Women's Issues in Thrombophilia

Women are affected by unique aspects of thrombosis during their reproductive life. Oral contraceptive use is associated with increased thrombotic risk, particularly in women with thrombophilia, and is dependent on pill composition. Pregnancy imposes changes in hemostasis manifested by an increase in the thrombotic risk. Because thrombosis is the leading cause of mortality at gestation, prediction, prevention, and treatment of venous thromboembolism and arterial thrombosis in pregnancy are of paramount importance.

The risk of thromboembolism in pregnancy is further elevated in women with inherited thrombophilia and in acquired thrombophilic states, such as antiphospholipid syndrome and thrombocythemia.

Recently, recurrent pregnancy loss and late gestational vascular complications have been reported in women with thrombophilia. Epidemiological studies of these associations and the role of antithrombotic therapy in pregnancy are currently under evaluation.

Adequate uteroplacental circulation is vital for fetal growth and development. Abnormalities of placental perfusion and local hemostatic alterations at the placental level can be detected in women with gestational vascular complications. Neonatal thrombosis is an uncommon but potentially devastating presentation that is frequently associated with thrombophilia.

This issue focuses on progress made in recent years in increasing our understanding of some of these aspects. In the first article, Hellgren describes the alterations in the hemostasis system during pregnancy. The balance of the hemostatic system during pregnancy is shifted toward hypercoagulability, likely in preparation for expedient arrest of bleeding when the placenta separates from the wall of the uterus. This change is reflected in the global clotting assays and in elevation of most procoagulant factors. Most of the anticoagulant factors remain normal. At the same time fibrinolysis is impaired. Increased thrombin generation is demonstrable by elevated levels of molecular markers of in vivo thrombin generation. At the time of delivery, platelets and clotting factors are consumed, reflecting the intense activation of the hemostatic system. Most of these changes return to normal within 4 to 6 weeks after delivery. If testing of the hemostasis system is needed, it should be performed 3 months after delivery to avoid potential interpretation errors.

The second contribution, by Conard and coworkers, addresses the issue of inherited thrombophilia and venous thromboembolism during pregnancy. It is well recognized that inherited defects in certain inhibitors of the clotting system or gene mutations in factor V or prothrombin are high risk factors for venous thromboembolism, but the extent to which they contribute to thromboembolism during pregnancy is not fully understood. There is some evidence, however, that pregnant women with thrombophilia, especially with defects in antithrombin, protein C, and protein S are at higher risk postpartum, in particular when acquired risk factors are also present. If prophylaxis is contemplated, the type of thrombophilia should be considered. In contrast, women who develop venous thromboembolism during pregnancy often have an underlying thrombophilic state. Screening these patients should be delayed at least until 3 months postpartum. Detailed recommendations for prophylaxis and treatment of these patients are described.

The next article, by Zotz and coworkers, addresses the issue of prediction, prevention, and treatment of venous thromboembolism during pregnancy. Again, inherited or acquired risk factors are reviewed and certain probabilities are calculated from the data presently available. These values assist in determining which women should receive prophylaxis and by what modality. Patients with a history of thrombotic events and the presence of one or more risk factors should be treated. Unfractionated heparin for prophylaxis has been largely replaced by low-molecular-weight heparins (LMWH) because of their better safety profile. Even treatment of venous thromboembolism is widely conducted with LMWH, although major studies are still lacking in the area of pregnancy and thrombosis. The various treatment options are comprehensively reviewed.

Clark and Greer next review the problems of arterial thrombosis in pregnancy. Apart from the already discussed thrombophilic states that may also lead to arterial thrombotic events, three groups of patients are highly susceptible during pregnancy: patients with prosthetic heart valves, sickle cell disorders, and thrombocythemia. Women with artificial heart valves (especially mechanical valves) are, like nonpregnant patients, usually taking oral anticoagulants. Because this therapy is associated with a high incidence of embryopathies, patients need to be switched to another anticoagulant, either unfractionated or LMWHs. This issue is extensively discussed and firm recommendations are made. Women with sickle cell diseases and with essential thrombocythemia are also at substantial risk of developing an arterial thrombotic event during pregnancy, and recommendations for proper management are given. Finally, the proper treatment of strokes and acute myocardial infarctions during pregnancy is discussed.

Brenner examines the relationship between thrombophilia and fetal loss. Although this issue is still controversial in the literature, the author makes a compelling case for such a relationship. Data presented seem to suggest that the risk of recurrent fetal loss is rather high in women with defects in the inhibitors of the clotting system, the factor V Leiden mutation (especially homozygous patients), prothrombin gene mutation G20210A, and hyperhomocysteinemia. Combined defects create additional risk factors. Histological examinations on the placentas of these patients indicate thrombotic changes and infarcts, suggesting that anticoagulant therapy might be useful in reducing these incidences. Several studies appear to indicate that LMWHs are the treatment of choice for these patients.

Inbal and Muszbek describe the relationship between pregnancy loss and clotting factor deficiencies. At this time only two factors are involved, factor XIII and fibrinogen. Factor XIII appears to play an important role in the implantation process and a lack of it may lead to periplacental hemorrhage and subsequent loss of the fetus. Factor XIII-A has been identified in several cell types of the placental bed. Replacement of factor XIII with concentrates or with cryoprecipitate prevents miscarriages and allows for successful completion of pregnancy. Of the disturbances associated with fibrinogen, afibrinogenemia and hypofibrinogenemia are linked to fetal losses. Dysfibrinogenemia, in contrast, is not associated with this problem. Limited experience suggests that with replacement of fibrinogen, these patients can successfully complete pregnancy.

The next article by Lanir and coworkers examines the presence and importance of components of the hemostasis system in the placenta. The placenta serves as the interface between the fetal and maternal circulatory systems and requires effective mechanisms for the activation of the clotting system and localization of this process to avoid undue fibrin depositions, which under certain pathological conditions are frequently observed. The placental vasculature, especially syncytiotrophoblasts and endothelial cells, express important activators and regulators of both the clotting and the fibrinolytic systems. This produces the potential for a rapid activation of the systems and localization of the process. Although all of these components have been identified in the placenta, little is known about their exact interplay and how dysregulation may lead to complications of pregnancy.

The interrelationship between hereditary thrombophilic states and complications of pregnancy, especially preeclampsia, abruptio placentae, intrauterine growth retardation, and others, is reviewed by Kupferminc and Eldor. Considerable evidence suggests that hereditary thrombophilia is associated with gestational vascular complications. Structural and thrombotic changes in the placentas of these patients support the evidence. In particular, defects such as factor V Leiden, the prothrombin gene mutation G20210A, and homozygous methylenetetrahydrofolate reductase (MTHFR) deficiencies appear to be associated with obstetric complications. However, other defects such as antithrombin deficiency and disturbances in the protein C pathway can also lead to these complications. All of these defects are comprehensively reviewed. In addition, the authors discuss the current treatment options. Aspirin, once widely used to reduce obstetric complications, was found to be of little value. Instead, much experience has been gathered with unfractionated heparins and LMWHs. LMWHs seem to be the safest and most effective modality to combat these problems, at least at this time.

The role of the antiphospholipid (aPL) syndrome in obstetric complications is reviewed by Galli and Barbui. The syndrome consists of the lupus anticoagulant and anticardiolipin antibodies and has long been associated with various obstetric problems. The incidence of this association is high (15 to 20%) but the mechanism(s) underlying these problems is not yet fully understood. A fairly common denominator is thrombosis of placental vessels, leading to abortions or fetal death. In addition, impairment of embryonic implantation has been associated with the aPL syndrome. The authors extensively review the present knowledge of this association and describe the status of management of these patients. The current standard treatment of pregnant, aPL-syndrome-positive patients is heparins (unfractionated or LMW) with or without low-dose aspirin. This treatment results in a significant increase in live birth rates.

In the next article, Griesshammer and coworkers review pregnancy outcomes in patients with essential thrombocythemia (ET). Because the clinical course of ET is often associated with thromboembolic events, especially arterial, pregnancy (with its own high thromboembolic risk) presents a challenge to obstetricians and hematologists. The risk of thromboembolic complications is not that high for the mother, but is rather prominent for the infants. Placental infarctions may lead to recurrent abortions, stillbirth, abruptio placentae, and a variety of other obstetric problems. The authors comprehensively review the literature on this subject and examine the best treatment modalities for this condition. From the data available, it appears that aspirin is the best management option for this particular situation. In high-risk patients, heparin may be added. There is little information available as yet on other antiplatelet medications. Cytoreductive therapy should be pursued only reluctantly; if needed, interferon-α appears to be the best option. Plateletpheresis is another option; it is safe but expensive.

Weiner and coworkers describe the status of the uterine placental circulation in women with thrombophilic conditions. The association between obstetric complications and thrombophilia is well recognized, but the underlying pathologies are less well understood. This is in part because of the difficulties in accurately assessing the placental circulation. The two currently used methods are described. One method examines placentas after delivery, and signs of damage have been reported in women who suffered from thrombophilia. The second method uses Doppler investigations of the uterine and umbilical arteries. These procedures can be done prior to delivery, and abnormalities have been identified that were ultimately associated with obstetric complications. When more data are accumulated, these studies could identify patients who should receive thromboprophylaxis.

Mac Gillavry and Prins review the issue of oral contraceptive (OC) use by women with inherited thrombophilic conditions. It has long been speculated that women who develop a thromboembolic event while taking OC might have an underlying thrombophilic state. The authors extensively review all studies that addressed this issue and conclude that an inherited state of thrombophilia indeed increases the risk of venous thromboembolism in OC users. It is speculated that women with thrombophilia and a history of thrombosis might have an even greater risk than asymptomatic carriers. Other contraceptive methods should be considered for the high-risk group, whereas clinical judgment and extensive discussions of the risk with the patients should prevail in asymptomatic women. Universal screening of all women prior to OC use is economically not justifiable, but women with a history of thrombosis should be screened for thrombophilia.

In the last contribution, Nowak-Göttl and associates address the issue of neonatal thromboembolism. In contrast to adults, neonates encounter far fewer thromboembolic events. When they occur, they are usually associated with a variety of underlying diseases and problems, and indwelling catheters or central lines clearly offer the highest risks. Little is known at this time about inherited or acquired thrombophilic states in neonates and their impact on thromboembolism. Laboratory investigations must take into consideration that most coagulation components in plasma of young infants are not normal. Clinical symptoms in neonates with thromboembolism somewhat resemble those seen in adults and most diagnoses can be confirmed by appropriate imaging techniques. Treatment modalities for neonates are heparins and/or thrombolytic agents, but little is known about long-term anticoagulation.

This issue contains a wealth of new information on the controversial concepts of thrombophilia and pregnancy, obstetric complications, and oral contraceptives. We wish to thank all authors for their excellent contributions and hope that readers will find this issue useful.