Thrombophilia In Pregnancy Research Articles

Thrombelastography monitoring of resistance to enoxaparin anticoagulation in thrombophilic pregnancy patients

The anticoagulant effect of enoxaparin is readily observed by Thrombelastography (TEG®), particularly on the reaction time ( R) to form a clot, and is completely reversed by heparinase. In this study, recalcified citrated whole blood with heparinase (CNHR) and without (CNR), along with TEG R time, was used to derive a delta R (CNR − CNHR). This delta R (Δ R) was then used to measure enoxaparin anticoagulation, which was correlated by linear regression ( r 2 = 0.806) with plasma anti-Xa in 48 thrombophilic pregnancy patients. In a follow up study whole blood from 15 thrombophilic and 15 normal pregnancy subjects was titrated ex vivo with enoxaparin and TEG Δ R determined. Linear dose responses (all r 2 > 0.9) of Δ R versus plasma enoxaparin concentration were obtained for each subject. A large variation in slope was observed for both thrombophilic (> 7 fold, 217 to 1588 s Δ R/unit anti-Xa) and normal (> 3 fold, 788 to 2758) pregnancy subjects. The average slope for the thrombophilic group (710 s Δ R/unit anti-Xa) was significantly ( P = 0.002) lower than the normal pregnancy group (1354 s), indicating resistance to enoxaparin anticoagulation in the thrombophilic group. This technique may help gauge the appropriate dose of enoxaparin for each individual, check for residual anticoagulation before invasive procedures, and perhaps help screen for thrombophilic subjects.

Is Homozygosity for the MTHFR C677T Mutation a Risk Factor for Miscarriage? — Likely.

Various hereditary thrombophilias such as activated protein C resistance, the factor V leiden mutation, the prothrombin G20210A mutation, protein S deficiency, hyperhomocysteinemia, or combinations of the above disorders have been linked to pregnancy loss at varying stages of gestation (Robertson L, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132(2):171–96; Seligsohn U, et al. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344(16):1222–31). The literature regarding methylenetetrahydrofolate reductase (MTHFR) mutations is confusing. Much of the evidence supporting a causal relationship between MTHFR mutations and early fetal loss comes from individual case reports with little outcome data. Three recent meta-analyses of thrombophilia in pregnancy concluded that although there may be a trend toward higher risk, the relationship between MTHFR mutations and spontaneous abortions is not truly significant (Robertson L, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132(2):171–96; Nelen WL, et al. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000; 74(6):1196–9; Rey E, et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361(9361):901–8). In contrast, a study supporting the role of MTHFR mutations in recurrent unexplained abortions found a 2–3 fold increased risk of early fetal loss among Caucasian females homozygous for the C677T mutation versus normal controls (Nelen WL, et al. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997; 350(9081):861). We present 5 patients with this genetic defect who presented consecutively to our clinic for decision making for future pregnancies. Each had strong histories of miscarriages after the 8th week of gestation. The clinical features of these patients are reported in the table below. [Display omitted] Each woman is Caucasian, and is homozygous for the MTHFR C677T mutation with no other acquired or hereditary thrombophilias. Homocysteine levels were also in normal range for each patient. Our case series of 5 Caucasian women gives support to the theory of a causal relationship between MTHFR mutations and fetal loss. We recommended anticoagulation with low-molecular weight or unfractionated heparin for each patient as a therapeutic intervention to reduce the risk of recurrent abortion in future pregnancies.

Thromboembolism and thrombophilia in pregnancy

Venous thromboembolism (VTE) is one of the leading causes of maternal mortality worldwide and is also the cause of significant maternal morbidity. This article discusses the risk factors for VTE in pregnancy, the management of the pregnant woman at risk both antenatally and post-partum, and the acute management of VTE when it occurs during pregnancy. The thrombophilias, both heritable and acquired, are becoming increasingly recognised as a cause of morbidity and mortality both within and outside pregnancy. There has been a recent increased interest in the thrombophilias and their link with recurrent miscarriage, preeclampsia, abruption and intrauterine growth restriction. The relationship between the thrombophilias and adverse pregnancy outcome is addressed in detail, with reference to the current literature available on this evolving subject.

Prophylaxis and treatment of thrombophilia in pregnancy

This review addresses the prophylaxis and treatment of thrombophilia in pregnancy, which is associated with increased risk of venous thromboembolism and placental vascular complications. Topics include preventing deep vein thrombosis recurrence in pregnant women with constitutional thrombophilias, using prophylactic heparins throughout pregnancy and postpartum anticoagulants. Cases of thrombosis still occur in the postpartum period and other therapeutics should be tested. Primary prophylaxis is acceptable for high-risk thrombophilias. Early pregnancy losses (before the 10th week) are not associated with constitutional thrombophilias. The natural prognosis of embryonic losses associated with current thrombogenic polymorphisms is good, unlike fetal losses associated with the same thrombophilias: in this case, a prophylactic low-molecular-weight heparin given from the beginning of the 8th week is more efficient than low-dose aspirin. Data are lacking on the prevention of severe preeclampsia, placental abruption, or intrauterine growth restriction in women with constitutional thrombophilias; preliminary results indicate that low-molecular-weight heparin may have some preventive effect. Specific studies are needed. Recent studies have shown the limits of available procedures for women with constitutional thrombophilia and have helped define the clinical situations in thrombophilia-related placental insufficiency in which prophylactic low-molecular-weight heparin may be indicated.

Elevated first trimester maternal levels of soluble fibrin polymer are associated with lower birthweight in twin gestation

We assessed soluble fibrin polymer longitudinally in normal pregnancy, thrombophilic pregnancy and twin gestation Thirty-three thrombophilic pregnancies, 34 uncomplicated multiple gestations and 23 singleton normal pregnancies were studied. Maternal plasma samples were collected in the first (6-12 weeks), 2nd (13-25 weeks) and 3rd trimesters of pregnancy (26-40 weeks) and were stored at -70 degrees C until assay. Soluble fibrin polymer was assayed by enzyme-linked immunosorbent assay (ABS, Copiague, New York, USA). Statistical analysis were made by Spearman test and Levine's test for equality of variance (P < 0.05). First soluble fibrin polymer maternal levels in twin gestation were significantly higher than in normal pregnancy and thrombophilic pregnancy, (23.8 +/- 4.5 mug/ml versus 9.2 +/- 3.1 and 10.0 +/- 2.0 mug/ml respectively, P < 0.005). Second and third trimester maternal levels of SFP in twins were also significantly higher than in normal pregnancy. First trimester soluble fibrin polymer was highly correlated with birthweight in twin gestation (r = -1, P < 0.01). In the third trimester, maternal soluble fibrin polymer correlated with placental weight in twin gestation (r = 0.639, P < 0.01). Overall, soluble fibrin polymer was correlated with placental weight and birthweight in the three groups but this did not reach statistical significance. Elevated maternal plasma levels of soluble fibrin polymer in twin gestation may derive from an accelerated coagulation process due to extensive vascular remodelling. Current studies are underway to determine the utility of soluble fibrin polymer in assessing fetal growth abnormalities.

Thrombophilia in Pregnancy: Maternal and Fetal Implications

Pregnancy is accompanied by altered levels of coagulation factors, which are likely responsible for an increased risk of thrombosis, including an increased risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction. Women with thrombophilia, an acquired or inherited predisposition to thrombosis, are at an even greater risk of thrombosis during pregnancy than other women. The presence of thrombophilia, which may protect women from blood loss at the time of childbirth, does not improve the outcome of pregnancy. Women with thrombophilia are more likely to experience placental abruption, preeclampsia, fetal growth restriction, stillbirth, and possibly recurrent miscarriage. There are no randomized trials of the use of anticoagulation to reduce maternal thromboembolism, but in women with thrombophilia and a history of thrombosis, anticoagulation is generally recommended. In women with thrombophilia and a history of poor pregnancy outcome, anticoagulation may improve fetal outcomes. Keywords: Pregnancy, thrombophilia, thrombosis, venous thromboembolism, miscarriage

Thrombophilia in pregnancy: a systematic review

Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0.74-34.40); early pregnancy loss (ORs, 1.40-6.25); late pregnancy loss (ORs, 1.31-20.09); pre-eclampsia (ORs, 1.37-3.49); placental abruption (ORs, 1.42-7.71) and intrauterine growth restriction (ORs, 1.24-2.92). Low-dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1.62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.

Thrombophilia and Severe Preeclampsia

The term thrombophilia is used to describe a heterogenous group of coagulation abnormalities (acquired or inherited) that are generally associated with increased risk of arterial and venous thrombosis.1 Antiphospholipid antibodies (APA) is the most frequent acquired thrombophilic disorder during pregnancy. It is generally diagnosed in the presence of elevated levels of IgG and IgM (GpL or MpL values ≥20) or the presence of lupus auticoagulant.2 The most common inherited thrombophilic disorders during pregnancy are mutations in factor V Leiden (FVL), prothrombin gene, and tetrahydrofolate reductase. During the past 2 decades, epidemiologic and case-control studies have evaluated the association between thrombophilias and adverse pregnancy outcome (APO), specifically, preeclampsia and intrauterine fetal growth restriction (IUGR).1–5 An association between severe preeclampsia at <34 weeks and APA was first reported by Branch et al in 1989.2 Based on this report, recommendations were made that women with severe preeclampsia at <34 weeks be screened for the presence of APA and be treated if positive in subsequent pregnancies. Since that publication, several studies were published supporting or refuting an association between these antibodies and preeclampsia.6,7 Indeed, a recent report concluded that data do not support routine testing for APA in women with early-onset preeclampsia.6 An association between preeclampsia and inherited thrombophilias was first reported by Dekker et al in 1995.8 Since then, a large number of retrospective and case-controlled studies have examined the association …

Thrombophilia in Pregnancy and its Role in Abortion

Inherited and acquired thrombophilia are the main cause of thrombosis in pregnant women. A growing number of reports over the last few years have suggested that these disorders are also associated with an increased incidence of vascular pathologies resulting in poor gestational outcome. This article discusses recent data concerning thrombophilia and vascular placental pathology, and discusses available therapeutic modalities to prevent placental vascular thrombosis and maximize successful gestational outcome.

Thrombophilia in pregnancy and its role in abortion

Inherited and acquired thrombophilia are the main cause of thrombosis in pregnant women. A growing number of reports over the last few years have suggested that these disorders are also associated with an increased incidence of vascular pathologies resulting in poor gestational outcome. This article discusses recent data concerning thrombophilia and vascular placental pathology, and discusses available therapeutic modalities to prevent placental vascular thrombosis and maximize successful gestational outcome.

Thrombophilia Screening in Pregnancy

Thromboembolism in pregnancy is a major contributor to pregnancy morbidity and mortality with potentially serious adverse effects for both mother and fetus. The purposes of this article are to explore the impact of heritable and acquired thrombophilias on pregnancy and to determine the appropriateness of screening for thrombophilias in pregnancy. In determining the appropriateness of screening, attention was given to the changes that occur in the coagulation and fibrinolytic systems during normal pregnancy. The impact of different heritable and acquired thrombophilias on maternal venous thromboembolism, fetal loss, and its impact on certain obstetric conditions are then explored. Guidelines and conclusions are made as to the appropriateness of screening. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to list the various thrombophilias associate with pregnancy, to describe the impact of thrombophilias on pregnancy, and to outline the appropriate screening guidelines for thrombophilias during pregnancy.

Elevated first trimester maternal levels of TpP are associated with birthweight in twin gestation

BIRTHWEIGHT IN TWIN GESTATION GABRIELE URBAN, MICHAEL PAIDAS, DEHUI KU, YALE ARKEL, CHARLES LOCKWOOD, Universita di Milano, Obstetrics and Gynecology, Monza, Italy, Italy, Yale University, Obstetrics, Gynecology and Reproductive Sciences, New Haven, Connecticut, New York University, Obstetric and Gyencology, New York City, New York OBJECTIVE: We assessed soluble fibrin polymer, Thrombus precursor Protein (TpP) longitudinally in normal pregnancy (NP) , thrombophilic pregnancy (TP) and twin gestation(TG). STUDY DESIGN: Thirty-three TP, 27 uncomplicated TG and 23 singleton NP were studied.Maternal plasma samples were collected in the first (6-12 weeks), second (13-25 weeks), and third trimester of pregnancy (26-40 weeks), stored at 70(C until assay.TpP was assayed by ELISA (ABS,Copiague, NY).Statistical analysis were made by Spearman test and Levene’s test for equality of variance (P ! .05). RESULTS: First TpP maternal levels in TG were significantly higher than in NP and TP, (23.8 G 4.5 mg/mL vs 9.2 G 3.1 and 10.0 G 2.0 mg/mL respectively, P ! .005). Second and third trimester maternal levels of TpP in twins were also significantly higher than in NP. First trimester TpP was highly correlated with birthweight in TG r = 1, P ! .01). In the third trimester, maternal TpP with placental weight in TG (r = .639, P ! .01). Overall, TpP was correlated with placental weight and birthweight in the three groups but this did not not reach statistical significance.

Inherited Thrombophilia in Pregnancy

Learning Objectives: After reading this issue, the participant should be able to: 1. Identify the most common thrombophilias and describe their relationship to adverse pregnancy outcomes, including venous thromboembolism, intrauterine growth retardation, placental abruption, preeclampsia, stillbirth, and miscarriage. 2. Describe the treatment of thrombophilia in pregnancy. 3. Explain the indications for testing for thrombophilia.

Thrombophilia and pregnancy

Pregnancy is hypercoagulable state. The field of thrombophilia; the tendency to thrombosis, has been developed rapidly and has been linked to many aspects of pregnancy. It is recently that severe pregnancy complications such as severe preeclampsia intrauterine growth retardation abruptio placentae and stillbirth has been shown to be associated with thrombophilia. Recurrent miscarriage and has also been associated with thrombophilia. Finally, thromboembolism in pregnancy as in the non-pregnant state is linked to thrombophilia. In this review all aspects of thrombophilia in pregnancy are discussed, and also all prophylactic and therapeutic implications.

Acquired thrombophilia in pregnancy: essential thrombocythemia.

The management of pregnant patients with essential thrombocythemia (ET) is a difficult problem. The clinical course of ET is mainly determined by thromboembolic complications. Pregnancy itself is a physiological hypercoagulable state. When ET affects women during pregnancy, an adverse outcome caused by thrombotic complications is a matter of concern. We reviewed 155 pregnancies in 86 women with ET. The success rate (baby alive) was 59%. First-trimester abortion was the most frequent complication and occurred in 31% of pregnancies. Placental infarction caused by thrombosis seemed to be the most consistent pathologic event. Maternal thrombotic or hemorrhagic complications were rare but were more common than those seen in normal pregnancy. Pregnancy itself does not appear to affect adversely the natural course and prognosis of ET. A meta-analysis revealed a significant benefit for aspirin in comparison to no treatment. If cytoreductive therapy becomes necessary, interferon alpha appears to be the drug of choice. The value of heparin prophylaxis has not been established but may have a role in selected cases.

The Management of Thrombophilia During Pregnancy: A Canadian Survey

Objective: To determine current Canadian practice patterns in the management of pregnant women with thrombophilia.Methods: Physician members of the Society of Obstetricians and Gynaecologists of Canada (SOGC) who provide obstetrical care were invited to complete a closed-ended questionnaire in which they were presented 5 clinical scenarios involving thrombophilic pregnancies and asked to give their management recommendations. The 5 scenarios presented in the survey were of a pregnant woman with (1) asymptomatic factor V Leiden (FVL), (2) asymptomatic FVL and a family history of venous thromboembolism (VTE), (3) FVL and recurrent fetal loss, (4) FVL and a previous VTE, or (5) antiphospholipid antibody syndrome and recurrent fetal loss.Results: Of the 1448 eligible SOGC members invited, 18 had moved with no forwarding address, and 662 (46.3% of the remainder) responded. The majority (65%) of the respondents were obstetricians and 51 % of them had a university-affiliated practice. In scenario 1, 26% of physicians indicated they would recommend some form of antepartum thromboprophylaxis, whereas in the remaining four scenarios, 58% to 84% would definitely recommend antepartum thromboprophylaxis.Conclusion: Most clinicians favour intervening with thromboprophylaxis in pregnant thrombophilic women rather than observing without prophylaxis. This tendency spans a wide range of clinical scenarios, despite a lack of evidence to support such decisions. This survey highlights the need to provide clinicians and women with evidence for the safety and effectiveness of prophylaxis, before these interventions become the default recommendation by clinicians caring for this prevalent group of women.

Inherited thrombophilia and stillbirth

Thrombophilias are inherited or acquired conditions that predispose individuals to thromboembolism. New inherited thrombophilias are recognized each year. Some, but not all, studies have found an association between inherited thrombophilias and adverse pregnancy outcomes, including fetal loss. The controversy regarding the clinical implications of thrombophilias in pregnancy is clouded by differences in study populations, the number of thrombophilias tested, interactions between thrombophilias, and the retrospective nature of most studies, just to name a few factors. The lack of adequately designed studies also extends to clinical management. Clear evidence to determine when to test, whom to test, which thrombophilias to test for, when to treat, and what to treat with is not available. Further studies to investigate these questions are urgently needed.

Congenital thrombophilia associated to obstetric complications.

During pregnancy there are hemostatic changes that result in a hypercoagulable state and can have thrombotic consequences. This condition can be aggravated in women who are carriers of congenital thrombophilic factors. This thrombotic tendency can manifest as thrombotic lesions in the placenta with compromise of utero-placental circulation, which are common characteristics present in obstetric complications, such as preeclampsia/eclampsia, miscarriage, fetal loss, intrauterine growth retardation, and abruptio placentae. In this paper we review data concerning about the association of congenital thrombophilia in pregnancy with obstetric complications, mainly preeclampsia and fetal loss, focusing in factor V Leiden and its related activated protein C resistance, prothrombin mutation G20210A and hyperhomocysteinemia related with C677T mutation of methylenetetrahydrofolate reductase. Although factor V Leiden has been the thrombophilic factor most studied, all three thrombophilic mutations have been related with obstetric complications; however, contradictory results about the specific association of each mutation with each type of obstetric complication are described. These discrepancies could obey to the ethnic difference of the studied groups, or to the fact that some studies were performed in closed populations with few migratory movement, where the genetic pool is relatively homogeneous, as well as the different inclusion and exclusion criteria. Even though this variability is present, the significance of recognizing true associations between these thrombophilic mutations and obstetric complications is essential in order to determine the likelihood of routinely screening for these conditions in pregnant women with risk factors for thrombosis and for carrying out specific prophylactic measures.

Die Anwendung von niedermolekularen Heparinen in der Schwangerschaft

Anticoagulant therapy for thromboprophylaxis in pregnancy usually consists of non-fractionated heparin (UFH) in a dose of 10,000 IU twice daily or of low molecular weight heparin (LMWH). The potential advantages of LMWH are based on the plasma half-life and on their 90 - 95% bioavailability after s.c. administration. The complication rate of a pooled evaluation of patients treated during pregnancy with LMWH was 3.4% for vaginal bleeding, 1.7% for deep vein thrombosis, 3% for spontaneous abortion, 0.1% for osteoporotic fracture and 0.05% for HIT II. Management of patients with hereditary hypercoagulable state in pregnancy is controversial because of the scarcity of data to guide decision making and because of inconsistencies among the available data. The working group of GTH thrombophilia in pregnancy recommended guidelines for the management of women who receive antithrombotic therapy for prophylaxis of venous thrombosis and pregnancy complications. Low-risk patients receiving post partum antithrombotic therapy, women with moderate risk LMWH from the first diagnosis of the pregnancy and patients with higher risk received therapeutic doses of LMWH. Patients with antiphospholipid antibody syndrome (APS) are associated with a high rate of adverse pregnancy complications and should be referred to a unit that specializes in the management of acquired thrombophilia in pregnancy.

Management of thrombophilia in pregnancy

Thromboembolism remains a major cause of maternal morbidity and mortality. The incidence of thrombosis associated with pregnancy is stated to be around 0.99% 1 but is greater in women with familial or acquired thrombophilia. Around 50% of pregnancies in women with antithrombin III deficiency are complicated by thrombosis. Anticoagulation throughout pregnancy and the puerperium is recommended in women with antithrombin III deficiency. Because thrombosis is less common in women with protein C or protein S deficiency less aggressive management may be appropriate during pregnancy but anticoagulation post partum is generally recommended. The most important acquired thrombophilic abnormality is the development of antiphospholipid antibodies (‘lupus anticoagulants’). Women with these antibodies may present major problems but no clear guidelines for their management currently exist. The majority of women with a history of thrombosis have no identifiable haemostatic abnormality. Management of pregnancy in these patients depends on individual circumstances.