Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium.

Venous thromboembolism (VTE) is a leading cause of maternal mortality. Few studies have evaluated the individual risk of gestational VTE associated with heritable thrombophilia, and current recommendations for antenatal thromboprophylaxis in women with severe thrombophilia such as homozygous factor V Leiden mutation (FVL) depend on a positive family history of VTE. To better stratify thromboprophylaxis in pregnancy, we aimed to estimate the individual probability (absolute risk) of gestational VTE associated with thrombophilia and to see whether these risk factors are independent of a family history of VTE in first-degree relatives. We studied 243 women with the first VTE during pregnancy and the puerperium and 243 age-matched normal women. Baseline incidence of VTE of 1:483 pregnancies in women ≥35 years and 1:741 deliveries in women <35 years was assumed, according to a recent population-based study. In women ≥35 years (<35 years), the individual probability of gestational VTE was as follows: 0.7% (0.5%) for heterozygous FVL; 3.4% (2.2%) for homozygous FVL; 0.6% (0.4%) for heterozygous prothrombin G20210A; 8.2% (5.5%) for compound heterozygotes for FVL and prothrombin G20210A; 9.0% (6.1%) for antithrombin deficiency; 1.1% (0.7%) for protein C deficiency; and 1.0% (0.7%) for protein S deficiency. These results were independent of a positive family history of VTE. We provide evidence that unselected women with these thrombophilias have an increased risk of gestational VTE independent of a positive family history of VTE. In contrast to current guidelines, these data suggest that women with high-risk thrombophilia should be considered for antenatal thromboprophylaxis regardless of family history of VTE.

Treatment of pregnancy-associated venous thromboembolism - position paper from the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH).

Venous thromboembolism (VTE) is a major cause of maternal morbidity during pregnancy and the postpartum period. However, because there is a lack of adequate study data, management strategies for pregnancy-associated VTE must be deduced from observational stu-dies and extrapolated from recommendations for non-pregnant patients. In this review, the members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH) have summarised the evidence that is currently available in the literature to provide a practical approach for treating pregnancy-associated VTE. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low molecular weight heparin (LMWH) is the anticoagulant treatment of choice in cases of acute VTE during pregnancy. No differences between once and twice daily LMWH dosing regimens have been reported, but twice daily dosing seems to be advisable, at least peripartally. It remains unclear whether determining dose adjustments according to factor Xa activities during pregnancy provides any benefit. Management of delivery deserves attention and mainly depends on the time interval between the diagnosis of VTE and the expected delivery date. In particular, if VTE manifests at term, delivery should be attended by an experienced multidisciplinary team. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months. Although recommendations are provided for the treatment of pregnancy-associated VTE, there is an urgent need for well-designed prospective studies that compare different management strategies and define the optimal duration and intensity of anticoagulant treatment.

Diagnosis of pregnancy-associated venous thromboembolism - position paper of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH).

Pregnancy and the postpartum period are associated with an increased risk of venous thromboembolism (VTE). Over the past decade, new diagnostic algorithms have been established, combining clinical probability, laboratory testing and imaging studies for the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the non-pregnant population. However, there is no such generally accepted algorithm for the diagnosis of pregnancy-associated VTE. Studies establishing clinical prediction rules have excluded pregnant women, and prediction scores currently in use have not been prospectively validated in pregnancy or during the postpartum period. D-dimers physiologically increase throughout pregnancy and peak at delivery, so a negative D-dimer test result, based on the reference values of non-pregnant subjects, becomes unlikely in the second and third trimesters. Imaging studies therefore play a major role in confirming suspected DVT or PE in pregnant women. Major concerns have been raised against radiologic imaging because of foetal radiation exposure, and doubts about the diagnostic value of ultrasound techniques in attempting to exclude isolated iliac vein thrombosis grow stronger as pregnancy progresses. As members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH), we summarise evidence from the available literature and aim to establish a more uniform strategy for diagnosing pregnancy-associated VTE.

Elevated lipoprotein(a) levels and homozygous human platelet antigen 1b (HPA-1b) genotype are risk factors for intrauterine growth restriction (IUGR).

The risk of premature manifestation of cardiovascular disease is higher in women after a maternal placental syndrome, especially with a history of fetal IUGR. Aim of the study was to assess hereditary risk factors for arterial thrombosis as risk factors for IUGR. 183 women with fetal IUGR birth weight below the 10th percentile for gestational age and 300 control women were evaluated using a case-control design. In 121 of the 183 women, the newborns' birth weight was below the 5th percentile for gestational age. A risk association could be shown for homozygous human platelet antigen 1b genotype (OR 3.2, P = 0.038) in women with a history for a newborn's birth weight below the 5th percentile. Elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 2.9, P = 0.048) also represent a risk association in the same group of subjects. So did elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 3.4, P = 0.015) in women with a history for a newborn's birth weight below the 10th percentile. Risk factors of arterial thrombosis such as platelet receptor genotypes associated with platelet thrombogenicity and elevated levels of lipoprotein(a) might be of importance in the pathogenesis of IUGR.

Successful use of danaparoid in two pregnant women with heart valve prosthesis and heparin-induced thrombocytopenia Type II (HIT).

Anticoagulant therapy with heparin for the prevention of thromboembolism in pregnant women with prosthetic heart valves is associated with an increased risk to the mother and/or the fetus. A life-threatening complication of the therapy with heparin is heparin-induced thrombocytopenia type II (HIT). danaparoid has not yet been reported to be safe and effective for this indication. This study reports on a 26-year-old woman with tricuspidal valve prosthesis and a 37-year-old woman with a St. Jude Medical mitral valve prosthesis who were anticoagulated with danaparoid during pregnancy because of HIT. Anti-Xa levels were between 0.6 and 1.2 IU/mL during pregnancy with target levels of 1.0 IU/mL. Cesarean section was performed at anti-Xa levels of 0.3 and 0.7 IU/mL. One woman developed a placental hematoma at the 32nd week of gestation, which did not increase over the following week. Both patients delivered healthy boys. Heparin-induced thrombocytopenia in pregnant women with prosthetic heart valve can be successfully managed with danaparoid.

Recombinant factor VIIa for the prophylaxis of perioperative hemorrhage in a patient with congenital factor XI deficiency undergoing brain tumor neurosurgery.

The authors report on the first successful use of recombinant activated factor VII for the prophylaxis of bleeding during brain tumor neurosurgery in a patient suffering from inherited factor XI deficiency. Using the agent, surgery was performed without any bleeding complications. In this setting, off-label use of recombinant activated factor VII appears to be a promising alternative for patients suffering from this rare hemostatic defect with hitherto limited therapeutic options.

Venous thromboembolism during pregnancy is not associated with persistent elevated activated protein C (APC) sensitivity ratio based on the endogenous thrombin potential.

Women who are using oral contraceptives can acquire APC resistance, measured by the effect of APC on the endogenous thrombin potential (ETP). The objective of our study was to examine whether persistentAPC resistance determined with an ETP-based normalized APC sensitivity ratio (nAPCsr) is a risk marker for venous thromboembolism in women with pregnancy-associated thromboembolism. We determined the activities of antithrombin, protein C, protein S, and performed a genetic analysis of factor V Leiden G1691A, prothrombin mutation G20210A, and methylenetetrahydrofolate reductase mutation (MTHFR C677T) in 65 women with venous thromboembolism during pregnancy or the puerperium and in 114 normal women. A significantly (p<0.05) higher nAPCsr was present in normal women using hormones, in younger women (

The polymorphism of platelet membrane integrin alpha2beta1 (alpha2807TT) is associated with premature onset of fetal loss.

Inherited thrombophilia could increase susceptibility to adverse pregnancy outcomes such as fetal loss. We determined the G1691A mutation of the factorV gene (FVL), the G20210A mutation of the prothrombin gene, the C677T polymorphism of the methylenetetrahydrofolate-reductase (MTHFR) gene, the HPA-1 polymorphism of the beta3 subunit of the platelet integrin alphaIIbbeta3 and the C807T polymorphism of the alpha2 subunit of integrin alpha2beta1 in 104 women with fetal loss and 277 normal women. In a subgroup analysis of women with recurrent early fetal loss (n=34), the prevalence of the genetic markers did not differ significantly between the women with early fetal loss and the normal women. However, in this subgroup of patients the onset of fetal loss was significantly earlier in women with the alpha2807TT genotype (7.1 +/- 1.9 vs. 8.8 +/- 1.5 weeks, p=0.001). No such significant difference was observed in carriers of the other genetic markers. In the subgroup analysis of women with late fetal loss (n=70), only the prevalence of heterozygous FVL was significantly associated with late fetal loss (odds ratio 3.2, p=0.002). There was no significant association of any genetic risk factor with premature fetal loss in the subgroup analysis of women with at least one late miscarriage. This study demonstrates a significant association of the alpha2807TT genotype of the platelet membrane integrin alpha2beta1 with premature onset of early fetal loss. It appears that this risk factor does not induce the pathomechanism, but modulates the course of fetal loss. Furthermore, our study confirms the association of FVL with late fetal loss.

Inherited thrombophilia and gestational venous thromboembolism.

Thromboembolic disease is a leading cause of maternal morbidity and mortality during pregnancy and the puerperium. To reduce the incidence of venous thromboembolism in pregnancy and improve outcomes, an individual risk stratification based on probability of thrombosis as a rationale for an individual risk-adapted prophylaxis is required. Within the past 10 years, a significant improvement in risk estimation has been achieved due to the identification of new genetic risk factors of thrombosis. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low--indicating that pregnancy-associated thrombosis is multicausal, resulting from the interaction of combined defects. A combination of the two genetic risk factors can increase the risk to a modest level (risk 1 in 25). In women with a single episode of prior thrombosis associated with a transient risk factor, for example, surgery or trauma, and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis appears also to be low. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (>10%) can be expected, supporting the indication for active antepartum and postpartum heparin prophylaxis. Despite the remarkable progress in risk stratification, the absolute magnitude of risk in many cases is unknown and current recommendations remain empirical.

Effect of hemostatic risk factors on the individual probability of thrombosis during pregnancy and the puerperium.

In a retrospective study of 190 women with a first history of venous thromboembolism during pregnancy and the puerperium and 190 age-matched women with at least one prior pregnancy and no history of venous thromboembolism, the individual probability of thrombosis was determined. Assuming an overall risk of 1 in 1500 pregnancies, the probability of pregnancy-related thrombosis in carriers of homozygous factor V Leiden was 1 in 80 (odds ratio 20.6, p=0.005) and among carriers of combined heterozygous factor V Leiden and heterozygous G20210A mutation in the prothrombin gene 1 in 20 (odds ratio 88, p<0.001). The probability of thrombosis per pregnancy among women with elevated levels of factor VIII:C (>172 % activity) was 1 in 385 (odds ratio 4.5, p<0.001) and among those with increased levels of von Willebrand factor antigen (>190 %) 1 in 435 (odds ratio 4.0, p=0.002), independent of elevated factor VIII:C levels. The high prevalence of combined and homozygous defects of hemostatic components (21.6%) in patients as compared with normal women (0.86%) supports the concept that venous thromboembolism is a multicausal disorder.

Inherited thrombophilia and gestational venous thromboembolism.

Thromboembolic disease remains a leading cause of maternal mortality during pregnancy and the puerperium. Rational and risk-adapted administration of heparin prophylaxis depends on the identification of those women who have an increased risk of thrombosis and the accurate quantification of this risk. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations, the risk of venous thromboembolism is low. Therefore, no heparin prophylaxis is recommended. A combination of the two genetic risk factors can increase the risk to a modest level of 1 in 25. In all women with prior thrombosis, the authors recommend heparin prophylaxis throughout pregnancy and postpartum for 6 weeks (inconsistent data). However, according to the American College of Chest Physicians recommendations, in the subgroup of women with an episode of prior thrombosis associated with a transient risk factor, such as surgery or trauma, and no additional genetic risk factor, clinical surveillance throughout pregnancy and heparin prophylaxis postpartum is possible. Despite the remarkable progress in risk stratification, the absolute magnitude of risk and the optimum management is, in many cases, an issue of ongoing debate.

Maternal IVS1-401 T allele of the estrogen receptor alpha is an independent predictor of late fetal loss.

OBJECTIVE: To investigate whether sequence variants in the gene encoding for estrogen receptor alpha (ER-alpha) are risk determinants for fetal loss. DESIGN: Case-control study. SETTING: University medical center. PATIENT(S): One hundred four women with a history of fetal loss and 277 healthy women with at least one previous pregnancy and no previous fetal loss. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The IVS1-401C/T polymorphism of the human ER-alpha, the G1691A mutation of the factor V gene (factor V Leiden), the G20210A mutation of the prothrombin gene, and the C677T polymorphism of the methylenetetrahydrofolate-reductase (MTHFR) gene were determined by polymerase chain reaction. RESULT(S): In the subgroup analysis of women with at least one late miscarriage (n = 70), the prevalences of the ER-alpha IVS1-401 T allele (T/T vs. C/C, odds ratio [OR]: 2.85, P=.018; T/T + C/T vs. C/C, OR: 2.28, P=.043) and of heterozygous factor V Leiden (OR, 3.2; P=.002) were significantly higher among women with late fetal loss than among healthy women. Carriers of both risk determinants have an at-least additive increase in risk for late abortions (OR, 7.0; P=.0004). The population of all late abortions that would be attributable to the genetic variants (population attributable risk) was 13.9% for factor V Leiden and 49.2% for the ER-alpha IVS1-401 T allele. CONCLUSION(S): Women with the IVS1-401 T allele of the ER-alpha and/or factor V Leiden are at increased risk for late fetal loss.

Prediction, prevention, and treatment of venous thromboembolic disease in pregnancy.

Pregnancy is recognized as an independent risk factor for venous thromboembolism leading to thromboembolic events, particularly in women with prior venous thrombosis, family history of thrombosis, or additional thrombophilic risk factors. To reduce the incidence of venous thromboembolism in pregnancy and improve outcomes, an individual risk stratification on the basis of probability of thrombosis as a rationale for an individual risk-adapted prophylaxis is required. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low. For this reason, routine thrombophilia screening of all pregnant women is not recommended. However, a combination of the two genetic risk factors can increase the risk to a modest level (risk 1 in 25). In women with a single episode of prior thrombosis associated with a transient risk factor (such as surgery or trauma) and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis also appears to be low. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (> 10%) can be expected, supporting the indication for active antepartum and postpartum heparin prophylaxis. In many cases, the absolute magnitude of risk is unknown or estimated, and recommendations are often empiric.

Clinical risk factors for deep venous thrombosis in pregnancy and the puerperium.

Thromboembolic events are among the leading causes of maternal mortality. Mutations in the genes for clotting factors are known, but anamnestic factors can be found in a proportion of women with deep venous thromboses (DVT) during pregnancy and the puerperium. We here describe the clinical factors and pregnancy outcomes of such a group of 70 women who were all operated on for DVT. Highest risk is conferred by a familial history of clotting disease and by known mutations of the clotting factors. This might be used to target a high risk group for preventive treatment.

Deep venous thrombosis during pregnancy and after delivery: indications for and results of thrombectomy.

PURPOSE: Pregnancy and the puerperium are time periods of an increased risk for venous thromboembolism. An ideal treatment should lead to complete restoration of the venous lumen, elimination of the embolic source, and prevention of severe postphlebitic syndrome. Anticoagulation therapy with heparin or thrombectomy are treatment options. In the current literature, these options are discussed controversially. METHODS: From January 1982 to December 2001, 97 women underwent (93% transfemoral) thrombectomy and construction of an arteriovenous fistula (AVF) for deep venous thrombosis related to pregnancy. The clinical and coagulation parameters were evaluated. The AVF was ligated 3 to 6 months later. Follow-up with duplex ultrasound scan, photoplethysmography, and strain-gauge plethysmography was completed in 87 women. RESULTS: Surgery was performed without any maternal death or pulmonary embolization. A cesarean section was carried out during the same anesthesia in 11 cases. Thrombectomy was completed with construction of a temporary AVF in 90 patients (92.8%). One fetal death occurred in the recovery room for unknown reasons. In the early postoperative course, 16 patients (16.5%) underwent redo surgery for rethrombosis with or without the occlusion of the fistula. In 14 of these patients, the venous system remained patent thereafter. Fetal or neonatal death occurred in five cases 2 to 10 weeks after surgery, mainly because of abruption of the placenta probably from anticoagulation. Among 247 preoperatively occluded anatomic regions, 221 could be restored, and the secondary patency rate amounted to 89.5%. After a mean follow-up period of 6 years, 49 patients (56.3%) were seen without a postphlebitic syndrome, and only three patients (3.5%) had had a leg ulcer develop. CONCLUSION: In experienced hands, venous thrombectomy is a safe method to prevent pulmonary embolism and postphlebitic syndrome in women during pregnancy and the puerperium. The frequency of a severe postphlebitic syndrome after our surgical approach is lower than the rates published for anticoagulation treatment alone.