Inherited or acquired coagulation disorders, defined as thrombophilia, are associated with a higher risk of arterial and venous thrombotic events. Presence of inherited thrombophilia is responsible for more than 60% of idiopathic (spontaneous or unprovoked) thromboembolic events.1 Therefore, a genetic diagnosis of thrombophilia, after a thrombotic event, has a major importance, not only to define its etiology but also to determine the duration of anticoagulant treatment and risk stratification for prophylaxis treatment.2
Isolated inherited thrombophilia may never have a clinical expression, but in the presence of another prothrombotic transitory condition, such as pregnancy, it may significantly increase the possibility of thromboembolic disease. Pregnancy determines a procoagulant status starting from the first trimester and lasting up to 12 weeks postpartum, resulting in a 5- to 7-fold increased risk of pregnant women, compared with nonpregnant women, to develop a thrombotic event.3 Meanwhile, there are data suggesting that there is an association between thrombophilia and occurrence of obstetric complications, such as preeclampsia, fetal growth restriction (FGR), neonatal thrombosis, prematurity, and spontaneous loss of pregnancies.3 However, there are controversial data regarding the management of thrombophilia in the setting of pregnancy. Moreover, even the anticoagulation therapy has benefit for women as treatment for venous thromboembolism during pregnancy, the evidence supporting prophylactic anticoagulation is less clear.4
Inherited thrombophilia includes a wide spectrum of isolated, but mostly associated, genetic abnormalities that involve either a gain in function for procoagulant natural factors or a weaker function of anticoagulant factors. Another incriminated mechanism with a genetic component refers to the damage in the fibrinolytic system, such as plasminogen activator inhibitor polymorphism (4G/5G PAI-1).4 Genetic thrombotic defects are divided into 2 groups. The first group includes well-defined genetic risk factors, whereas the second group includes potential risks factors for thrombophilia. Well-defined risk factors are resistance to activated protein C (PC) [due to the presence of factor V Leiden (FVL)], prothrombin G20210A gene mutation, high levels of factor VIII (FVIII) with high activity of homocysteine, and natural anticoagulant deficiencies of antithrombin, PC, and/or protein S (PS).4 Furthermore, these well-defined risk factors may be classified depending on the magnitude of the risk to determine the occurrence of thromboembolic disease and on the association with other favorable factors. The interpretation of a positive test for thrombophilia in pregnant women is difficult because they have many natural changes within the coagulation system, so the genetic diagnosis has a major importance.
This review will summarize the impact of each inherited prothrombotic factor on cardiovascular and pregnancy outcomes and will discuss the role of the prophylactic and therapeutic anticoagulation therapy for the peripartum period for women diagnosed with inherited thrombophilia.
GENERAL ASPECTS OF HEMOSTASIS
Hemostasis, the complex process that helps maintaining blood flow through a natural balance between procoagulant and anticoagulant mechanisms, is classically described as occurring in 2 stages: primary hemostasis, resulting in the white clot, and secondary hemostasis, with its intrinsic and extrinsic pathways concluding in 1 common path, which results in the final red clot.5 In the primary hemostasis, main elements participating are the platelets, the damaged vascular wall, and the adhesive proteins. Secondary hemostasis occurs in many stages: initiation, amplification, propagation, and stabilization.5 The entire process is controlled by several natural inhibitors (fibrinolytic system) that limit the clot formation, thus preventing thrombus propagation. This equilibrium is disturbed whenever the natural procoagulant activity is increased or the activity of occurring inhibitors is decreased by permanent (hematological diseases) or temporary situations (pregnancy and sepsis).6Table 1 presents the coagulation factors and their activity during the hemostatic process.
In the initiation stage, tissue factor from the damaged vessel is expressed and binds coagulation factor VII, which activates factors IX and X, resulting in a complex that binds thrombin (coagulation factor II), which gets activated (IIa). The amplification stage comprises thrombin activation through coagulation factors VIII and V.5 In the propagation stage, all these enzymes as 2 complexes, tenase (factors VIIIa and IXa) and prothrombinase (factors Va and Xa), continue to generate thrombin and subsequently fibrin by activating the circulating fibrinogen, resulting in the clot formation.5 The stabilization stage is mediated by fibrin stabilizing factor XIII. New coagulation concept describes also a thrombin-activatable fibrinolysis inhibitor that protects the clot from fibrinolysis (Figure 1).7
In the propagation stage, action many natural controlling molecules. Thus, PC and PS are 2 natural anticoagulant enzymes, which act as cofactors, their role being to inactivate factors V and VIII from the coagulation cascade and to determine a reversible inhibition of the prothrombinase complex.5
To limit the clot development, there is a parallel natural process, fibrinolysis, in which 2 factors released by the vascular endothelium, tissue plasminogen activator (t-PA), and urokinase plasminogen activator activate the circulating plasminogen resulting in generation of plasmin. The latter has 2 main roles: splitting the fibrin formed and inhibiting a new propagation.5 t-PA and urokinase plasminogen activator are regulated by 2 inhibitors: plasminogen activator inhibitors I and II (PAI I and PAI II) (Figure 2).8
PHYSIOLOGIC CHANGES IN HEMOSTASIS DURING PREGNANCY
To prevent excessive bleeding during delivery, normal pregnancy is associated with several hemostatic changes. Starting from the first trimester and lasting up to 12 weeks postpartum, pregnancy determines hypercoagulability by modifying hemostasis at 3 levels: decreased platelet count, increased procoagulant activity, and decreased fibrinolysis activity.9 Changes during pregnancy begin with an increased resistance to activated PC and a decreased PS activity. Moreover, a pregnant woman has higher serum levels of I, VII, VIII, IX, X, XII, and von Willebrand factors and also higher activity of fibrinolysis inhibitors.9 All these changes develop as pregnancy progresses. Thus, in late pregnancy, coagulation activity is almost twice that in the nonpregnant women, but with normal delivery, these changes are self-limiting.10 These changes are interpreted as being due to hormonal changes, especially increased estrogen levels, as pregnancy progresses.9
Low number of platelets is due to hemodilution, but also to peripheral destruction as a result of the increase in cell volume.10 In the third trimester of pregnancy, the number of platelets varies around 80,000 to 150,000 cells per mm³.9
Regarding procoagulant activity, there is an increase of the plasma fibrinogen level up to 200% higher in the third trimester compared with the nonpregnant state, but also of factors von Willebrand, VIII, X, XII, and XIII.8,10 The highest values are recorded for factor VII at the end of the third trimester. Factors II, V, and IX have a slight increase at the beginning of the first trimester, then their values get stabilized. Factor XI is the only factor about which there are no clear data, as there are some sources that support the increase in its values, but other sources that show its decrease during pregnancy.10 Antithrombin III remains in the normal range, but there is an increased resistance to activated PC and a decrease of PS activity.9
Low fibrinolytic activity is characterized by a markedly increased levels of plasminogen activator inhibitors 1 and -2 (PAI-1 and PAI-2). Thus, activity of tissue plasminogen activator (t-PA) decreases during pregnancy.10 Endothelial cells release PAI-1, and the placenta releases PAI-2, which is found only in the plasma of a gestational woman. Furthermore, there are many data suggesting a strong correlation between placental weight and PAI-2 levels. Thrombin-activatable fibrinolysis inhibitor has slightly higher values in the third trimester of pregnancy.11
Hemostasis should not be tested earlier than 3 months after delivery, and after finishing lactation, to rule out influences of pregnancy.10 Because of these changes, prothrombin time and activated partial thromboplastin time are shortened. Meanwhile, because of fibrinolytic changes, there is an increase in D-dimer values, which makes difficult to use this parameter in the exclusion of venous thromboembolism in pregnant women.10
Inherited thrombophilia is a genetic disease, caused by structural or quantitative abnormalities of one or more factors involved in hemostasis, clinical expression being an increase in blood coagulation. So far, hundreds of genetic mutations were included in the etiology of inherited thrombophilia.12 The most used classification is the one proposed by Fogarty in 2009 (Table 2).12 As it is described in Table 2, population groups with high- and low-risk inherited thrombophilia are clearly defined by the presence of personal history of thrombotic events and by the type of genetic defect. The group with an intermediate risk of thrombotic events includes thrombophilia not classified as high risk, with a family history of venous thrombotic events. In other words, it refers to any type of genetic change, different from those integrated in high risk, in people with a positive family history of thrombotic events.12 Another classification divides the mutations into 2 groups: well defined and potential risk factors for thrombophilia.2 A crucial difference in the clinical impact is made by the extent of genetic modification, heterozygous or homozygous, and also by its dominance allele (dominant or regressive). More than 60% of patients with idiopathic venous thromboembolic events have inherited thrombophilia.13,14 Even if a positive genetic diagnosis of thrombophilia implies a risk of thrombotic events, most patients will never have such an event, but this risk is higher, as other conditions are associated, such as pregnancy.2 Therefore, it is important to understand that a clinical expression of thrombophilia is generated by an interaction between a genetic anomaly and one or more acquired conditions.
Well-defined types of thrombophilia
FVL is a genetically modified variant of factor V. This variant has a natural resistance to PC (which in normal conditions inhibits factor V by cleavage); therefore, the presence of FVL implies a hypercoagulant status. FVL is the most common form of inherited thrombophilia, having a prevalence of 8% in the European population.13–16 The heterozygous form of FVL (the presence of the mutation in 1 allele) increases the thrombotic risk by 3–8 times, while having 2 copies (homozygous pattern) increases the risk by 80 times. The most frequent manifestation of thrombotic effect of FVL is deep venous thrombosis (DVT) of the lower limbs, followed by DVT of the upper limbs. Impact on arterial thrombotic events is not very well established; there are data suggesting a weak association between FVL and arterial thrombosis.2
Prothrombin (factor II) gene mutation G20210A
Prothrombin (factor II) gene mutation G20210A, identified in 1996, is the second most common type of inherited thrombophilia.2 The consequence of its presence is an increased level of prothrombin by 133%, with a hypercoagulability state (homozygous pattern).16 The prevalence in the general population is 1%–4%.13 Risk of occurrence of thrombotic venous events caused by the presence of this mutation (homozygous pattern) is increased by 2- to 4-fold.17 There are no data related to the association between prothrombin mutation and arterial thrombosis.
Antithrombin III (AT III) deficiency
Antithrombin III (AT III) deficiency is a serious risk factor for developing thrombosis, especially in the homozygous type, when clinical manifestations appear before age 25 years.2,18–20 AT III deficiency has been reported with a prevalence of 0.02%–0.2% (1 in 500–1 in 5000) in the general population.13 Basically, there are 2 main types of antithrombin III deficiency.2,18,20 Type I is a quantitative defect of normal antithrombin through a genetic production deficit; type II is a qualitative anomaly through malfunctioning protein.2 The main problem in genetic diagnosis of AT III deficiency is that the current antithrombin antigen assays do not permit the detection of qualitative deficiencies.2 AT III deficiency implies a 7-fold higher risk of venous thrombotic episodes. Moreover, the risk of recurrence is approximately 2.7%/year, despite anticoagulation.13
PC deficiency is also, similar with AT III deficiency, classified in a quantitative and qualitative genetic defect. There are no differences regarding the clinical impact between these types. PC deficiency is found in 0.2% of the general population.13 Clinical manifestations in PC deficiency are extremely varied. The thrombotic risk in PC deficiency is usually increased by more than 7-fold. In the heterozygous form, it can range from asymptomatic to warfarin-induced skin necrosis and venous thrombotic episodes.13,21–23 The homozygous form may determine mild symptoms but also, depending of the number of affected alleles, it can determine massive skin bleeding with thrombosis and extensive necrosis, which is a life-threatening situation.13
PS deficiency can be divided into 3 forms: type I is a decrease in total PS, mostly due to decreased synthesis; type II is a low level of PS activity; and type III is a decreased level of free PS, but a normal activity of total PS.2 So far, more than 70 different mutations have been described.2 The prevalence of PS deficiency is unknown because there is no standardized method for its detection.13 It is associated with an 8.5-fold increased risk of venous thrombosis.13
Potential risk factors for thrombophilia
Hyperhomocysteinemia is a procoagulant status related to the occurrence of arterial thrombotic events. In Europe, the lowest allele frequency is found in northern countries and the highest in the Mediterranean region.13 Homocysteine is a naturally occurring amino acid produced by methylation from methionine. Homocysteine accumulates in the body because the biochemical transformation process is not working properly (low levels of vitamin B6, B12, or folic acid, implied in the homocysteine metabolism) or because of a genetic modification of the enzyme implied in its metabolism, methylenetetrahydrofolate reductase (MTHFR).24,25 There are 2 mutations documented to have clinical impact: the most common, C677T mutation, is associated with a decrease of the enzyme activity, resulting in hyperhomocysteinemia, and the second, A1298C mutation, which presents a milder effect on homocysteine levels.13 Not all people will develop high homocysteine levels. Although these mutations do impair the regulation of homocysteine, adequate folate levels can annulate this defect.2
Plasminogen activator inhibitors (PAI I and II)
Plasminogen activator inhibitors (PAI I and II) role on the prothrombotic status is still unclear. A single genetic modification in PAI I is described, which may be associated with high plasma activity of PAI I.2 The genetic defect is located in the 4G site, whereas the 5G allele binds both enhancer and suppressor molecules. As a result, individuals with 4G/5G or 4G/4G genotypes have an increased level of transcription and consequently a higher PAI I protein level, with a higher prothrombotic status than individuals with 5G/5G polymorphism.2 The true prevalence of PAI I and II is not well established because of lack of standardized activity assays.26 Moreover, the clinical impact of this deficit is also not clear; there are contradictory data regarding the impact on the occurrence of thrombotic events, and the current guidelines do not recommend any type of prophylaxis in this deficit.
INHERITED THROMBOPHILIA IN PREGNANCY
The relationship between the mother and fetus is intermediated by the placenta, an organ whose formation, structure, and function have bidirectional genetic determinism, the mother, and the product of conception. Although there are few and contradictory studies, with a small sample size, the accepted conclusion stipulates that the presence of inherited thrombophilia in the mother is related to an increased risk of pregnancy complications, such as spontaneous loss of pregnancies, preeclampsia, and intrauterine FGR. Furthermore, given the physiological changes in hemostasis, pregnant women with inherited thrombophilia have an increased risk of venous and arterial thrombotic disease.27–29
Spontaneous loss of pregnancies
The term “miscarriage” refers to a spontaneous loss of a fetus before it reaches viability. According to the definition of the World Health Organization, it is a loss of a pregnancy before the completion of 20 gestational weeks or fetal weight of <500 g.29 According to the definition of Royal College of Obstetricians and Gynaecologists, recurrent miscarriage or abortive disease is defined as the loss of 3 or more consecutive pregnancies before the 24th week of gestation.28–31 Mechanisms of abortive disease in pregnant women with inherited thrombophilia are related to spontaneous microthrombotic events on placental blood vessels, leading to inadequate placental perfusion, which determines placental infarction and a reduction in trophoblast invasion and chronic hypoxia.32–35
The first study related to abortive disease was conducted by Preston et al in 1996 in 571 women with different types of inherited thrombophilia. The strongest association was between complex procoagulant genetic defects and miscarriage, rather than isolated defects. AT III deficiency was the most frequent independent thrombophilic state related with spontaneous loss of pregnancies, followed by PC deficiency, PS deficiency, and FVL.28,36 In 2006, Robertson et al,34 in a systematic review, showed that there is a significant association between miscarriage in the first and second trimesters of pregnancy and FVL and prothrombin gene mutation, whereas “late” miscarriage, in the third trimester of pregnancy, is associated with the same mutations, but also with PS and PC deficiencies.28,34–38 In a retrospective cohort review published in 2018, Dobson and Jayaprakasan30 showed a similar prevalence of inherited thrombophilia, most frequent with FVL, in a population with a history of recurrent miscarriage and in a population with thrombotic diseases.
Abnormal early trophoblastic invasion may result in either early miscarriage or potential viable pregnancies, complicated by intrauterine growth restriction (IUGR) or PE. As we mentioned previously, thrombophilia determines placental infarction and abnormal trophoblast invasion and chronic hypoxia. These mechanisms are associated with increased resistance in the uterine arteries, measured by Doppler ultrasonography.32 Meanwhile, treatment with low-molecular-weight heparin (LMWH) of pregnant women with thrombophilia can reduce all these pregnancy complications (miscarriage, preeclampsia, and IUGR).38,39
In 2006, Wu et al40 showed the association between thrombophilia and increased risk of developing preeclampsia, the highest risk being for hyperhomocysteinemia. Furthermore, Robertson et al showed a modest association between preeclampsia and the presence of FVL heterozygous, prothrombin 20210A mutation, and MTHFR C677T homozygous.36 Data from a retrospective cohort published by Leduc et al41 in 2016 suggested that combined treatment with dalteparin and acid acetylsalicylic decreased the risk of preeclampsia by 20% and the risk of IUGR by 30% in women with inherited thrombophilia. Similarly, Kupferminc et al42 in 2011 showed that women with thrombophilia and previously severe pregnancy complications had a reduced rate of recurrence under LMWH treatment. In contrary, according to the study by Rodger et al,43 carriers of FVL or prothrombin gene mutation are not at significant risk of pregnancy complications. Moreover, there are many reports from different ethnic populations with different types of genetic coagulant factor defects, in which there were no associations found with preeclampsia.44,45 Therefore, even if some studies suggest an association between thrombophilia and adverse pregnancy outcomes, there is a heterogeneity given by geographic locations, race or ethnicity, which do not permit a clear causal relationship.46
Inherited thrombophilia has an increased risk of venous thrombosis of 7-fold in heterozygote and 80-fold in homozygote carriers.47,48 In the presence of another procoagulant condition, such as pregnancy, the risk of developing venous thrombosis is even higher. The incidence of DVT and pulmonary embolism (PE) in a pregnant population is between 1 in 1000 to 1 in 2000 deliveries.49 Pregnant women have a 4- to 6-fold higher risk of DVT/PE compared with nonpregnant age-matched women, the risk being even greater during the postpartum period.50 Presence of FVL, AT III gene mutation, prothrombin gene mutation, and genetic deficit of PC and PS are inherited defects related with thrombotic events during pregnancy. These genetic anomalies are responsible for more than 50% of maternal venous thrombotic events.51–53 Moreover, a significant additional risk is given by the family history of thrombotic events, irrespective of thrombophilia, in such situation risk being increased 2- to 4-fold.42
There are few studies evaluating the role of inherited thrombophilia in stroke occurring during pregnancy or in the postpartum period. Even if we have data regarding the relationship between inherited thrombophilia and stroke in young population, none of these studies was addressed specifically to the pregnant women. In 2011, Hamzi et al54 performed a large meta-analysis, in which they found that MTHFR C677T mutation, FVL, and prothrombin G20210A gene mutation are associated significantly with ischemic stroke, but, again, there are no data reported specifically for pregnant women. Meanwhile, the incidence of ischemic stroke in pregnant women cannot be evaluated correctly because of preexistent associated risk factors, such as arterial hypertension, preeclampsia, cesarean delivery, vascular wall fragility, and high levels of steroid hormones.
Although there are some isolated publications, which showed an association between thrombophilia and FGR or prematurity, large meta-analyses of inherited thrombophilia did not demonstrate a significant association.55 In 2018, Perés Wingeyer et al56 suggested that FVL might have a significant impact on FGR, although other previously published studies did not find any relationship between FGR and FVL.57–62 Prothrombin G20210A and AT III gene mutations were also studied in relation with FGR, with contradictory results.63–65
SCREENING FOR INHERITED THROMBOPHILIA
Screening for inherited thrombophilia in unselected population is not recommended because of the low frequency and low penetration of these genetic defects and mainly because there are no important therapeutic implications. Long-term anticoagulant prophylaxis is associated with lack of cost-effectiveness, and higher risk of bleeding, by comparison with theoretical number of prevented thrombotic cases.66 Therefore, in young women, before pregnancy, there are no specific indications for inherited thrombophilia testing. During pregnancy and puerperium, there is no strong evidence on which to base recommendations regarding whom to test or the optimal panel of tests.52,53,66 Even so, the American College of Obstetricians and Gynecologists guidelines recommend screening for inherited thrombophilia only in 2 situations: first, in case of personal history of venous thromboembolism that was associated with a transient risk factor, and second, in case of first-degree relative with a history of high-risk thrombophilia. In any other situations, such as recurrent fetal loss or placental abruption, thrombophilia testing is not routinely recommended.53 Only Royal College of Obstetricians and Gynaecologists recommends screening for FVL, prothrombin mutation, and PS deficiency for women with a history of second trimester miscarriage.66
Anticoagulant treatment in pregnant women with inherited thrombophilia is curative or prophylactic. Curative treatment follows the current guidelines applicable to the general population, with no particularities for pregnant women.
Decision to recommend thromboprophylaxis with anticoagulant treatment in pregnant women with inherited thrombophilia is determined by history of venous thromboembolism, type and associated risk of inherited thrombophilia, and presence of additional risk factors.52 Even if warfarin, LMWH, and unfractionated heparin do not accumulate in breast milk and do not induce an anticoagulant effect to the fetus, according to the risk–benefit ratio, LMWHs (enoxaparin, dalteparin, and tinzaparin) are the preferred agents for prophylaxis in pregnancy.53 The initiation of prophylactic treatment with a heparin is recommended to be started in the first trimester of pregnancy and discontinued before delivery (at the labor onset or before scheduled caesarian delivery).52 After giving birth, the anticoagulation will be reinitiated after 4–6 hours for unfractionated heparin and after 6–12 hours for LMWH.52 Treatment duration and doses vary among European guidelines, from the Royal College of Obstetricians and Gynaecologists, and the American guidelines, from the American College of Obstetricians and Gynecologists.52,53 Both societies classify the regimens of anticoagulation therapy into 3 types, depending on the quantity and modality of daily administration (Table 3). These types are called (by consensus) “prophylactic, “intermediate, and “therapeutic” doses.
Choosing a type of anticoagulation regime is based on the genetic category of thrombophilia (high or low thrombotic risk) and on the personal history of thrombotic events (primary or secondary prophylaxis).52,53 Thus, for pregnant women with high-risk thrombophilia mutations, current European guidelines recommend anticoagulation antepartum and postpartum, with therapeutic doses if they have a positive personal history of thrombotic event (secondary prophylaxis) and with intermediate doses if they do not have a personal history of thrombotic events (primary prophylaxis).52 In both situations, treatment is continued 6 weeks after delivery.52 American guidelines consider many criteria when deciding the anticoagulant therapy for a pregnant woman, such as severity of inherited thrombophilia, family history of thrombotic events, and additional risk factors such as cesarean delivery, obesity, and prolonged immobility.53 Thus, for a pregnant woman with high-risk thrombophilia, for secondary prophylaxis, or positive family history of thrombotic events in a first-degree relative, prophylactic, intermediate, or therapeutic doses can be chosen, depending on additional risk factors. Treatment is recommended to be continued for 6–8 weeks after giving birth.53 For women with high-risk thrombophilia, but no personal or family history of thrombotic events, decision is made between the intermediate and prophylactic doses, depending on additional risk factors mentioned previously (cesarean delivery, obesity, and prolonged immobility).52,53 For pregnant women with low-risk thrombophilia and no personal history of thrombotic events, anticoagulation therapy is not indicated.52,53 For pregnant women with low-risk thrombophilia and a positive personal history of thrombotic event, the European guidelines indicate intermediate doses of anticoagulation, whereas American guidelines recommend prophylactic or intermediate doses, according to the presence of additional risk factors.52,53 American guidelines of anticoagulation in pregnancy uses the Fogarty classification, described previously.12 Thus, pregnant women with intermediate risk are in fact low risk inherited defects, with additional risk factors (positive family history of thrombotic event); accordingly, they will receive intermediate doses of oral anticoagulation. Table 3 summarizes the doses of anticoagulation therapy for pregnant women with inherited thrombophilia.52,53
The association between 2 procoagulant conditions, inherited thrombophilia and pregnancy, has an important impact for the mother and fetus. All the potential pregnancy complications related to the inherited thrombophilia, such as thrombotic events, miscarriage, preeclampsia, and FGR, have a significant prevalence, being an important public health problem. Thromboprophylaxis recommendation with anticoagulant treatment in pregnant women with inherited thrombophilia is determined by history of venous thromboembolism, type and associated risk of inherited thrombophilia, and presence of additional risk factors.
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