Antithrombotic Therapy and Pregnancy: Consensus Report and Recommendations for Prevention and Treatment of Venous Thromboembolism and Adverse Pregnancy Outcomes

Duhl, Adam J.; Paidas, Michael J.; Ural, Serdar H.; Branch, Ware; Casele, Holly L.; Cox-Gill, Joan; Hamersley, Sheri L.; Hyers, Tom M.; Katz, Vern L.; Kuhlmann, Randall S.; Nutescu, Edith A.; Thorp, JM; Zehnder, James L.

doi:10.1097/01.aoa.0000326376.74250.dd

Cited by 35 publications

(43 citation statements)

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“…The diagnosis and indication for anticoagulant therapy was based on recognized clinical and laboratory criteria. 20,21 Gestational age was established based on menstrual date and/or ultrasonographic examination prior to 20 weeks' gestation. Inclusion criteria for the heparin study group included: gestational age Ͻ14 weeks, absence of anticoagulant therapy at enrollment, and a plan for clinically indicated anticoagulant treatment during the current pregnancy.…”

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confidence: 99%

Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy

et al. 2011

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Background-Alterations in circulating levels of pro-and antiangiogenic factors have been associated with adverse pregnancy outcomes. Heparin is routinely administered to pregnant women, but without clear knowledge of its impact on these factors. Methods and Results-We conducted a longitudinal study of 42 pregnant women. Twenty-one women received prophylactic heparin anticoagulation, and 21 healthy pregnant women served as controls. Compared with gestational age-matched controls, heparin treatment was associated with increased circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1) in the third trimester (PϽ0.05), in the absence of preeclampsia, placental abruption, or fetal growth restriction. Heparin had no effect on circulating levels of vascular endothelial growth factor, placenta growth factor, or soluble endoglin as assessed by ELISA. In vitro, low-molecular weight and unfractionated heparins stimulated sFlt-1 release from placental villous explants, in a dose-and time-dependent manner. This effect was not due to placental apoptosis, necrosis, alteration in protein secretion, or increased transcription. Western blot analysis demonstrated that heparin induced shedding of the N-terminus of Flt-1 both in vivo and in vitro as indicated by a predominant band of 100 -112 kDa. By using an in vitro angiogenesis assay, we demonstrated that serum of heparin-treated cases inhibited both basal and vascular endothelial growth factor-induced capillary-like tube formation. Conclusions-Heparin likely increases the maternal sFlt-1 through shedding of the extracellular domain of Flt-1 receptor.Our results imply that upregulation of circulating sFlt-1 immunoreactivity in pregnancy is not always associated with adverse outcomes, and that heparin's protective effects, if any, cannot be explained by promotion of angiogenesis. (Circulation. 2011;124:2543-2553.)Key Words: anticoagulation Ⅲ angiogenesis Ⅲ sFlt-1 Ⅲ heparin Ⅲ pregnancy A successful pregnancy outcome requires the proper functioning of the molecular mechanisms responsible for regulating vascular endothelial homeostasis at both the systemic and local decidual/placental levels. 1 Derangements of these mechanisms can lead to major pregnancy-related complications. Recent studies have focused on how alterations in placental trophoblast production of angiogenic proteins may help to explain the pathogenesis of preeclampsia, 2,3 placental abruption, 4 intrauterine growth restriction, and stillbirth. 5 A unifying theory is that excessive release of antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) by hypoxic trophoblasts, antagonize proangiogenic factors such as vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). 3 This phenomenon causes aberrant placental angiogenesis and vasculogenesis. 6 The end result is an increasingly dysfunctional placenta with local and systemic vascular endothelial damage, activation of inflammatory pathways, and enhanced platelet turnover, which result in the...

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confidence: 99%

Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy

et al. 2011

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“…Administration (FDA) as a risk category "B" for use during pregnancy and have not been associated with any foetal abnormality or specific incidence of birth defects 4,5 .…”

Section: Lmwhs Are Classified By the Food And Drugmentioning

confidence: 99%

Effects of enoxaparin and unfractionated heparin in prophylactic and therapeutic doses on the fertility of female Wistar rats

Figueiró-Filho

Aydos²,

Senefonte³

et al. 2014

Acta Cir. Bras.

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PURPOSE:To evaluate the effects of exposure of enoxaparin and unfractionated heparin (UFH) in prophylactic and therapeutic doses on the fertility rates of pregnant healthy Wistar rats. METHODS:Enoxaparin and UFH were administered in prophylactic doses 1 mg/Kg/day 72 UI/Kg/day, and in therapeutic doses at 2 mg/kg/day 400UI/Kg/day. The rats were divided into five groups. The number of live and dead foetuses was quantified. The uterine horns were dissected and the presence of early and late reabsorptions (abortions) was determined. A p<0.05 was considered statistically significant. RESULTS:We did not observe statistically significant differences between groups when comparing the average weight of the foetuses and placentas, rate of female VS males, rates of pre-implantation loss (RPL), rates of efficiency implantation (REI), rates of postimplantation loss (RPIL) and rates of foetal viability (RFV). CONCLUSIONS:There was no significant effect on fertility with the use of anticoagulant drugs in pregnant healthy Wistar rats.

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“…A genomic test for the FVL mutation has been commercially available since 2003, but recent consensus recommendations differ on the indications that require screening among pregnant women, and the strength of evidence underlying these recommendations is weak. 9,10 The FVL mutation affects an estimated 5% of European Americans, and estimates range from 0.5 to 2.5% among Americans of other ancestries. 11 Heterozygous carriers of the FVL mutation have a three-to eightfold increased risk of experiencing venous thromboembolisms (VTEs) and homozygous carriers are estimated to have a further elevated risk wherein the estimates range from a nine-to 80-fold increased risk as compared with noncarriers.…”

confidence: 99%

A risk–benefit analysis of factor V Leiden testing to improve pregnancy outcomes: a case study of the capabilities of decision modeling in genomics

Bajaj

Veenstra

2013

Genetics in Medicine

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Decision-analytic methods are often used in health-care decision making to quantify the anticipated clinical risks and benefits of implementing a proposed intervention. These methods provide a framework for transparently assembling data and estimating the effects of an intervention on health outcomes. 1 Although these methods have been used to assess a multitude of interventions, it is unclear whether they are capable of adequately capturing clinical and personal utility of genomic testing.Specifically, genomic testing in complex indications may be challenging to represent within the context of a traditional decision-analytic framework that uses quality-adjusted lifeyears (QALYs) as a summary measure of benefit. 2 Genomic tests impart knowledge to both the patient and provider. To the extent that this information guides treatment decisions, the impact on health outcomes is relatively straightforward to capture using decision-analytic methods. 3 However, complexity arises due to the inherent value the information obtained from a genomic test may have to the patient. This information has potential to be the source of anxiety or to relieve anxiety, may have implications for reproductive decisions, and has implications for others, as spouses of carriers are affected by the decisions informed with this knowledge and relatives of a mutation-positive patient learn that they have a higher likelihood to be carriers. [4][5][6][7][8] The growing availability and use of genomic tests merit closer examination of the role of decision modeling in assessing the clinical and personal utility of testing.The objective of this study was to explore the capability and flexibility of decision-analytic methods to examine a complex case study involving genomic testing: the use of factor V Leiden (FVL) testing to improve pregnancy outcomes. A genomic test for the FVL mutation has been commercially available since 2003, but recent consensus recommendations differ on the indications that require screening among pregnant women, and the strength of evidence underlying these recommendations is weak. 9,10 The FVL mutation affects an estimated 5% of European Americans, and estimates range from 0.5 to 2.5% among Americans of other ancestries. 11 Heterozygous carriers of the FVL mutation have a three-to eightfold increased risk of experiencing venous thromboembolisms (VTEs) and homozygous carriers are estimated to have a further elevated risk wherein the estimates range from a nine-to 80-fold increased risk as compared with noncarriers. 12 Furthermore, studies have indicated a potential association between the FVL mutation and risk of recurrent pregnancy loss (RPL) and other adverse pregnancy outcomes. 13 However, the uncertainty in study findings and strong influence of patient values and preferences for medical treatment during pregnancy have not allowed decision makers to impart strong recommendations on the clinical scenarios that warrant FVL testing and treatment. 9Purpose: We sought to assess the benefits, risks, and personal utility of fac...

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Antithrombotic Therapy and Pregnancy: Consensus Report and Recommendations for Prevention and Treatment of Venous Thromboembolism and Adverse Pregnancy Outcomes

Cited by 35 publications

References 146 publications

Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy

Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy

Effects of enoxaparin and unfractionated heparin in prophylactic and therapeutic doses on the fertility of female Wistar rats

A risk–benefit analysis of factor V Leiden testing to improve pregnancy outcomes: a case study of the capabilities of decision modeling in genomics

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