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Abstract

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.

Keywords

pregnancy prevention risk factors therapy venous thrombosis

Epidemiology

Pregnancy is recognized as a ‘thrombogenic state’ and thromboembolic disease is a leading cause of maternal morbidity and mortality during pregnancy and the puerperium. The risk of venous thromboembolism is 5–6-times higher among pregnant women than among nonpregnant women of similar age [1 –3]. The incidence of venous thromboembolism associated with pregnancy and the puerperium is approximately 1/1000 to 1/2000 deliveries [1 –4].

The majority of venous thrombotic events in pregnancy occur antepartum, although the postpartum period poses a greater risk per time. Thus, the risk of puerperal deep-vein thrombosis is threefold higher than antenatal (0.18 vs 0.065 deep venous thromboses/100 woman-years). The risk for puerperal pulmonary embolism appears almost eightfold higher (0.07 puerperal vs 0.009 antenatal pulmonary embolisms/100 woman-years) [5]. Almost 40% of postpartum venous thromboembolisms are observed after discharge from hospital [6].

The overall incidence of fatal pulmonary embolism in pregnancy decreased dramatically from the 1950s to the present day; however, pulmonary embolism remains a leading cause of maternal mortality in the Western world [7].

Bearing this in mind, it is important to develop strategies to, first, estimate the individual risk of thrombosis during pregnancy and, second, be able to carry out specific, risk-adapted prophylaxis (e.g., anticoagulation with heparins) in cases where there is danger of thrombosis. However, this requires statistically firmed knowledge regarding the relative and absolute risks of all possible hereditary and acquired risk factors for venous thromboembolic events.

Pregnancy as an expositional risk determinant

In 1847, Virchow postulated three main causes of thrombosis, including alterations of the vessel wall, venous stasis and changes in the composition of blood [8]. These abnormalities, leading to venous thromboembolism, all occur during pregnancy and the puerperium.

Pregnancy is an acquired and also independent risk condition for venous thromboembolism. During normal pregnancy, the plasma concentrations and activities of several proteins involved in blood coagulation and fibrinolysis change. These alterations can promote coagulation (e.g., increase in fibrinogen, factor VIII:C and von Willebrand factor), reduce anticoagulation (decrease in protein S and antithrombin) and inhibit fibrinolysis (increase in plasminogen activator inhibitors 1 and 2), representing the ‘physiological preparation’ for the hemostatic challenge of delivery [9].

The venous system of the lower extremities is particularly vulnerable to stasis as a result of the compression by the gravid uterus [10 –12]. Endothelial damage to pelvic vessels can occur during vaginal or abdominal delivery [13]. Further acquired risk determinants, which in the course of pregnancy and the puerperium do significantly increase the thrombotic risk, include maternal age (women older than 35 years), obesity (weight over 80 kg), high parity (four or more), infection, personal or family history of venous thromboembolism, and cesarean section (particularly emergency cesarean section) [13 –17].

Pregnancy & hereditary risk determinants of venous thrombosis

Just 20 years ago the relevance of familial disposition to thrombosis, that is, hereditary thrombophilia, as a cause of venous pregnancy-associated thromboembolism was unknown or underestimated. At that point in time, only antithrombin deficiency was known as the most important hereditary risk factor for thrombophilia [18].

Due to the rarity of this defect in the population, antithrombin deficiency was only diagnosed in a few women with thrombophilic diathesis during pregnancy and the puerperium. This situation has changed fundamentally in the past 10 years. Since 1994, further genetically determined risk factors for thrombophilia have been identified, for example the G1691A mutation of the factor V gene (factor V Leiden) [19] and the G20210A mutation of the factor II (prothrombin) gene [20], in addition to the already known deficiencies of proteins C and S.

Approximately 50% of all patients with venous thromboembolism during pregnancy and the puerperium, and approximately 15% of the average population, are carriers of these genetically determined markers of thrombophilia [18]. The prevalence and distribution of the hereditary risk factors is thus relatively high in the average population (e.g., factor V Leiden up to 8%; prothrombin mutation G20210A approximately 2%).

However, the presence of a hereditary risk factor alone does on no account presuppose deep venous thrombosis. Based on Virchow's Triad (stasis, alterations of the vessel wall and changes in the composition of blood) [8], which is still valid in its main features, the etiology of venous thromboembolic events by today's understanding originates from the multifactorial interaction of acquired and genetic risk determinants and the resulting risk constellations [21].

Antithrombin, protein C & protein S

It is well established that patients with severe deficiencies of antithrombin, protein C and protein S have a markedly increased risk of venous thromboembolism [21,22]. However, the clinical relevance, particularly the predictive value of mild deficiencies of antithrombin, protein C and protein S, has been discussed controversially and is still an unsolved problem.

Tables 1 & 2 summarize the individual probability (absolute risk) of venous thromboembolism for different degrees of these deficiencies among women during the course of pregnancy and the puerperium. As anticipated, mild deficiencies (e.g., antithrombin activities between 70 and 85%), which represent the majority of clinical cases, are associated with a lower risk compared with deficiencies below 60%.

Table 1.

Comparison of the current recommendations by the American College of Chest Physicians and the Specified Unicentric Recommendations for risk-adapted heparin prophylaxis and therapy in pregnancy using unfractioned heparin and low-molecular-weight heparin for women with prior venous thromboembolism.

ACCP recommendations*		Specified Unlcentric Recommendations for risk-adapted heparin prophylaxis and therapy (Düsseldorf Medical Center)

Risk group	Recommendations for heparin prophylaxis and therapy‡	Risk category	Risk group (detailed stratification in consideration of hereditary or congenital defects and family history)	Absolute risk of thrombosis during pregnancy and puerperium (as known)	Recommendations for heparin prophylaxis and therapy‡
Thrombosis in current pregnancy	Therapeutic dose of LMWH or intravenous UFH continuously (aPTT therapeutic for at least 5 days) Subsequently therapeutic dose subcutaneous UFH or LMWH and at least 6 weeks postpartum (Grade 1C) Terminate heparin therapy 24 h before elective labor induction (Grade 1C)	High risk		>20% (in case of inadequate anticoagulant response) [55]	Therapeutic dose of LMWH throughout pregnancy and at least 6 weeks postpartum. Alternatively continuation with ~70% dose from 8 weeks after thrombotic event
Women with recurrent (≥2) thrombotic events and/or long-term anticoagulation (e.g., singular thrombotic event – idiopathic or associated with thrombophilia)	Therapeutic dose of UFH or LMWH throughout pregnancy antepartum, followed by resumption of long-term anticoagulation postpartum (Grade 2C)	High riskIntermediate risk	Women with familial thrombophilia and deficiency of antithrombin, protein C or protein SWomen with recurrent thrombosis associated with a transient risk factor (e.g., surgery) and no thrombophilic risk factor (long-term anticoagulation postpartum may not be indicated)	11–40% [23 –26]§2–17% [23 –26]§0–22% [23 –26]§	Therapeutic dose of LMWH throughout pregnancy and at least 6 weeks postpartumIntermediate ‘half therapeutic’ dose throughout pregnancy and at least 6 weeks postpartum
Women with history of thrombosis, antithrombin deficiency, combined heterozygous or homozygous for G20210A mutation of prothrombin/G1691A mutation of factor V Leiden	Intermediate ‘half therapeutic’ dose or UFH in moderate dose (Grade 2C)	High risk#Intermediate risk	Prior thrombosis associated with transient risk-factors and antithrombin-deficiency Type 1 and distinct family history#Prior thrombosis associated with a transient risk factor and homozygous for G20210A mutation of prothrombin or G1691A mutation of factor V Leiden	11–40% [23 –26]§9% [39]	Therapeutic dose of LMWH throughout pregnancy and at least 6 weeks postpartumIntermediate ‘half therapeutic’ dosage throughout pregnancy and at least 6 weeks postpartum
Women with a singular thrombotic event and thrombophilia (defect verified by laboratory) or familial thrombophilia, not receiving long-term anticoagulation	Prophylactic or intermediate dose of LMWH or minidose or moderate dose of UFH, additional anticoagulation postpartum (Grade 2C).	Moderate risk	Women with factor V Leiden or heterozygous for G20210A mutation of prothrombin	~10% (?) [45,48]	Prophylactic dose throughout pregnancy and at least 6 weeks postpartum
Women with a singular thrombotic event and thrombophilia (defect verified by laboratory) or familial thrombophilia, not receiving long-term anticoagulation (cont.)	Prophylactic or intermediate dose of LMWH or minidose or moderate dose of UFH, additional anticoagulation postpartum (Grade 2C).	Intermediate risk	Women with familial thrombophilia and deficiency of protein C or protein S	2–17% [23 –26]§0–22% [23 –26]§	Intermediate ‘half therapeutic’ dose throughout pregnancy and at least 6 weeks postpartum
Women with a singular idiopathic thrombotic event, not receiving long-term anticoagulation	Prophylactic or intermediate dose of LMWH or minidose or moderate dose of UFH or clinical observation§ with anticoagulation postpartum (Grade 2C).	Moderate risk	Women with or without factor V Leiden or G20210A mutation of prothrombin	13% [45]13% [48]	Prophylactic dose throughout pregnancy and at least 6 weeks postpartum
Women with a singular idiopathic thrombotic event associated with a transient risk factor no longer persisting. No thrombophilic risk factor.	Clinical observation§ and anticoagulation postpartum (Grade 1C)	Low-to-moderate risk	Women without hereditary risk factors Triggered idiopathic	0% [45] − 9% [48]¶8% [45] −13% [48]¶7% [46]¶	Prophylactic dose throughout pregnancy and postpartum or clinical observation§ and anticoagulation postpartum (inconsistent data)
Prior event was associated with pregnancy or use of oral contraceptives or existence of additional risk factors (e.g., adipositas)	Prophylactic dose throughout pregnancy and postpartum (Grade 2C)	Moderate risk	Women with or without factor V Leiden or G20210A mutation of prothrombin	5.5% [48]	Prophylactic dose throughout pregnancy and postpartum

Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden and costs. Grade 2 suggests that individual patients' values may lead to different choices. Grade ‘C limits the recommendation in so far as the available studies only have observational character or are a generalization of study results from other patient groups [56]. In all women with previous deep-vein thrombosis, antenatally and postpartum, the ACCP suggests use of graduated elastic compression stockings (Grade 2C).

‡

For dosage definition see Table 3.

Clinical observation refers to vigilance and aggressive investigation of women with symptoms suspicious of a thromboembolic event.

Women with spontaneous thromboses and antithrombin deficiency or homozygous for FV Leiden or prothrombin G20210A see above in risk group ‘Women with long-term anticoagulation’.

No difference between women with and without FV Leiden/Prothrombin G20210A.

ACCP: American College of Chest Physicians; aPTT: Activated partial thromboplastin time; LMWH: Low-molecular-weight heparin; UFH: Unfractionated heparin.

Table 2.

ACCP recommendations*		Specified Unicentric Recommendations for risk-adapted heparin prophylaxis and therapy (Düsseldorf Medical Center)

Risk group	Recommendations for heparin prophylaxis and therapy‡	Risk category	Risk group (detailed stratification in consideration of hereditary or congenital defects and family history)	Absolute risk of thrombosis during pregnancy and puerperium (as known)	Recommendations for heparin prophylaxis and therapy‡
Women with antithrombin deficiency, combined heterozygous or homozygous prothrombin G20210A/factor V Leiden	Prophylactic dose (Grade 2C)	Intermediate riskModerate risk	Women with antithrombin deficiency Type I (<60%) with/without familial thrombophiliaWomen with combined heterozygous prothrombin mutation/factor V LeidenFactor V Leiden homozygous unselectedFactor V Leiden homozygous and familial thrombophilia	4% [42]>10% [23 –26]§5% [27,42]1.5% [36,42]<17% [39,40,57,58]	Prophylactic dose With positive family history intermediate ‘half therapeutic’ dose throughout and at least 6 weeks postpartumProphylactic dose throughout pregnancy and at least 6 weeks postpartum
All other women with thrombophilia (laboratory approved anomaly)	Clinical observation§ or prophylactic dose of LMWH or minidose of UFH, additional anticoagulation postpartum (Grade 2C).	Moderate riskLow risk	No familial thrombophilia and deficiency of protein C (<60%) or protein S (<45%)Heterozygous for factor V Leiden or prothrombin G20210A	0.2–2% [5,26,27]0.2–7% [26,42]~0.25%[5,15,27,34,42]	Prophylactic dose throughout pregnancy and at least 6 weeks postpartumNo routine antepartum prophylaxis, except in case of additional risk factors¶ Prophylactic dose peri- and postpartum over 4–6 weeks

‡

For dosage definition see Table 3.

Clinical observation refers to vigilance and aggressive investigation of women with symptoms suspicious of a thromboembolic event.

Additional risk factors are immobilization/hospitalization, surgery, infection and thrombophlebitis.

ACCP: American College of Chest Physicians; LMWH: Low molecular weight heparin; UFH: Unfractionated heparin.

Much of our present knowledge of the risk of venous thromboembolism in pregnant and postpartum women with inhibitor deficiencies is derived from family studies, which are likely to overestimate the risk for unselected women with these defects, particularly for those with mild deficiencies. In these studies, the absolute risk of thromboembolism among antithrombin-deficient pregnant women not receiving anticoagulant therapy was judged to be up to 40% (3–40% in the antenatal period and 0–20% in the puerperium) [23 –26]. For pregnant women with abnormalities of the protein C and S systems not receiving anticoagulant therapy, the risk of thrombosis during pregnancy ranged from 3–10% for protein C deficiency and from 0–6% for protein S deficiency. In postpartum, the risk was 7–19% for protein C deficiency and 7–22% for protein S deficiency [23 –26]. In contrast to these results obtained from family studies, a much lower risk is found in unselected women [27,42]. The most likely explanation for this observation is that familial thrombophilia is caused by multigenic effects. Thus, in each of the families, several known and unknown risk factors of thrombosis are present, contributing to an overestimation of a single risk factor under study [21].

Resistance to activated protein C & G1691A mutation in the factor V gene (factor V Leiden)

Factor V Leiden is the most common heritable thrombophilic defect in Caucasians and is found in approximately 5% (2–15%) of the Western population [28]. The defect results from the substitution of adenine for guanine at nucleotide 1691 of the factor V gene (G1691A), which causes the arginine at residue 506 of the factor V molecule to be replaced by glutamine (Arg506Gln) [19]. This mutation slows down the proteolytic degradation of factor Va, leading to an augmented generation of thrombin [22]. Resistance to activated protein C (APC), first described by Dahlbäck in 1993, is the resulting in vitro phenomenon caused by factor V Leiden [29].

Resistance to APC has been found in 46–60% of women with venous thromboembolism during pregnancy and the puerperium [30,31]. The frequency of factor V Leiden among pregnant women with thromboembolism varies between 8 and 46% [5,27,31 –34,42]. The risk of venous thromboembolism during pregnancy and the puerperium among heterozygous carriers of the factor V Leiden increases approximately 4- to 16-fold [27,33 –35,42], leading to an absolute risk of pregnancy-associated thromboembolism among carriers of heterozygous factor V Leiden of approximately one thromboembolic event in 400 pregnancies [5,27,35,42]. Higher risk estimations are likely to overestimate the effect of factor V Leiden due to inclusion of thrombophilic families (see below).

To date, there are only limited data regarding the risk of pregnancy-associated venous thromboembolism among unselected homozygous carriers of factor V Leiden G1691A. In our study [36], the relative risk of 25 for venous thromboembolism associated with homo-zygosity for factor V Leiden is lower than the estimated 80-fold increased risk reported in the Leiden Thrombophilia Study [37]. However, the relative risk found in our analysis is in accordance with a recently published pooled analysis of eight case–control studies, in which a relative risk of only 10 was reported [38]. Assuming an incidence of one thromboembolic event in 1500 pregnancies, the probability of thrombosis in pregnancy among unselected carriers of homozygous factor V Leiden is approximately one thromboembolic event in 70 pregnancies.

In contrast to these results obtained from unselected patients, a much higher risk was found in women with previous venous thromboembolism and in women with symptomatic relatives. The risk for pregnancy-associated venous thromboembolism was significantly increased in women with homozygous factor V Leiden and previous venous thromboembolism [39]. Almost 10% of pregnancies were complicated by deep venous thrombosis, with or without prior venous thromboembolism. Furthermore, in a retrospective family study, the risk of pregnancy-associated venous thromboembolism in women with a symptomatic first-degree relative was 17% per pregnancy [40].

G20210A mutation in the prothrombin gene

The G20210A mutation in the 3′ untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and a significantly increased risk of venous thromboembolism [20]. The heterozygous mutation is present in approximately 2% of the healthy population, with ethnic and regional differences [41].

The relative risk of venous thromboembolism in pregnancy and the puerperium among carriers of the G20210A prothrombin gene mutation ranges from 2–16 [27,33 –35]. Assuming an incidence of one thromboembolic event in 1500 pregnancies, the probability of thrombosis in pregnancy among carriers of a heterozygous mutation in the prothrombin gene is approximately one thromboembolic event in 200–500 pregnancies [27,35] ( Table 2 ).

Combined deficiency of factor V Leiden & prothrombin gene mutation G20210A

Most genetic risk determinants cause only a mild risk of thrombosis. With a risk of pregnancy-associated thrombosis of one in 200–400 pregnancies in carriers of a heterozygous factor V Leiden or prothrombin gene mutation, the majority of pregnant women who are carriers need not expect a thromboembolic event during pregnancy or the puerperium [27,42]. Only the combination of several genetic and/or acquired risk factors precipitates the manifestation of a thromboembolic event. The interaction between factor V Leiden and the prothrombin gene mutation G20210A is an example of the synergism of thrombophilic risk factors. A heterozygote carrier of factor V Leiden or the prothrombin gene mutation G20210A has an approximately fivefold increase in the relative risk for thrombosis. On the other hand, a combined deficiency of factor V Leiden and the prothrombin gene mutation G20210A causes approximately a 90-fold increase in the individual risk for venous thromboembolism [42]. This illustrates that the interaction of several risk factors does not have an additive effect, but has a multiplicative or supramultiplicative effect on the thrombosis risk. Thus, the combination of factor V Leiden and the prothrombin gene mutation G20210A yields a thrombosis probability of approximately 4–5% per pregnancy [27,35,42] ( Table 2 ). This finding is especially relevant due to the high prevalence of a combined deficiency in the population of approximately 1 in 1000 individuals.

Identification of patients at risk

In order to reduce the occurrence of venous thromboembolisms, it is necessary to estimate the individual risk of thrombosis based on a statistically evaluated risk stratification. The results on thromboses probability can be consulted for this and these can form the basis for an individualized, risk-adapted thromboembolic prophylaxis.

Venous thromboembolism during pregnancy is of multicausal origin and results from the interaction of different risk determinants. The absolute thrombosis risk is decisively determined by the presence of a positive patient and/or family anamnesis of venous thromboembolic events and evidence of hereditary and/or acquired thrombophilic risk factors. Approximately 70% of all women with venous thromboembolism during pregnancy and the puerperium have acquired and/or hereditary thrombophilic risk factors or a positive patient and/or family history of venous thromboembolic events [18]. It is crucial to develop and implement methods for individual risk stratification in order to identify women at higher risk of pregnancy-related thrombosis [43,44]. The history of venous thromboembolic events is of considerable importance for the assessment of the individual thrombosis risk.

Women with a prior thromboembolic event are at an increased risk for recurrent venous thrombosis during a future pregnancy [45 –47]. The type of prior thromboembolism (idiopathic vs transient risk situation) seems to particularly influence the thrombosis risk. In a prospective study of pregnant women with a history of thromboembolic events, a low absolute risk of 2.4% (3/125 women) for recurrence of antepartal thrombosis in the absence of antithrombotic prophylaxis was found [45]. There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episode of thrombosis that was associated with a temporary risk factor. Among the 51 women with genetic risk factors or a previous episode of idiopathic thrombosis, or both, three (5.9%) had an antepartum recurrence of venous thromboembolism.

In two retrospective studies, on the other hand, high antepartal thrombosis risk without antithrombotic prophylaxis was proven. Pabinger and colleagues found an antepartal risk of recurrence of 6.2% [46]. We found an antepartal thrombosis risk of 7.7% in women not given thrombosis prophylaxis [47,48]. There were no significant differences concerning the thrombosis risk in women with or without thrombophilic risk factors and between women with prior spontaneous thrombosis (13%) and thrombosis in a defined risk situation (9%). Another retrospective study evaluated the rate of recurrence per 100 patient-years in 109 women with at least one pregnancy after the thromboembolic event, which was 10.9% compared with 3.7% in nonpregnant women [49].

In assessing the individual thrombosis risk, a positive family history of venous thromboembolic events is of substantial significance. Thus, members of families with hereditary thrombophilia show a higher prevalence of genetic risk factors and a higher relative risk of venous thrombosis than consecutive patients with the same deficiencies or mutations [44]. Independent of particular genetic risk markers, the age of members of thrombophilic families at the time of the initial thromboembolic event is considerably lower than the age at which venous thromboses occur in consecutively examined patients [24]. The same is true for thrombophilic families without identifiable risk markers. These findings indicate the presence of further, to date unknown, hereditary risk factors. One can therefore assume that the combination of a positive family history and a defined genetic defect is associated with a higher risk of thrombosis during pregnancy than evidence of a hereditary risk factor alone.

Risk-adapted prophylaxis & therapy

In 2004, updated recommendations were published by the American College of Chest Physicians (ACCP) for risk-adapted therapy and prophylaxis of thrombosis during pregnancy [50]. They are itemized in Table 1 for women with an acute event during current pregnancy and for women with prior thromboembolism. In Table 2, recommendations are given for risk-adapted prophylaxis in women without a prior thromboembolic event.

Depending on the quality of the underlying data, the recommendations are classified as grade 1 or grade 2. Grade 1 indicates that the benefits of the recommendation are superior to the accompanying disadvantages (e.g., risk, burdens and cost). Grade 2 is an indication that individual patient characteristics may necessitate a different decision for therapy to the recommendations. Most recommendations are only grade 2, owing to inadequate data; that is, a different therapy decision may be necessary due to the individual risk constellation of the particular patient.

For better assessment of the individual thrombosis risk we have also listed the published absolute risks in Tables 1 & 2 depending on proof of hereditary risk factors and patient and family anamnesis. Newer study results on recurrent risk of thromboembolic events, which were released after the publication of the ACCP recommendations [50], have been considered. The information on absolute thrombosis risk can be helpful when deciding on an individual, risk-adapted prophylaxis.

Anticoagulatory therapy during pregnancy and the puerperium is indicated for the prevention and therapy of venous thromboembolism, and for the prevention and therapy of systemic embolisms in patients with mechanic valvular transplants. Thrombosis prophylaxis can be given as unfractionated heparin as well as low-molecular-weight heparin (LMWH) (for dosage see Table 3). In many cases, there is no evidence for an optimal dosage strategy and recommendations are empirical. Advantages of LMWH are a low rate of heparin-induced thrombocytopenia Type II, a lower osteoporosis rate and a lower rate of allergic skin reactions, but the same prophylactic antithrombotic effectiveness [51 –54]. We recommend the use of LMWH. Pre-existing oral anticoagulation, for example, due to prior thromboembolic events, should be completed by the sixth week of pregnancy to prevent embryopathies.

Table 3.

Dosage recommendations for risk-adapted heparin prophylaxis and therapy during pregnancy and the puerperium.

	Low-molecular-weight heparin dose		Unfractionated heparin dose*
		Minidose	5000 IU s.c. q 12 h
Prophylactic dose	Enoxaparin 40 mg (4000 IU) s.c. q 24 h Dalteparin 5000 IU s.c. q 24 h Nadroparin 4000 IU s.c. q 24 h	Prophylaxis adjusted (moderate dose)	Anti-factor Xa activity 0.1–0.3 IU/ml (3 h after s.c. administration) e.g., 2×10000 IU s.c. q 24 h
Intermediate ‘half therapeutic’ dose	Enoxaparin 40 mg (4000 IU) s.c. q 12 h Dalteparin 5000 IU s.c. q 12 h
Therapeutic dose‡	Weight-adapted as recommended 1–2 × s.c. q 24 hEnoxaparin 1 mg/kg s.c. q 12 h or 1.5 mg/kg s.c. q 24 hDalteparin 100 IU/kg s.c. q 12 h or 200 IU/kg s.c. q 24 hTinzaparin 175 mg/kg s.c. q 24 h	Therapeutic dose adjusted‡	aPTT 6 h after s.c. administration in the therapeutic range (e.g., 60–80 s) e.g., 2 × 15000–30000 IU s.c. q 24 h

According to American College of Chest Physicians recommendations. Anti-factor Xa activity is lower with unfractionated heparin than with low-molecular-weight heparin.

‡

As the half-life of low-molecular-weight heparin is shorter in pregnancy, twice-daily dosing is preferable, at least in the initial treatment phase.

aPTT: Activated partial thromboplastin time, IU: International Unit; q: Every; s.c.: Subcutaneous.

Despite clear progress in risk stratification, the available studies in many cases do not allow for a definitive recommendation for heparin prophylaxis. Therefore, current guidelines can only be of orienting assistance to the consulting physician and need additional individual re-evaluation of risk.

Future perspective

Despite the remarkable progress in risk stratification, the precise magnitude of risk is currently unknown in many cases, such as deficiency of antithrombin, protein C or protein S without prior thrombosis, and recommendations for prophylaxis are often empirical. Thus, further studies are needed to characterize the risk depending on the degree of deficiency (i.e., antithrombin, protein C or protein S) and the family history.

A positive family history of thrombosis is associated with an increased risk of venous thrombo-embolism, even in the absence of a defined hereditary thrombophilic marker. Thus, other currently unknown hereditary risk factors appear to exist and require identification. It is possible that new screening assays that are able to give a general estimation of the thrombotic risk (e.g., endogenous thrombin potential) will, in future, help to identify women at risk, even when the exact defect is not known.

Executive summary

Venous thromboembolism in pregnancy is multicausal, resulting from the interaction of combined defects.

The absolute risk for thrombosis is influenced by the kind of prior thrombotic event (idiopathic vs transient risk situation), family history of thrombosis (thrombophilic family) and the presence of hereditary and acquired risk factors of thrombosis.

Women without prior thrombosis

Women who carry a single defect, such as heterozygous factor V Leiden or prothrombin G20210A mutation, have a low risk of pregnancy-associated thrombosis (approximately 1 in 400). Heparin prophylaxis is not required.

Women who are carriers of a homozygous or combined heterozygous defect of factor V Leiden and prothrombin G20210A mutation have a disproportionally higher risk (approximately 1 in 20). Heparin prophylaxis throughout pregnancy plus postpartum for 6 weeks is recommended.

Women with deficiencies of protein C and antithrombin, who belong to a thrombophilic family, have a high risk (probability for thrombosis: >10%). Heparin prophylaxis/treatment is recommended.

Women with prior thrombosis

The authors recommend heparin prophylaxis throughout pregnancy and postpartum for 6 weeks in all women with an episode of prior thrombosis (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.

Footnotes

Supported by an institutional grant (#9772153) of the Faculty of Medicine, Heinrich Heine University, Düsseldorf, Germany.

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Inherited Thrombophilia and Gestational Venous Thromboembolism

Abstract

Keywords

Epidemiology

Pregnancy as an expositional risk determinant

Pregnancy & hereditary risk determinants of venous thrombosis

Antithrombin, protein C & protein S

Resistance to activated protein C & G1691A mutation in the factor V gene (factor V Leiden)

G20210A mutation in the prothrombin gene

Combined deficiency of factor V Leiden & prothrombin gene mutation G20210A

Identification of patients at risk

Risk-adapted prophylaxis & therapy

Future perspective

Footnotes

References