min, 1 h, 90 min, 2 h, 3 h, 4 h, 6 h, 8 h, and 10 h after either LMWH or 5000 i.u. (aPTT) UFH: aPTT, thrombin time, anti-Xa activity (S 2222, Coatest heparin), and anti-IIa activity (Chromozym TH). Bleeding time, platelet count, and adrenalin-, collagen-, and ADP-induced platelet aggregation were assessed before and 3 h after administration. After application of 1500 i.u. LMWH 1 and LMWH 2, the anti-Xa and anti-IIa levels were already significantly higher than after 5000 i.u. UFH. 2500 i.u. LMWH 1 and LMWH 2 evoked significantly greater prolongations of aPTT and thrombin time values than did 5000 i.u. UFH. This was not the case after 1000 and 1500 i.u. LMWH. The half-lives of anticoagulatory effects after LMWH were markedly longer than after UFH. Platelet function was not altered by any of the heparins tested. Our results indicate that LMWH cause anticoagulatory effects in vivo that cannot be predicted by in vitro studies and that the appropriate single dosages of LMWH in subcutaneous perioperative thrombosis prophylaxis have to be estimated by dosage determinations in healthy subjects.     

Neutralization of the antithrombotic effects of heparin and Fraxiparin by protamine sulfate.

In general, the in vitro anti Xa activity of low molecular weight heparins is neutralized to a lesser degree than the anti Xa activity of unfractionated heparin. To determine whether these differences occur in vivo, a rabbit stasis thrombosis model and a rat laser-induced thrombosis model were utilized. In the laser model, a similar degree of neutralization of the antithrombotic activity of heparin and Fraxiparin was obtained. However, in the stasis thrombosis model, significant antithrombotic activity of Fraxiparin remained after equigravimetric protamine administration. Ex vivo APTT, thrombin time, Heptest, amidolytic anti Xa and anti IIa assays were performed. A coefficient (r = .806) was obtained for the correlation of Heptest activity to antithrombotic effect in the stasis thrombosis model, while the coefficients obtained for the other tests ranged from .152-.570. However, after neutralization by protamine, the thrombin time exhibited the highest correlation coefficient (r = .685) between ex vivo activity and residual antithrombotic effect. Since Fraxiparin retains antithrombotic activity after protamine administration, clinical benefit may be observed for this low molecular weight heparin as compared to unfractionated heparin after neutralization.     

The effect of calcium chloride on anti-Xa activity of heparin and its molecular weight fractions

The anti-Xa activities of unfractionated heparin (UFH) and nine low molecular weight heparins (LMWH) have been measured in the presence and absence of 3 mM CaCl2, using bovine Factor Xa, purified human ATIII and an amidolytic assay. The addition of CaCl2 increased the activity of UFH by 93%, but the effect on LMWH was less, ranging from -20% to +55%. Studies of gel filtration fractions of UFH showed marked Mr dependence of the CaCl2 effect in the range 4,000-12,000. The differences among the various LMW heparins with respect to the effect of CaCl2 were closely correlated with the amount of polysaccharide above an Mr of 6,500. Kinetic studies confirmed the potentiation of the activity of UFH with bovine Xa and showed an even more marked effect using human Xa.     

Covalent antithrombin-heparin complexes

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have been utilized as primary anticoagulants for thrombosis prophylaxis and treatment. However, a number of biophysical and safety limitations have led to development of new anticoagulants. Covalent antithrombin-heparin (ATH) complexes may address many of these issues. Early ATH products were prepared that had increased intravenous half-lives relative to UFH but lacked any improvement in anti-factor Xa activity or had no catalytic activity or reactivity against thrombin. However, a recent conjugate developed by Chan et al. has displayed a number of superior properties. Chan et al. ATH has an increased direct thrombin inhibition rate and can catalyze coagulant enzyme inhibition by exogenous antithrombin with very high specific activity. Unlike UFH, clot-bound thrombin is readily inhibited by ATH and, at similar antithrombotic efficacy, the ATH has improved bleeding profiles compared to heparins. Given the preclinical findings, Chan et al. ATH may warrant clinical trial testing for control of clot propagation.     

Antithrombotic and anticoagulant activity of depolymerized fragment of the glycosaminoglycan extracted from Stichopus japonicus Selenka.

The antithrombotic and anticoagulant activities of depolymerized fragment (DHG-1) of glycosaminoglycan extracted from Stichopus japonicus Selenka (FGAG) were compared with those of unfractionated heparin (UFH) or low molecular weight heparin (LMWH). DHG-1 at more than 0.3 mg/kg i.v. significantly prevented death of mice treated with thrombin (800 U/kg i.v.). Under the same conditions, FGAG, UFH and LMWH significantly prevented death of mice at more than 0.3, 0.3 and 0.6 mg/kg i.v., respectively. In normal plasma, the concentration required to double the activated partial thromboplastin time (doubling APTT) of DHG-1, FGAG, LMWH and UFH were 12.0, 2.4, 5.8, and 1.2 micrograms/ml, respectively. In antithrombin III (AT III)-depleted plasma, doubling APTT of DHG-1, FGAG, and UFH were 11.3, 2.1, and 18.5 micrograms/ml, respectively. Prothrombin activation in contact-activated plasma was inhibited completely for 60 s at doubling APTT by all glycosaminoglycans used in this study. DHG-1, however, showed much less antithrombin activity than UFH as tested by thrombin clotting time in plasma and chromogenic assay in the presence of AT III. Moreover, DHG-1 showed much less inhibitory activity on factor Xa, factor IXa, and glass surface-induced factor IXa generation than UFH. These results suggested that DHG-1 is one of the promising antithrombotic agents with quite different anticoagulant property from UFH or LMWH.     

Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are used for prophylaxis and treatment of thrombosis. However, UFH has a short plasma half-life and variable anticoagulant response in vivo due to plasma or vessel wall protein binding and LMWH has a decreased ability to inactivate thrombin, the pivotal enzyme in the coagulation cascade. Covalent linkage of antithrombin to heparin gave a complex (ATH) with superior anticoagulant activity compared to UFH and LMWH, and longer intravenous half-life compared to UFH. We found that plasma proteins bound more to UFH than ATH, and least to LMWH. Also, UFH bound significantly more to endothelial cells than ATH, with 100% of UFH and 94% of ATH binding being on the cell surface and the remainder was endocytosed. Competition studies with UFH confirmed that ATH binding was likely through its heparin moiety. These findings suggest that differences in plasma protein and endothelial cell binding may be due to available heparin chain length. Although ATH is polydisperse, the covalently-linked antithrombin may shield a portion of the heparin chain from association with plasma or endothelial cell surface proteins. This model is consistent with ATH's better bioavailability and more predictable dose response.     

Discordance between the anti-Xa activity and the antithrombotic activity of an ultra-low molecular weight heparin fraction

The relationship between the in vivo antithrombotic effect of heparin and ex vivo anti-Xa activity has been investigated using an animal thrombosis model. Three low molecular weight heparins were compared with the standard heparin from which they were fractionated. All four heparins showed a dose-dependent antithrombotic effect enabling the relative antithrombotic and anti-Xa activities to be compared over a dosage range. A correlation between ex vivo anti-Xa heparin levels and antithrombotic effect was demonstrated for the standard (MW 16,000), intermediate (MW 7,600) and low (MW 4,600) molecular weight heparins but not for the ultra-low molecular weight (MW 3,000) fraction. The lack of relationship between anti-Xa activity and inhibition of thrombosis for the very low molecular weight fraction indicates that a very high anti-Xa activity (measured in vitro or ex vivo) is not always predictive of in vivo antithrombotic efficacy. These findings suggest that other properties of low molecular weight heparins contribute to their antithrombotic effectiveness.     

Circulating activities during constant infusion of heparin or a low molecular weight derivative (enoxaparine): failure to demonstrate any circadian variations

We compared in six patients successively treated with an unfractionated heparin (UFH) and a low molecular weight heparin (LMWH) the variations in plasma anti-Xa activity, measured in a chromogenic assay, during a 36 h constant infusion. The values varied in a wider range during UHF infusion, but remained in the therapeutic range except once in one patient. No circadian rhythm could be demonstrated in our six patients. LMWH infusion yielded very constant anti-Xa circulating activities. In both cases, there were no significant modifications of three proteins with high heparin affinity (antithrombin III, heparin cofactor II, histidine-rich glycoprotein). Our results suggest that the circadian rhythm of the biological activities previously observed in patients treated with constant heparin infusion using clotting method is due to other factors than heparin itself.     

Antithrombotic and anticoagulant activities of a low molecular weight fucoidan by the subcutaneous route

Fucoidans (high-molecular-weight sulfated polysaccharides extracted from brown seaweeds) have anticoagulant and antithrombotic effects. They inhibit thrombin by catalyzing both serpins (antithrombin and heparin cofactor II) according to their chemical structures and origins. In this study, a low-molecular-weight (LMW) fucoidan of 8 kDa was obtained by chemical degradation of a high-molecular-weight fraction. The antithrombotic and anticoagulant activities of this new compound were compared to those of a low-molecular-weight heparin (LMWH), dalteparin, following subcutaneous administration to rabbits. This LMW fucoidan exhibited dose-related venous antithrombotic activity, with an ED80 of about 20 mg/kg, 2 h after a single subcutaneous injection. Its activity was comparable to that of dalteparin (close to 200 anti-Xa IU/kg) and was maximal 30 min after a single subcutaneous injection. The activity remained stable (about 70%) from 1 to 4 h after injection, but disappeared by 8 h. The antithrombotic activity was not associated with either a prolongation of the thrombin clotting time (TCT) or an increase in anti-Xa activity, contrary to dalteparin. A slight prolongation of APTT occurred with both compounds. This venous antithrombotic activity was associated with a decrease in ex vivo thrombin generation and with a significant increase in the lag phase in a thrombin generation test. LMW fucoidan thus has potent antithrombotic activity and a potentially weaker haemorrhagic effect (i.e. a smaller effect on coagulation tests and a smaller prolongation of the bleeding time) than dalteparin.     

A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment

The pharmacokinetics of a heparin fragment of low molecular weight (LMWH) of 4000-5000 D and unfractioned standard heparin (UFH) have been studied after i.v. injections of different doses and infusions in 8 humans. The heparin activity was significantly higher and the effect on APTT lower after LMWH fragment as compared to UFH in the same doses. The half-life of heparin activity was about 1 hr for UFH and about 2 hr for LMWH. LMWH was found to be eliminated according to first order kinetics and there were no signs of dose dependency.     

Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential

Thrombin generation is decreased and delayed in plasma from newborns and children compared to adults. We hypothesized that lower doses of heparinoid anticoagulants are required to give similar thrombin generation in newborn (umbilical cord) and child plasmas compared to that of adults. Thrombin generation was performed in either the absence or presence of unfractionated heparin (UFH), low molecular weight heparin (LMWH) or a covalent antithrombin-heparin complex (ATH). After contact activation and recalcification of each plasma, thrombin activity was measured by periodic sub-sampling into chromogenic substrate. UFH inhibited thrombin generation to a greater extent compared to LMWH in all plasmas. Cord plasma was more sensitive to inhibition and displayed a greater difference in the effectiveness of UFH compared to LMWH than other plasmas. Lower concentrations of UFH and LMWH were required to inhibit thrombin generation in cord and child plasmas compared to adult plasma. In comparison, ATH strongly inhibited thrombin generation in all 3 plasmas. Similar peak thrombin concentrations were observed at lower ATH concentrations (0.1 U/mL) compared to either UFH (0.25 U/mL) or LMWH (0.25 U/mL). As with UFH and LMWH, cord plasma was more sensitive to inhibition by ATH than the other plasmas and lower ATH concentrations inhibited thrombin generation in cord and child plasmas compared to adult plasma. Decreased thrombin generation with heparinoids in cord and child plasmas compared to adult plasma coincided with decreased rates of prothrombin consumption and increased proportion of thrombin-alpha2-macroglobulin inhibitor complexes. In summary, lower doses of UFH, LMWH or ATH result in similar peak thrombin generation in newborn and child plasmas compared to adult plasma. Cord plasma was the most sensitive to inhibition, with ATH being more effective than UFH or LMWH.     

Management of pregnant women with mechanical heart valve prosthesis: Thromboprophylaxis with Low molecular weight heparin

IntroductionPregnancy increases the risk of mechanical heart valve (MHV) thrombosis. Warfarin is protective, but implies risks to the fetus. Unfractionated heparin (UFH) is less effective but does not harm the fetus. In general, anticoagulation is more stable and predictable with low molecular weight heparin (LMWH) than with UFH.MethodRetrospective study of 12 pregnancies with MHV; 6 in aortic, 4 in mitral, and 2 in both positions, treated with therapeutic doses of subcutaneous LMWH twice daily throughout pregnancy. Doses were adjusted using anti-Xa monitoring. The frequency of thrombo-embolism with various anticoagulation regimes was calculated based on a literature review.ResultsMedian LMWH dose was 15500 IU/24 h, range 10000–20000 IU/24 h; median dose 257 IU/kg/24 h. Median peak LMWH in blood plasma ranged 0.54–0.92 anti-Xa U/mL. Thromboembolism developed in two women with aortic MHV despite LMWH levels in target range. One had systemic embolic episodes; in the other woman valve thrombosis was successfully thrombolysed. Both had initially received subtherapeutic doses. Thrombo-embolism was not observed in ten pregnancies treated as recommended. The pregnancies resulted in thirteen healthy babies; eight delivered by Cesarean section. Bleeding occurred in two women after Cesarean section due to preeclampsia.ConclusionTreatment with adjusted therapeutic doses of LMWH was successful in 10 of 12 pregnancies, and was not associated with fetal complications. Thromboembolism occurred in two pregnancies, possibly attributed to subtherapeutic doses of LMWH during the initial 3 weeks. Compared to UFH prophylaxis, therapeutic doses of LMWH appears to be more efficacious.     

Pre-clinical pharmacological profile of the novel glycoconjugate Org 36764 with both factor Xa and thrombin (IIa) inhibitory activities

Org 36764, is an antithrombin III (AT) and thrombin binding carbohydrate, which accelerates the inactivation of both factor Xa and thrombin by AT. It displays in buffer an anti-Xa and anti-thrombin activity of 415 and 2 U/mg, respectively, compared to 172 and 114 U/mg, respectively, for unfractionated heparin (UFH), Org 36764 does not cross-react with HIT (heparin induced thrombocytopenia) antibodies and is not neutralised by PF4. In experimental models in rats, on a molar basis. Org 36764 was more active than the pentasaccharide SanOrg 34006 (= AT binding domain of Org 36764) in arterial thrombosis, but both were equally active in venous thrombosis. In arterial thrombosis following endothelial damage by ferric chloride, Org 36764 was more active than the LMW heparin enoxaparin and SanOrg 34006 and similar active to UFH. At AT saturating doses the bleeding enhancement was not more than 3.5 times the control value. Org 36764 was more active in suppressing in vivo thrombus formation on stents than UFH. SanOrg 34006 or a combination of ticlopidine and aspirin. The results indicate that the novel drug Org 36764 is a drug with antithrombotic potential against venous and arterial thrombosis.     

Comparative antithrombotic and hemorrhagic effects of dermatan sulfate, heparan sulfate and heparin

Dermatan sulfate and heparan sulfate are currently under development as potential antithrombotic drugs. In our studies we have evaluated the relative antithrombotic and bleeding effects of these two agents in comparison to heparin, the commonly used anticoagulant. In a rabbit model of stasis thrombosis, a 500 micrograms/kg IV dose of dermatan or heparan produced 50-60% inhibition of induced in vivo thrombosis. At 750 micrograms/kg, both agents produced greater than 75% inhibition of thrombosis. Ex vivo measurement of plasma samples obtained from these animals demonstrated variable clotting effects at the lower dose and a proportional increase in the clotting activity at the higher dose. No anti-Xa or anti-IIa activity was observed in any sample. In contrast, animals treated with only 100 micrograms/kg heparin showed complete inhibition of induced thrombosis with significant anti-Xa and anti-IIa activities as well as prolongation of the clotting assays (APTT, TT and HeptestR). In the hemorrhagic studies utilizing a rabbit ear blood loss model, a 5.0 mg/kg IV dose of dermatan or heparan produced much less blood loss than heparin. On a gravimetric basis, dermatan and heparan were 10 fold less hemorrhagic than heparin. These results indicate that the relative contribution of plasmatic and cellular sites to the mediation of the antithrombotic action of heparin, dermatan and heparan differ. Although the antithrombotic dosages of dermatan and heparan are higher than heparin, due to the different mechanisms of action of each agent, a better safety index may be provided by dermatan and heparan than heparin.     

Antithrombotic activity of a synthetic heparin pentasaccharide in a rabbit stasis thrombosis model using different thrombogenic challenges

A synthetic pentasaccharide, representing the critical sequence required in heparin for binding to antithrombin III (AT III), produces strong anti-factor Xa activity in vitro in the presence of AT III and is devoid of any activity directed towards thrombin. This pentasaccharide provides a unique tool to study the question of whether an agent capable of inhibiting factor Xa but devoid of anti-factor IIa activity in vitro, has the capacity to produce an antithrombotic effect in vivo. We have previously demonstrated in a rabbit stasis thrombosis model using a human serum challenge, a significant antithrombotic effect of the pentasaccharide. This finding and discrepancies with some earlier reports on the antithrombotic actions of other oligosaccharide fragments, led us to extend these studies. Four modifications of the stasis thrombosis model were developed using the following thrombogenic challenges selected for their specified induction sites of thrombosis, thromboplastin, an activated prothrombin complex concentrate, a non-activated prothrombin complex concentrate administered simultaneously with Russell's viper venom, and factor Xa. Dose-dependent antithrombotic responses were obtained in all four systems with ED50 values between 25-43 ug/kg for pentasaccharide as compared to 16-47 ug/kg for heparin. Complete inhibition of induced thrombosis was obtained in all four systems for pentasaccharide. Ex vivo analysis revealed expected anti-factor Xa levels but no anti-factor IIa activity. It is concluded that an oligosaccharide with high anti-factor Xa activity and devoid of anti-factor IIa activity is capable of inhibiting thrombosis induced in rabbit stasis models, but that higher dosages than heparin are required for this effect.     

VERY LOW DOSES OF UNFRACTIONATED HEPARIN POTENTIATE THE ANTI-Xa ACTIVITY OF LOW MOLECULAR WEIGHT HEPARIN (ENOXAPARIN)

Some previous reports indicated that a minimal amount of anti-IIa is necessary for the optimal anti-Xa activity of low molecular weight heparin (LMW-H). To know if we could improve the prophylactic activity of LMW-H, providing a mild antithrombin effect, we conducted an experiment in which we administered subcutaneously to 10 volunteers, very low doses of unfractionated heparin (UFH), (1000 IU), a LMW-H (enoxaparin, 2000 IU = 20mg), or both heparins together on alternate days, and measure the anti-Xa activity before, and 4 hours after injection. We found that the anti-Xa activity in the first group (UFH), increased by 33%, over the basal values; in the second group (LMW-H), by 93%, but it increased by 282%, in the third group (UFH + LMW-H) showing clearly (p<0.0069), that UFH could increase synergistically, more than additive, the anti-Xa activity of enoxaparin. The impact on the cost-effectiveness of antithrombotic prophylaxis and the therapeutic results with the herein combined scheme should be evaluated. Copyright © 1997 Elsevier Science Ltd     

Analysis of unfractionated heparin dose requirements to target therapeutic anti-Xa intensity during pregnancy

Introduction

Unfractionated heparin (UFH) does not cross the placenta and has demonstrated utility in the prevention and treatment of thrombosis during pregnancy. Limited information is available to guide initiation and monitoring of therapeutic UFH targeting an anti-Xa concentration of 0.3-0.7 u/ml during pregnancy. The objective of this study was to describe UFH doses and monitoring strategies required to achieve and maintain therapeutic anti-Xa intensity in a cohort of women treated with UFH during pregnancy.

Materials/Methods

Patients prescribed anti-Xa adjusted UFH during pregnancies occurring between January 1998 and March 2005 were included.

Results

A total of 39 pregnancies for 37 women were identified. Unfractionated heparin doses were titrated to achieve a mid-interval anti-Xa level of 0.3-0.7 u/ml. Patients required a median 6.5 days and a mean UFH dose of 403.5 u/kg/day to achieve therapeutic anti-Xa levels. Most anti-Xa levels were within the target range (59%). The final UFH dose/kg required at the end of pregnancy was similar to that at the first therapeutic level (P > 0.05); however some patients did require dose modification. Patients required a mean 14.1 anti-Xa determinations and 4.6 dose modifications during a mean 23.9 weeks of antenatal UFH therapy. Patient weight and UFH dose at the first therapeutic anti-Xa level were correlated (r = 0.383, P = 0.018).

Conclusions

Pregnant women required a mean UFH dose of 403.5 u/kg/day to achieve midinterval anti-Xa levels of 0.3-0.7 u/ml. The required dose was correlated with patient weight and most anti-Xa measurements were within the target range.