Anticoagulant efficacy and immunogenicity of the selective factor Xa inhibitor antistasin following subcutaneous administration in the rhesus monkey.

The antithrombotic efficacy and duration of action of a single subcutaneous administration of the selective factor Xa inhibitor recombinant antistasin (rATS) was evaluated in a rhesus monkey model of mild disseminated intravascular coagulation. rATS (1 mg/kg) was shown to be fully effective and comparable to standard heparin (1,000 U/kg) in the suppression of thromboplastin-induced fibrinopeptide A generation for at least 5 h following a single subcutaneous administration. The absorption rate of rATS, as measured by ex vivo activated partial thromboplastin times (aPTT), mirrored that of standard heparin exhibiting peak anticoagulant activity between 1 and 2 h post administration. The anticoagulant effects of a single rATS dose lasted for longer than 30 h maintaining an aPTT value at least 2-fold higher than baseline. Repeated subcutaneous administrations of rATS resulted in the generation of fully neutralizing antibodies. These results suggest that specific factor Xa inhibition may be as effective as standard heparin in the treatment of venous thrombosis. Due to its antigenicity however, rATS is probably not suitable for chronic subcutaneous anticoagulant therapy.     

Characteristics and motives of women choosing elective induction of labour

Personal characteristics of healthy term pregnant women who chose elective induction or spontaneous onset of labour and the motives for their choice were assessed. Almost 50% of 237 women with uncomplicated pregnancies opted for elective induction when offered the opportunity. These women appeared to have had more complaints during their pregnancy and menstrual periods, more complications in their obstetrical history and to be more anxious about their labour than women who chose a spontaneous onset of labour. Predominant motives were a feeling of safety and the desire to shorten the duration of pregnancy. These characteristics and motives seem to reflect a lack of trust in physical reproductive functions. It is concluded that in evaluating effects of elective induction of labour, pre-existing differences between women who choose elective induction and women who opt for a spontaneous onset must be taken into account.     

Monitoring unfractionated heparin with the aPTT: time for a fresh look

Laboratory monitoring is widely recommended to measure the anticoagulant effect of unfractionated heparin and to adjust the dose to maintain levels in the target therapeutic range. The most widely used laboratory assay for monitoring unfractionated heparin therapy is the activated partial thromboplastin time (aPTT). A fixed therapeutic range for the aPTT of 1.5 to 2.5 times the control value has become widely accepted, but the evidence supporting this range is weak and the clinical validity of using the aPTT for predicting thrombotic or bleeding events is questionable. The aPTT test is also affected by numerous preanalytic and analytic variables that are unrelated to the anticoagulant effect of unfractionated heparin, further eroding its potential value for monitoring unfractionated heparin treatment. Unfractionated heparin dose appears to be more important than the aPTT in predicting clinical efficacy. Despite serious limitations, the reliance on the aPTT is likely to continue because of its ready availability and familiarity of clinicians with the test. The focus of clinicians who manage unfractionated heparin therapy should be to ensure that an adequate starting dose of unfractionated heparin is used and that the aPTT method is standardized. Future research efforts should be directed towards developing methods to improve standardization of the aPTT assay for monitoring unfractionated heparin. Direct measures of the concentration of unfractionated heparin in the blood are attractive because these assays are not affected by many of the biologic variables that interfere with the aPTT and may be suitable for automation. However, currently available unfractionated heparin assays are much more expensive than the aPTT, are not widely available, and their validity has not been adequately assessed in clinical outcome studies.     

Biological activity and safety of the subcutaneous administration of high doses of low molecular weight heparin for 8 days in human volunteers

This study reports on the biological activity and safety of high dose low molecular weight (LMW) heparin therapy administered by two subcutaneous (s.c.) injections daily for 8 days in healthy human volunteers. Group 1 received 2 x 30 aPTT units LMW heparin/kg bodyweight, and group 2 received 2 x 50 aPTT units/kg per day. In group 1, activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) were uniformly prolonged by 3-5 sec 4 hrs after s.c. administration of heparin. Heptest coagulation time values were prolonged consistently as well by 57 sec on day 1 to 68 sec on day 8. Factor Xa inhibition measured by the S 2222 chromogenic substrate method continuously increased from 0.16 units/ml on day 1 to 0.28 units/ml on day 8. In group 2 prolongation of a aPTT and TCT values increased from 6 sec on day 1 to 15 sec on day 8 and of Heptest time from 70 sec on day 1 to 110 sec on day 8. S 2222 method showed factor Xa inhibitory activity which increased from 0.5 units/ml on day 1 to 0.75 units/ml on day 8. The clinical tolerance of the treatment was good. No changes in clinical chemistry parameters were detected, except for a reversible increase of serum transaminases. The coagulation studies demonstrate accumulation of LMW heparin when high doses are given twice daily. The half life of LMW heparin of factor Xa inhibition increases with increasing doses. Heptest coagulation values were prolonged to 4-6 times the normal values during administration of heparin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long duration of anticoagulant activity and protective effects of acharan sulfate in vivo

INTRODUCTION: We previously reported that a new glycosaminoglycan, acharan sulfate (AS) from the African giant snail Achatina fulica showed anticoagulant activity in vitro, but was much less active when compared to heparin. In the present study, the anticoagulant activity of AS was investigated in vivo. METHODS: AS and heparin were administered to mice and rats in various doses and the anticoagulant activities were measured by aPTT assay. Both were also compared in a thrombin-induced lethality animal model. As one of the possible mechanisms, AS-thrombin interaction was studied by using surface plasmon resonance spectroscopy. RESULTS: Intravenous administration of AS to mice prolonged the clotting time (aPTT) in a time and dose-dependent manner. Although the anticoagulant activity was low in rats, it steadily increased over 5 h after administration of AS (30 mg/kg). In contrast, the increase in aPTT induced by 5 mg/kg of heparin was restored to a normal level after 3 h. In a thrombin-induced lethality model in mice, AS (20 mg/kg) protected against lethality by 80%, while heparin (20 mg/kg) did not show any protective activity beyond 3.5 h post-administration. AS could be also detected in plasma even 5 h after i.v. administration to rats. The binding constant (K(D)) of AS to thrombin was 7.27 x 10(-6) M, corresponding to moderate binding affinity. CONCLUSIONS: These results show that the longer duration of AS in blood could prolong the clotting time determined by aPTT and offering protection against thrombin-induced lethality. One possible mechanism may result from AS-thrombin interaction.     

Low molecular weight heparin Novo (LHN-1) does not cross the placenta during the second trimester of pregnancy

Unfractionated heparin (UF-H) has been the drug of choice for the treatment of thromboembolic disorders during pregnancy. Low molecular weight heparin (LMW-H) preparations may present some advantages over UF-H. They have longer half-lives and a better bioavailability after subcutaneous (s. c.) injection and may cause less bleeding. It has not yet been established whether LMW-H Novo (LHN-1) crosses the placenta. 17 women admitted for abortion during the second trimester of pregnancy (induced by application of prostaglandine PGE2 gel at a concentration of 0.25 mg/ml into the cervix) were given s. c. 35 anti-Xa units per kg of body weight of LHN-1 (Novo). 10 patients not receiving LHN-1 and their fetuses served as a control group. 7 women in whom the time interval between injection of LHN-1 and expulsion of the fetus was less than 3 h or more than 7 h were excluded from further study. In one fetus blood collection failed. Anti-Xa and anti-IIa levels increased approximately ten-fold in women receiving LHN-1 [anti-Xa units/ml from 0.02 +/- 0.01 (mean +/- SD) to 0.17 +/- 0.01, p less than 0.001; anti-Ha units/ml from less than 0.01 +/- 0.01 to 0.07 +/- 0.03], but remained below the detection limit in their fetuses as well as in the women and fetuses of the control group. We conclude that LHN-1 at these doses does not cross the placenta during the second trimester of pregnancy to suggest that LHN-1 may be a safe alternative to heparin in the management of the thromboembolic complications during pregnancy.     

Influence of heparin treatment on biochemical markers of an activation of the coagulation system.

Monitoring of anticoagulant treatment is not yet satisfactory. Otherwise optimal treatment control in special situations as low dose heparin prophylaxis in hip surgery or high dose anticoagulant treatment in patients after coronary stent implantation may be desirable. Recently available thrombin markers were analyzed in 51 patients under low dose (group 1) and 30 patients under high dose therapy with unfractionated heparin (group 2a and b) as well as in controls (n = 26). Before therapy these parameters were significantly elevated in both patient groups. Elevated thrombin-antithrombin III-complexes (TAT) despite adequate prolongation of aPTT under high dose heparin in 38.2% of patients indicate that therapeutic concentrations of heparin in these cases are insufficient for depressing this parameter completely. During low dose therapy only prothrombin fragment (F1 + 2) significantly decreased. This may be explained by catalytic induction of TAT-complex formation by heparin. Decrease of D-Dimer under heparin therapy in both groups does not parallel with TAT and F1 + 2 but was more prolonged. This can be explained by dependence of the D-Dimer level on spontaneous fibrinolytic activity and by a longer plasma half-life as well as a chronic and continuous fibrinolytic process in an older thrombus. In conclusion, thrombin markers seem to be helpful in estimating anticoagulant treatment efficacy. As a consequence, anticoagulant treatment has to be intensified in high-risk patients for complete depression of these markers. Whether the benefit of higher heparin doses is worth the risk of drug-induced hemorrhage, however, remains to be clarified in clinical studies.     

Treatment of deep venous thrombosis with low-molecular-weight heparin during pregnancy

Low-molecular-weight (LMW) heparins have been shown to be at least as effective as unfractionated (UF) heparin in the treatment of deep venous thrombosis (DVT) in nonpregnant subjects. LMW heparins have been shown to be safe when used during pregnancy as they do not cross the placenta. Up to now, they have been used mainly in thromboprophylaxis during pregnancy and rarely in the treatment of acute DVT in pregnant women. In a prospective observational study, we compared the effectiveness and safety of the LMW heparin, dalteparin, with UF heparin in the initial treatment (first week) of DVT during pregnancy. After confirmation of DVT by ultrasonography, 10 women were treated with UF heparin (25,430 IU/day, mean) and 21 women with dalteparin (16,000 IU/day, mean) for 7 days and, thereafter, all women were given treatment doses of LMW heparin for another 2 weeks. The dose was then gradually decreased and kept at a high prophylactic dose until delivery. One patient in the dalteparin group had recurrence of DVT 2 weeks after starting the treatment. No differences were observed between the groups in symptoms or bleeding complications during pregnancy and delivery. Our results indicate that LMW heparin is as effective and safe as UF heparin for the first week of treatment, but LMW heparin has the advantage of being easily administered and few laboratory controls are required.     

Spontaneous platelet aggregation in heparinised blood during pregnancy

A marked increase in spontaneous platelet aggregation in whole blood was found during pregnancy. The increased spontaneous aggregation was most evident in whole blood anticoagulated with heparin; it was less marked in blood that contained citrate as anticoagulant. Studies of blood that contained both anticoagulants indicated that it is heparin that potentiates aggregation in blood taken during pregnancy rather than citrate that inhibits it. Increased spontaneous aggregation was seen in normotensive pregnancy, in pregnancy complicated by essential hypertension and in pregnancy-induced hypertension. In normotensive pregnancy it was evident at 16 weeks gestation but in pregnancy complicated with essential hypertension it was not evident until 24 weeks gestation. For all the women spontaneous aggregation had returned to normal six weeks after delivery.     

At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects

Combined effects of heparin and protamine on plasma clot structure and platelet function were studied. Anticoagulant effects were monitored as changes in aPTT. Clot structure was defined in terms of fibrin fiber mass/length ratio (μ) and clot elastic modulus (EM). Platelet function was studied utilizing platelet aggregation and platelet force development (PFD) measurements. Heparin (1 U/ml) prolonged the aPTT from 30 to >300 seconds, reduced PFD from 5,100 to 0 dynes, decreased μ (in batroxobin-induced gels) from 1.36 to 1.08 × 10¹³ daltons/cm and decreased clot EM from 9,600 to 2000 dynes/cm². Varying amounts of protamine reversed these effects: 16 μg/ml normalized the aPTT, 20 μg/ml normalized PFD, 32 μg/ml corrected μ, and 20 μg/ml returned EM to baseline. At high heparin concentrations (4 U/ml), protamine concentrations which corrected anticoagulant effects were inadequate to reverse antiplatelet effects. A protamine concentration of 40 μg/ml normalized the aPTT and μ, but 140 μg/ml of protamine was required to reverse heparin suppression of force development and clot elastic modulus. Excess protamine inhibited clotting and platelet function. In plasma containing 1 u heparin/ml, 140 μg protamine/ml reduced PFD by 83%, prolonged the aPTT by 63%, and reduced clot EM by 75%. In heparin free plasma, >75 μg protamine/ml prolonged the aPTT. Thus, platelet function and clot structure are sensitive to protamine during heparin neutralization, and anti-platelet effects of heparin may persist when the aPTT is completely corrected. Excess protamine inhibits platelet function and compromises clot structure.     

Effects of argatroban and heparin on thrombus formation and tissue plasminogen activator-induced thrombolysis in a microvascular thrombosis model

Effects of (2R,4R)-4-methyl-1-[N(2)-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidine-carboxylic acid monohydrate (argatroban) and unfractionated heparin (UFH) were compared with respect to thrombus formation and tissue-type plasminogen activator (t-PA)-induced thrombolysis in a microvasculature thrombosis model. The antithrombotic activities of anticoagulants were evaluated with respect to the time required for the initiation of thrombus formation (T(i)) and the time required for the thrombus to stop blood flow (T(s)). The effects of anticoagulants administered with t-PA were evaluated by percent stenosis of the vessel and percent area of the thrombus. Argatroban (1-3 mg/kg/bolus) significantly prolonged T(i) and T(s) in a dose-dependent fashion compared to control. Argatroban (3 mg/kg/bolus) significantly prolonged both the T(i) and T(s) more effectively than UFH (100 anti-XaU (a-XaU)/kg/bolus), despite equivalent prolongation of the activated partial thromboplastin time (aPTT). Higher doses of UFH (300-500 a-XaU/kg) were required to significantly prolong T(i) and T(s), but at these doses, UFH caused over-prolongation of aPTT (>180 s), which might consequently cause bleeding complications. Argatroban (0.1-0.3 mg/kg/h) significantly accelerated thrombolysis by t-PA in both a dose- and time-dependent fashion. Although argatroban (0.1-0.2 mg/kg/h) did not significantly prolong the aPTT and bleeding time (BT) as compared with control, it significantly accelerated thrombolysis by t-PA at these doses of lower bleeding risk. Argatroban (0.3 mg/kg/h) significantly enhanced thrombolysis by t-PA, while UFH (12.5 anti-XaU/kg/h) attenuated it again, despite equivalent prolongation of the aPTT and BT. We conclude that argatroban seems to be a more efficient and safer anticoagulant than UFH for the prevention of thrombus formation and acceleration of t-PA-induced thrombolysis.     

Inhibition of low molecular weight heparin by protamine chloride in vivo

To determine the antagonization of anticoagulant and lipolytic effects of a low molecular weight [LMW] heparin preparation protamine chloride was given intravenously after i.v. injection of LMW or normal heparin. The effects of normal heparin on factor Xa, thrombin, aPTT, lipoprotein [LPL] and hepatic triglyceride lipase [HTGL] activities were neutralized immediately by i.v. protamine. The inhibition of thrombin and aPTT by LMW heparin were also abolished, whereas the effects on LPL and HTGL were counteracted to 80% and on factor Xa only to 40% by i.v. protamine chloride. No rebound of the anticoagulant or lipolytic effect was detected. It is assumed that haemorrhagic complication during therapy can be antagonized by protamine chloride. The incomplete inhibitory effect of protamine chloride on LPL, HTGL and factor Xa activities of LMW heparin indicate that protamine chloride requires more than 14 saccharide units in the heparin molecule for interaction.     

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.     

The use of enoxaparin in children with acute, nonhemorrhagic ischemic stroke

The use of low-molecular-weight heparin offers multiple advantages over unfractionated heparins in pediatric patients with acute ischemic stroke. The safety and efficacy of low-molecular-weight heparin have been demonstrated in adults, but less is known about their use in children. This study reviews retrospectively the use of low-molecular-weight heparin in children with acute, ischemic, nonhemorrhagic strokes. A database search was used to locate all children who experienced an ischemic stroke between July 1991 and January 2001 and who were subsequently treated with low-molecular-weight heparin. Eight children were identified (aged 37 months to 17 years; median age, 133 months) who were treated with the low-molecular-weight heparin enoxaparin. Enoxaparin was used in one case as the sole treatment, in six cases as a bridge to oral anticoagulant therapy with warfarin, and in one case as a replacement treatment after several days of warfarin therapy. The median duration of treatment with enoxaparin was 4 days. During this period, no major bleeding complications were observed, and no new thrombi or extensions of thrombi occurred. One patient did experience mild oozing at an intravenous site, and another experienced an episode of epistaxis. Enoxaparin was discontinued in one patient because of discomfort associated with the subcutaneous injections. Although the number of patients was limited, it appears that enoxaparin is a safe and efficacious alternative to the use of unfractionated heparin in children with acute, nonhemorrhagic ischemic stroke.     

The effect of dermatan sulfate on in vitro human plasma coagulation, platelet aggregation and beta TG/PF4 release

We evaluated the in vitro anticoagulant action of dermatan sulfate (DS) (aPTT, antiXa, anti-thrombin) and its effect on human platelet aggregation and beta TG/PF4 release induced by threshold doses of aggregating agents, compared with standard heparin (SH). In pooled plasma, DS prolonged aPTT much less than SH, had no measurable antiXa activity, showed an anti-thrombin activity similar to that shown by SH at a tenfold higher dilution. DS had no direct effect on human platelet aggregation and beta TG/PF4 release. Moreover it did not significantly affect platelet aggregation and release by ADP and collagen, whereas it completely inhibited platelet aggregation and beta TG/PF4 release by thrombin. These data in vitro confirm that thrombin inhibition induced by DS is accompanied by a far lesser aPTT prolongation compared to heparin, without any appreciable interference with platelet function.     

Activity of a sub-cutaneously administered novel mixed micellar formulation of argatroban in rat and rabbit models of venous thrombosis

We studied the antithrombotic activity of a mixed micellar formulation containing 14 mg/ml argatroban administered by the subcutaneous (s.c.) route in rat and rabbit models of venous thrombosis. The effects on bleeding time in the rat tail transection bleeding time test were also studied. In a tissue factor-dependent arterio-venous shunt model, argatroban treatment led to dose-dependent reduction in thrombus weight with an estimated ID50 of 1.8 mg/kg s.c. In the same model, heparin had an estimated ID50 of 179 IU/kg. The antithrombotic activity of argatroban was accompanied by increases in the thrombin and ecarin clotting times but not the aPTT, whereas heparin increased the thrombin time and aPTT but not the ecarin clotting times. Argatroban also inhibited thrombus formation in a rabbit model of thromboplastin + stasis induced thrombosis in the rabbit jugular vein with an estimated ID50 of 1 mg/kg s.c. When tested in the rat tail transection bleeding time test, the mixed micellar formulation of argatroban caused significant increases in the bleeding time as from 8 mg/kg s.c., while heparin significantly increased the bleeding time at 800 U/kg. Mixed micellar argatroban appears to have a superior safety margin to heparin in terms of antithrombotic efficacy and bleeding risk. Thus, a mixed micellar formulation of argatroban, which markedly enhances its solubility, could be useful as a potential antithrombotic agent for subcutaneous administration.     

Additive effects of anticoagulants: recombinant human activated protein C and heparin or melagatran, in tissue factor-activated umbilical-cord plasma

Severe sepsis in children or adults may cause a life-threatening coagulopathy, with widespread consumption of activated protein C (APC); recombinant human APC (rhAPC) is a promising candidate anticoagulant treatment. We investigated the effects of rhAPC and other anticoagulants on coagulation triggered by adding small quantities of lipidated tissue factor to human umbilical-cord plasma in vitro. rhAPC, unfractionated heparin (UH), and melagatran (a direct thrombin inhibitor) were studied individually, and in combinations of rhAPC with either UH or melagatran. rhAPC alone dose-dependently prolonged the activated partial-thromboplastin time (aPTT) but not the prothrombin time (PT), and dose-dependently suppressed two indices of thrombin generation, namely prothrombin fragment F 1.2 (F 1.2) generation and thrombin-antithrombin (TAT) complex formation. UH alone dose-dependently prolonged the aPTT but not the PT, while melagatran alone dose-dependently prolonged both the aPTT and the PT. Adding either UH or melagatran dose-dependently augmented the capacity of rhAPC to suppress F 1.2 generation (with addition of UH showing a greater effect) and TAT formation (with addition of melagatran showing a greater effect). Both the capacity of UH to prolong the aPTT and the capacity of melagatran to prolong the aPTT and the PT were augmented by adding rhAPC. In our in-vitro study, adding either UH or melagatran augmented the capacity of rhAPC to suppress thrombin generation in human umbilical-cord plasma, with the anticoagulant effect of melagatran being more predictable than that of UH. Hence, combining rhAPC with melagatran might be a valuable therapeutic option in patients with severe sepsis.     

Impaired platelet function and peripartum bleeding in women with Gaucher disease

The risk of bleeding during delivery may be increased in women with Gaucher disease. We aimed to evaluate potential predictors for peripartum haemorrhage (PPH) during childbirth in these patients, while focusing upon coagulation tests and platelet function assays. Women with type 1 Gaucher disease who gave birth at Sheba Medical Center between 1999-2009 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, delivery and pregnancy outcome. PPH was defined as excessive bleeding during or immediately following delivery. Coagulation studies and platelet function tests, including aggregometry and cone and platelet (CPA) analyses, were performed on all women. We compared women with PPH (bleeders) and non-bleeders. Furthermore, women with abnormal CPA platelet function tests were compared with those with normal CPA platelet function with regards to the risk for PPH in at least one pregnancy. Forty-five pregnancies of 20 women were studied. Six women received enzyme replacement therapy during pregnancy. Mean platelet count prior to delivery was 83,000/μl ± 35,000/μl. Fourteen out of 45 (31%) deliveries were complicated by PPH. Neither thrombocytopenia nor enzyme therapy predicted PPH. Twelve out of 13 women with PPH (92.3%) versus 2/7 non-bleeders (28.6%) had impaired platelet aggregation (less than the 3rd percentile of normal average aggregate size values), when tested by CPA, (odds ratio [OR] 17.8, 95% confidence interval [CI] 2.5; 126.2; p=0.007). Notably, 78.6% of women with impaired CPA aggregation developed PPH during at least one delivery, as opposed to 16.7% of those with normal CPA platelet function tests (OR 11.6, 95% CI 1.7-77.7, p=0.018). In conclusion, women with type 1 Gaucher disease who have abnormal platelet function tests may have an increased risk of PPH.     

Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry

Venous thromboembolism (VTE) occurs infrequently during pregnancy, and issues concerning its natural history, prevention and therapy remain unresolved. RIETE is an ongoing registry of consecutive patients with objectively confirmed, symptomatic acute VTE. In this analysis, we compared the clinical characteristics and outcome for all enrolled pregnant and postpartum women with acute VTE, and all non-pregnant women in the same age range. Up to May 2005, 11,630 patients were enrolled in RIETE, of whom 848 (7.3%) were women aged <47 years. Of them, 72 (8.5%) were pregnant, 64 (7.5%) postpartum. Pregnant women presented less often with symptomatic pulmonary embolism (11%) than non-pregnant women (39%). VTE developed during the first trimester in 29 (40%) pregnant patients; in the second in 13; in the third in 30. Thrombophilia tests were more often positive in women who had VTE during the first trimester (odds ratio [OR]: 4.4; 95% CI: 0.9-2.4; p=0.037). Most patients in all three groups were initially treated with low-molecular-weight heparin (LMWH). As for long-term therapy, 75% of pregnant women received LMWH until delivery. There were no maternal deaths, and no pregnant patient had recurrence or bled before delivery. However, after delivery one patient (1.4%) developed recurrent thrombosis, four (5.6%) had major bleeding. In conclusion, VTE developed during the first trimester in 40% of the pregnant women, thus suggesting that thromboprophylaxis, when indicated during pregnancy, should start in the first trimester. No patient showed recurrence or bled before delivery, but after delivery the risk of bleeding exceeded the risk of recurrences.     

Risks to the fetus of anticoagulant therapy during pregnancy

The use of anticoagulants during pregnancy is problematic because of the potential adverse effects to the mother and the fetus. Heparin does not cross the placenta, and thus, it was surprising that a recent report concluded that heparin therapy during pregnancy was as risky as oral anticoagulant therapy. Therefore, we performed a literature review of fetal/infant outcomes following anticoagulant therapy during pregnancy. We examined 186 reports which described fetal/infant outcomes in 1,325 pregnancies associated with anticoagulant therapy. The rates of adverse fetal/infant outcomes including death, prematurity and cogenital malformations following treatment with heparin, oral anticoagulants, or both were calculated. The previously described high rate of adverse fetal/infant outcomes with heparin-treated patients, could be accounted for by the frequent use of heparin in pregnancies with comorbid conditions independently associated with adverse outcomes and by reports of uncomplicated prematurity. After excluding such pregnancies, outcomes in heparin-treated patients are similar to the normal population.