Prophylaxis and treatment of thrombophilia in pregnancy

PURPOSE OF REVIEW: This review addresses the prophylaxis and treatment of thrombophilia in pregnancy, which is associated with increased risk of venous thromboembolism and placental vascular complications. RECENT FINDINGS: 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. SUMMARY: 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.     

Inherited thrombophilia in arterial disease: a selective review

Thrombophilia may be defined as an acquired or congenital abnormality of hemostasis predisposing to thrombosis. Because arterial thrombosis is usually linked with classical risk factors such as smoking, hypertension, dyslipidemia, or diabetes, a thrombophilia workup is usually not considered in case of arterial thrombosis. The most accepted inherited hemostatic abnormalities associated with venous thromboembolism are factor V Leiden (FVL) and factor II (FII) G20210A mutations, as well as deficiencies in antithrombin (AT), protein C (PC), and protein S (PS). This review focuses on the link between these abnormalities and arterial thrombosis. Overall, the association between these genetic disorders and the three main arterial complications (myocardial infarction [MI], ischemic stroke [IS], and peripheral arterial disease [PAD]) is modest. Routine screening for these disorders is therefore not warranted in most cases of arterial complications. However, when such an arterial event occurs in a young person, inherited abnormalities of hemostasis seem to play a role, particularly when associated with smoking or oral contraceptive use. These abnormalities also seem to play a role in the risk of premature occlusion after revascularization procedures. Therefore thrombophilia tests may be informative in a very restricted population with arterial events. Anticoagulants rather than antiplatelet therapy may be preferable for these patients, although this remains to be proven.     

Prophylaxis and treatment of venous thromboembolism in individuals with inherited thrombophilia

Venous thromboembolism (VTE) susceptibility genes are widely diffuse in the general population, but clinical penetrance of genotypes is incomplete and has variable expressivity. Therefore, the indiscriminate search for carriers is of doubtful utility and potentially detrimental for screened individuals. A targeted screening in kindreds in which VTE already occurred can be more fruitful in identifying individuals sharing with the proband one or more known susceptibility genes (possibly cosegregating with other ones still unknown). Clinical penetrance is variable, and is higher in the relatively rare deficiencies of antithrombin (AT), protein C (PC), or protein S (PS), and lower in the presence of the common polymorphisms factor V Leiden and prothrombin G20210A. Women with inherited thrombophilia should be warned about the thrombotic risk associated with the use of oral contraceptives or hormonal replacement treatment. Moreover, prophylaxis during puerperium and surgery or after trauma is warranted. The absolute risk associated with such situations is low but not negligible in the presence of deficiencies of AT, PC, or PS, homozygous conditions, and carriership of multiple defects. In such cases primary prophylaxis should be applied also during pregnancy and in general should be more stringent; moreover, in these patients the option for indefinite duration of secondary anticoagulant prophylaxis after VTE should be considered because of the relevant risk of recurrent VTE. In all cases, a careful balance of benefits and risks associated with prophylactic measures should be achieved, and patient preferences should be considered.     

Hereditary and acquired thrombophilia

During the past decade knowledge about the etiology of venous thromboembolism has increased tremendously. Inherited and acquired risk factors for venous thromboembolism are common in patients as well as in the general population. Whether the presence of most of these risk factors has consequences for the management of symptomatic and asymptomatic individuals is not fully clear at present. Therefore, while searching for new thrombophilic defects, it is crucial to determine the absolute risk for (recurrent) venous thromboembolism as well as other clinical manifestations in carriers. However, tentative guidelines for managing patients and their families are given in this review.     

Inherited thrombophilia

There is limited evidence that certain heritable thrombophilias may be associated with an increased risk of peripheral vascular disease. In particular, increased activated protein C resistance and FV Leiden have been described as being more prevalent in patients with peripheral arterial disease. There is no clear evidence at present, however, that other heritable thrombophilias are associated with an increased risk of arterial occlusive disease. Heritable thrombophilia, in particular FV Leiden, may be associated with an increased risk of vascular reconstruction failure but there is a lack of evidence to show that intervention with anticoagulants influences the outcome of graft surgery in these patients.     

Definition of thrombophilia

Thrombophilia is characterized by clinical tendency to thrombosis or molecular abnomalities of hemostasis that predisposes to thromboembolic disease. Hereditary thrombophilia may be due to antithrombin deficiency, or protein C or protein S deficiency. More recently, other molecular abnormalities have been described: activated protein C resistance due to factor V Leiden, G 20210 A polymorphism on the prothrombin gene, increased factor VIII plasma levels or hyperhomocysteinemia. Acquired thrombophilia is frequently associated with the antiphospholipid syndrome characterized by thrombosis and presence of lupus anticoagulant or phospholipid-binding antibodies. In some cases, no molecular abnormality is found despite recurrent thrombosis observed in patient and his/her family. This situation can be considered as clinical thrombophilia.     

Inherited thrombophilia and pregnancy loss

A growing body of evidence obtained during the past 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control and cross-sectional studies have demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss.Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins (LMWH) are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.     

Acute coronary and peripheral arterial thrombosis following percutaneous coronary intervention in a patient with previously undiagnosed inherited thrombophilia

Following pretreatment with ticlopidine 250 mg bid for three days, a 40-year-old man underwent successful angioplasty and stenting of the proximal left anterior descending coronary artery and balloon dilation of the midcircumflex coronary artery without stenting. He subsequently developed acute coronary thromboses at both arterial sites and cardiogenic shock. The patient survived after an additional percutaneous coronary intervention (PCI) and intra-aortic balloon pump assistance. This was followed by peripheral arterial thrombosis requiring repeated therapeutic interventions. Laboratory tests for thrombophilia revealed the presence of a G20210A prothrombin gene mutation. Two years later the patient remained free of angina and claudication, and underwent an unremarkable maximum exercise treadmill test. This is the first reported case of acute, multiple coronary and peripheral arterial thrombosis following PCI in a patient with previously unsuspected inherited thrombophilia. Inherited thrombophilia should be considered as a possible cause of arterial thrombosis following PCI.     

Pregnancy failure and heritable thrombophilia

Heritable thrombophilia is associated with an increased risk for pregnancy failure, defined as sporadic and recurrent miscarriage, late fetal loss, and other vascular pregnancy complications such as preeclampsia and intrauterine growth retardation. The pathogenesis is likely to include effects on trophoblast differentiation and not solely hypercoagulability. This is in line with the observation that most recurrent miscarriages occur early. Therapeutic options include aspirin as well as low-molecular-weight heparin. However, in women with heritable thrombophilia and unexplained recurrent pregnancy loss, evidence is not available as published trials have not used an adequate comparator (no treatment or placebo). Currently, randomized controlled trials with no treatment or placebo are being carried out and results should be awaited before implementing a potentially harmful intervention in pregnant women with heritable thrombophilia and a history of pregnancy failure. Both infertility and pregnancy failure are extremely distressing for couples with the desire to have children. Pregnancy failure comprises (recurrent) early miscarriage, as well as late pregnancy loss. The role of heritable thrombophilia in pregnancy failure is reviewed, with a focus on recurrent miscarriage, in terms of epidemiology, etiology, and potential therapeutic implications.     

Inherited thrombophilia and venous thromboembolism

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.     

Inherited thrombophilia and fetal loss

Acquired thrombophilia is a well-established cause of pregnancy loss. Increasing numbers of recent observations suggest that inherited thrombophilia is not only associated with gestational thromboembolism but is also a major cause of fetal loss. This review focuses on association of fetal loss with inherited thrombophilias, including dysfibrinogenemia and protein C, protein S, and antithrombin III deficiencies. Activated protein C resistance and factor V Leiden mutation are frequent causes of pregnancy loss. Thrombophilic states such as factor V Leiden and hyperhomocysteinemia may also play a role in other gestational vascular complications, including intrauterine growth restriction, preeclampsia, and placental abruption. Preliminary reports suggest that antithrombotic therapy may be of value in this setting. The potential application of antithrombotic modalities to prevent fetal loss in women with thrombophilia is discussed.     

Heritable thrombophilia and childhood thrombosis

Thrombotic problems are rare during childhood but are increasingly recognized, particularly in tertiary care paediatric populations, and represent a different spectrum of disorders to those seen in adults. An understanding of the aetiological factors involved in the pathogenesis of these events is important both for prevention and management. A number of inherited prothrombotic defects have been shown to be independent risk factors for thromboembolism in adult studies, and may also contribute to thrombotic events in childhood. Homozygous deficiencies of naturally occurring inhibitors of coagulation are clearly associated with major prothrombotic disorders, often presenting in the perinatal period. The association of other inherited prothrombotic disorders with thrombosis in childhood is less well defined. The prevalence of heritable thrombophilia varies in different clinical settings and the risks associated with individual defects has only been addressed in a small number of studies to date. Additional acquired risk factors are also present in a high percentage of cases and again differ from those seen in adult thrombosis. Further studies are required to assess the risks associated with heritable thrombophilia during infancy and childhood, and to define the place of thrombophilia screening in paediatric practice.     

Maternal thrombophilia and neonatal thrombosis

In neonates and infants, numerous clinical and environmental conditions lead to elevated thrombin generation and subsequent thrombus formation. Genetic prothrombotic defects (protein C, protein S and antithrombin deficiency, mutations of coagulation factor V and factor II, elevated lipoprotein (a)) have been established as risk factors of thromboembolic events in neonates and infants. The interpretation of the laboratory evaluation relies on age-dependent normal reference values. Because appropriate clinical trials are missing in these age groups, treatment recommendations are adapted from small-scale studies in neonates and infants and from guidelines relating to adult patient protocols. Secondary long-term anticoagulation should be administered on an individual basis.